WO2021063346A1 - Kras g12c inhibitor and application thereof - Google Patents

Kras g12c inhibitor and application thereof Download PDF

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WO2021063346A1
WO2021063346A1 PCT/CN2020/118772 CN2020118772W WO2021063346A1 WO 2021063346 A1 WO2021063346 A1 WO 2021063346A1 CN 2020118772 W CN2020118772 W CN 2020118772W WO 2021063346 A1 WO2021063346 A1 WO 2021063346A1
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alkyl
alkoxy
group
amino
cycloalkyl
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郭洪利
陈涛
周峰
高大新
陈大为
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上海迪诺医药科技有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound that inhibits the activity of KRAS G12C.
  • the present invention relates to a compound that irreversibly inhibits the activity of KRAS G12C, including its pharmaceutical composition and its application as a cancer therapeutic agent.
  • the RAS gene family mainly includes three genes, KRAS, NRAS and HRAS.
  • the RAS gene is a proto-oncogene, which becomes an oncogene with carcinogenic activity after being activated.
  • RAS encodes a group of monomeric globular proteins (21kD) composed of 188-189 amino acids, called p21 protein or RAS protein.
  • the RAS protein is a GDP/GTP binding protein, which can cycle between the inactive GDP binding state and the active GTP binding state, acting as a "molecular switch".
  • the GDP/GTP cycle of RAS is activated by guanine nucleotide exchange factors (such as SOS or RASGRP) and inactivated by GTPase initiating proteins (GAPs, such as p120GAP or neurofibroma protein).
  • GAPs GTPase initiating proteins
  • the interaction between GAPs and RAS can greatly accelerate the conversion of GTP to GDP. Turn off the switch to inactivate RAS. Any mutation that affects the interaction between RAS and GAP or the ability to convert GTP back to GDP will cause RAS to continue to activate, and thus cause damage to the cell. Extended signal.
  • RAS can regulate cell proliferation, differentiation and senescence through a variety of important signal pathways, the prolonged activation of downstream signal pathways (for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) will eventually lead to the occurrence of cancer .
  • downstream signal pathways for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL
  • the RAS protein includes a highly conserved N-terminal G-binding domain, which also contains a nucleotide-binding p-loop and switch I (residues 30-40) and switch II (residues 60-76).
  • the p-loop is the rigid part of the binding domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16), which is necessary for amino acid binding and hydrolysis.
  • Threonine-35 and glycine-60 in Switch I and Switch II can form hydrogen bonds with the ⁇ -phosphate/ester of GTP to maintain the active conformation of Switch I and II regions, respectively. After GTP hydrolysis and phosphate/ester release, both can relax into the inactive GDP conformation.
  • the RAS protein also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the cell membrane (Jonathan et al. Nature Reviews, 2016, 15: 771-785).
  • the RAS gene can be continuously activated through point mutation, overexpression, gene insertion and translocation.
  • the most common one is point mutation. About 30% of human malignancies have RAS gene point mutations.
  • the most common is the point mutation of KRAS.
  • the common mutation sites are codons 12, 13, and 61, among which codon 12 is the most common mutation.
  • G12C mutation is one of the most frequently occurring mutations, and this mutation is found in about 13% of malignant tumors. Among them, the incidence of G12C mutation in non-small cell lung cancer is about 11%, and the incidence of G12C mutation in colorectal cancer, pancreatic cancer and endometrial cancer is about 1%-4% (Hobbs et al. J Cell Sci, 2016, 129: 1287-1292; Prior et al. Cancer Res, 2012, 72: 2457-67).
  • KRAS especially mutants including KRAS G12C
  • KRAS G12C KRAS mutant inhibitors
  • the technical problem to be solved by the present invention is to provide a novel compound that inhibits the activity of KRAS G12C, which can effectively treat various diseases related to KRAS G12C, such as cancer.
  • the present invention provides a compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts;
  • the ⁇ and ⁇ bonds are single bonds or double bonds, respectively;
  • X is N or CR 2 ;
  • Y is C(O) and Z is NR 3 ; when the ⁇ bond is a double bond, Y and Z are independently N or CR 2 respectively ;
  • W When the ⁇ bond is a single bond, W is N and V is CH 2 or C(O); when the ⁇ bond is a double bond, W is C and V is CR 4 or N;
  • U and M are each independently N, C or CH;
  • the A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
  • the B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
  • R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
  • R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
  • R 2 is hydrogen, hydroxy, halo, cyano, amino, -R A, -NR A R B , -OR A , or -SR A;
  • R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
  • R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
  • R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
  • R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR' 2 ; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
  • R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
  • R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 al
  • R A is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3 -10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 membered heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl group or a 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
  • R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl
  • R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-
  • R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1 -6 alkylamino-C 1-6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 ring Alkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1 -4 alkyl, -(CH 2 ) n -N(CN)R', -(CH
  • R' is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
  • R" is hydrogen or C 1-6 alkyl
  • n is an integer from 0 to 4.
  • the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
  • the ⁇ and ⁇ bonds are single bonds or double bonds, respectively;
  • X is N or CH
  • ⁇ bond is a single bond
  • Y is C(O) and Z is NR 3
  • Y and Z are N or CR 2 respectively;
  • W When the ⁇ bond is a single bond, W is N and V is CH 2 or C(O); when the ⁇ bond is a double bond, W is C and V is CR 4 or N;
  • U and M are each independently N, C or CH;
  • the A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
  • the B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
  • R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
  • R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
  • R 2 is -R A , -NR A R B , -OR A or -SR A ;
  • R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
  • R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
  • R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
  • R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR' 2 ; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
  • R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
  • R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 al
  • R A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 Member heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl or 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
  • R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl
  • R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-
  • R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C
  • R' is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
  • R" is hydrogen or C 1-6 alkyl
  • n is an integer from 0 to 4.
  • the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
  • the ⁇ and ⁇ bonds are double bonds respectively;
  • U and M are respectively N and C independently;
  • Ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl
  • Ring B is The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
  • R is a C 6-10 aryl group or a 5-10 membered heteroaryl group; said R is unsubstituted or optionally substituted by 1 to 4 R 7 groups in any position;
  • R 1 is a C 2-4 alkenyl group; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups at any position;
  • R 2 is -OR A ;
  • R 6 is hydrogen, a C 1-6 alkyl group or a C 1-6 alkoxy group; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, and cyano groups. The substituents of the C 1-4 alkoxy group and the C 1-4 alkoxy group are substituted at any position;
  • R 7 is hydrogen, hydroxy, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 3 -8 cycloalkyl or 3-8 membered heterocycloalkyl;
  • R 8 is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino- C 1-4 alkyl or C 1-6 alkylamino-C 1-4 alkyl;
  • R A is C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or -C 1-6 alkyl heterocycloalkyl 3-10 - C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c at an arbitrary position;
  • R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl or halogenated C 1-4 alkoxy.
  • the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
  • R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl , 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is Unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl at any position;
  • R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
  • R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C
  • the alpha bond is a double bond; the beta bond is a single bond or a double bond.
  • the ⁇ and ⁇ bonds are respectively double bonds; X is N; W is C, V is CR 4 or N; Y is CR 2 ; Z is N.
  • the ⁇ bond is a double bond; the ⁇ bond is a single bond; X is N; W is C and V is CR 4 or N; Y is C(O) and Z is NR 3 ;
  • the A ring is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl.
  • the A ring is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazole Group, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl Or tetrazolyl.
  • the A ring is furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl.
  • the A ring is 2,3-dihydrofuranyl.
  • the A ring has any of the following structures:
  • the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
  • the A ring has any of the following structures:
  • the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
  • the B ring has any of the following structures:
  • the ring B is unsubstituted or optionally substituted by 1 to 3 R 6 at any position, and R 6 is defined as described above.
  • the R 6 is H, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CN, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 OCH 3 or -CH 2 OCH 3 .
  • the B ring is
  • the B ring is
  • the 9-14 membered fused heterocycloalkyl is obtained by condensing a monocyclic heterocycloalkyl with a phenyl, naphthyl, pyridyl, pyrimidinyl, or pyrazinyl group Group, preferably 9-membered or 13-membered condensed heterocycloalkyl, for example: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzo[c][1,2 ]Oxaborolanyl, 1,3-dihydronaphtho[2,1-c][1,2]oxaborolanyl, 1,3-dihydronaphtho[2,3-c] [1,2] Oxaboranyl and the like.
  • the R is phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 1H-benzo[d]imidazole-2( 3H)-keto, 1H-indazolyl, phthalazinyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl, 3-hydroxy-1,3 -Dihydronaphtho[2,1-c][1,2]oxaborolanyl or 1-hydroxy-1,3-dihydronaphtho[2,3-c][1,2]oxa Boronpentyl; the R is unsubstituted or optionally substituted by 1 to 5, 1 to 4 or 1 to 3 R 7 at any position, and R 7 is defined as described above.
  • the R 7 is hydrogen, halogen, hydroxy, amino, cyano, C 1-4 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1 -3 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -B(OH) 2 .
  • the R 7, C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, amino, fluoro, chloro
  • the substituents of, methyl, trifluoromethyl and trifluoromethoxy are substituted at any position.
  • the R is any of the following structures:
  • the R is any of the following structures:
  • the R is any of the following structures:
  • the R 1 is wherein, R 8a is H, D, halogen or C 1-3 alkoxy-C 1-4 alkyl; R 8b and R 8c are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1- 4- alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; Wherein, the C 1-6 alkylamino-C 1-4 alkyl group, 5-10 membered heteroaryl group, 3-10 membered heterocycloalkyl group, 5-10 heteroaryl-C 1-4 alkyl group or 3 -10 Heterocycloalkyl-C 1-4 alkyl is unsubstituted,
  • the R 1 is Wherein, R 8a is H, D or halogen; R 8b and R 8c are as defined above.
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R A is a C 1-6 alkyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl -C 1-4 alkyl, C 3-8 cycloalkyl -C 1-4 alkyl or -C 1-4 3-8 membered heterocycloalkyl group; the R A is unsubstituted or is selectively 1 to 5 R c are substituted at any position; the definition of R c is as described above.
  • the R 2 is -OR A; R A is as previously defined.
  • the R 2 is any of the following structures:
  • the R 2 is any of the following structures:
  • the R 2 is -NR A R B ; the definitions of R A and R B are as described above.
  • the R 2 is any of the following structures:
  • the R 2 is a 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
  • the R 2 is a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
  • the R 2 is any of the following structures:
  • the R 2 is H or CN.
  • the R 3 is cyclohexyl, cyclopropylmethyl, phenyl, pyridyl, pyrimidinyl, thiazole or 1H-pyrazolyl; the R 3 is unsubstituted or is optionally substituted by 1 to Three substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl are substituted at any position.
  • the R 3 is any of the following structures:
  • the R 4 is hydrogen, halogen, C 2-4 alkenyl, C 1-4 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1 -3 alkoxy or C 3-6 cycloalkyl.
  • the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is the compound represented by formula (II), its isomer, stable Isotope derivatives or pharmaceutically acceptable salts:
  • ring A, ring B, X, U, M, R, R 1 , R 2 and R 4 are as defined above.
  • the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is of formula (IIA), (IIB), (IIC) or (IID )
  • Ring B, R, R A, R 1 and R 5 are as previously described.
  • the present invention also provides a method for preparing the compound represented by formula (I), which is any of the following methods:
  • Method 1 In the solvent, the compound represented by formula II-1 and R-L are coupled to obtain the compound represented by formula II,
  • Suzuki coupling reaction Lev is Cl, Br or I, L is boronic acid or boronic acid ester group; or Lev is boronic acid or boronic acid ester group, L is Cl, Br or I; Suzuki coupling reaction conditions are Common reaction conditions in the art, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride/sodium carbonate aqueous solution system or For the tetratriphenylphosphine palladium/sodium carbonate aqueous system, the reaction temperature is preferably 80-120°C, and the reaction time is preferably 0.5-16 hours.
  • Stille coupling reaction where Lev is Cl, Br or I, L is -Sn(CH 3 ) 3 or -Sn(n-Bu) 3 ; or Lev is -Sn(CH 3 ) 3 or -Sn( n-Bu) 3 , L is Cl, Br or I; Stille coupling reaction conditions are common reaction conditions in the field, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably tetrakistriphenylphosphine palladium/iodine Copper chloride, tetrakistriphenylphosphine palladium/tris(2-furyl)phosphorus or bistriphenylphosphine palladium dichloride/tris(2-furyl)phosphorus, the reaction conditions are preferably microwave or sealing at 80 ⁇ 160°C React in the tube for 0.5 to 4 hours.
  • Method 2 In a solvent, the compound represented by formula II-2 is reacted with R 1 (CO)Cl or (R 1 (CO)) 2 O under basic conditions to obtain the compound represented by formula II,
  • the solvent shown is preferably dichloromethane; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35° C.; and the reaction time is preferably 0.5 to 6 hours.
  • Method 3 In the solvent, the compound represented by formula II-2 and R 1 (CO)OH are condensed to obtain the compound represented by formula II,
  • the solvent shown is preferably dichloromethane and/or ethyl acetate; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35°C; the condensing agent is preferably HATU or 1-Propyl phosphoric anhydride; the reaction time is preferably 0.5-6 hours.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) can be synthesized by general chemical methods.
  • the salt can be prepared by reacting a free base or acid with an equivalent or excess acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of active components and pharmaceutically acceptable excipients; the active components include the compound represented by formula (I), its isomers and pharmaceutically acceptable One or more of acceptable salts.
  • the active ingredient may also include other therapeutic agents for cancer.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) and the like.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil
  • adsorption promoters such as quaternaryl, sodium glyceryl tristearate, coconut
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
  • disintegrants such as agar and kelp powder.
  • any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an injection that is isotonic with blood.
  • any carriers commonly used in the art can also be used.
  • usual dissolving agents, buffers and analgesics can also be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually 5-95% by mass, preferably 30-80% by mass. %.
  • the method of administration of the pharmaceutical composition is not particularly limited.
  • various dosage forms can be selected for administration.
  • tablets, pills, solutions, suspensions, emulsions, granules or capsules can be administered orally; injections can be administered alone or mixed with delivery fluids for injection (such as glucose solution and amino acid solution) for intravenous injection; suppositories are for administration
  • delivery fluids for injection such as glucose solution and amino acid solution
  • suppositories are for administration The medicine reaches the rectum.
  • the present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of KRAS G12C inhibitors.
  • the present invention also provides the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a medicine for the treatment of KRAS G12C-mediated related diseases application.
  • the related disease is cancer.
  • the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
  • the present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating and/or alleviating cancer.
  • the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition for preparing treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer and/ Or the application of colorectal cancer drugs.
  • the present invention also provides the application of the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the treatment of cancer.
  • the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer, intrauterine Application in membrane cancer and/or colorectal cancer.
  • the present invention still further provides a method for treating cancer with the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition, which comprises: administering to a mammal a dose required for treatment
  • the compound as described in formula (I), its isomer or pharmaceutically acceptable salt, or a pharmaceutical composition comprises: administering to a mammal a dose required for treatment
  • the compound as described in formula (I), its isomer or pharmaceutically acceptable salt, or a pharmaceutical composition
  • the mammal is preferably a human.
  • the present invention further provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/ Or the treatment method is used in combination to treat and/or alleviate related diseases mediated by KRAS G12C.
  • the KRAS G12C-mediated related disease is cancer.
  • the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
  • the present invention preferably uses the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/or treatments.
  • the method is used in combination to treat and/or alleviate cancers mediated by KRAS G12C.
  • the KRAS G12C-mediated cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
  • the other types of therapeutic agents can be combined with the compound represented by formula (I) into a single-administration therapeutic dosage form, or a treatment that is administered separately and sequentially Dosage form.
  • the present invention further provides a combined preparation, comprising a compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition and other types of therapeutic agents for the treatment of cancer and / Or combination of treatment methods.
  • the cancer includes metastatic and non-metastatic cancers, as well as family hereditary and sporadic cancers, as well as solid tumors and non-solid tumors.
  • the cancer may include, but are not limited to: eye cancer, bone cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma) , Medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, endometrial cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, kidney cancer (including adenocarcinoma and Wilms cancer), oral cancer (including squamous cell carcinoma) Cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, liver cancer, sarcoma, skin cancer , Lymphatic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphoc
  • C tq refers to the range from the start point to the end point, where t and q and each point in the range are integers, representing the number of carbon atoms, for example, C 1-4 means that the number of carbon atoms is 1, 2, 3 Or 4; C 1-6 means that the number of carbon atoms is 1, 2, 3, 4, 5 or 6; C 3-8 means that the number of carbon atoms is 3, 4, 5, 6, 7 or 8; C tq can follow any Groups containing carbon atoms are used in combination to limit the number of carbon atoms, such as C 1-6 alkyl, C 1-4 alkylene, C 3-8 cycloalkyl, C 6-10 aryl, C 1 -4 alkoxy, C 3-8 cycloalkyl C 1-4 alkyl and the like.
  • alkyl refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4 or 1-3 carbons Atom
  • representative examples of alkyl include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, N-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl,
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms.
  • Cycloalkyl is preferably 3-10 membered monocyclic alkyl or partially unsaturated 4-6 membered cycloalkyl, more preferably 3-8 or 3-6 membered monocyclic alkyl, for example: cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged cyclic group”, “fused cycloalkyl” and “spirocycloalkyl”.
  • the monocyclic cycloalkyl or polycyclic cycloalkyl can be linked to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur or boron.
  • the shaped group can be monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic group.
  • the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and heterocycloalkyl Nitrogen, carbon, sulfur or boron atoms in can optionally be oxidized.
  • the nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or a quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl” is preferably a 3-10 membered monocyclic heterocycloalkyl, more preferably a 3-8 or 4-8 membered monocyclic heterocycloalkyl.
  • Representative examples include but are not limited to: aziridinyl, tetrahydrofuran-2-yl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, pyrrolidinyl , Piperazinyl, homopiperazinyl, 1,4-dioxanyl, pyranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, 2,3-dihydrofuranyl, 2 ,5-Dihydrofuryl, dihydropyrazolyl, 2,3-dihydro-1H-pyrrolidinyl, 2,5-dihydro-1H-pyrrolidinyl, 1,
  • Polycyclic heterocycloalkyl includes “fused heterocycloalkyl”, “spiroheterocyclic group” and “bridged heterocyclyl”, “fused heterocycloalkyl” includes fused to aryl, cycloalkyl , Heterocycloalkyl or heteroaryl monocyclic heterocycloalkyl ring, condensed heterocycloalkyl includes but not limited to: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl Hydroisobenzofuranyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopiperanyl, 1,2,3,4-tetrahydroquinolinyl, benzo[d][1 ,3]dioxolanyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl 3-hydroxy-1,3-dihydronaphtho[2,1-
  • Spiroheterocyclic group refers to a bicyclic group formed by two heterocycloalkyl groups or one cycloalkyl group and one heterocycloalkyl group sharing one carbon atom. Spiro heterocyclic group includes but is not limited to: Wait.
  • Bridged heterocyclic group means that any two unlinked ring atoms of a monocyclic heterocycloalkyl group are connected by a straight chain group formed by 1 to 3 additional carbon atoms or heteroatoms (the straight chain group The group is selected from but not limited to: -CH 2 -, -O-, -NH-, -S-, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, -CH 2 NH-,- CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 NHCH 2 -), bridged heterocyclic groups include but are not limited to:
  • the bicyclic heterocycloalkyl group is preferably a 7 to 12-membered bicyclic heterocycloalkyl group.
  • the monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can be linked to the parent molecule through any ring atom on the ring.
  • the aforementioned ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to the connection between a cycloalkyl group and the core structure through an alkyl group.
  • cycloalkylalkyl encompasses the definitions of alkyl and cycloalkyl described above.
  • heterocycloalkylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
  • heterocycloalkylalkyl encompasses the definitions of alkyl and heterocycloalkyl as described above.
  • alkenyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C 2-4 alkenyl refers to an alkenyl group having 2-4 carbon atoms
  • C 2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms, including vinyl and propenyl. , Butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
  • alkynyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.
  • alkoxy refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms connected through an oxygen bridge, including alkyloxy, cycloalkyloxy and heterocycloalkyloxy.
  • alkoxy encompasses the definitions of alkyl, heterocycloalkyl, and cycloalkyl described above.
  • aryl refers to any stable 6-14 membered all-carbon monocyclic or fused bicyclic aromatic group with a conjugated ⁇ -electron system, in which at least one ring of the fused bicyclic aromatic group is an aromatic ring
  • the aryl group is preferably 6-10 members, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
  • heteroaryl refers to an aromatic ring group formed by replacing at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which can be a 5-6 membered monocyclic structure or 7-12
  • the membered bicyclic structure is preferably a 5-10 membered heteroaryl group.
  • the number of heteroatoms is preferably 1, 2 or 3, including: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazine-3(2H)-keto, 1H-benzo[d] Imidazole-2(3H)-keto, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Azolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1H-indazolyl, isoindazole Group, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolinyl, is
  • arylalkyl refers to the connection between the aryl group and the core structure through an alkyl group.
  • arylalkyl encompasses the definitions of alkyl and aryl as described above.
  • heteroarylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
  • heteroarylalkyl encompasses the above definitions of alkyl and heteroaryl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl encompasses the definitions of halogen and alkyl above.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy encompasses the definitions of halogen and alkoxy above.
  • amino refers to -NH 2 .
  • alkylamino means that at least one hydrogen atom on an amino group is replaced by an alkyl group, including “monoalkylamino” and "dialkylamino". Examples include but are not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 3 )(CH 2 CH 2 CH 3 ).
  • aminoalkyl means that any hydrogen atom on the alkyl group is replaced by an amino group, and examples include but are not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 . Therefore, “aminoalkyl” and “alkylamino” encompass the definitions of alkyl and amino as described above.
  • alkylaminoalkyl means that any hydrogen atom on the alkyl group is replaced by an alkylamino group. Examples include but are not limited to: -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 NHCH 3 .
  • alkylaminoalkyl encompasses the definitions of alkylamino and alkyl as described above.
  • hydroxy refers to -OH.
  • hydroxyalkyl means that any hydrogen atom on the alkyl group is replaced by a hydroxyl group. Examples include but are not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH , -CH(CH 3 ) 2 OH.
  • hydroxyalkyl encompasses the above definitions of hydroxyl and alkyl.
  • alkoxyalkyl means that any hydrogen atom on the alkyl group is replaced by an alkoxy group, and examples include but are not limited to: -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 .
  • alkoxyalkyl encompasses the definitions of alkoxy and alkyl as described above.
  • acyl refers to -C(O)R.
  • cyano refers to -CN.
  • room temperature in the present invention refers to 15-30°C.
  • the term "optionally substituted by 1-3 groups at any position" refers to any 1, 2, or 3 of the 1, 2, or 3 atoms specified on the group.
  • any combination of variables is allowed only if the combination will produce a stable compound.
  • each variable when any variable occurs more than once in the composition or structure of a compound, its definition in each case is independent.
  • each R 5 substituent is an independent substituent, which may be the same or different.
  • the compound represented by formula (I) in any of the embodiments described in the present invention includes isotopic derivatives thereof.
  • the isotopically substituted derivatives include: any hydrogen atom (1 to 5) in formula (I) is substituted by 1 to 5 deuterium atoms; any carbon atom (1 to 5) in formula (I) 3) Isotope substituted derivatives obtained by substituting 1 to 3 C 14 atoms or isotopic substituted derivatives obtained by substituting any oxygen atom in formula (I) with 1 to 3 O 18 atoms.
  • the "pharmaceutically acceptable salt” of the present invention is discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and has been discussed by medicinal chemists. It is obvious that the salt is basically non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • the compound of the present invention may have an acidic group, a basic group or an amphoteric group.
  • Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, such as: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-
  • its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkane. Salts formed from base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
  • the “isomer” in the present invention means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and single diastereomers, and all these isomers, including Both stereoisomers and geometric isomers are included in the present invention.
  • the compound of formula (I) or its salt exists in a stereoisomeric form (for example, it contains one or more asymmetric carbon atoms)
  • the individual stereoisomers (enantiomers and non- Enantiomers) and their mixtures are included in the scope of the present invention.
  • the present invention also includes individual isomers of the compound or salt represented by formula (I), and mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the present invention includes: mixtures of stereoisomers, and purified enantiomers or enantiomer/diastereomer enriched mixtures.
  • the present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers.
  • the present invention includes all combinations and subsets of stereoisomers of all specific groups as defined above.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the structures of all the compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • Liquid mass spectrometry is determined by Agilent 1200HPLC/6120 mass spectrometer, using chromatographic column: Xtimate C18, 3.0 ⁇ 50mm, 3 ⁇ m, column temperature 40°C; or by Thermo UltiMate 3000HPLC/MSQ PLUS mass spectrometer, using column XBridge C18, 3.0 ⁇ 50mm, 3.5 ⁇ m, column temperature 30°C.
  • Agilent gradient elution condition 1 95-5% solvent A 1 and 5-95% solvent B 1 (0-2.0 minutes), then 95% solvent B 1 and 5% solvent A 1 (hold for 1.1 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume.
  • Solvent A 1 0.01% trifluoroacetic acid (TFA) in water; solvent B 1 : 0.01% trifluoroacetic acid in acetonitrile; the percentage is the volume percentage of the solute in the solution.
  • Thermo gradient elution condition 2 95-5% solvent A 2 and 5-95% solvent B 2 (0-2 minutes), then 95% solvent B 2 and 5% solvent A 2 (hold for 1.8 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume.
  • Solvent A 2 10 mM ammonium bicarbonate aqueous solution; Solvent B 2 : Acetonitrile.
  • All the compounds of the present invention can be separated by preparative high performance liquid chromatograph or fast column chromatography.
  • the preparative high performance liquid chromatograph uses Shimadzu LC-20 for preparative liquid chromatography, and the column is: Xtimate 21.2*250mm, 10 ⁇ m.
  • Mobile phase A 10mmol/L ammonium bicarbonate aqueous solution
  • mobile phase B acetonitrile
  • gradient elution condition 1 mobile phase B from 10% to 30%, elution time 5 minutes; mobile phase B from 30% to 60%, Elution time 15 minutes
  • Condition 2 Mobile phase B from 15% to 25%, Elution time: 5 minutes, Elution mobile phase B from 25% to 55%, Elution time 15 minutes
  • Condition 3 Mobile phase B From 15% to 30%, elution time: 5 minutes, elution mobile phase B from 30% to 65%, elution time 15 minutes
  • condition 4 mobile phase B from 0% to 35%, elution time: 5 Minutes, elution mobile phase B from 35% to 60%, elution time 15 minutes
  • condition 5 mobile phase B from 10% to 40%, elution
  • Mobile phase A 0.1% trifluoroacetic acid aqueous solution
  • mobile phase B acetonitrile
  • gradient elution condition 6 mobile phase B from 15% to 25%, elution time 5 minutes, 25% to 55%, elution time 15 minutes
  • Condition 7 mobile phase B from 15% to 30%, elution time 5 minutes, 30% to 60%, elution time 15 minutes
  • Condition 8 mobile phase B from 15% to 45%, elution time 5 minutes , 45% to 80%, elution time 15 minutes.
  • Detection wavelength 214nm&254nm
  • flow rate 15.0mL/min.
  • Flash column chromatography uses Agela Technologies MP200, and the matched normal phase separation column is Flash column Silica-CS (25g, 40g, 80g, 120g, or 330g), Tianjin Bonaageer, the elution system is ethyl acetate/petroleum ether, or dichloromethane/methanol; the reverse-phase separation column is a C18 reverse-phase column (12g, 20g, or 40g), Changzhou Santai Technology, the elution system It is acetonitrile/0.1% trifluoroacetic acid aqueous solution or acetonitrile/10mmol/L ammonium bicarbonate aqueous solution.
  • Thin layer silica gel plate is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the microwave reaction used in the embodiment of the present invention Initiator+Microwave System EU (356006) type microwave reactor. Unless otherwise specified in the present invention, the reactions in all the examples were carried out under a nitrogen atmosphere or an argon atmosphere.
  • the hydrogen atmosphere refers to the reaction system connected to a hydrogen balloon with a volume of about 1L.
  • Step 2 Combine 1-Benzylmethyl-N-(2-fluoroethyl)azetidin-3-amine (4g, 14.1mmol), iodoethane (3.3g, 21.1mmol) and potassium carbonate (5.8 g, 42.2 mmol) of acetonitrile (50 mL) mixture was stirred at 40°C for 20 hours in a sealed tube.
  • Step 3 Combine 1-Benzylmethyl-N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (1g, 3.19mmol), ammonium formate (4g, 63.8mmol), hydrogen Palladium oxide on carbon (1 g) was added to methanol (20 mL), and the reaction system was replaced with nitrogen three times, and then stirred at 60°C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (466 mg) as a yellow oil. m/z: [M+H] + 147.2.
  • Step 1 Combine 1-chloro-2,6-dibromo-4-fluorobenzene (1.0g, 3.47mmol), benzophenone imine (754mg, 4.16mmol), t-BuONa (500mg, 5.21mmol), An anhydrous toluene (30 mL) solution of BINAP (324 mg, 0.52 mmol) and Pd 2 (dba) 3 (156 mg, 0.17 mmol) was replaced with nitrogen and stirred at 80° C. for 16 hours.
  • Step 2 Under the protection of nitrogen, the isopropenyl borate pinacol ester (293mg, 1.74mmol), 3-bromo-5-fluoro-4-iodoaniline (500mg, 1.58mmol), potassium phosphate (1.01g, 4.75mmol) ) And PdCl 2 dppf . CH 2 Cl 2 (130 mg, 0.16 mmol) in 1,4-dioxane (25 mL) was stirred at 80°C for 16 hours.
  • Step 3 Add 3-bromo-5-fluoro-4-(prop-1-en-2-yl)aniline (272mg, 1.18mmol) and platinum carbon (30mg) to ethyl acetate (20mL) and methanol (25mL ), stirring at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 3-bromo-5-fluoro-4-isopropylaniline (250 mg) as a yellow oil. m/z: [M+H] + 232.0.
  • Step 1 Under ice bath conditions, add sodium hydrogen (60%, 3.74g, 93.5mmol) to a solution of 6-chloro-5-iodopyrazine-2-amine (9.56g, 37.4mmol) in DMF (58mL), The reaction mixture was stirred for 40 minutes, and p-methoxybenzyl chloride (14.6 g, 93.5 mmol) was slowly added to the above reaction solution and stirring was continued for 2 hours.
  • Step 2 Add 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)pyrazine-2-amine (2.5g, 5.10mmol), 2,2-difluoro-2-( Methyl fluorosulfonyl)acetate (2.9g, 15.0mmol) and cuprous iodide (2.86g, 15.0mmol) were suspended in anhydrous DMF (70mL) solution, and the reaction solution was stirred at 100°C for 4 hours under the protection of nitrogen.
  • Step 2 Combine 2-(bis(4-methoxybenzyl)amino)-6-chloroisonicotinonitrile (8.7g, 37.4mmol), N-iodosuccinimide (5.73g, 25.5mmol) Dissolved in anhydrous DMF (70mL), the reaction mixture was stirred at 100°C overnight, diluted with ethyl acetate (500mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Add 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-iodoisonicotinonitrile (8.0g, 15.4mmol), 2,2-difluoro-2- (Fluorosulfonyl) methyl acetate (8.9g, 46.2mmol) and cuprous iodide (8.8g, 46.2mmol) were suspended in anhydrous DMF (120mL) solution, and the reaction system was stirred at 100°C for 4 hours under nitrogen protection .
  • Step 2 Under nitrogen protection at -10°C, slowly add n-butyllithium (2.5M tetrahydrofuran solution, 1.2mL, 2.8mmol) to 3-methoxy-1-(2-methoxyethoxy)
  • naphthalene 0.5 g, 2.34 mmol
  • tetramethylethylenediamine 0.35 mL, 3.0 mmol
  • hexachloroethane solid (0.87 g, 3.66 mmol
  • reaction solution was warmed to room temperature, quenched by adding water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Combine 2-chloro-3-methoxy-1-(2-methoxyethoxy)naphthalene (0.5g, 1.98mmol) and hydrogen chloride (4.0M 1,4-dioxane solution, 4.0mL) in dichloromethane (10mL) solution was stirred at room temperature for 1.5 hours, then, saturated aqueous sodium bicarbonate was added to adjust the pH to 7.0, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-Chloro-3-methoxynaphthalen-1-ol (0.41 g) is a yellow solid. m/z: [M+H] + 209.0.
  • Step 4 Under ice bath conditions, add trifluoromethanesulfonic anhydride (0.7g, 2.5mmol) to 2-chloro-3-methoxynaphthalene-1-ol (0.4g, 1.92mmol) and triethylamine (0.8 mL, 5.76 mmol) in dichloromethane (5 mL). The reaction solution was stirred at 0°C for 2 hours. The reaction was quenched by adding water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate) to obtain the corresponding borate.
  • Step 1 Under ice bath conditions, to 2,4-dichloro-5-fluoroaniline (2.62g, 14.6mmol) and sodium carbonate (2.65g, 25mmol) in methyl tert-butyl ether (60mL) solution was added three Fluoroacetic anhydride (3.78g, 18mmol), the reaction solution was stirred at room temperature for 12 hours, diluted with n-hexane and filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Add 4-bromo-2,6-difluorobenzonitrile (25g, 0.11mol), ammonia water (100mL) and isopropanol (60mL) into the sealed tube, and stir the reaction system at 90°C for 16 hours. After the reaction solution was cooled to room temperature, it was poured into water, a large amount of solids were precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 1-1 (23.2g) as a gray solid. m/z: [M+H] + 215.0.
  • Step 2 Under ice bath conditions, add sodium hydrogen (60%, 1.1g, 27.9mmol) to a solution of 2,2-diethoxyethanol (3.7g, 27.9mmol) in DMF (60mL) in batches to obtain The mixture was stirred at 0°C for 1 hour. Next, Intermediate 1-1 (5 g, 23.3 mmol) was added to the above reaction solution, and stirred at 50°C for 1 hour.
  • Step 4 A mixed solution of intermediate 1-3 (0.33 g, 1.39 mmol) in formic acid (12 mL) and concentrated sulfuric acid (0.3 mL) was stirred at 100° C. for 0.5 hours. The reaction solution was cooled to room temperature and poured into water. A large amount of solids precipitated out, filtered off with suction, and the filter cake was vacuum dried to obtain Intermediate 1-4 (0.21 g) as a yellow solid. m/z: [M+H] + 264.8.
  • Step 5 To the 1,4-dioxane (16mL) solution of Intermediate 1-4 (350mg, 1.32mmol) and N,N-dimethylaniline (1.78g, 14.7mmol) was added phosphorus oxychloride (1.6 mL), the reaction solution was stirred at 110°C for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 1-5 (crude product) as a yellow solid. m/z: [M+H] + 282.8.
  • Step 3 Add phosphorus oxychloride (2mL) to the solution of Intermediate 2-2 (100mg, 0.36mmol) and N,N-dimethylaniline (0.2mL) in 1,4-dioxane (5mL) The reaction solution was stirred at 110°C for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 2-3 (crude) as a yellow solid. m/z: [M+H] + 316.8.
  • Step 2 To a solution of chloral hydrate (3.9g, 23.6mmol), concentrated hydrochloric acid (5mL), anhydrous sodium sulfate (13.4g, 94.3mmol) in water (50mL) was added Intermediate 3-1 (2.5g, 11.8) mmol) in DMF (25 mL). After the resulting mixture was stirred at 90°C for 30 minutes, hydroxylamine hydrochloride (4.9 g, 70.7 mmol) was added, and stirring was continued at 90°C overnight. The reaction was quenched by adding ice water, the resulting mixture was stirred for 15 minutes, filtered, and the filter cake was washed with water and dried in vacuo to obtain Intermediate 3-2 (2.9 g) as a yellow solid. m/z: [M+H] + 284.5.
  • Step 3 A solution of Intermediate 3-2 (2.9g, 10.2mmol) in concentrated sulfuric acid (20mL) was stirred at 60°C for 1.5 hours, then carefully added to ice water, the reaction mixture was filtered, the filter cake was washed with water and dried in vacuo The intermediate 3-3 (2.7g) was obtained as a brown solid. m/z: [M+H] + 267.8.
  • Step 5 Under ice bath conditions, add HATU to a solution of Intermediate 3-4 (1.6g, 6.3mmol), ammonium chloride (3.3g, 62.5mmol), DIPEA (2.4g, 18.8mmol) in DMF (50mL) (1.6g, 6.3mmol), the resulting mixture was stirred at room temperature for 2 days, and water (10mL) was added to quench the reaction.
  • the reaction solution was purified by Flash column chromatography (30% acetonitrile in ammonium bicarbonate aqueous solution) to obtain Intermediate 3-5 (630mg) is a pale yellow solid. m/z: [M+H] + 256.8.
  • Step 6 Intermediate 3-5 (300mg, 1.2mmol) and urea (3.5g, 58.8mmol) were melted at 180°C and stirred for 2 hours, then cooled to 80°C, water (15mL) was added and stirred for 5 minutes, and the reaction mixture was filtered The filter cake was washed with water and dried in vacuo to obtain Intermediate 3-6 (330 mg) as a pale yellow solid. m/z: [M+H] + 280.8.
  • Step 1 To a solution of Intermediate 2-3 (1.1g, 3.56mmol) and DIPEA (14.1g, 109mmol) in 1,4-dioxane (60mL) was added (S)-2-(piperazine-2 -Base) acetonitrile dihydrochloride (0.86 g, 4.43 mmol) in acetonitrile (10 mL). The reaction solution was stirred at 50° C. for 2 hours, and the reaction was quenched with water. The aqueous phase was extracted with dichloromethane, and the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 4-1 (crude) as a yellow oil. m/z: [M+H] + 406.0.
  • Step 4 A mixed solution of Intermediate 4-3 (110 mg, 0.19 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to obtain Intermediate 4-4 ( Crude product) is yellow oil. m/z: [M+H] + 485.2.
  • Step 5 Under ice bath conditions, add acrylic anhydride (39mg, 0.31mmol) in anhydrous dichloromethane to the solution of Intermediate 4-4 (crude) and DIPEA (0.5mL) in anhydrous dichloromethane (6mL) dropwise (1mL) solution.
  • the reaction solution was stirred at room temperature for 6 hours, and the reaction was quenched with water.
  • Intermediate 4-5 (70 mg) is a yellow oil. m/z: [M+H] + 539.2.
  • Steps 2 to 4 Using the synthesis method of Steps 3 to 5 of Intermediate 4-5, react with Intermediate 4-6 to obtain 4-7 as a yellow oil. m/z: [M+H] + 514.2.
  • Step 2&3 Using the synthesis method of Steps 4 to 5 of Intermediate 4-5, react with Intermediate 5-1 to obtain 5-3 as a brown oil. m/z: [M+H] + 552.2.
  • Step 1&2 Same as Intermediate 4-5 Step 3&4.
  • Step 3 Under ice bath conditions, to a solution of Intermediate 4-4 (100mg, 0.2mmol) in anhydrous ethyl acetate (3mL) were added triethylamine (0.23mL, 1.6mmol) and 2-fluoroacrylic acid (36mg , 0.4 mmol) and 1-propyl phosphoric anhydride (50% ethyl acetate solution, 0.6 mmol).
  • Step 1 To (E)-4-bromobut-2-enoic acid (170mg, 1.03mmol) in dichloromethane (5mL) was added oxalyl chloride (1.5mL), the reaction solution was stirred at 70°C for 3 hours Concentrate directly under reduced pressure.
  • Step 1 Using the synthesis method of Intermediate 5-1, Intermediate 4-2 is reacted with N-ethyl-N-(2-fluoroethyl)azetidin-3-amine to obtain Intermediate 7-1. m/z: [M+H] + 616.2.
  • Step 2 Under ice bath conditions, add hydrogen chloride (4M 1,4-dioxane (4 mL) to the anhydrous 1,4-dioxane (4 mL) solution of Intermediate 7-1 (150 mg, 0.24 mmol) Solution, 2mL), after the addition, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain Intermediate 7-2 (crude product) as a pale yellow solid. m/z: [M+H] + 516.2.
  • Step 3 Under an ice-water bath, add 2-fluoroacrylic acid (97.7 mg, 1.1 mmol) to a solution of Intermediate 7-2 (crude) and triethylamine (0.7 mL, 5.43 mmol) in anhydrous ethyl acetate (10 mL) And 1-propyl phosphoric anhydride (50% ethyl acetate solution, 1.63 mmol), after the addition, the reaction system was raised to room temperature, and stirring was continued for 3 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by prep-TLC (100% ethyl acetate) to obtain Intermediate 7-3 (80 mg) as a pale yellow solid. m/z: [M+H] + 588.2.
  • Step 1&2 Intermediate 3-7 (350mg, 1.09mmol), DIPEA (427mg, 3.3mmol), (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (261mg, 1.32mmol)
  • DMSO 15.0 mL
  • Boc 478 mg, 2.19 mmol
  • the reaction system was stirred at room temperature for 30 minutes and then water (50 mL) was added to quench the reaction.
  • the phases were extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure.
  • m/z [M+H] + 606.2.
  • Step 3 Mix Intermediate 8-2 (180mg, 297 ⁇ mol), N-methyl-L-prolinol (171mg, 1.48mmol), DIPEA (192mg, 1.48mmol) and cesium carbonate (557mg, 1.48mmol) in 1
  • the 4 dioxane (5 mL) mixture was stirred at 165°C for 3 hours in a sealed tube.
  • Step 4 To a solution of Intermediate 8-3 (230 mg, 393 ⁇ mol) in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain Intermediate 8-4 (crude product) as a brown solid. m/z: [M+H] + 487.2.
  • Step 1 Under ice bath conditions, sodium hydrogen (60%, 2.23 g, 93 mmol) was added to a solution of allyl alcohol (6.36 mL, 93 mmol) in anhydrous DMF (15 mL), and the reaction solution was raised to room temperature and stirred for 1.5 hours. A solution of 2-amino-4-bromo-6-fluorobenzonitrile (10g, 46.5mmol) in anhydrous DMF (5mL) was added dropwise to the above reaction solution, and the resulting mixture was stirred at room temperature for 10 hours, and quenched by adding water (500mL) Reaction, filtration, and vacuum drying of the filter cake gave Intermediate 9-1 (11.7 g) as a yellow solid. m/z: [M+H] + 253.0.
  • Step 4 At -78°C, pass ozone in the mixed solution of intermediate 9-3 (10g, 23.7mmol) in dichloromethane (50mL) and methanol (50mL) for 15 minutes, and then discharge the remaining ozone in the reaction solution Then sodium borohydride (13.5 g, 356 mmol) was added, and the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding water (100 mL), the organic phase was separated, washed with dilute hydrochloric acid (1M, 20 mL), and concentrated under reduced pressure to obtain Intermediate 9-4 (8.0 g) as a yellow solid. m/z: [M+H] + 343.0.
  • Step 5 Under ice bath conditions, slowly add DIAD (5.54 mL, 28.1 mmol) to a solution of Intermediate 9-4 (8.0 g, 23.4 mmol), triphenylphosphine (7.4 g, 28.1 mmol) in tetrahydrofuran (150 mL) .
  • Step 7 Heat Intermediate 9-6 (300mg, 1.17mmol) and urea (3.5g, 58.5mmol) to 180°C, stir for 2 hours in a molten state, then cool to 100°C, add water (15mL) and stir for 1 hour. The temperature was lowered to 0°C and filtered. The filter cake was washed with water and dried in vacuo to obtain Intermediate 9-7 (330 mg) as a pale yellow solid. m/z: [M+H] + 283.0.
  • Step 8 Intermediate 9-7 (330 mg, 1.17 mmol) and N,N dimethylaniline (0.5 mL) were added to phosphorus oxychloride (10 mL), and the reaction system was stirred at 110° C. for 2 hours. Then it was directly concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with ice water, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 9-8 (crude) as a yellow solid. m/z: [M+H] + 319.0.
  • Steps 9-13 Using the synthesis method of Intermediate 4-5, react with Intermediate 9-8 to obtain Intermediate 9-13 as a yellow solid. m/z: [M+H] + 541.0.
  • Step 3 Intermediate 10-2 (1.2 g, 4.5 mmol) and potassium hydroxide aqueous solution (2M, 22 mL) were added to ethanol (30 mL), and the reaction solution was refluxed and stirred at 90° C. for 12 hours.
  • Intermediate 10-3 (1.1 g) was purified as a white solid. m/z: [M+H] + 287.0.
  • Step 4 Intermediate 10-3 (800mg, 2.8mmol) and urea (8.4g, 140mmol) were mixed uniformly and heated to 180°C and stirred for 1.5 hours.
  • the reaction solution was cooled to room temperature, water (15mL) was added, then stirred at 100°C for 1 hour, filtered under reduced pressure, the filtrate was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated under reduced pressure.
  • Step 6&7 Intermediate 10-5 (310 mg, 0.87 mmol) and phosphorus oxychloride (10 mL) in N,N-xylidine (0.5 mL) were stirred at 110°C for 2 hours. Concentrate under reduced pressure. Under ice bath conditions, ethyl acetate (50 mL) was added to the residue, then washed with ice water, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 10-6.
  • Steps 10&11 Under ice bath conditions, disperse sodium hydrogen (26mg, 0.65mmol) in anhydrous DMF (5mL) solution, and add ((2S,4R)-4-fluoro-1-methylpyrrolidine dropwise under the protection of nitrogen -2-yl) methanol in DMF solution (87 mg, 0.65 mmol, 0.5 mL), the reaction solution was stirred at this temperature for 0.5 hours, and then the DMF solution of intermediate 10-9 (80 mg, 0.13 mmol, 0.5 mL) was added dropwise To the above reaction solution, after the addition, continue to stir for 0.5 hours in an ice bath to obtain a reaction solution containing intermediate 10-10.
  • Steps 12 & 13 To intermediate 10-11 (83 mg, 0.13 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction solution was stirred for 2 hours and then concentrated under reduced pressure to obtain Intermediate 10-12. Under ice bath conditions, to a solution of Intermediate 10-12 and DIPEA (0.2 mL) in anhydrous dichloromethane (2 mL) was slowly added a dichloromethane solution (0.5 M, 0.3 mL) of acrylic anhydride. The reaction solution was continuously stirred at this temperature for 10 minutes.
  • Step 1&2 Same as Step 3&4 of Intermediate 4-7.
  • Step 1 To a solution of 2-amino-4-bromo-6-fluorobenzonitrile (23.6g, 110mmol) in anhydrous acetonitrile (370mL) was added N-iodosuccinimide (27.2g, 121mmol) and Trifluoroacetic acid (25g, 220mmol), the reaction system was stirred at room temperature for 1.5 hours in the dark and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated sodium bisulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was slurried with dichloromethane at °C, filtered, and the filter cake was vacuum dried to obtain Intermediate 13-1 (22.3g) as an off-white solid. m/z: [M+H] + 340.8.
  • Step 2 Add bistriphenylphosphorus palladium dichloride (4.59g, 6.54mmol) to Intermediate 13-1 (22.3g, 65.4mmol), (E)-styrylboronic acid (14.5g, 98.1mmol)
  • a mixed solution of potassium carbonate (18.1 g, 131 mmol) in toluene (200 mL) and ethanol (50 mL) the reaction system was replaced with nitrogen three times and stirred overnight at 80° C., cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with water and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Add hydrogen peroxide (30%, 9mL) dropwise to intermediate 13-2 (6.92g, 21.8mmol) and potassium carbonate (6.03g, 43.6mmol) in DMSO (90mL) solution, and the reaction system is stirred at room temperature for 1.5 hours . Then the reaction solution was poured into ice water, a large amount of solids precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 13-3 (7.03 g) as a yellow solid. m/z: [M+H] + 335.0.
  • Step 4 To a solution of Intermediate 13-3 (7.03 g, 21 mmol) in tetrahydrofuran (212 mL) was added triphosgene (6.22 g, 21 mmol), and the reaction system was stirred at room temperature overnight. After concentration under reduced pressure, it was poured into ice water, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, filtered with suction, the filter cake was washed with petroleum ether and dried in vacuo to obtain Intermediate 13-4 (7.1 g) as a yellow solid. m/z: [M+H] + 361.0.
  • Step 5 Intermediate 13-4 (10.7g, 29.5mmol) was added to phosphorus oxychloride (106mL), and then N,N-dimethylaniline (10.6mL) was added, and the reaction system was stirred at 110°C for 2 hours . Phosphorus oxychloride was removed by concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution.
  • Step 6 Under ice bath conditions, mix (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (5.88g, 29.7mmol) and DIPEA (10.5g, 80.9mmol) in DMF (60mL) Replace with nitrogen, add a solution of intermediate 13-5 (10.7g, 27.0mmol) in DMF (100mL) dropwise to the above reaction solution, and then add (Boc) 2 O (29.4g, 135mmol) and DIPEA (25.6g, 198mmol), and the reaction system was stirred overnight at room temperature.
  • Step 8 To the mixed solution of Intermediate 13-7 (2.63g, 3.95mmol) in dichloromethane (36mL) and water (6mL) was added N-methyl-N-morpholine oxide (0.93g, 7.9mmol) and Potassium osmate dihydrate (0.15 g, 0.4 mmol), and the reaction system was stirred at room temperature overnight.
  • Step 10 Under ice bath conditions, add sodium carbonate (0.37 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol) in ethanol (20 mL) and water (10 mL) to a mixed solution of intermediate 13-9 (2.07 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol). g, 3.5 mmol) in water (10 mL), and the reaction system was stirred overnight at room temperature.
  • Step 11 Under ice bath conditions, add potassium tert-butoxide (0.56g, 5.0mmol) to a solution of Intermediate 13-10 (2.02g, 3.3mmol) in tetrahydrofuran (100mL), and stir the reaction system at 0°C for 15 minutes Then, it was raised to room temperature and stirred for 1.5 hours. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 12 Under ice bath conditions, add 1,4-dioxane solution (4M, 2.5 mL) of hydrogen chloride dropwise to the solution of Intermediate 13-11 (170 mg, 290 ⁇ mol) in dichloromethane (5 mL), and the reaction system Stir at 0°C for 1 hour. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-12 (200 mg) as an off-white solid. m/z: [M+H] + 486.2.
  • Step 13 DIPEA (0.5 mL), 2-fluoroacrylic acid (99 mg, 0.6 mmol) and HATU (171 mg, 0.45 mmol) were added to the solution of Intermediate 13-12 (200 mg, crude product) in anhydrous DMF (5 mL), respectively.
  • the reaction mixture was stirred overnight at room temperature, and saturated aqueous sodium bicarbonate solution was added to quench the reaction.
  • the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Under ice bath conditions, add sodium hydrogen (60%, 0.88g, 0.022mol) to 2,2-ethoxyethanol (2.8g, 0.021mmol) in anhydrous tetrahydrofuran (50mL) solution in batches, and react The mixture was stirred at 10°C for 1 hour. Then a tetrahydrofuran solution (10 mL) of methyl 4-bromo-2,6-difluorobenzoate (5 g, 0.02 mol) was slowly added dropwise to the above reaction mixture.
  • Step 2 A toluene (80 mL) suspension of polyphosphoric acid (11.4 g, 33.7 mmol) was stirred at 60° C. for 30 minutes. Then, a toluene solution (20 mL) of Intermediate 15-1 (4.1 g, 11.2 mmol) was added to the above suspension, the reaction system was stirred at 60°C for 1 hour and then concentrated under reduced pressure.
  • Step 4 Add oxalyl chloride (372 mg, 2.93 mmol) dropwise to the solution of Intermediate 15-3 (630 mg, 2.44 mmol) in anhydrous 1,2-dichloroethane (20 mL), and the reaction solution was stirred at 80°C for 2 hour. Then the reaction solution was cooled with an ice-water bath, and a solution of 2-isopropylaniline (660 mg, 4.88 mmol) in anhydrous 1,2-dichloroethane (5 mL) was slowly added dropwise to the above reaction solution.
  • Step 5 At -20°C, slowly add LiHMDS (1M tetrahydrofuran solution, 4.3 mL) to the intermediate 15-4 (0.82 g, 1.96 mmol) in anhydrous tetrahydrofuran (30 mL) solution, and the resulting mixture slowly rises
  • LiHMDS Li tetrahydrofuran solution
  • anhydrous tetrahydrofuran (30 mL) solution anhydrous tetrahydrofuran (30 mL) solution
  • the resulting mixture slowly rises
  • the reaction with saturated aqueous ammonium chloride solution (20 mL)
  • extract the aqueous phase with ethyl acetate separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use petroleum
  • the ether/ethyl acetate mixed solvent (1/1, 30 mL) was slurried, filtered, and the filter cake was vacuum dried to obtain Intermediate 15-5 (680 mg) as
  • Step 6 To a solution of Intermediate 15-5 (0.3 g, 0.75 mmol) in anhydrous acetonitrile (30 mL) were sequentially added triethylamine (455 mg, 4.5 mmol) and phosphorus oxychloride (691 mg, 4.5 mmol). The reaction mixture was stirred at 80°C for 2 hours, and then directly concentrated under reduced pressure to obtain Intermediate 15-6 (crude product) as a yellow solid.
  • Step 1 Intermediate 1-6 (120mg, 0.28mmol), (5-methyl-1H-indazol-4-yl)boronic acid (80mg, 0.45mmol), cesium carbonate (92mg, 0.28mmol) and PdCl 2 dppf .
  • CH 2 Cl 2 (15 mg, 0.02 mmol)
  • 1,4-dioxane (12 mL) and water (1 mL) was replaced with nitrogen three times, and the reaction system was stirred at 90° C. for 12 hours.
  • Step 2 A mixture of compound 1A (110 mg, 0.23 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 1B (crude) as a yellow oil. m/z: [M+H] + 385.0.
  • Step 3 To the dichloromethane (20 mL) solution of compound 1B (crude) and DIPEA (1 mL) was added dropwise a dichloromethane solution (1M, 25 mg, 0.28 mL) of acryloyl chloride, and the reaction solution was stirred at room temperature for 30 minutes. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 1) to obtain compound 1-1-1 (33.1 mg, two-step yield: 32%) as a yellow solid.
  • Step 1 To the solution of Intermediate 1-5 (425mg, 1.5mmol) and triethylamine (0.62ml, 4.5mmol) in dichloromethane (10mL) was added (S)-2-(1-acryloylpiperazine- 2-yl)acetonitrile hydrochloride (480 mg, 2.7 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 Under the protection of nitrogen, compound 3A (0.11g, 0.26mmol), Intermediate 2 (0.11g, 0.38mmol), PdCl 2 dppf . CH 2 Cl 2 (32mg, 0.04mmol) and sodium carbonate (1.0M, A mixed solution of 0.78 mL) of water (0.8 mL) and 1,4-dioxane (7 mL) was reacted at 100°C under microwave conditions for 1 hour, then the reaction system was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was decompressed After concentration, it was purified by prep-HPLC (condition 2) to obtain compound 1-1-2 (36 mg, yield: 28%) as an off-white solid.
  • Step 1 Under ice bath conditions, add sodium hydrogen (60%, 56mg, 1.38mmol) to a solution of N-methyl-L-prolinol (159mg, 1.38mmol) in DMF (12mL) in batches. After stirring at 0°C for 1 hour, Intermediate 2-4 (63.5 mg, 0.13 mmol) was added to the above reaction solution, and the resulting mixture was stirred at room temperature for 2 hours.
  • Step 2 Combine compound 4A (29mg, 53.1 ⁇ mol), (5-methyl-1H-indazol-4-yl)boronic acid (19mg, 106 ⁇ mol), sodium carbonate aqueous solution (0.26mL, 1M) and PdCl 2 dppf .
  • Step 3 A solution of compound 4B (17 mg, 28.5 ⁇ mol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain compound 4C (crude) as a yellow oil. m/z: [M+H] + 497.8.
  • Step 4 Add acryloyl chloride (2.8 mg, 31.3 ⁇ mol) in dichloromethane (5 mL) dropwise to the dichloromethane (5 mL) solution of compound 4C (crude) and DIPEA (0.5 mL), and the reaction solution is stirred at room temperature for 10 minute. After quenching the reaction with water, it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 4) to obtain compound 1-2-1 (3.56 mg, two-step yield: 23%) as a white solid.
  • Step 1 The intermediate 2-6 (100mg, 0.18mmol), N-methyl-L-prolinol (238mg, 2.06mmol), cesium carbonate (268mg, 0.82mmol) and DIPEA (505mg, 3.91mmol)
  • the 1,4-dioxane (15 mL) mixture was placed in a sealed tube, replaced with nitrogen, and stirred at 150°C for 3 hours.
  • the reaction solution was cooled to room temperature and diluted with ethyl acetate.
  • the organic phase was washed with water.
  • the organic phase was separated and concentrated under reduced pressure.
  • Step 2 Compound 6A (40mg, 64.6 ⁇ mol), (5-methyl-1H-indazol-4-yl)boronic acid (57mg, 323 ⁇ mol), sodium carbonate aqueous solution (0.30mL, 1M) and PdCl 2 dppf .
  • Step 3 A mixture of compound 6B (45 mg, 67.1 ⁇ mol) and 10% palladium-carbon (45 mg) in methanol (20 mL) was replaced with hydrogen and stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain compound 6C (crude) as a yellow solid. m/z: [M+H] + 537.4.
  • Step 4 To the dichloromethane (8mL) solution of compound 6C (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (2mL) of acrylic acid chloride (6.1mg, 67.1 ⁇ mol), and the reaction mixture was stirred at room temperature for 3 hour. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 2) to obtain compound 1-2-2 (6 mg, two-step yield: 13%) as a white solid.
  • Step 1 Combine Intermediate 4-3 (100mg, 0.17mmol), Intermediate 3 (57mg, 0.19mmol), aqueous sodium carbonate (0.85mL, 0.85mmol) and PdCl 2 dppf.CH 2 Cl 2 (14mg, 0.017mmol) The mixture of 1,4-dioxane (5 mL) in) was replaced with nitrogen three times, and the reaction system was microwaved at 110° C. for 1 hour.
  • Step 2 A mixed solution of compound 9A (crude product) in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 9B (crude product) as a yellow oil. m/z: [M+H] + 575.4.
  • Step 3 To the dichloromethane (3mL) solution of compound 9B (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (0.1mL, 0.25M) of acrylic anhydride, and the reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with water, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 6) to obtain compound 1-2-3 (1.65 mg, three-step yield: 13%) as a yellow solid.
  • Step 2 At -40°C, slowly add boron tribromide (0.2 mL) dropwise to a solution of compound 12A (5 mg, 7.2 ⁇ mol) in tetrahydrofuran (2 mL), and the reaction solution was slowly warmed to room temperature and stirred for 1 hour.
  • the reaction solution was reduced to 0°C, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12B (crude) as a yellow solid.
  • Step 3 Under ice bath conditions, add a dichloromethane solution (0.85M, 0.016mL) of acryloyl chloride to compound 12B (crude) and triethylamine (0.05mL, 0.36mmol) in dichloromethane (1mL), The reaction system was stirred at room temperature for 0.5 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in acetonitrile (2 mL), ammonia water (1 mL) was added, and the resulting mixture was stirred at room temperature for 0.5 hours. The mixture was directly purified by prep-HPLC (condition 2) to obtain compound 1-2-4 (0.42 mg, two-step yield: 9%) as a white solid. m/z: [M+H] + 637.3.
  • Example 8 2-((2S)-1-acryloyl-4-(4-(2,3-dichloro-5-hydroxyphenyl)-7-(((S)-1-methylpyrrolidine) 2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-2-6)
  • Step 2 To the 1,4-dioxane (2mL) solution of compound 8A (30mg, 46.4 ⁇ mol) was added the 1,4-dioxane solution (0.2mL, 4M) of hydrogen chloride, and the reaction solution was stirred at room temperature for 1 After hours, it was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to obtain compound 1-3-1 (12.0 mg, yield: 43%) as a yellow solid.
  • intermediate 2 (3-fluoro-5-hydroxyphenyl)boronic acid, intermediate 4, 5-amino-2-methylphenylboronic acid Pinacol ester, intermediates 5, 10, 6, 7, 11, 5-amino-2-fluorophenylboronic acid pinacol ester, 4-amino-2-chlorophenylboronic acid pinacol ester, intermediates 8, 9 , (2-fluoro-4-hydroxyphenyl)boronic acid, (2-chloro-5-hydroxyphenyl)boronic acid, 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)aniline, (2,3-difluoro-4-hydroxyphenyl)boronic acid, (3-chloro-4-hydroxyphenyl)boronic acid, (2 -Chloro-4-hydroxyphenyl)boronic acid, intermediate 12, (5-amino-2,3-difluorophenyl)boronic acid,
  • Trifluoroacetic acid (1 mL) was added to a dichloromethane (3 mL) solution of compound 13A (40 mg, 0.05 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 8) to obtain compound 1-5-1 (5.95 mg, yield: 14%) as a pale yellow solid. m/z: [M+H] + 587.2.
  • Step 2 Trifluoroacetic acid (1 mL) was added to the dichloromethane (1 mL) solution of compound 16C (15 mg, 0.02 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 1-5-2 (0.72 mg, yield: 6%) as a pale yellow solid. m/z: [M+H] + 626.2.
  • Example 17 1-(7-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )Furo[2,3-f]quinazolin-9-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (compound 1- 6-1) Synthesis
  • Step 1 Mix Intermediate 4-2 (200mg, 0.39mmol), Intermediate 1 (118mg, 0.37mmol), sodium carbonate aqueous solution (1.95mL, 1M) and Pd(PPh 3 ) 4 (45mg, 0.04mmol) in 1
  • the mixture of ,4-dioxane (20 mL) was placed in a microwave tube, the reaction system was replaced with nitrogen, and the reaction was performed in a microwave at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure.
  • Step 2 Combine compound 17A (220mg, 0.36mmol), (6-methylpyridin-3-yl)boronic acid (128mg, 0.93mmol), aqueous sodium carbonate (1.8mL, 1M) and Pd(PPh 3 ) 4 (86mg , 0.09mmol) of 1,4-dioxane (20mL) mixture was placed in a microwave tube, the reaction system was replaced with nitrogen and then microwaved at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure.
  • Step 3 A mixture of compound 17B (120mg, 0.18mmol) in methanol (10mL) and hydrochloric acid (1mL, 1M) was stirred at 50°C for 3 hours and then directly concentrated under reduced pressure to obtain compound 17C (75mg, yield: 79%) as Yellow solid. m/z: [M+H] + 527.2.
  • Step 4 To compound 17C (75mg, 0.14mmol) and DIPEA (0.5mL) in dichloromethane (5mL) solution was added dropwise acryloyl anhydride (0.6mL, 0.5M dichloromethane solution), and the reaction mixture was stirred at room temperature 3 hours. The reaction was quenched with ammonia water (5 mL), the resulting mixture was stirred at room temperature for 2 hours, and then directly concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 5) to obtain compound 1-7-1 (7.12 mg, yield: 9%) is a white solid.
  • Step 1 Under the protection of nitrogen, the intermediate 6-1 (130mg, 0.23mmol), pinacol diborate (120mg, 0.47mmol), PdCl 2 dppf . CH 2 Cl 2 (38mg, 0.05mmol) and potassium acetate
  • 1,4-dioxane 5 mL
  • ethyl acetate 50 mL
  • saturated brine saturated brine
  • the organic phase was separated and concentrated under reduced pressure to obtain compound 18A (crude) as a yellow solid.
  • Step 2 Add 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine (70mg, 0.33 mmol), Pd(PPh 3 ) 4 (53 mg, 0.046 mmol) and aqueous sodium carbonate (1.0 M, 0.7 mL). The reaction system was blown with nitrogen for 2 minutes, and reacted in a microwave at 120°C for 0.5 hours. The reaction system was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with saturated brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 6) to obtain compound 1-8-1 (4.3 mg, Yield: 3%) is a white solid.
  • Example 21 1-(4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )-1H-pyrazolo[3,4-f]quinazolin-9-yl)piperazin-1-yl)prop-2-en-1-one (Compound 2-1-1)
  • Step 1 The intermediate 3-9 (106mg, 0.2mmol), N-methyl-L-prolinol (111mg, 0.8mmol), DIPEA (250mg, 0.4mmol) and cesium carbonate (188mg, 0.5mmol)
  • the 1,4 dioxane (2.5 mL) solution was stirred at 170°C for 3 hours in a sealed tube.
  • Step 2 The compound 7A (46.8mg, 74.2 ⁇ mol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxoboran-2-yl)-1H-indazole (30.5mg, 89.1 ⁇ mol), PdCl 2 dppf .
  • CH 2 Cl 2 (6mg, 7.3 ⁇ mol), sodium carbonate aqueous solution (1M, 222 ⁇ mol) ) 1,4 dioxane (25 mL) mixture was replaced with nitrogen 3 times.
  • Step 3 Add trifluoroacetic acid (1 mL) dropwise to a solution of compound 7B (40.3 mg, 52.6 ⁇ mol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature for 5 hours and then concentrated under reduced pressure to obtain compound 7C (crude product) as a brown solid. m/z: [M+H] + 498.3.
  • Step 4 Under an ice water bath, DIPEA (17.1 mg, 133 ⁇ mol) and acrylic anhydride (5.6 mg, 44.2 ⁇ mol) were added to the dichloromethane (3 mL) solution of compound 7C (crude product), respectively. The reaction solution was stirred at room temperature for 5 minutes, and 1 drop of ammonia was added to quench the reaction. The resulting mixture was concentrated under reduced pressure and purified by prep-HPLC (condition 2) to obtain compound 2-1-1 (3.01 mg, two-step yield: 12%) It is a white solid.
  • Step 2 Under ice bath conditions, dissolve compound 20A (40 mg, 0.06 mmol) in acetonitrile (5 mL), add aqueous lithium hydroxide solution (1M, 0.6 mL), and stir the reaction system at this temperature for 1 hour. Then it was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated, and the residue was purified by prep-HPLC (condition 5) to obtain compound 3-2-1 (3.9 mg, yield: 11%) It is a white solid.
  • Example 26 2-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-1-(2- Synthesis of fluoroacryloyl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 3-3-1)
  • Example 27 6-Amino-2-(9-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-7-(((S )-1-Methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-4-yl)-3-(trifluoromethyl) Synthesis of isonicotinonitrile trifluoroacetate (compound 3-3-2)
  • Step 1 Under the protection of nitrogen, 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-(trifluoromethyl)isonicotinonitrile (130mg, 0.28mmol), 12-2( 120mg, 0.19mmol), PdCl 2 dppf . CH 2 Cl 2 (30mg, 0.04mmol) and potassium fluoride (120mg, 2.07mmol) in 1,4-dioxane and water (6.6mL/3.0mL) mixed solution Microwave reaction at 120°C for 0.5 hour.
  • Step 3 Under ice bath conditions, add compound 19B (70 mg, 0.12 mmol), 1-propyl phosphoric anhydride (50% ethyl acetate solution, 2.40 mmol) and DIPEA (774 mg, 6.0 mmol) in anhydrous ethyl acetate/ 2-Fluoroacrylic acid (53 mg, 0.59 mmol) was added to the dichloromethane (10.0 mL/2.0 mL) solution, and the reaction solution was stirred at room temperature for 1 hour.
  • Example 29 1-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-3-methylpiper Synthesis of azin-1-yl)prop-2-en-1-one (compound 3-3-10)
  • Step 1 To a solution of Intermediate 15-7 (95mg, 0.16mmol) in 1,4-dioxane (5mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (58mg, 0.33 mmol), Pd(PPh 3 ) 4 (19 mg, 0.016 mmol) and aqueous sodium carbonate (0.48 mL, 0.48 mmol). After bubbling the reaction mixture with nitrogen for 1-2 minutes, it was reacted at 160°C for 0.5 hours under microwave conditions, and then the reaction solution was cooled to room temperature and concentrated under reduced pressure. 4) Purified compound 10A (79 mg, yield: 76%) as a pale yellow solid. m/z: [M+H] + 633.3.
  • Step 2 A mixed solution of compound 10A (79 mg, 0.12 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 10B (crude product) as a yellow solid.
  • Step 3 Under an ice-water bath, add DIPEA (78mg, 0.60mmol) and acrylic anhydride in dichloromethane (0.25M, 0.59mL, 0.15mmol) to a solution of compound 10B (crude) in anhydrous dichloromethane (10mL). ). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 4-1-1 (24.3 mg , Yield: 34%) is a white solid.
  • Step 1 Using the synthetic method of compound 10A, intermediate 15-8 is reacted with (5-methyl-1H-indazol-4-yl)boronic acid to obtain compound 11A as a white solid. m/z: [M+H] + 692.2.
  • Step 2 To a methanol (30 mL) solution of compound 11A (100 mg, 0.14 mmol) was added palladium on carbon (10%, 60 mg), the reaction system was replaced with hydrogen 3 times, and then stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 11B (75 mg, yield: 92%) as a white solid. m/z: [M+H] + 558.3.
  • Step 3 Under ice bath conditions, add DIPEA (50mg, 0.39mmol) and acrylic anhydride in dichloromethane (0.3M, 0.54 mL, 0.16 mmol). After the reaction mixture was stirred at this temperature for 5 hours, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (, condition 7) to obtain compound 4-1-2 (4.1 mg, yield: 5%) is a white solid.
  • Step 1 Using the synthetic method of compound 10A, the intermediate 15-7 is reacted with 4-fluoro-6-methoxyphenylboronic acid to obtain compound 15A as a pale yellow solid. m/z: [M+H] + 627.4.
  • Step 3 Under ice bath conditions, add DIPEA (260 mg, 2.10 mmol) and acrylic anhydride in dichloromethane (0.30M, 0.85) to a solution of compound 15B (130 mg, 0.21 mmol) in anhydrous dichloromethane (10 mL). mL, 0.26 mmol). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (2.5 mL) was added to quench the reaction, and then the stirring was continued for 2 hours. The resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to obtain compound 4- 1-3 (30.9 mg, yield: 26%) is a white solid.
  • Step 1 A mixture of compound 15-9 (350 mg, 0.59 mmol) in dichloromethane (16 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain compound 14A (crude product) as a yellow oil. m/z: [M+H] + 497.2.
  • Step 3 Compound 14B (55mg, 0.10mmol), Intermediate 2 (54mg, 0.20mmol), sodium carbonate aqueous solution (1M, 0.30mL) and Pd(PPh 3 ) 4 (12mg, 0.01mmol) 1,4-bis
  • the oxane (2 mL) mixture was added to the microwave tube, and after nitrogen bubbling for 1-2 minutes, the reaction system was reacted in a microwave at 130° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 7) to obtain compound 4-1-4 (16.6 mg, yield: 27%) as a white solid.
  • the Phospho-ERK1/2 (THR202/TYR 204) (Cisibo, 64ERKPEH) kit was used to detect the phosphorylation level of ERK1/2 in human pancreatic cancer cells Mia Paca-2, and the phosphorylation level of ERK1/2 was used to study The inhibitory effect of the compound on KRAS.
  • the experiment was carried out according to the manufacturer's experimental protocol.
  • On the first day adjust the density of the MIA PaCa-2 cell (ATCC) suspension to 2.1 ⁇ 10 5 cells/mL, and spread it in a 96-well plate at 95ul/well, then the number of cells per well will be 2 ⁇ 10 4.
  • the culture plate was placed in an incubator at 37°C and 5% CO 2 for overnight culture.
  • the compound was diluted with 100% DMSO gradient, and then further diluted with complete medium (DMDM+10%FBS+1%P/S) to become the compound working solution, and 5ul/well was added to 96-well cell culture plate at 37 Incubate in a 5% CO 2 incubator for 4 hours.
  • Compound number IC 50 ( ⁇ M) Compound number IC 50 ( ⁇ M) 1-1-1 11.930 1-4-66 0.0069 1-1-2 0.5201 1-4-67 0.0045 1-2-1 0.6361 1-4-68 0.0004 1-2-2 0.0665 1-4-69 0.1030 1-2-3 0.1229 1-4-70 0.0019
  • the method of cell proliferation experiment is used to evaluate the biological activity of the compound.
  • 3000 Miapaca-2 human pancreatic cancer cells (Nanjing Kebai) were planted in 96-well plates, and the cells were cultured in Dulbecco's Modified Eagle's matrix and 10% fetal bovine serum. The culture environment was 37°C and 5% CO 2 . On the second day, the stock solution of the test compound is dissolved in DMSO and added to the medium of the indicated concentration, and incubated for 72 hours. The concentration of the test compound ranges from 1.5 nM to 100 ⁇ M. Negative control cells were treated with vehicle only. Use the Cell Titer-Glo test kit (Cell Titer-glo, Promega) to evaluate cell viability under the instructions of the product manual. Use Graphpad software to analyze the data, and obtain IC 50 values and compound fitting curves (see Table 18 for the results).

Abstract

A novel KRAS G12C inhibitor. A compound represented by formula (I) and an isomer or pharmaceutically acceptable salt thereof have the following structure. The compound represented by formula (I) and a composition thereof may effectively treat diseases related to KRAS G12C, such as cancer.

Description

KRAS G12C抑制剂及其应用KRAS G12C inhibitor and its application
本申请要求申请日为2019年09月30日的中国专利申请CN201910941868.4、申请日为2019年12月27日的中国专利申请CN201911377525.6、申请日为2020年1月20日的中国专利申请CN202010065672.6的优先权。本申请引用上述中国专利申请的全文。This application requires the Chinese patent application CN201910941868.4 with the application date of September 30, 2019, the Chinese patent application CN201911377525.6 with the application date of December 27, 2019, and the Chinese patent application with the application date of January 20, 2020 Priority of CN202010065672.6. This application quotes the full text of the aforementioned Chinese patent application.
技术领域Technical field
本发明涉及一种新型的抑制KRAS G12C活性的化合物。特别地，本发明涉及不可逆地抑制KRAS G12C活性的化合物、包括其药物组合物及其作为癌症治疗剂的应用。The present invention relates to a novel compound that inhibits the activity of KRAS G12C. In particular, the present invention relates to a compound that irreversibly inhibits the activity of KRAS G12C, including its pharmaceutical composition and its application as a cancer therapeutic agent.
背景技术Background technique
RAS基因家族主要包括KRAS、NRAS和HRAS三个基因。RAS基因是原癌基因，其被激活后就成为了具有致癌活性的癌基因。RAS编码一组由188-189个氨基酸组成的单体球状蛋白质(21kD)，被称为p21蛋白或RAS蛋白。RAS蛋白是GDP/GTP结合蛋白，其可以在无活性的GDP结合状态和有活性的GTP结合状态之间循环，起到“分子开关”的作用。RAS的GDP/GTP循环受到鸟嘌呤核苷酸交换因子(例如：SOS或RASGRP)的活化及GTP酶启动蛋白(GAPs，例如：p120GAP或神经纤维瘤蛋白)的灭活。GAPs与RAS相互作用可以极大的加速GTP转化为GDP，关闭开关使RAS失活，影响RAS和GAP相互作用或将GTP转化回GDP能力的任何突变都将使得RAS持续激活，并且因此产生对细胞的延长信号。由于RAS可以通过多种重要的信号通路调节细胞的增值、分化和衰老，下游信号通路(例如：PI3K-AKT-mTOR、RAF-MEK-ERK、RALGDS-RAL)的延长激活最终会导致癌症的发生。The RAS gene family mainly includes three genes, KRAS, NRAS and HRAS. The RAS gene is a proto-oncogene, which becomes an oncogene with carcinogenic activity after being activated. RAS encodes a group of monomeric globular proteins (21kD) composed of 188-189 amino acids, called p21 protein or RAS protein. The RAS protein is a GDP/GTP binding protein, which can cycle between the inactive GDP binding state and the active GTP binding state, acting as a "molecular switch". The GDP/GTP cycle of RAS is activated by guanine nucleotide exchange factors (such as SOS or RASGRP) and inactivated by GTPase initiating proteins (GAPs, such as p120GAP or neurofibroma protein). The interaction between GAPs and RAS can greatly accelerate the conversion of GTP to GDP. Turn off the switch to inactivate RAS. Any mutation that affects the interaction between RAS and GAP or the ability to convert GTP back to GDP will cause RAS to continue to activate, and thus cause damage to the cell. Extended signal. Since RAS can regulate cell proliferation, differentiation and senescence through a variety of important signal pathways, the prolonged activation of downstream signal pathways (for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) will eventually lead to the occurrence of cancer .
RAS蛋白包括高度保守的N末端G结合域，该结合域还包含了结合核苷酸的p环和开关I(残基30-40)和开关II(残基60-76)。其中p环是具有保守氨基酸残基(甘氨酸12、苏氨酸26和赖氨酸16)的结合域的刚性部分，对于氨基酸结合和水解是必须的。开关I和开关II中苏氨酸-35和甘氨酸-60可以和GTP的γ-磷酸盐/酯形成氢键，分别维持开关I和II区域的处于活性构象。在GTP水解和磷酸盐/酯释放后，两者可松弛成非活性GDP构象。另外，RAS蛋白还包括称为CAAX盒的C末端延伸部分，其可以进行翻译后修饰并负责将蛋白靶向至细胞膜(Jonathan et al.Nature Reviews,2016,15:771-785)。The RAS protein includes a highly conserved N-terminal G-binding domain, which also contains a nucleotide-binding p-loop and switch I (residues 30-40) and switch II (residues 60-76). The p-loop is the rigid part of the binding domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16), which is necessary for amino acid binding and hydrolysis. Threonine-35 and glycine-60 in Switch I and Switch II can form hydrogen bonds with the γ-phosphate/ester of GTP to maintain the active conformation of Switch I and II regions, respectively. After GTP hydrolysis and phosphate/ester release, both can relax into the inactive GDP conformation. In addition, the RAS protein also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the cell membrane (Jonathan et al. Nature Reviews, 2016, 15: 771-785).
RAS基因可以通过点突变、过表达以及基因***及转位来使得RAS处于持续激活状态，其中最常见的就是点突变，约30％的人类恶性肿瘤存在RAS基因的点突变。最常见的是KRAS的点突变，常见的突变位点是12、13、61密码子，其中又以12位密码子突变最为常见。这些激活的突变通过失活内源性GTP酶活性并引起GTP酶活化蛋白抵抗，从而增加GTP结合态的RAS蛋白含量(Zenker et al.J Med Genet,2007,44:131-135)。The RAS gene can be continuously activated through point mutation, overexpression, gene insertion and translocation. The most common one is point mutation. About 30% of human malignancies have RAS gene point mutations. The most common is the point mutation of KRAS. The common mutation sites are codons 12, 13, and 61, among which codon 12 is the most common mutation. These activated mutations inactivate the endogenous GTP enzyme activity and cause GTP enzyme activation protein resistance, thereby increasing the GTP-bound RAS protein content (Zenker et al. J Med Genet, 2007, 44: 131-135).
KRAS的异常表达在所有恶性肿瘤中占20％，其中G12C突变是最常发生的突变中的一种，约在13％的恶性肿瘤中发现这种突变。其中，非小细胞肺癌中G12C突变发生率约为11％，结直肠癌、胰腺癌和子宫内膜癌中G12C突变发生率约为1％-4％(Hobbs et al.J Cell Sci,2016,129:1287-1292；Prior et al.Cancer Res,2012,72:2457-67)。Abnormal expression of KRAS accounts for 20% of all malignant tumors. G12C mutation is one of the most frequently occurring mutations, and this mutation is found in about 13% of malignant tumors. Among them, the incidence of G12C mutation in non-small cell lung cancer is about 11%, and the incidence of G12C mutation in colorectal cancer, pancreatic cancer and endometrial cancer is about 1%-4% (Hobbs et al. J Cell Sci, 2016, 129: 1287-1292; Prior et al. Cancer Res, 2012, 72: 2457-67).
越来越多的研究已经表明KRAS，特别是包括KRAS G12C在内的突变体在恶性肿瘤中的关键作用，使得KRAS成为制药行业中重要的靶标，但是到目前还没有相关的药物上市，因此，急需开发新型的包括KRAS G12C在内的KRAS突变体抑制剂。More and more studies have shown that KRAS, especially mutants including KRAS G12C, play a key role in malignant tumors, making KRAS an important target in the pharmaceutical industry, but so far there is no relevant drug on the market. Therefore, There is an urgent need to develop new KRAS mutant inhibitors including KRAS G12C.
发明内容Summary of the invention
本发明所要解决的技术问题在于，提供了一种新型的抑制KRAS G12C活性的化合物，可以有效治疗与KRAS G12C相关的各种疾病，例如癌症。The technical problem to be solved by the present invention is to provide a novel compound that inhibits the activity of KRAS G12C, which can effectively treat various diseases related to KRAS G12C, such as cancer.
本发明提供了一种如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐；The present invention provides a compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts;
Figure PCTCN2020118772-appb-000001
Figure PCTCN2020118772-appb-000001
其中，among them,
α和β键分别为单键或双键；The α and β bonds are single bonds or double bonds, respectively;
X为N或CR 2； X is N or CR 2 ;
β键为单键时，Y为C(O)，Z为NR 3；β键为双键时，Y和Z分别独立地为N或CR 2； When the β bond is a single bond, Y is C(O) and Z is NR 3 ; when the β bond is a double bond, Y and Z are independently N or CR 2 respectively ;
α键为单键时，W为N，V为CH 2或C(O)；α键为双键时，W为C，V为CR 4或N； When the α bond is a single bond, W is N and V is CH 2 or C(O); when the α bond is a double bond, W is C and V is CR 4 or N;
U和M分别独立地为N、C或CH；U and M are each independently N, C or CH;
A环为苯基、3-8元环烷基、5-6元杂芳基或4-8元杂环烷基；所述A环为未取代，或者选择性地被1～3个R 5基团取代在任意位置； The A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
B环为5-10元杂环烷基；所述B环为未取代，或者选择性被1～3个R 6基团取代在任意位置； The B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
R为C 6-10芳基、5-10元杂芳基或9-14元稠合杂环烷基；所述R为未取代或者选择性被1个或多个R 7基团取代在任意位置； R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
R 1为C 2-4烯基、C 2-4炔基或部分不饱和的C 4-6环烷基；所述R 1为未取代或者选择性被1～3个R 8基团取代在任意位置； R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
R 2为氢、羟基、卤素、氰基、氨基、-R A、-NR AR B、-OR A或-SR A； R 2 is hydrogen, hydroxy, halo, cyano, amino, -R A, -NR A R B , -OR A , or -SR A;
R 3为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基或5-10杂芳基-C 1-4烷基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、氧代基、卤代C 1-6烷基、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、4-6元杂环烷基或4-6元杂环烷基-C 1-4烷基的取代基取代在任意位置； R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
R 4为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基或C 3-8环烷基； R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
R 5为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、酰基、C 3-8元环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基或-B(OR”) 2； R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
R 6为氢、氧代基、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(O)OR’或-C(O)NR’ 2；R 6中，所述C 1-6烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR'2; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
R 7为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基、5-10元杂芳基-C 1-4烷基、-NH-C 3-6环烷基、-(CH 2) nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”) 2、-OC(O)R”、-OC(O)N(R”) 2或-B(OR”) 2；R 7中，所述C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基或5-10元杂芳基-C 1-4烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR', -NHC(O)R", -C(O)R", -C(O)N(R") 2 ,- OC (O) R ", - OC (O) N (R") 2 or -B (oR ") 2; R 7 , said C 3-8 cycloalkyl, C 3-8 cycloalkyl -C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkane Group, 5-10 membered heteroaryl or 5-10 membered heteroaryl-C 1-4 alkyl is unsubstituted or optionally selected from 1 to 3 halogen, hydroxy, amino, carboxy, cyano, C 1 Substituents of -4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
R 8为氢、氘、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基；其中，所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代，或者选择性被1～3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置； R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 alkyl are substituted at any position;
R A为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基、3-10元杂环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基或5-10元杂芳基-C 1-6烷基；所述R A为未取代或者选择性被一个或多个R c取代在任意位置； R A is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3 -10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 membered heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl group or a 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
R B为氢、氰基、羟基或C 1-6烷基； R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl;
或者，R A和R B相互连接形成4-8杂环烷基；所述杂环烷基为未取代或者选择性被1～3个选自羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、酰基、C 1-4烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基和5-10元杂芳基-C 1-4烷基的取代基取代在任意位置； Alternatively, R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1- The substituents of 4- alkyl, C 6-10 aryl-C 1-4 alkyl and 5-10 membered heteroaryl-C 1-4 alkyl are substituted at any position;
R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-6烷基、C 1-4烷氧基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷氨基-C 1-6烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基、-(CH 2) n-N(CN)R’、-(CH 2) n-C(O)R’、-(CH 2) n-C(O)N(R’) 2、-(CH 2) n-S(O) 2N(R’) 2、-(CH 2) n-NR”C(O)R’、-(CH 2) n-NR”S(O) 2R’或-(CH 2) n-B(OR”) 2；R c中，所述C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基为未取代或者选择性被1-3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、C 1-4烷氨基和C 1-4烷基的取代基取代在任意位置； R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1 -6 alkylamino-C 1-6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 ring Alkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1 -4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C(O)R', -(CH 2 ) n -C(O)N(R') 2 , -(CH 2 ) n -S(O) 2 N(R') 2 , -(CH 2 ) n -NR”C(O)R', -(CH 2 ) n -NR”S(O) 2 R'or -(CH 2 ) n -B(OR") 2 ; in R c , the C 1-4 alkylene group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 Membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycle Alkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl are unsubstituted or optionally selected from 1-3 Substituents from halogen, hydroxy, amino, cyano, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 alkyl are substituted at any position;
R’为氢、C 1-4烷基、卤代C 1-4烷基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、6-10元杂芳基、C 6-10芳基-C 1-4烷基或6-10元杂芳基-C 1-4烷基； R'is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
R”为氢或C 1-6烷基； R" is hydrogen or C 1-6 alkyl;
n为0到4的整数；n is an integer from 0 to 4;
并且，排除以下情况：A环为苯基或1,3-二氧杂环戊烯基时，R 2为氢。 In addition, the following cases are excluded: when the A ring is a phenyl group or a 1,3-dioxolyl group, R 2 is hydrogen.
以下所述的如式(I)所述的所有实施方案及各变量的组合均包含在本发明如式I所示的结构式的范围中。All the embodiments described in formula (I) and the combinations of variables described below are included in the scope of the structural formula shown in formula I of the present invention.
在一些实施方案中，所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：In some embodiments, the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
其中，α和β键分别为单键或双键；Among them, the α and β bonds are single bonds or double bonds, respectively;
X为N或CH；X is N or CH;
β键为单键时，Y为C(O)，Z为NR 3；β键为双键时，Y和Z分别为N或CR 2； When the β bond is a single bond, Y is C(O) and Z is NR 3 ; when the β bond is a double bond, Y and Z are N or CR 2 respectively;
α键为单键时，W为N，V为CH 2或C(O)；α键为双键时，W为C，V为CR 4或N； When the α bond is a single bond, W is N and V is CH 2 or C(O); when the α bond is a double bond, W is C and V is CR 4 or N;
U和M分别独立地为N、C或CH；U and M are each independently N, C or CH;
A环为苯基、3-8元环烷基、5-6元杂芳基或4-8元杂环烷基；所述A环为未取代，或者选择性地被1～3个R 5基团取代在任意位置； The A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
B环为5-10元杂环烷基；所述B环为未取代，或者选择性被1～3个R 6基团取代在任意位置； The B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
R为C 6-10芳基、5-10元杂芳基或9-14元稠合杂环烷基；所述R为未取代或者选择性被1个或多个R 7基团取代在任意位置； R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
R 1为C 2-4烯基、C 2-4炔基或部分不饱和的C 4-6环烷基；所述R 1为未取代或者选择性被1～3个R 8基团取代在任意位置； R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
R 2为-R A、-NR AR B、-OR A或-SR A； R 2 is -R A , -NR A R B , -OR A or -SR A ;
R 3为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基或5-10杂芳基-C 1-4烷基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、氧代基、卤代C 1-6烷基、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、4-6元杂环烷基或4-6元杂环烷基-C 1-4烷基的取代基取代在任意位置； R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
R 4为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基或C 3-8环烷基； R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
R 5为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、酰基、C 3-8元环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基或-B(OR”) 2； R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
R 6为氢、氧代基、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6 烷氧基、-C(O)OR’或-C(O)NR’ 2；R 6中，所述C 1-6烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR'2; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
R 7为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基、5-10元杂芳基-C 1-4烷基、-NH-C 3-6环烷基、-(CH 2) nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”) 2、-OC(O)R”、-OC(O)N(R”) 2或-B(OR”) 2；R 7中，所述C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基或5-10元杂芳基-C 1-4烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR', -NHC(O)R", -C(O)R", -C(O)N(R") 2 ,- OC (O) R ", - OC (O) N (R") 2 or -B (oR ") 2; R 7 , said C 3-8 cycloalkyl, C 3-8 cycloalkyl -C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkane Group, 5-10 membered heteroaryl or 5-10 membered heteroaryl-C 1-4 alkyl is unsubstituted or optionally selected from 1 to 3 halogen, hydroxy, amino, carboxy, cyano, C 1 Substituents of -4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
R 8为氢、氘、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基；其中，所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代，或者选择性被1～3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置； R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 alkyl are substituted at any position;
R A为C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基、3-10杂环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基或5-10元杂芳基-C 1-6烷基；所述R A为未取代或者选择性被一个或多个R c取代在任意位置； R A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 Member heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl or 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
R B为氢、氰基、羟基或C 1-6烷基； R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl;
或者，R A和R B相互连接形成4-8杂环烷基；所述杂环烷基为未取代或者选择性被1～3个选自羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、酰基、C 1-4烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基和5-10元杂芳基-C 1-4烷基的取代基取代在任意位置； Alternatively, R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1- The substituents of 4- alkyl, C 6-10 aryl-C 1-4 alkyl and 5-10 membered heteroaryl-C 1-4 alkyl are substituted at any position;
R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-6烷基、C 1-4烷氧基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷氨基-C 1-6烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基、-(CH 2) n-N(CN)R’、-(CH 2) n-C(O)R’、-(CH 2) n-C(O)N(R’) 2、-(CH 2) n-S(O) 2N(R’) 2、 -(CH 2) n-NR”C(O)R’、-(CH 2) n-NR”S(O) 2R’或-(CH 2) n-B(OR”) 2；R c中，所述C 1-6烷氧基、C 1-6烷氨基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基为未取代或者选择性被1-3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、C 1-4烷氨基和C 1-4烷基的取代基取代在任意位置； R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C(O)R', -(CH 2 ) n -C(O)N(R') 2 , -(CH 2 ) n- S(O) 2 N(R') 2 , -(CH 2 ) n -NR”C(O)R', -(CH 2 ) n -NR”S(O) 2 R'or -(CH 2 ) n -B(OR”) 2 ; In R c , the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl -C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl is unsubstituted or optionally selected from 1-3 halogen, hydroxyl, amino, cyano, C 1-4 alkoxy The substituents of C 1-4 alkylamino group, C 1-4 alkylamino group and C 1-4 alkyl group are substituted at any position;
R’为氢、C 1-4烷基、卤代C 1-4烷基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、6-10元杂芳基、C 6-10芳基-C 1-4烷基或6-10元杂芳基-C 1-4烷基； R'is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
R”为氢或C 1-6烷基； R" is hydrogen or C 1-6 alkyl;
n为0到4的整数。n is an integer from 0 to 4.
在一些实施方案中，所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：In some embodiments, the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
其中，α和β键分别为双键；Among them, the α and β bonds are double bonds respectively;
X为N；W为C，V为CH或N；Y为CR 2；Z为N； X is N; W is C, V is CH or N; Y is CR 2 ; Z is N;
U和M分别独立地为N、C；U and M are respectively N and C independently;
A环为5-6元杂芳基或5-6元杂环烷基；Ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl;
B环为
Figure PCTCN2020118772-appb-000002
所述B环为未取代，或者选择性被1～3个R 6基团取代在任意位置； Ring B is
Figure PCTCN2020118772-appb-000002
The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
R为C 6-10芳基或5-10元杂芳基；所述R为未取代或者选择性被1～4个R 7基团取代在任意位置； R is a C 6-10 aryl group or a 5-10 membered heteroaryl group; said R is unsubstituted or optionally substituted by 1 to 4 R 7 groups in any position;
R 1为C 2-4烯基；所述R 1为未取代或者选择性被1～3个R 8基团取代在任意位置； R 1 is a C 2-4 alkenyl group; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups at any position;
R 2为-OR A； R 2 is -OR A ;
R 6为氢、C 1-6烷基或C 1-6烷氧基；R 6中，所述C 1-6烷基为未取代或者选择性被1～3个选自卤素、羟基、氰基和C 1-4烷氧基的取代基取代在任意位置； R 6 is hydrogen, a C 1-6 alkyl group or a C 1-6 alkoxy group; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, and cyano groups. The substituents of the C 1-4 alkoxy group and the C 1-4 alkoxy group are substituted at any position;
R 7为氢、羟基、卤素、氰基、氨基、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、C 3-8环烷基或3-8元杂环烷基； R 7 is hydrogen, hydroxy, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 3 -8 cycloalkyl or 3-8 membered heterocycloalkyl;
R 8为氢、氘、卤素、C 1-6烷基、C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基或C 1-6烷氨基-C 1-4烷基； R 8 is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino- C 1-4 alkyl or C 1-6 alkylamino-C 1-4 alkyl;
R A为C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基或3-10杂环烷基-C 1-6烷基；所述R A为未取代或者选择性被一个或多个R c取代在任意位置； R A is C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or -C 1-6 alkyl heterocycloalkyl 3-10 - C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c at an arbitrary position;
R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。 R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl or halogenated C 1-4 alkoxy.
在一些实施方案中，所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：In some embodiments, the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
其中，R 3为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基或5-10杂芳基-C 1-4烷基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 3-6环烷基的取代基取代在任意位置； Wherein, R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl , 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is Unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl at any position;
R 7为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基、5-10元杂芳基-C 1-4烷基、-NH-C 3-6环烷基、-(CH 2) nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”) 2、-OC(O)R”、-OC(O)N(R”) 2或-B(OR”) 2； R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR', -NHC(O)R", -C(O)R", -C(O)N(R") 2 ,- OC(O)R", -OC(O)N(R") 2 or -B(OR") 2 ;
R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-6烷基、C 1-4烷氧基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷氨基-C 1-6烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基、-(CH 2) n-N(CN)R’、-(CH 2) n-C(O)R’、-(CH 2) n-C(O)N(R’) 2、-(CH 2) n-S(O) 2N(R’) 2、-(CH 2) n-NR”C(O)R’、-(CH 2) n-NR”S(O) 2R’或-(CH 2) n-B(OR”) 2；R c中，所述C 1-6烷氧基、C 1-6烷氨基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基为未取代或者选择性被1-3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、C 1-4烷氨基和C 1-4烷基的取代基取代在任意位置。 R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C(O)R', -(CH 2 ) n -C(O)N(R') 2 , -(CH 2 ) n- S(O) 2 N(R') 2 , -(CH 2 ) n -NR”C(O)R', -(CH 2 ) n -NR”S(O) 2 R'or -(CH 2 ) n -B(OR”) 2 ; In R c , the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 membered cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl -C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl is unsubstituted or optionally selected from 1-3 halogen, hydroxyl, amino, cyano, C 1-4 alkoxy The substituents of the C 1-4 alkylamino group, C 1-4 alkylamino group, and C 1-4 alkyl group are substituted at any positions.
在一些实施方案中，α键为双键；β键为单键或双键。In some embodiments, the alpha bond is a double bond; the beta bond is a single bond or a double bond.
在一些实施方案中，α和β键分别为双键；X为N；W为C，V为CR 4或N；Y为CR 2；Z为N。 In some embodiments, the α and β bonds are respectively double bonds; X is N; W is C, V is CR 4 or N; Y is CR 2 ; Z is N.
在一些实施方案中，α键为双键；β键为单键；X为N；W为C，V为CR 4或N；Y为C(O)，Z为NR 3； In some embodiments, the α bond is a double bond; the β bond is a single bond; X is N; W is C and V is CR 4 or N; Y is C(O) and Z is NR 3 ;
在一些实施方案中，所述A环为5-6元杂芳基或5-6元杂环烷基。In some embodiments, the A ring is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl.
在一些实施方案中，所述A环为吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1,2,4-三氮唑基、1,2,3-三氮唑基或四氮唑基。In some embodiments, the A ring is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazole Group, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl Or tetrazolyl.
在一些实施方案中，所述A环为呋喃基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1,2,4-三氮唑基、1,2,3-三氮唑基或四氮唑基。In some embodiments, the A ring is furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl.
在一些实施方案中，所述A环为2,3-二氢呋喃基。In some embodiments, the A ring is 2,3-dihydrofuranyl.
在一些实施方案中，所述A环为如下任一结构：In some embodiments, the A ring has any of the following structures:
Figure PCTCN2020118772-appb-000003
Figure PCTCN2020118772-appb-000004
Figure PCTCN2020118772-appb-000005
所述A环为未取代，或者选择性被1～3个R 5取代在任意位置，R 5定义如前所述。
Figure PCTCN2020118772-appb-000003
Figure PCTCN2020118772-appb-000004
Figure PCTCN2020118772-appb-000005
The A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
在一些实施方案中，所述A环为如下任一结构：In some embodiments, the A ring has any of the following structures:
Figure PCTCN2020118772-appb-000006
所述A环为未取代，或者选择性被1～3个R 5取代在任意位置，R 5定义如前所述。
Figure PCTCN2020118772-appb-000006
The A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
在一些实施方案中，所述B环为如下任一结构：In some embodiments, the B ring has any of the following structures:
Figure PCTCN2020118772-appb-000007
Figure PCTCN2020118772-appb-000008
所述B环为未取代，或者选择性被1～3的R 6取代在任意 位置，R 6定义如前所述。
Figure PCTCN2020118772-appb-000007
Figure PCTCN2020118772-appb-000008
The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 at any position, and R 6 is defined as described above.
在一些实施方案中，所述R 6为H、-CH 3、-CF 3、-CHF 2、-CH 2CN、-CH 2OH、-CH 2CH 2OH 、-CH 2CH 2OCH 3或-CH 2OCH 3。 In some embodiments, the R 6 is H, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CN, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 OCH 3 or -CH 2 OCH 3 .
在一些实施方案中，所述B环为
Figure PCTCN2020118772-appb-000009
Figure PCTCN2020118772-appb-000010
In some embodiments, the B ring is
Figure PCTCN2020118772-appb-000009
Figure PCTCN2020118772-appb-000010
在一些实施方案中，所述B环为
Figure PCTCN2020118772-appb-000011
In some embodiments, the B ring is
Figure PCTCN2020118772-appb-000011
在一些实施方案中，所述R中，所述9-14元稠合杂环烷基为单环杂环烷基和苯基、萘基、吡啶基、嘧啶基、吡嗪基稠合得到的基团，优选为9元或13元稠合杂环烷基，例如：吲哚啉基、2,3-二氢苯并呋喃基、1,3-二氢苯并[c][1,2]氧杂硼戊环基、1,3-二氢萘并[2,1-c][1,2]氧杂硼戊环基、1,3-二氢萘并[2,3-c][1,2]氧杂硼戊环基等。In some embodiments, in the R, the 9-14 membered fused heterocycloalkyl is obtained by condensing a monocyclic heterocycloalkyl with a phenyl, naphthyl, pyridyl, pyrimidinyl, or pyrazinyl group Group, preferably 9-membered or 13-membered condensed heterocycloalkyl, for example: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzo[c][1,2 ]Oxaborolanyl, 1,3-dihydronaphtho[2,1-c][1,2]oxaborolanyl, 1,3-dihydronaphtho[2,3-c] [1,2] Oxaboranyl and the like.
在一些实施方案中，所述R为苯基、萘基、吡啶基、喹啉基、异喹啉基、2,3-二氢苯并呋喃基、1H-苯并[d]咪唑-2(3H)-酮基、1H-吲唑基、酞嗪基、1-羟基-1,3-二氢苯并[c][1,2]氧杂硼戊环基、3-羟基-1,3-二氢萘并[2,1-c][1,2]氧杂硼戊环基或1-羟基-1,3-二氢萘并[2,3-c][1,2]氧杂硼戊环基；所述R为未取代或者选择性被1～5、1～4或1～3个R 7取代在任意位置，R 7定义如前所述。 In some embodiments, the R is phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 1H-benzo[d]imidazole-2( 3H)-keto, 1H-indazolyl, phthalazinyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl, 3-hydroxy-1,3 -Dihydronaphtho[2,1-c][1,2]oxaborolanyl or 1-hydroxy-1,3-dihydronaphtho[2,3-c][1,2]oxa Boronpentyl; the R is unsubstituted or optionally substituted by 1 to 5, 1 to 4 or 1 to 3 R 7 at any position, and R 7 is defined as described above.
在一些实施方案中，所述R 7为氢、卤素、羟基、氨基、氰基、C 1-4烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-6烷氨基、C 3-6环烷基、3-6元杂环烷基或-B(OH) 2。 In some embodiments, the R 7 is hydrogen, halogen, hydroxy, amino, cyano, C 1-4 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1 -3 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -B(OH) 2 .
在一些实施方案中，所述R 7中，所述C 3-6环烷基或3-6元杂环烷基为未取代或者选择性被1～3个选自羟基、氨基、氟、氯、甲基、三氟甲基和三氟甲氧基的取代基取代在任意位置。 In some embodiments, the R 7, C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, amino, fluoro, chloro The substituents of, methyl, trifluoromethyl and trifluoromethoxy are substituted at any position.
在一些实施方案中，所述R为如下任一结构：In some embodiments, the R is any of the following structures:
Figure PCTCN2020118772-appb-000012
Figure PCTCN2020118772-appb-000012
Figure PCTCN2020118772-appb-000013
Figure PCTCN2020118772-appb-000013
在一些实施方案中，所述R为如下任一结构：In some embodiments, the R is any of the following structures:
Figure PCTCN2020118772-appb-000014
Figure PCTCN2020118772-appb-000014
Figure PCTCN2020118772-appb-000015
Figure PCTCN2020118772-appb-000015
在一些实施方案中，所述R为如下任一结构：In some embodiments, the R is any of the following structures:
Figure PCTCN2020118772-appb-000016
Figure PCTCN2020118772-appb-000016
在一些实施方案中，所述R 1为
Figure PCTCN2020118772-appb-000017
其中，R 8a为H、D、卤素或C 1-3烷氧基-C 1-4烷基；R 8b和R 8c分别独立地为H、D、卤素、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-4烷基、C 1-3烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基；其中，所述C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基为未取代，或者选择性被1～3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置。 In some embodiments, the R 1 is
Figure PCTCN2020118772-appb-000017
Wherein, R 8a is H, D, halogen or C 1-3 alkoxy-C 1-4 alkyl; R 8b and R 8c are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1- 4- alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; Wherein, the C 1-6 alkylamino-C 1-4 alkyl group, 5-10 membered heteroaryl group, 3-10 membered heterocycloalkyl group, 5-10 heteroaryl-C 1-4 alkyl group or 3 -10 Heterocycloalkyl-C 1-4 alkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano, C 1-4 alkoxy, oxo and C 1 -4 The substituent of the alkyl group is substituted at any position.
在一些实施方案中，所述R 1为
Figure PCTCN2020118772-appb-000018
其中，R 8a为H、D或卤素；R 8b和R 8c的定义如前所述。 In some embodiments, the R 1 is
Figure PCTCN2020118772-appb-000018
Wherein, R 8a is H, D or halogen; R 8b and R 8c are as defined above.
在一些实施方案中，所述R 1为
Figure PCTCN2020118772-appb-000019
In some embodiments, the R 1 is
Figure PCTCN2020118772-appb-000019
在一些实施方案中，所述R A为C 1-6烷基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、5-6元杂芳基-C 1-4烷基、C 3-8环烷基-C 1-4烷基或3-8元杂环烷基-C 1-4烷基；所述R A为未取代或者选择性被1～5个R c取代在任意位置；R c的定义如前所述。 In some embodiments, R A is a C 1-6 alkyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl -C 1-4 alkyl, C 3-8 cycloalkyl -C 1-4 alkyl or -C 1-4 3-8 membered heterocycloalkyl group; the R A is unsubstituted or is selectively 1 to 5 R c are substituted at any position; the definition of R c is as described above.
在一些实施方案中，所述R 2为-OR A；R A的定义如前所述。 In some embodiments, the R 2 is -OR A; R A is as previously defined.
在一些实施方案中，所述R 2为如下任一结构： In some embodiments, the R 2 is any of the following structures:
Figure PCTCN2020118772-appb-000020
Figure PCTCN2020118772-appb-000020
Figure PCTCN2020118772-appb-000021
Figure PCTCN2020118772-appb-000021
Figure PCTCN2020118772-appb-000022
Figure PCTCN2020118772-appb-000022
在一些实施方案中，所述R 2为如下任一结构： In some embodiments, the R 2 is any of the following structures:
Figure PCTCN2020118772-appb-000023
Figure PCTCN2020118772-appb-000023
在一些实施方案中，所述R 2为-NR AR B；R A和R B的定义如前所述。 In some embodiments, the R 2 is -NR A R B ; the definitions of R A and R B are as described above.
在一些实施方案中，所述R 2为如下任一结构： In some embodiments, the R 2 is any of the following structures:
Figure PCTCN2020118772-appb-000024
Figure PCTCN2020118772-appb-000024
Figure PCTCN2020118772-appb-000025
Figure PCTCN2020118772-appb-000025
在一些实施方案中，所述R 2为5-10元杂芳基或3-10元杂环烷基；所述5-10元杂芳基或3-10元杂环烷基为未取代或者选择性被一个或多个R c取代在任意位置。 In some embodiments, the R 2 is a 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
在一些实施方案中，所述R 2为5-6元杂芳基或4-8元杂环烷基；所述5-10元杂芳基或3-10元杂环烷基为未取代或者选择性被一个或多个R c取代在任意位置。 In some embodiments, the R 2 is a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
在一些实施方案中，所述R 2为如下任一结构：
Figure PCTCN2020118772-appb-000026
Figure PCTCN2020118772-appb-000027
In some embodiments, the R 2 is any of the following structures:
Figure PCTCN2020118772-appb-000026
Figure PCTCN2020118772-appb-000027
在一些实施方案中，所述R 2为H或CN。 In some embodiments, the R 2 is H or CN.
在一些实施方案中，所述R 3为环己基、环丙基甲基、苯基、吡啶基、嘧啶基、噻唑或1H-吡唑基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 3-6环烷基的取代基取代在任意位置。 In some embodiments, the R 3 is cyclohexyl, cyclopropylmethyl, phenyl, pyridyl, pyrimidinyl, thiazole or 1H-pyrazolyl; the R 3 is unsubstituted or is optionally substituted by 1 to Three substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl are substituted at any position.
在一些实施方案中，所述R 3为如下任一结构： In some embodiments, the R 3 is any of the following structures:
Figure PCTCN2020118772-appb-000028
Figure PCTCN2020118772-appb-000028
在一些实施方案中，所述R 4为氢、卤素、C 2-4烯基、C 1-4烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基或C 3-6环烷基。 In some embodiments, the R 4 is hydrogen, halogen, C 2-4 alkenyl, C 1-4 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1 -3 alkoxy or C 3-6 cycloalkyl.
在一些实施方案中，所述如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐为式(II)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐：In some embodiments, the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is the compound represented by formula (II), its isomer, stable Isotope derivatives or pharmaceutically acceptable salts:
Figure PCTCN2020118772-appb-000029
Figure PCTCN2020118772-appb-000029
其中，A环、B环、X、U、M、R、R 1、R 2和R 4的定义如前所述。 Wherein, ring A, ring B, X, U, M, R, R 1 , R 2 and R 4 are as defined above.
在一些实施方案中，所述如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐为式(IIA)、(IIB)、(IIC)或(IID)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐：In some embodiments, the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is of formula (IIA), (IIB), (IIC) or (IID ) The compound, its isomer, stable isotope derivative or pharmaceutically acceptable salt:
Figure PCTCN2020118772-appb-000030
Figure PCTCN2020118772-appb-000030
其中，B环、R、R A、R 1和R 5的定义如前所述。 Wherein the definition of Ring B, R, R A, R 1 and R 5 are as previously described.
所述如式(I)所示化合物、其异构体或药学上可接受的盐为如下任一结构：The compound represented by formula (I), its isomer or pharmaceutically acceptable salt has any of the following structures:
Figure PCTCN2020118772-appb-000031
Figure PCTCN2020118772-appb-000031
Figure PCTCN2020118772-appb-000032
Figure PCTCN2020118772-appb-000032
Figure PCTCN2020118772-appb-000033
Figure PCTCN2020118772-appb-000033
所述如式(I)所示化合物、其异构体或药学上可接受的盐为如下任一结构：The compound represented by formula (I), its isomer or pharmaceutically acceptable salt has any of the following structures:
Figure PCTCN2020118772-appb-000034
Figure PCTCN2020118772-appb-000034
Figure PCTCN2020118772-appb-000035
Figure PCTCN2020118772-appb-000035
Figure PCTCN2020118772-appb-000036
Figure PCTCN2020118772-appb-000036
Figure PCTCN2020118772-appb-000037
Figure PCTCN2020118772-appb-000037
Figure PCTCN2020118772-appb-000038
Figure PCTCN2020118772-appb-000038
Figure PCTCN2020118772-appb-000039
Figure PCTCN2020118772-appb-000039
Figure PCTCN2020118772-appb-000040
Figure PCTCN2020118772-appb-000040
Figure PCTCN2020118772-appb-000041
Figure PCTCN2020118772-appb-000041
所述如式(I)所示化合物、其异构体或药学上可接受的盐为如下任一结构：The compound represented by formula (I), its isomer or pharmaceutically acceptable salt has any of the following structures:
Figure PCTCN2020118772-appb-000042
Figure PCTCN2020118772-appb-000042
所述如式(I)所示化合物、其异构体或药学上可接受的盐为如下任一结构：The compound represented by formula (I), its isomer or pharmaceutically acceptable salt has any of the following structures:
Figure PCTCN2020118772-appb-000043
Figure PCTCN2020118772-appb-000043
Figure PCTCN2020118772-appb-000044
Figure PCTCN2020118772-appb-000044
Figure PCTCN2020118772-appb-000045
Figure PCTCN2020118772-appb-000045
本发明还提供了如式(I)所示化合物的制备方法，其为如下任一方法：The present invention also provides a method for preparing the compound represented by formula (I), which is any of the following methods:
方法1：溶剂中，如式II-1所示化合物和R-L通过偶联反应得到如式II所示化合物，Method 1: In the solvent, the compound represented by formula II-1 and R-L are coupled to obtain the compound represented by formula II,
Figure PCTCN2020118772-appb-000046
Figure PCTCN2020118772-appb-000046
1)Suzuki偶联反应：其中，Lev为Cl、Br或I，L为硼酸或硼酸酯基；或者Lev为硼酸或硼酸酯基，L为Cl、Br或I；Suzuki偶联反应条件为本领域常见的反应条件，溶剂优选为1,4-二氧六环，催化体系优选[1,1'‐双(二苯基膦基)二茂铁]二氯化钯/碳酸钠水溶液体系或四三苯基膦钯/碳酸钠水溶液体系，反应温度优选80～120℃，反应时间优选0.5～16小时。1) Suzuki coupling reaction: Lev is Cl, Br or I, L is boronic acid or boronic acid ester group; or Lev is boronic acid or boronic acid ester group, L is Cl, Br or I; Suzuki coupling reaction conditions are Common reaction conditions in the art, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride/sodium carbonate aqueous solution system or For the tetratriphenylphosphine palladium/sodium carbonate aqueous system, the reaction temperature is preferably 80-120°C, and the reaction time is preferably 0.5-16 hours.
2)Stille偶联反应：其中，Lev为Cl、Br或I，L为-Sn(CH 3) 3或-Sn(n-Bu) 3；或者Lev为-Sn(CH 3) 3或-Sn(n-Bu) 3，L为Cl、Br或I；Stille偶联反应条件为本领域常见的反应条件，溶剂优选为1,4-二氧六环，催化体系优选四三苯基膦钯/碘化亚铜、四三苯基膦钯/三(2-呋喃基)磷或双三苯基膦二氯化钯/三(2-呋喃基)磷，反应条件优选80～160℃下微波或封管中反应0.5～4小时。 2) Stille coupling reaction: where Lev is Cl, Br or I, L is -Sn(CH 3 ) 3 or -Sn(n-Bu) 3 ; or Lev is -Sn(CH 3 ) 3 or -Sn( n-Bu) 3 , L is Cl, Br or I; Stille coupling reaction conditions are common reaction conditions in the field, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably tetrakistriphenylphosphine palladium/iodine Copper chloride, tetrakistriphenylphosphine palladium/tris(2-furyl)phosphorus or bistriphenylphosphine palladium dichloride/tris(2-furyl)phosphorus, the reaction conditions are preferably microwave or sealing at 80～160℃ React in the tube for 0.5 to 4 hours.
方法2：溶剂中，如式II-2所示化合物和R 1(CO)Cl或(R 1(CO)) 2O在碱性条件下反应得到如式II所示化合物， Method 2: In a solvent, the compound represented by formula II-2 is reacted with R 1 (CO)Cl or (R 1 (CO)) 2 O under basic conditions to obtain the compound represented by formula II,
Figure PCTCN2020118772-appb-000047
Figure PCTCN2020118772-appb-000047
其中，所示溶剂优选为二氯甲烷；碱优选为三乙胺或N,N-二异丙基乙胺；反应温度优选为0～35℃；反应时间优选为0.5～6小时。Among them, the solvent shown is preferably dichloromethane; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35° C.; and the reaction time is preferably 0.5 to 6 hours.
方法3：溶剂中，如式II-2所示化合物和R 1(CO)OH通过缩合反应得到如式II所示化合物， Method 3: In the solvent, the compound represented by formula II-2 and R 1 (CO)OH are condensed to obtain the compound represented by formula II,
Figure PCTCN2020118772-appb-000048
Figure PCTCN2020118772-appb-000048
其中，所示溶剂优选为二氯甲烷和/或乙酸乙酯；碱优选为三乙胺或N,N-二异丙基乙胺；反应温度优选为0～35℃；缩合剂优选为HATU或1-丙基磷酸酐；反应时间优选为0.5～6小时。Among them, the solvent shown is preferably dichloromethane and/or ethyl acetate; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35°C; the condensing agent is preferably HATU or 1-Propyl phosphoric anhydride; the reaction time is preferably 0.5-6 hours.
所述如式(I)所示化合物，其药学上可接受的盐可通过一般的化学方法合成。The pharmaceutically acceptable salt of the compound represented by formula (I) can be synthesized by general chemical methods.
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。In general, the salt can be prepared by reacting a free base or acid with an equivalent or excess acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
本发明还提供了一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如式(I)所示化合物、其异构体和药学上可接受的盐中的一 种或多种。The present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of active components and pharmaceutically acceptable excipients; the active components include the compound represented by formula (I), its isomers and pharmaceutically acceptable One or more of acceptable salts.
所述药物组合物中，所述活性组分还可包括癌症的其它治疗剂。In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer.
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。In the pharmaceutical composition, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and/or excipient.
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。According to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) and the like.
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。In order to shape the pharmaceutical composition in the form of a tablet, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrant, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.; disintegration inhibitors, such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil; adsorption promoters, such as quaternary amine bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerin, starch, etc.; adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants, Such as pure talc, stearate, boric acid powder and polyethylene glycol. Ordinary coating materials can also be selected to make sugar-coated tablets, gelatin film-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets according to needs.
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如***树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。In order to shape the pharmaceutical composition in the form of pills, any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。In order to shape the pharmaceutical composition in the form of suppositories, any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。In order to prepare a pharmaceutical composition in the form of an injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an injection that is isotonic with blood. When preparing injections, any carriers commonly used in the art can also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan and the like. In addition, usual dissolving agents, buffers and analgesics can also be added.
本发明中，所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually 5-95% by mass, preferably 30-80% by mass. %.
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. According to the patient's age, sex and other conditions and symptoms, various dosage forms can be selected for administration. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules can be administered orally; injections can be administered alone or mixed with delivery fluids for injection (such as glucose solution and amino acid solution) for intravenous injection; suppositories are for administration The medicine reaches the rectum.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述 药物组合物在制备KRAS G12C抑制剂中的应用。The present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of KRAS G12C inhibitors.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物在制备用于治疗KRAS G12C介导的相关疾病的药物中的应用。所述相关疾病为癌症。进一步，所述癌症为肿瘤细胞DNA中含有G12C突变的KRAS基因的癌症。The present invention also provides the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a medicine for the treatment of KRAS G12C-mediated related diseases application. The related disease is cancer. Further, the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物在制备治疗和/或缓解癌症药物中的应用。The present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating and/or alleviating cancer.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物在制备治疗和/或缓解非小细胞肺癌、胰腺癌和/或结直肠癌药物中的应用。The present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition for preparing treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer and/ Or the application of colorectal cancer drugs.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物在治疗癌症中的应用。The present invention also provides the application of the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the treatment of cancer.
本发明还提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物在治疗和/或缓解非小细胞肺癌、胰腺癌、子宫内膜癌和/或结直肠癌中的应用。The present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer, intrauterine Application in membrane cancer and/or colorectal cancer.
本发明还进一步提供了用所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物治疗癌症的方法，包括：给予哺乳动物治疗所需剂量的如式(I)所述化合物、其异构体或药学上可接受的盐，或药物组合物。The present invention still further provides a method for treating cancer with the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition, which comprises: administering to a mammal a dose required for treatment The compound as described in formula (I), its isomer or pharmaceutically acceptable salt, or a pharmaceutical composition.
所述哺乳动物，优选人。The mammal is preferably a human.
本发明还进一步提供了所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物还可和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗和/或缓解由KRAS G12C介导的相关疾病。所述的KRAS G12C介导的相关疾病为癌症。进一步，所述癌症为肿瘤细胞DNA中含有G12C突变的KRAS基因的癌症。The present invention further provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/ Or the treatment method is used in combination to treat and/or alleviate related diseases mediated by KRAS G12C. The KRAS G12C-mediated related disease is cancer. Further, the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
本发明优选用所述如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物还可和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗和/或缓解由KRAS G12C介导的癌症。进一步，所述KRAS G12C介导的癌症为肿瘤细胞DNA中含有G12C突变的KRAS基因的癌症。The present invention preferably uses the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/or treatments. The method is used in combination to treat and/or alleviate cancers mediated by KRAS G12C. Further, the KRAS G12C-mediated cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
所述其它种类的治疗剂(例如：用于治疗癌症的其它种类的治疗剂)可以和所述的如式(I)所示化合物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。The other types of therapeutic agents (for example: other types of therapeutic agents for the treatment of cancer) can be combined with the compound represented by formula (I) into a single-administration therapeutic dosage form, or a treatment that is administered separately and sequentially Dosage form.
本发明还进一步提供一种联合制剂，包括如式(I)所示化合物、其异构体或药学上可接受的盐，或所述药物组合物和其它种类的用于治疗癌症的治疗剂和/或治疗方法合用。The present invention further provides a combined preparation, comprising a compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition and other types of therapeutic agents for the treatment of cancer and / Or combination of treatment methods.
本发明中，所述的癌症包括转移性的和非转移性的癌症，也包括家族遗传性的和偶发性的癌症，还可包括固体肿瘤和非固体肿瘤。In the present invention, the cancer includes metastatic and non-metastatic cancers, as well as family hereditary and sporadic cancers, as well as solid tumors and non-solid tumors.
所述癌症的具体例子可包括但不限于：眼癌、骨癌、肺癌(包括小细胞肺癌、非小细胞肺癌)、胃癌、胰腺癌、乳腺癌、***癌、脑癌(包括恶性胶质瘤、成神经管细胞 瘤)、卵巢癌、膀胱癌、子***、子宫内膜癌、输卵管癌、腹膜癌、睾丸癌、肾癌(包括腺癌和肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、肝癌、肉瘤、皮肤癌、淋巴性白血病(包括急性淋巴细胞白血病、淋巴瘤、骨髓瘤、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)、髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)和AIDs相关的白血病中的一种或多种。Specific examples of the cancer may include, but are not limited to: eye cancer, bone cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma) , Medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, endometrial cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, kidney cancer (including adenocarcinoma and Wilms cancer), oral cancer (including squamous cell carcinoma) Cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, liver cancer, sarcoma, skin cancer , Lymphatic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), One or more of myeloid-related leukemia (including acute myeloid leukemia and chronic myeloid leukemia) and AIDs-related leukemia.
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings:
术语“C t-q”是指包括起点到终点的范围，其中t和q及其范围中的各点均为整数，表示碳原子的数目，例如C 1-4表示碳原子数目为1、2、3或4；C 1-6表示碳原子数目为1、2、3、4、5或6；C 3-8表示碳原子数目为3、4、5、6、7或8；C t-q可以跟任何包含碳原子的基团联合使用用于限定碳原子的个数，例如C 1-6烷基、C 1-4亚烷基、C 3-8环烷基、C 6-10芳基、C 1-4烷氧基、C 3-8环烷基C 1-4烷基等。 The term “C tq ”refers to the range from the start point to the end point, where t and q and each point in the range are integers, representing the number of carbon atoms, for example, C 1-4 means that the number of carbon atoms is 1, 2, 3 Or 4; C 1-6 means that the number of carbon atoms is 1, 2, 3, 4, 5 or 6; C 3-8 means that the number of carbon atoms is 3, 4, 5, 6, 7 or 8; C tq can follow any Groups containing carbon atoms are used in combination to limit the number of carbon atoms, such as C 1-6 alkyl, C 1-4 alkylene, C 3-8 cycloalkyl, C 6-10 aryl, C 1 -4 alkoxy, C 3-8 cycloalkyl C 1-4 alkyl and the like.
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基，优选1-10个碳原子，更优选1-8，1-6，1-4或1-3个碳原子，烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、正己基、正庚基、辛基、壬基、癸基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、4,4-二甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。The term "alkyl" refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4 or 1-3 carbons Atom, representative examples of alkyl include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, N-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentan Base, 3-methylpentyl, 4-methylpentyl, 4,4-dimethylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethyl Pentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers.
术语“亚烷基”是指包含1-20个碳原子的饱和直链或支链非桥连性的二价烷基，优选1-6个碳原子，更优选1-4或1-3个碳原子，例如亚甲基(＝CH 2)、亚乙基(＝CHCH 3)、2-异丙亚基(＝CH(CH 3) 2)等。 The term "alkylene" refers to a saturated linear or branched non-bridging divalent alkyl group containing 1-20 carbon atoms, preferably 1-6 carbon atoms, more preferably 1-4 or 1-3 Carbon atoms, for example, methylene (=CH 2 ), ethylene (=CHCH 3 ), 2-isopropylidene (=CH(CH 3 ) 2 ), and the like.
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的单环或多环基团。“环烷基”优选3-10元单环烷基或部分不饱和的4-6元环烷基，更优选3-8或3-6元单环烷基，例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环丁烯基、环戊烯基、环己烯基。“多环环烷基”包括“桥环基”、“稠合环烷基”和“螺环烷基”。单环环烷基或多环环烷基可以通过环上任意的碳原子链接到母体分子上。The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms. "Cycloalkyl" is preferably 3-10 membered monocyclic alkyl or partially unsaturated 4-6 membered cycloalkyl, more preferably 3-8 or 3-6 membered monocyclic alkyl, for example: cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. "Polycyclic cycloalkyl" includes "bridged cyclic group", "fused cycloalkyl" and "spirocycloalkyl". The monocyclic cycloalkyl or polycyclic cycloalkyl can be linked to the parent molecule through any carbon atom on the ring.
术语“杂环烷基”指由碳原子以及选自氮、氧、硫或硼等杂原子组成的饱和或部分不饱和(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，优选为单环、双环或三环基团，在本发明中，杂环烷基中杂原子个数优选1、2、3或4，杂环烷基中的氮、碳、硫或硼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。“单环杂环烷基”优选3-10元单环杂环烷基，更优选3-8或4-8元单环杂环烷基。代表性例子包括但不限于：氮丙啶基、四氢呋喃-2-基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物-4-基、哌啶基、吡咯烷基、哌嗪基、高哌嗪基、1,4-二氧六环基、吡喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、2,3-二氢呋喃基、2,5-二氢呋喃基、二氢吡唑基、2,3-二氢-1H-吡咯烷基、2,5-二氢-1H-吡咯烷基、1,1-二氧化四氢-2H-噻喃基、1-亚氨基-1-氧化四氢-2H-噻喃基、1,1-二氧化四氢噻吩基、1-亚氨基-1-氧化四氢噻吩基、1,1-二氧化-3,4-二氢-2H-噻喃基、1-亚氨基-1-氧化-3,4-二氢-2H-噻喃基、1,1-二氧化-2,3-二氢噻吩基、1-亚氨基-1-氧化-2,3-二氢噻吩基、1,3-二氧戊环基、1,3-二氧杂环戊烯基、1,3-氧硫杂戊环基、1,3-氧硫杂环戊烯基、1,4-二氧杂-2-己烯基、3,4-二氢-2H-吡喃基、3,6-二氢-2H-吡喃基、1,2,3,4-四氢吡嗪基、1,2,3,4-四氢吡啶基、1,2,3,6-四氢吡啶基等。“多环杂环烷基”包括“稠合杂环烷基”、“螺杂环基”和“桥杂环基”，“稠合杂环烷基”包含稠合到芳基、环烷基、杂环烷基或杂芳基的单环杂环烷基环，稠合杂环烷基包括但不限于：吲哚啉基、2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基、苯并[d][1,3]二氧戊环基、1-羟基-1,3-二氢苯并[c][1,2]氧杂硼戊环基
Figure PCTCN2020118772-appb-000049
3-羟基-1,3-二氢萘并[2,1-c][1,2]氧杂硼戊环基
Figure PCTCN2020118772-appb-000050
1-羟基-1,3-二氢萘并[2,3-c][1,2]氧杂硼戊环基
Figure PCTCN2020118772-appb-000051
Figure PCTCN2020118772-appb-000052
等。“螺杂环基”是指两个杂环烷基或一个环烷基和一个杂环烷基共用一个碳原子形成的双环基团，螺杂环基包括但不限于：
Figure PCTCN2020118772-appb-000053
Figure PCTCN2020118772-appb-000054
等。“桥杂环基”是指单环杂环烷基任意两个不相链接的环原子被1到3个额外的碳原子或杂原子形成的直链基团桥连接(所述的直链基团选自但不限于：-CH 2-、-O-、-NH-、-S-、-CH 2CH 2-、-CH 2O-、-CH 2S-、-CH 2NH-、-CH 2CH 2CH 2-、 -CH 2OCH 2-、-CH 2CH 2O-、-CH 2CH 2NH-、-CH 2NHCH 2-)，桥杂环基包括但不限于：
Figure PCTCN2020118772-appb-000055
Figure PCTCN2020118772-appb-000056
Figure PCTCN2020118772-appb-000057
所述双环杂环烷基优选为7到12元双环杂环烷基。单环杂环烷基和双环杂环烷基可以通过环上任意的环原子链接到母体分子上。上述环原子特指组成环骨架的碳原子和/或氮原子。 The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur or boron. The shaped group can be monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic group. In the present invention, the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and heterocycloalkyl Nitrogen, carbon, sulfur or boron atoms in can optionally be oxidized. The nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or a quaternary ammonium salt. The "monocyclic heterocycloalkyl" is preferably a 3-10 membered monocyclic heterocycloalkyl, more preferably a 3-8 or 4-8 membered monocyclic heterocycloalkyl. Representative examples include but are not limited to: aziridinyl, tetrahydrofuran-2-yl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, pyrrolidinyl , Piperazinyl, homopiperazinyl, 1,4-dioxanyl, pyranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, 2,3-dihydrofuranyl, 2 ,5-Dihydrofuryl, dihydropyrazolyl, 2,3-dihydro-1H-pyrrolidinyl, 2,5-dihydro-1H-pyrrolidinyl, 1,1-tetrahydro-2H -Thiopyranyl, 1-imino-1-oxotetrahydro-2H-thiopyranyl, 1,1-dioxide tetrahydrothienyl, 1-imino-1-oxotetrahydrothienyl, 1,1- Dioxide-3,4-dihydro-2H-thiopyranyl, 1-imino-1-oxide-3,4-dihydro-2H-thiopyranyl, 1,1-dihydro-2,3-dioxide Hydrothienyl, 1-imino-1-oxo-2,3-dihydrothienyl, 1,3-dioxolane, 1,3-dioxolyl, 1,3-oxosulfur Heteropentyl, 1,3-oxathiol, 1,4-dioxa-2-hexenyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro -2H-pyranyl, 1,2,3,4-tetrahydropyrazinyl, 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, etc. "Polycyclic heterocycloalkyl" includes "fused heterocycloalkyl", "spiroheterocyclic group" and "bridged heterocyclyl", "fused heterocycloalkyl" includes fused to aryl, cycloalkyl , Heterocycloalkyl or heteroaryl monocyclic heterocycloalkyl ring, condensed heterocycloalkyl includes but not limited to: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl Hydroisobenzofuranyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopiperanyl, 1,2,3,4-tetrahydroquinolinyl, benzo[d][1 ,3]dioxolanyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl
Figure PCTCN2020118772-appb-000049
3-hydroxy-1,3-dihydronaphtho[2,1-c][1,2]oxaborolanyl
Figure PCTCN2020118772-appb-000050
1-hydroxy-1,3-dihydronaphtho[2,3-c][1,2]oxaborolanyl
Figure PCTCN2020118772-appb-000051
Figure PCTCN2020118772-appb-000052
Wait. "Spiroheterocyclic group" refers to a bicyclic group formed by two heterocycloalkyl groups or one cycloalkyl group and one heterocycloalkyl group sharing one carbon atom. Spiro heterocyclic group includes but is not limited to:
Figure PCTCN2020118772-appb-000053
Figure PCTCN2020118772-appb-000054
Wait. "Bridged heterocyclic group" means that any two unlinked ring atoms of a monocyclic heterocycloalkyl group are connected by a straight chain group formed by 1 to 3 additional carbon atoms or heteroatoms (the straight chain group The group is selected from but not limited to: -CH 2 -, -O-, -NH-, -S-, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, -CH 2 NH-,- CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 NHCH 2 -), bridged heterocyclic groups include but are not limited to:
Figure PCTCN2020118772-appb-000055
Figure PCTCN2020118772-appb-000056
Figure PCTCN2020118772-appb-000057
The bicyclic heterocycloalkyl group is preferably a 7 to 12-membered bicyclic heterocycloalkyl group. The monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can be linked to the parent molecule through any ring atom on the ring. The aforementioned ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此，“环烷基烷基”包含上述烷基和环烷基的定义。The term "cycloalkylalkyl" refers to the connection between a cycloalkyl group and the core structure through an alkyl group. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl described above.
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂环烷基烷基”包含上述烷基和杂环烷基的定义。The term "heterocycloalkylalkyl" refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group. Thus, "heterocycloalkylalkyl" encompasses the definitions of alkyl and heterocycloalkyl as described above.
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。术语“C 2-4烯基”是指具有2-4个碳原子的烯基，术语“C 2-6烯基”是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。所述的烯基可以被取代。 The term "alkenyl" refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond. The term "C 2-4 alkenyl" refers to an alkenyl group having 2-4 carbon atoms, and the term "C 2-6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms, including vinyl and propenyl. , Butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3个碳碳三键，优选存在1个碳碳三键。术语“C 2-6炔基”是指具有2-6个碳原子的炔基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。 The term "alkynyl" refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond. The term "C 2-6 alkynyl" refers to an alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，包含烷基氧基、环烷基氧基和杂环烷基氧基。由此，“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。The term "alkoxy" refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms connected through an oxygen bridge, including alkyloxy, cycloalkyloxy and heterocycloalkyloxy. Thus, "alkoxy" encompasses the definitions of alkyl, heterocycloalkyl, and cycloalkyl described above.
术语“芳基”是指任何稳定的6-14元具有共轭π电子体系全碳单环或稠合双环芳香族基团，所述稠合双环芳香族基团中至少有一个环为芳环，所述芳基优选为6-10元，例如：苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。The term "aryl" refers to any stable 6-14 membered all-carbon monocyclic or fused bicyclic aromatic group with a conjugated π-electron system, in which at least one ring of the fused bicyclic aromatic group is an aromatic ring The aryl group is preferably 6-10 members, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，其可为5-6元单环结构或7-12元双环结构，优选5-10元杂芳基。在本发明中，杂原子个数优选1、2或3，包括:吡啶基、嘧啶基、吡嗪基、哒嗪基、哒嗪-3(2H)-酮基、1H-苯并[d]咪唑-2(3H)-酮基、呋喃基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基、1H-吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、 苯并噻吩基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、喹唑啉基等。The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which can be a 5-6 membered monocyclic structure or 7-12 The membered bicyclic structure is preferably a 5-10 membered heteroaryl group. In the present invention, the number of heteroatoms is preferably 1, 2 or 3, including: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazine-3(2H)-keto, 1H-benzo[d] Imidazole-2(3H)-keto, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Azolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1H-indazolyl, isoindazole Group, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此，“芳基烷基”包含上述烷基和芳基的定义。The term "arylalkyl" refers to the connection between the aryl group and the core structure through an alkyl group. Thus, "arylalkyl" encompasses the definitions of alkyl and aryl as described above.
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂芳基烷基”包含上述烷基和杂芳基的定义。The term "heteroarylalkyl" refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group. Thus, "heteroarylalkyl" encompasses the above definitions of alkyl and heteroaryl.
术语“卤素”表示氟、氯、溴或碘。The term "halogen" means fluorine, chlorine, bromine or iodine.
术语“卤代烷基”是指被卤素任意取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。The term "haloalkyl" refers to an alkyl group optionally substituted by halogen. Thus, "haloalkyl" encompasses the definitions of halogen and alkyl above.
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此，“卤代烷氧基”包含以上卤素和烷氧基的定义。The term "haloalkoxy" refers to an alkoxy group optionally substituted by halogen. Thus, "haloalkoxy" encompasses the definitions of halogen and alkoxy above.
术语“氨基”是指-NH 2。术语“烷氨基”是指氨基上至少一个氢原子被烷基所取代，包括“单烷氨基”和“双烷氨基”，例子包括但不限于：-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、-N(CH 2CH 2CH 3) 2、-N(CH 3)(CH 2CH 3)、-N(CH 3)(CH 2CH 2CH 3)。术语“氨基烷基”是指烷基上任意一个氢原子被氨基所取代，例子包括但不限于：-CH 2NH 2、-CH 2CH 2NH 2。由此，“氨基烷基”和“烷氨基”包含上述烷基和氨基的定义。 The term "amino" refers to -NH 2 . The term "alkylamino" means that at least one hydrogen atom on an amino group is replaced by an alkyl group, including "monoalkylamino" and "dialkylamino". Examples include but are not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 3 )(CH 2 CH 2 CH 3 ). The term "aminoalkyl" means that any hydrogen atom on the alkyl group is replaced by an amino group, and examples include but are not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 . Therefore, "aminoalkyl" and "alkylamino" encompass the definitions of alkyl and amino as described above.
术语“烷氨基烷基”是指烷基上任意一个氢原子被烷氨基所取代，例子包括但不限于：-CH 2N(CH 3) 2、-CH 2CH 2N(CH 3) 2、-CH 2CH 2CH 2N(CH 3) 2、-CH 2NHCH 3。由此，“烷氨基烷基”包含上述烷氨基和烷基的定义。 The term "alkylaminoalkyl" means that any hydrogen atom on the alkyl group is replaced by an alkylamino group. Examples include but are not limited to: -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 NHCH 3 . Thus, "alkylaminoalkyl" encompasses the definitions of alkylamino and alkyl as described above.
术语“羟基”是指-OH。术语“羟基烷基”是指烷基上任意一个氢原子被羟基所取代，例子包括但不限于：-CH 2OH、-CH 2CH 2OH、-CH 2CH 2C(CH 3) 2OH、-CH(CH 3) 2OH。由此，“羟基烷基”包含上述羟基和烷基的定义。 The term "hydroxy" refers to -OH. The term "hydroxyalkyl" means that any hydrogen atom on the alkyl group is replaced by a hydroxyl group. Examples include but are not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH , -CH(CH 3 ) 2 OH. Thus, "hydroxyalkyl" encompasses the above definitions of hydroxyl and alkyl.
术语“烷氧基烷基”是指烷基上任意一个氢原子被烷氧基所取代，例子包括但不限于：-CH 2OCH 3、-CH 2CH 2OCH 3。由此，“烷氧基烷基”包含上述烷氧基和烷基的定义。 The term "alkoxyalkyl" means that any hydrogen atom on the alkyl group is replaced by an alkoxy group, and examples include but are not limited to: -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 . Thus, "alkoxyalkyl" encompasses the definitions of alkoxy and alkyl as described above.
术语“酰基”是指-C(O)R”。The term "acyl" refers to -C(O)R".
术语“氧代基”是指＝O，例如羰基(-CO-)、亚硝基(-N＝O)、亚磺酰基(-SO-)或磺酰基(-SO 2-)中的＝O部分。 The term "oxo" refers to =0, such as =0 in carbonyl (-CO-), nitroso (-N=O), sulfinyl (-SO-) or sulfonyl (-SO 2 -) section.
术语“氰基”是指-CN。The term "cyano" refers to -CN.
术语“羧基”是指-C(O)OH。The term "carboxy" refers to -C(O)OH.
本发明所述“室温”是指15-30℃。The "room temperature" in the present invention refers to 15-30°C.
本发明中，除非另有说明，术语“选择性被1-3个基团取代在任意位置”是指基团上所指定的1个、2个或3个原子的任何1个、2个或3个氢原子用所指定的基团取代， 条件是不超过指定原子的正常化合价，所述取代均为本领域常见的合理取代，例如＝O不能取代在芳基上。In the present invention, unless otherwise specified, the term "optionally substituted by 1-3 groups at any position" refers to any 1, 2, or 3 of the 1, 2, or 3 atoms specified on the group. The 3 hydrogen atoms are replaced with the designated group, provided that the normal valence of the designated atom is not exceeded, and the substitutions are reasonable substitutions commonly used in the art, for example, =0 cannot be substituted on an aryl group.
本发明中，当与取代基的键合显示与连接环中两个原子的键合相交时，那么这样的取代基可键合在环上的任何可键合的环原子。In the present invention, when the bond to the substituent shows that it intersects with the bond connecting two atoms in the ring, then such a substituent can be bonded to any bondable ring atom on the ring.
本发明中，任何变量的组合只有在这种组合会产生稳定的化合物的情况下才被允许。In the present invention, any combination of variables is allowed only if the combination will produce a stable compound.
本发明中，任何变量在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，A环被1-3个R 5基团取代时，每个R 5取代基均是独立取代基，可以相同也可以不同。 In the present invention, when any variable occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, when the A ring is substituted by 1-3 R 5 groups, each R 5 substituent is an independent substituent, which may be the same or different.
本发明中所述的任何实施方案中的所述的如式(I)所示的化合物包括其同位素衍生物。所述的同位素取代衍生物包括：式(I)中任意的氢原子(1到5)被1到5个氘原子取代得到的同位素取代衍生物；式(I)中任意的碳原子(1到3)被1到3个C 14原子取代得到的同位素取代衍生物或式(I)中任意的氧原子被1到3个O 18原子取代得到的同位素取代衍生物。 The compound represented by formula (I) in any of the embodiments described in the present invention includes isotopic derivatives thereof. The isotopically substituted derivatives include: any hydrogen atom (1 to 5) in formula (I) is substituted by 1 to 5 deuterium atoms; any carbon atom (1 to 5) in formula (I) 3) Isotope substituted derivatives obtained by substituting 1 to 3 C 14 atoms or isotopic substituted derivatives obtained by substituting any oxygen atom in formula (I) with 1 to 3 O 18 atoms.
本发明所述的“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或***等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团，典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐，例如：盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D，L)-酒石酸，柠檬酸，马来酸，(D，L)-苹果酸，富马酸，丁二酸、琥珀酸盐、乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合物含有酸性基团时，其药学上可接受的盐还可以包括：碱金属盐，例如钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。The "pharmaceutically acceptable salt" of the present invention is discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and has been discussed by medicinal chemists. It is obvious that the salt is basically non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. The compound of the present invention may have an acidic group, a basic group or an amphoteric group. Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, such as: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-sulfonate, mandelate, pyruvate, stearin Salt, ascorbate, salicylate. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkane. Salts formed from base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
本发明所述“异构体”是指本发明的式(I)化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。在本发明中，式(I)化合物或其盐以立体异构的形式(例如，其含有一个或多个不对称碳原子)存在时，单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式(I)表示的化合物或盐的单独异构体，以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括：立体异构体的混合物，以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。 本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。The "isomer" in the present invention means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and single diastereomers, and all these isomers, including Both stereoisomers and geometric isomers are included in the present invention. In the present invention, when the compound of formula (I) or its salt exists in a stereoisomeric form (for example, it contains one or more asymmetric carbon atoms), the individual stereoisomers (enantiomers and non- Enantiomers) and their mixtures are included in the scope of the present invention. The present invention also includes individual isomers of the compound or salt represented by formula (I), and mixtures with isomers in which one or more chiral centers are inverted. The scope of the present invention includes: mixtures of stereoisomers, and purified enantiomers or enantiomer/diastereomer enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all specific groups as defined above.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
具体实施方式Detailed ways
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。 The structures of all the compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代二甲亚砜(DMSO-d 6)，四甲基硅烷作为内标(TMS)。 The 1 H NMR chemical shift (δ) is recorded in PPM (10 -6 ). NMR was performed by Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated dimethyl sulfoxide (DMSO-d 6 ), and tetramethylsilane as internal standard (TMS).
液质联用(LCMS)由Agilent 1200HPLC/6120质谱仪测定，使用色谱柱：Xtimate C18,3.0×50mm，3μm，柱温40℃；或由Thermo UltiMate 3000HPLC/MSQ PLUS质谱仪测定，使用色谱柱XBridge C18，3.0×50mm，3.5μm，柱温30℃。Agilent梯度洗脱条件一：95-5％溶剂A 1和5-95％溶剂B 1(0-2.0分钟)，然后95％溶剂B 1和5％溶剂A 1(保持1.1分钟)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 1：0.01％三氟乙酸(TFA)的水溶液；溶剂B 1：0.01％三氟乙酸的乙腈溶液；百分数为溶质占溶液的体积百分数。Thermo梯度洗脱条件二：95-5％溶剂A 2和5-95％溶剂B 2(0-2分钟)，然后95％溶剂B 2和5％溶剂A 2(保持1.8分钟)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 2：10mM的碳酸氢铵的水溶液；溶剂B 2：乙腈。 Liquid mass spectrometry (LCMS) is determined by Agilent 1200HPLC/6120 mass spectrometer, using chromatographic column: Xtimate C18, 3.0×50mm, 3μm, column temperature 40℃; or by Thermo UltiMate 3000HPLC/MSQ PLUS mass spectrometer, using column XBridge C18, 3.0×50mm, 3.5μm, column temperature 30℃. Agilent gradient elution condition 1: 95-5% solvent A 1 and 5-95% solvent B 1 (0-2.0 minutes), then 95% solvent B 1 and 5% solvent A 1 (hold for 1.1 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume. Solvent A 1 : 0.01% trifluoroacetic acid (TFA) in water; solvent B 1 : 0.01% trifluoroacetic acid in acetonitrile; the percentage is the volume percentage of the solute in the solution. Thermo gradient elution condition 2: 95-5% solvent A 2 and 5-95% solvent B 2 (0-2 minutes), then 95% solvent B 2 and 5% solvent A 2 (hold for 1.8 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume. Solvent A 2 : 10 mM ammonium bicarbonate aqueous solution; Solvent B 2 : Acetonitrile.
本发明所有化合物可通过制备高效液相色谱仪、或快速柱层析进行分离。All the compounds of the present invention can be separated by preparative high performance liquid chromatograph or fast column chromatography.
制备高效液相色谱仪(prep-HPLC)使用岛津LC-20制备液相色谱，色谱柱为：Xtimate 21.2*250mm，10μm。流动相A：10mmol/L碳酸氢铵水溶液，流动相B：乙腈，梯度洗脱条件1：流动相B从10％到30％，洗脱时间5分钟；流动相B从30％到60％，洗脱时间15分钟；条件2：流动相B从15％到25％，洗脱时间：5分钟，洗脱流动相B从25％到55％，洗脱时间15分钟；条件3：流动相B从15％到30％，洗脱时间：5分钟，洗脱流动相B从30％到65％，洗脱时间15分钟；条件4：流动相B从0％到35％，洗脱时间：5分钟，洗脱流动相B从35％到60％，洗脱时间15分钟；条件5：流动相B从10％到40％，洗脱时间：5分钟，洗脱流动相B从40％到80％，洗脱时间15分钟。流动相A：0.1％三氟乙酸水溶液，流动相B：乙腈，梯度洗脱条件6：流动相B从15％到25％，洗脱时间5分钟，25％到55％，洗脱时间15分钟；条件7：流动相B从15％到30％，洗脱时间5分钟，30％到60％，洗脱时间15分钟；条件8：流动相B从15％到45％，洗脱时间5分钟，45％到80％，洗脱时间15分钟。检测波长：214nm&254nm；流速：15.0mL/ 分钟。The preparative high performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 for preparative liquid chromatography, and the column is: Xtimate 21.2*250mm, 10μm. Mobile phase A: 10mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, gradient elution condition 1: mobile phase B from 10% to 30%, elution time 5 minutes; mobile phase B from 30% to 60%, Elution time 15 minutes; Condition 2: Mobile phase B from 15% to 25%, Elution time: 5 minutes, Elution mobile phase B from 25% to 55%, Elution time 15 minutes; Condition 3: Mobile phase B From 15% to 30%, elution time: 5 minutes, elution mobile phase B from 30% to 65%, elution time 15 minutes; condition 4: mobile phase B from 0% to 35%, elution time: 5 Minutes, elution mobile phase B from 35% to 60%, elution time 15 minutes; condition 5: mobile phase B from 10% to 40%, elution time: 5 minutes, elution mobile phase B from 40% to 80 %, the elution time is 15 minutes. Mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile, gradient elution condition 6: mobile phase B from 15% to 25%, elution time 5 minutes, 25% to 55%, elution time 15 minutes ; Condition 7: mobile phase B from 15% to 30%, elution time 5 minutes, 30% to 60%, elution time 15 minutes; Condition 8: mobile phase B from 15% to 45%, elution time 5 minutes , 45% to 80%, elution time 15 minutes. Detection wavelength: 214nm&254nm; flow rate: 15.0mL/min.
快速柱层析(Flash柱层析)(flash system/CheetahTM)使用的是Agela Technologies MP200，配套使用的正相分离柱为Flash columm Silica-CS(25g、40g、80g、120g、或330g)，天津博纳艾杰尔，洗脱体系为乙酸乙酯/石油醚，或二氯甲烷/甲醇；反相分离柱为C18反相柱(12g、20g、或40g)，常州三泰科技，洗脱体系为乙腈/0.1％三氟乙酸水溶液或乙腈/10mmol/L碳酸氢铵水溶液。Flash column chromatography (Flash system/CheetahTM) uses Agela Technologies MP200, and the matched normal phase separation column is Flash column Silica-CS (25g, 40g, 80g, 120g, or 330g), Tianjin Bonaageer, the elution system is ethyl acetate/petroleum ether, or dichloromethane/methanol; the reverse-phase separation column is a C18 reverse-phase column (12g, 20g, or 40g), Changzhou Santai Technology, the elution system It is acetonitrile/0.1% trifluoroacetic acid aqueous solution or acetonitrile/10mmol/L ammonium bicarbonate aqueous solution.
薄层硅胶板(prep-TLC)是烟台黄海HSGF254或青岛GF254硅胶板。Thin layer silica gel plate (prep-TLC) is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
本发明实施例中所述微波反应使用
Figure PCTCN2020118772-appb-000058
Initiator+Microwave System EU(356006)型微波反应器。本发明无特殊注明外，所有实施例中的反应均在氮气氛或氩气氛下进行。 The microwave reaction used in the embodiment of the present invention
Figure PCTCN2020118772-appb-000058
Initiator+Microwave System EU (356006) type microwave reactor. Unless otherwise specified in the present invention, the reactions in all the examples were carried out under a nitrogen atmosphere or an argon atmosphere.
氢气氛是指反应体系连接一个约1L容积的氢气气球。The hydrogen atmosphere refers to the reaction system connected to a hydrogen balloon with a volume of about 1L.
本发明实施例中使用的缩写含义如下：The meanings of abbreviations used in the embodiments of the present invention are as follows:
PdCl 2dppf .CH 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；HATU：O-(7-氮杂苯并***-1-基)-N,N,N’,N’-四甲基脲；TBSCl：叔丁基二甲基氯硅烷；DMF：N,N-二甲基甲酰胺；DMSO：二甲亚砜；DIAD：偶氮二甲酸二异丙酯；(Boc) 2O：二碳酸二叔丁酯；DIPEA：N,N-二异丙基乙基胺；NCS：N-氯代丁二酰亚胺；LiHMDS：二(三甲基硅基)氨基锂；t-BuONa：叔丁醇钠；BINAP：1,1'-联萘-2,2'-双二苯膦；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(PPh 3) 4：四(三苯基膦)钯。 PdCl 2 dppf . CH 2 Cl 2 : [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex; HATU: O-(7-azabenzotriazole -1-yl)-N,N,N',N'-tetramethylurea; TBSCl: tert-butyldimethylchlorosilane; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide ; DIAD: diisopropyl azodicarboxylate; (Boc) 2 O: di-tert-butyl dicarbonate; DIPEA: N,N-diisopropylethylamine; NCS: N-chlorosuccinimide ; LiHMDS: lithium bis(trimethylsilyl)amide; t-BuONa: sodium tert-butoxide; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium; Pd (PPh 3) 4: tetrakis (triphenylphosphine) palladium.
中间体的合成：Synthesis of intermediates:
(S)-(1-(2,2-二氟乙基)吡咯烷-2-基)甲醇(S)-(1-(2,2-Difluoroethyl)pyrrolidin-2-yl)methanol
Figure PCTCN2020118772-appb-000059
Figure PCTCN2020118772-appb-000059
向L-脯氨醇(505mg，5mmol)的乙腈(10mL)溶液中加入2,2-二氟乙基三氟甲磺酸酯(1.1g，5.04mmol)和碳酸钾(760mg，5.5mmol)，反应体系在0℃搅拌1小时，然后升至室温继续搅拌3小时。加入水(100mL)淬灭反应，水相用乙酸乙酯萃取3次，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得(S)-(1-(2,2-二氟乙基)吡咯烷-2-基)甲醇(600mg)为黄色油状物。m/z:[M+H] +166.2。 To a solution of L-prolinol (505mg, 5mmol) in acetonitrile (10mL) was added 2,2-difluoroethyl triflate (1.1g, 5.04mmol) and potassium carbonate (760mg, 5.5mmol), The reaction system was stirred at 0°C for 1 hour, and then raised to room temperature to continue stirring for 3 hours. The reaction was quenched by adding water (100 mL), the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to Flash column chromatography (petroleum ether/ethyl acetate) = 3/1) Purified to obtain (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (600mg) as a yellow oil. m/z: [M+H] + 166.2.
(S)-(1-(2-氟乙基)吡咯烷-2-基)甲醇(S)-(1-(2-Fluoroethyl)pyrrolidin-2-yl)methanol
Figure PCTCN2020118772-appb-000060
Figure PCTCN2020118772-appb-000060
冰水浴下，向L-脯氨醇(2.07g，0.02mol)和碳酸钾(3g，0.02mol)的乙腈(40mL)溶液中加入对甲苯磺酸氟乙酯(4.91g，0.02mol)。反应体系室温搅拌12小时。反应液用硅藻土过滤，滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝9/1)纯化得(S)-(1-(2-氟乙基)吡咯烷-2-基)甲醇(0.5g)为黄色油状物。m/z:[M+H] +148.2。 Under an ice water bath, fluoroethyl p-toluenesulfonate (4.91 g, 0.02 mol) was added to a solution of L-prolinol (2.07 g, 0.02 mol) and potassium carbonate (3 g, 0.02 mol) in acetonitrile (40 mL). The reaction system was stirred at room temperature for 12 hours. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=9/1) to obtain (S)-(1-(2-fluoroethyl)pyrrolidine- 2-yl)methanol (0.5 g) is a yellow oil. m/z: [M+H] + 148.2.
N-乙基-N-(2-氟乙基)氮杂环丁-3-胺N-ethyl-N-(2-fluoroethyl)azetidin-3-amine
Figure PCTCN2020118772-appb-000061
Figure PCTCN2020118772-appb-000061
步骤1：将3-氨基-1-二苯甲基氮杂环丁烷(5g，21mmol)，1-溴-2-氟乙烷(3.2g，25.2mmol)和碳酸钾(7.2g，52.5mmol)的乙腈(50mL)混合物在封管中80℃下搅拌48小时。反应液冷却至室温后过滤，滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝20/1)纯化得到1-二苯甲基-N-(2-氟乙基)氮杂环丁-3-胺(4.5g)为白色固体。m/z:[M+H] +285.2。 Step 1: Combine 3-amino-1-diphenylmethylazetidine (5g, 21mmol), 1-bromo-2-fluoroethane (3.2g, 25.2mmol) and potassium carbonate (7.2g, 52.5mmol) ) In acetonitrile (50 mL) was stirred in a sealed tube at 80°C for 48 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=20/1) to obtain 1-benzylmethyl-N-(2-fluoroethyl)nitrogen Etan-3-amine (4.5 g) is a white solid. m/z: [M+H] + 285.2.
步骤2：将1-二苯甲基-N-(2-氟乙基)氮杂环丁-3-胺(4g，14.1mmol)，碘乙烷(3.3g，21.1mmol)和碳酸钾(5.8g，42.2mmol)的乙腈(50mL)混合物在封管中40℃搅拌20小时。反应液过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/1)纯化得1-二苯甲基-N-乙基-N-(2-氟乙基)氮杂环丁-3-胺(3g)为黄色油状物。m/z:[M+H] +313.2。 Step 2: Combine 1-Benzylmethyl-N-(2-fluoroethyl)azetidin-3-amine (4g, 14.1mmol), iodoethane (3.3g, 21.1mmol) and potassium carbonate (5.8 g, 42.2 mmol) of acetonitrile (50 mL) mixture was stirred at 40°C for 20 hours in a sealed tube. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain 1-benzylmethyl-N-ethyl-N-(2-fluoroethyl) ) Azetidin-3-amine (3g) is a yellow oil. m/z: [M+H] + 313.2.
步骤3：将1-二苯甲基-N-乙基-N-(2-氟乙基)氮杂环丁-3-胺(1g，3.19mmol)，甲酸铵(4g，63.8mmol)，氢氧化钯碳(1g)加入到甲醇(20mL)中，反应体系用氮气置换3次，然后在60℃下搅拌6小时。反应液过滤，滤液减压浓缩得到N-乙基-N-(2-氟乙基)氮杂环丁-3-胺为(466mg)为黄色油状物。m/z:[M+H] +147.2。 Step 3: Combine 1-Benzylmethyl-N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (1g, 3.19mmol), ammonium formate (4g, 63.8mmol), hydrogen Palladium oxide on carbon (1 g) was added to methanol (20 mL), and the reaction system was replaced with nitrogen three times, and then stirred at 60°C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (466 mg) as a yellow oil. m/z: [M+H] + 147.2.
3-氟-4-氯-5-溴苯胺3-fluoro-4-chloro-5-bromoaniline
Figure PCTCN2020118772-appb-000062
Figure PCTCN2020118772-appb-000062
向3-氟-5-溴苯胺(600mg，3.16mmol)的DMF(15mL)溶液中分批加入NCS(506mg，3.79mmol)。反应液室温下搅拌3小时，加水淬灭反应，水相用乙酸乙酯萃取，分离有机相并用饱和食盐水洗，分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得到3-氟-4-氯-5-溴苯胺(310mg)为黄色固体。m/z:[M+H] +224.0； 1H NMR(400MHz,DMSO-d 6):δ6.77(dd,J＝2.4,1.6Hz,1H),6.52(dd,J＝2.4,11.6Hz,1H),5.84(s,2H)。 To a solution of 3-fluoro-5-bromoaniline (600 mg, 3.16 mmol) in DMF (15 mL) was added NCS (506 mg, 3.79 mmol) in batches. The reaction solution was stirred at room temperature for 3 hours. Water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The organic phase was separated and washed with saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was subjected to Flash column chromatography (petroleum ether/ethyl acetate). Ester=3/1) Purification gave 3-fluoro-4-chloro-5-bromoaniline (310mg) as a yellow solid. m/z: [M+H] + 224.0; 1 H NMR (400MHz, DMSO-d 6 ): δ 6.77 (dd, J = 2.4, 1.6 Hz, 1H), 6.52 (dd, J = 2.4, 11.6 Hz ,1H),5.84(s,2H).
3-溴-2-氯-5-氟苯胺3-bromo-2-chloro-5-fluoroaniline
Figure PCTCN2020118772-appb-000063
Figure PCTCN2020118772-appb-000063
步骤1：将1-氯-2,6-二溴-4-氟苯(1.0g，3.47mmol)，二苯甲酮亚胺(754mg，4.16mmol)，t-BuONa(500mg，5.21mmol)，BINAP(324mg，0.52mmol)和Pd 2(dba) 3(156mg，0.17mmol)的无水甲苯(30mL)溶液用氮气置换后在80℃下搅拌16小时。反应液过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝15/1)纯化得化合物3-溴-2-氯-N-(二苯亚甲基)-5-氟苯胺(1.1g)为白色固体。m/z:[M+H] +388.0。 Step 1: Combine 1-chloro-2,6-dibromo-4-fluorobenzene (1.0g, 3.47mmol), benzophenone imine (754mg, 4.16mmol), t-BuONa (500mg, 5.21mmol), An anhydrous toluene (30 mL) solution of BINAP (324 mg, 0.52 mmol) and Pd 2 (dba) 3 (156 mg, 0.17 mmol) was replaced with nitrogen and stirred at 80° C. for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=15/1) to obtain the compound 3-bromo-2-chloro-N-(diphenylmethylene)-5 -Fluoroaniline (1.1 g) is a white solid. m/z: [M+H] + 388.0.
步骤2：冰浴条件下，向3-溴-2-氯-N-(二苯亚甲基)-5-氟苯胺(1.1g，2.84mmol)的四氢呋喃(20mL)溶液中加入盐酸(2M，1.4mL)，反应液在室温下搅拌2小时。反应液用乙酸乙酯萃取，合并有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得到3-溴-2-氯-5-氟苯胺(600mg)为黄色油状物。m/z:[M+H] +224.0。 Step 2: Under ice bath conditions, to a solution of 3-bromo-2-chloro-N-(benzylidene)-5-fluoroaniline (1.1g, 2.84mmol) in tetrahydrofuran (20mL) was added hydrochloric acid (2M, 1.4 mL), the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 3-bromo-2-chloro-5-fluoroaniline ( 600mg) is a yellow oil. m/z: [M+H] + 224.0.
4-溴-1-氟萘-2-醇4-bromo-1-fluoronaphthalene-2-ol
Figure PCTCN2020118772-appb-000064
Figure PCTCN2020118772-appb-000064
冰水浴下，向4-溴萘-2-醇(200mg，0.9mmol)的二氯甲烷(3mL)溶液中分别加入N-氟代双苯磺酰胺(347mg，1.1mmol)和四氯化锆(12mg，0.05mmol)，反应液室温搅拌过夜。然后用饱和碳酸氢钠水溶液洗涤，分离有机相并用无水硫酸钠干燥、过滤、滤液减压浓缩。残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得到4-溴-1-氟萘-2-醇(75mg)为白色固体。 1H NMR(400MHz,DMSO-d 6):δ8.13-8.11(m,1H),7.91-7.81(m,1H),7.52-7.47(m,3H),5.43(br.s,1H)。 Under ice water bath, to 4-bromonaphthalene-2-ol (200mg, 0.9mmol) in dichloromethane (3mL) solution was added N-fluorobisbenzenesulfonamide (347mg, 1.1mmol) and zirconium tetrachloride ( 12mg, 0.05mmol), the reaction solution was stirred overnight at room temperature. Then it was washed with saturated sodium bicarbonate aqueous solution, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 4-bromo-1-fluoronaphthalene-2-ol (75 mg) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ): δ8.13-8.11 (m, 1H), 7.91-7.81 (m, 1H), 7.52-7.47 (m, 3H), 5.43 (br.s, 1H).
3-溴-5-氟-4-异丙基苯胺3-bromo-5-fluoro-4-isopropylaniline
Figure PCTCN2020118772-appb-000065
Figure PCTCN2020118772-appb-000065
步骤1：冰浴条件下，向3-氟-5-溴苯胺(1.8g，9.5mmol)的N,N-二甲基甲酰胺(36mL)溶液中加入N-碘代丁二酰亚胺(2.3g，10.4mmol)，反应液室温搅拌2小时。加水(10mL)淬灭反应，水相用乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤、 滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得3-溴-5-氟-4-碘苯胺(2.7g)为白色固体。m/z:[M+H] +316.0。 Step 1: Under ice bath conditions, add N-iodosuccinimide ( 2.3g, 10.4mmol), the reaction solution was stirred at room temperature for 2 hours. The reaction was quenched by adding water (10 mL), the aqueous phase was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to Flash column chromatography (petroleum ether/ethyl acetate = 10/ 1) Purified to obtain 3-bromo-5-fluoro-4-iodoaniline (2.7g) as a white solid. m/z: [M+H] + 316.0.
步骤2：氮气保护下，将异丙烯基硼酸频哪醇酯(293mg，1.74mmol)，3-溴-5-氟-4-碘苯胺(500mg，1.58mmol)，磷酸钾(1.01g，4.75mmol)和PdCl 2dppf .CH 2Cl 2(130mg，0.16mmol)的1,4-二氧六环中(25mL)混合物在80℃搅拌16小时。过滤、滤液减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得3-溴-5-氟-4-(丙-1-烯-2-基)苯胺(272mg)为黄色油状物。m/z:[M+H] +230.2。 Step 2: Under the protection of nitrogen, the isopropenyl borate pinacol ester (293mg, 1.74mmol), 3-bromo-5-fluoro-4-iodoaniline (500mg, 1.58mmol), potassium phosphate (1.01g, 4.75mmol) ) And PdCl 2 dppf . CH 2 Cl 2 (130 mg, 0.16 mmol) in 1,4-dioxane (25 mL) was stirred at 80°C for 16 hours. Filter, concentrate the filtrate under reduced pressure, and purify the residue by Flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain 3-bromo-5-fluoro-4-(prop-1-en-2-yl)aniline (272mg) is a yellow oil. m/z: [M+H] + 230.2.
步骤3：将3-溴-5-氟-4-(丙-1-烯-2-基)苯胺(272mg，1.18mmol)与铂碳(30mg)加入到乙酸乙酯(20mL)与甲醇(25mL)中，氢气氛下室温搅拌16小时。反应液过滤、滤液减压浓缩后得3-溴-5-氟-4-异丙基苯胺(250mg)为黄色油状物。m/z:[M+H] +232.0。 Step 3: Add 3-bromo-5-fluoro-4-(prop-1-en-2-yl)aniline (272mg, 1.18mmol) and platinum carbon (30mg) to ethyl acetate (20mL) and methanol (25mL ), stirring at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 3-bromo-5-fluoro-4-isopropylaniline (250 mg) as a yellow oil. m/z: [M+H] + 232.0.
3-溴-4-环丙基-5-氟苯胺3-bromo-4-cyclopropyl-5-fluoroaniline
利用3-溴-5-氟-4-异丙基苯胺步骤1和2的合成方法，将步骤2中的异丙烯基硼酸频哪醇酯替换为环丙基硼酸反应得到3-溴-4-环丙基-5-氟苯胺为无色油状物。m/z:[M+H] +232.0。 Using the synthetic methods of steps 1 and 2 of 3-bromo-5-fluoro-4-isopropylaniline, the isopropenyl boronic acid pinacol ester in step 2 is replaced with cyclopropyl boronic acid to obtain 3-bromo-4- Cyclopropyl-5-fluoroaniline is a colorless oil. m/z: [M+H] + 232.0.
N,N-二-Boc-2-氨基-4-溴-5-氯吡啶N,N-Di-Boc-2-amino-4-bromo-5-chloropyridine
Figure PCTCN2020118772-appb-000066
Figure PCTCN2020118772-appb-000066
将(Boc) 2O(1.04g，4.77mmol),三乙胺(483mg，4.77mmol)和4-二甲氨基吡啶(58.3mg，0.48mmol)加入到2-氨基-4-溴-5-氯吡啶(330mg，1.59mmol)的四氢呋喃(5mL)溶液中，氮气保护下室温搅拌4小时。加水淬灭反应，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝0～10％)纯化得到N,N-二-Boc-2-氨基-4-溴-5-氯吡啶(400mg)为白色固体。m/z:[M+Na] +429.3。 (Boc) 2 O (1.04g, 4.77mmol), triethylamine (483mg, 4.77mmol) and 4-dimethylaminopyridine (58.3mg, 0.48mmol) were added to 2-amino-4-bromo-5-chloro In a solution of pyridine (330 mg, 1.59 mmol) in tetrahydrofuran (5 mL), the mixture was stirred at room temperature under nitrogen for 4 hours. The reaction was quenched by adding water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (petroleum ether/ethyl acetate = 0-10%) purified to obtain N,N-di-Boc-2-amino-4-bromo-5-chloropyridine (400mg) as a white solid. m/z: [M+Na] + 429.3.
6-氯-N,N-二(4-甲氧基苄基)-5-(三氟甲基)吡嗪-2-胺6-Chloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyrazine-2-amine
Figure PCTCN2020118772-appb-000067
Figure PCTCN2020118772-appb-000067
步骤1：冰浴条件下，向6-氯-5-碘吡嗪-2-胺(9.56g，37.4mmol)的DMF(58mL)溶液中加入钠氢(60％，3.74g，93.5mmol)，反应混合物搅拌40分钟，将对甲氧基苄氯(14.6g，93.5mmol)缓慢加入到上述反应液中继续搅拌2小时。用冰水淬灭反应，用硫酸氢钾水溶液(1M)调节pH值至7-8，水相用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化得6-氯-5-碘-N,N-二(4-甲氧基苄基)吡嗪-2-胺(10.6g)为淡黄色固体。m/z: [M+H] +495.9。 Step 1: Under ice bath conditions, add sodium hydrogen (60%, 3.74g, 93.5mmol) to a solution of 6-chloro-5-iodopyrazine-2-amine (9.56g, 37.4mmol) in DMF (58mL), The reaction mixture was stirred for 40 minutes, and p-methoxybenzyl chloride (14.6 g, 93.5 mmol) was slowly added to the above reaction solution and stirring was continued for 2 hours. The reaction was quenched with ice water, the pH was adjusted to 7-8 with aqueous potassium hydrogen sulfate (1M), the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed After concentration, the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)pyrazine-2- The amine (10.6 g) is a pale yellow solid. m/z: [M+H] + 495.9.
步骤2：将6-氯-5-碘-N,N-二(4-甲氧基苄基)吡嗪-2-胺(2.5g，5.10mmol)，2,2-二氟-2-(氟磺酰基)乙酸甲酯(2.9g，15.0mmol)和碘化亚铜(2.86g，15.0mmol)悬浮于无水DMF(70mL)溶液中，反应液在氮气保护下100℃搅拌4小时。反应混合物冷却至室温后用乙酸乙酯(50mL)和冰水(30mL)稀释，过滤，滤液用饱和食盐水洗涤，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩，残留物经过Flash柱层析(石油醚/乙酸乙酯＝6/1)纯化得6-氯-N,N-二(4-甲氧基苄基)-5-(三氟甲基)吡嗪-2-胺(2.0g)为淡黄色固体。m/z:[M+H] +438.0。 Step 2: Add 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)pyrazine-2-amine (2.5g, 5.10mmol), 2,2-difluoro-2-( Methyl fluorosulfonyl)acetate (2.9g, 15.0mmol) and cuprous iodide (2.86g, 15.0mmol) were suspended in anhydrous DMF (70mL) solution, and the reaction solution was stirred at 100°C for 4 hours under the protection of nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and ice water (30 mL), filtered, the filtrate was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to Flash Purified by column chromatography (petroleum ether/ethyl acetate=6/1) to obtain 6-chloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyrazine-2-amine (2.0g) is a pale yellow solid. m/z: [M+H] + 438.0.
6-(二(4-甲氧基苄基)氨基)-2-氯-3-(三氟甲基)异烟腈6-(Bis(4-methoxybenzyl)amino)-2-chloro-3-(trifluoromethyl)isonicotinonitrile
Figure PCTCN2020118772-appb-000068
Figure PCTCN2020118772-appb-000068
步骤1：将2,6-二氯-4-氰基吡啶(5.0g，28.9mmol)，对甲氧基苄氯(8.92g，34.7mmol)和DIPEA(26mL,145mmol)溶于无水1,4-二氧六环(55mL)中，反应混合物120℃搅拌过夜。减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化得2-(二(4-甲氧基苄基)氨基)-6-氯异烟腈(9.8g)为黄色固体。m/z:[M+H] +394.0。 Step 1: Dissolve 2,6-dichloro-4-cyanopyridine (5.0g, 28.9mmol), p-methoxybenzyl chloride (8.92g, 34.7mmol) and DIPEA (26mL, 145mmol) in anhydrous 1, In 4-dioxane (55 mL), the reaction mixture was stirred at 120°C overnight. Concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 2-(bis(4-methoxybenzyl)amino)-6-chloroisonicotinonitrile (9.8g) ) Is a yellow solid. m/z: [M+H] + 394.0.
步骤2：将2-(二(4-甲氧基苄基)氨基)-6-氯异烟腈(8.7g，37.4mmol)，N-碘代丁二酰亚胺(5.73g，25.5mmol)溶于无水DMF(70mL)中，反应混合物在100℃下搅拌过夜，乙酸乙酯(500mL)稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得6-(二(4-甲氧基苄基)氨基)-2-氯-3-碘异烟腈(9g)为黄色固体。m/z:[M+H] +522.0。 Step 2: Combine 2-(bis(4-methoxybenzyl)amino)-6-chloroisonicotinonitrile (8.7g, 37.4mmol), N-iodosuccinimide (5.73g, 25.5mmol) Dissolved in anhydrous DMF (70mL), the reaction mixture was stirred at 100°C overnight, diluted with ethyl acetate (500mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Purified by Flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-iodoisonicotinonitrile (9g) as yellow solid. m/z: [M+H] + 522.0.
步骤3：在室温下将6-(二(4-甲氧基苄基)氨基)-2-氯-3-碘异烟腈(8.0g，15.4mmol)，2,2-二氟-2-(氟磺酰基)乙酸甲酯(8.9g，46.2mmol)和碘化亚铜(8.8g，46.2mmol)悬浮于无水DMF(120mL)溶液中，反应体系氮气保护下在100℃下搅拌4小时。反应混合物冷却至室温，乙酸乙酯(500mL)稀释，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得6-(二(4-甲氧基苄基)氨基)-2-氯-3-(三氟甲基)异烟腈(8.0g)为黄色固体。m/z:[M+H] +463.0。 Step 3: Add 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-iodoisonicotinonitrile (8.0g, 15.4mmol), 2,2-difluoro-2- (Fluorosulfonyl) methyl acetate (8.9g, 46.2mmol) and cuprous iodide (8.8g, 46.2mmol) were suspended in anhydrous DMF (120mL) solution, and the reaction system was stirred at 100°C for 4 hours under nitrogen protection . The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to Flash column chromatography (petroleum ether/ethyl acetate = 10/1) Purified 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-(trifluoromethyl)isonicotinonitrile (8.0 g) as a yellow solid. m/z: [M+H] + 463.0.
4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
Figure PCTCN2020118772-appb-000069
Figure PCTCN2020118772-appb-000069
步骤1：氮气保护下，向3-溴-5-氟-2-甲基苯胺(4.8g，23.5mmol)的异丙醇(35mL) 溶液中加入NCS(3.5g，25.9mmol)，反应体系80℃下搅拌2小时后直接浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/1)纯化得3-溴-4-氯-5-氟-2-甲基苯胺(2.6g)为黄色固体。Step 1: Under the protection of nitrogen, add NCS (3.5g, 25.9mmol) to a solution of 3-bromo-5-fluoro-2-methylaniline (4.8g, 23.5mmol) in isopropanol (35mL), the reaction system is 80 After stirring for 2 hours at ℃, it was directly concentrated. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=2/1) to obtain 3-bromo-4-chloro-5-fluoro-2-methylaniline (2.6g ) Is a yellow solid.
步骤2：向3-溴-4-氯-5-氟-2-甲基苯胺(1.5g，6.12mmol)的乙酸(25mL)溶液中加入亚硝酸钠(549mg，7.96mmol)，反应液室温搅拌过夜后直接浓缩。残留物用Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化后得到4-溴-5-氯-6-氟-1H-吲唑(628mg)为黄色固体。Step 2: Add sodium nitrite (549mg, 7.96mmol) to the solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (1.5g, 6.12mmol) in acetic acid (25mL), and stir the reaction solution at room temperature Concentrate directly after overnight. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 4-bromo-5-chloro-6-fluoro-1H-indazole (628 mg) as a yellow solid.
步骤3：向4-溴-5-氯-6-氟-1H-吲唑(575mg，2.3mmol)的二氯甲烷(10mL)溶液中分别加入3,4-二氢吡喃(387mg，4.6mmol)和对甲苯磺酸(44mg，0.23mmol)，反应液室温搅拌2小时后直接浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得到4-溴-5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑(821mg)为黄色固体。Step 3: Add 3,4-dihydropyran (387mg, 4.6mmol) to 4-bromo-5-chloro-6-fluoro-1H-indazole (575mg, 2.3mmol) in dichloromethane (10mL) respectively ) And p-toluenesulfonic acid (44mg, 0.23mmol). The reaction solution was stirred at room temperature for 2 hours and then concentrated directly. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 4-bromo-5- Chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (821 mg) is a yellow solid.
2-氯-3-甲氧基萘-1-基三氟甲磺酸酯2-chloro-3-methoxynaphthalene-1-yl trifluoromethanesulfonate
Figure PCTCN2020118772-appb-000070
Figure PCTCN2020118772-appb-000070
步骤1：把氯甲基甲醚(1.1g，13.8mmol)加入到3-甲氧基萘-1-醇(2.0，11.5mmol)和DIPEA(1.97g，23.0mmol)的二氯甲烷(20mL)溶液中。反应液在室温下搅拌4小时后直接减压浓缩，残留物经Flash柱层析(乙酸乙酯/石油醚＝0％-20％)纯化得3-甲氧基-1-(2-甲氧基乙氧基)萘(2g)为无色油状物。m/z:[M+H] +219.2。 Step 1: Add chloromethyl methyl ether (1.1g, 13.8mmol) to 3-methoxynaphthalene-1-ol (2.0, 11.5mmol) and DIPEA (1.97g, 23.0mmol) in dichloromethane (20mL) In solution. The reaction solution was stirred at room temperature for 4 hours and then directly concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether=0%-20%) to obtain 3-methoxy-1-(2-methoxy Ethoxy) naphthalene (2g) is a colorless oil. m/z: [M+H] + 219.2.
步骤2：-10℃，氮气保护下，把正丁基锂(2.5M的四氢呋喃溶液，1.2mL，2.8mmol)缓慢加入到3-甲氧基-1-(2-甲氧基乙氧基)萘(0.5g，2.34mmol)，四甲基乙二胺(0.35mL，3.0mmol)的四氢呋喃(5mL)溶液中，反应液在-10℃下搅拌1.5小时。然后，把六氯乙烷固体(0.87g，3.66mmol)分批加入到上述反应液中。反应液升至室温，加水淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物经Flash柱层析(乙酸乙酯/石油醚＝0％-16％)纯化得2-氯-3-甲氧基-1-(2-甲氧基乙氧基)萘(0.5g)为无色油状物。m/z:[M+H] +253.2； 1H NMR(400MHz,DMSO-d 6):δ8.02(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),7.60-7.49(m,1H),7.49-7.42(m,1H),7.37(s,1H),5.26(s,2H),3.97(s,3H),3.61(s,3H)。 Step 2: Under nitrogen protection at -10°C, slowly add n-butyllithium (2.5M tetrahydrofuran solution, 1.2mL, 2.8mmol) to 3-methoxy-1-(2-methoxyethoxy) In a solution of naphthalene (0.5 g, 2.34 mmol) and tetramethylethylenediamine (0.35 mL, 3.0 mmol) in tetrahydrofuran (5 mL), the reaction solution was stirred at -10°C for 1.5 hours. Then, hexachloroethane solid (0.87 g, 3.66 mmol) was added to the above reaction solution in batches. The reaction solution was warmed to room temperature, quenched by adding water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (ethyl acetate/petroleum ether=0%- 16%) was purified to obtain 2-chloro-3-methoxy-1-(2-methoxyethoxy)naphthalene (0.5g) as a colorless oil. m/z:[M+H] + 253.2; 1 H NMR(400MHz,DMSO-d 6 ):δ8.02(d,J=8.2Hz,1H), 7.88(d,J=8.2Hz,1H), 7.60-7.49 (m, 1H), 7.49-7.42 (m, 1H), 7.37 (s, 1H), 5.26 (s, 2H), 3.97 (s, 3H), 3.61 (s, 3H).
步骤3：将2-氯-3-甲氧基-1-(2-甲氧基乙氧基)萘(0.5g，1.98mmol)和氯化氢(4.0M的1,4-二氧六环溶液，4.0mL)的二氯甲烷(10mL)溶液在室温下搅拌1.5小时，然后，加入饱和的碳酸氢钠水溶液调pH＝7.0，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩后得2-氯-3-甲氧基萘-1-醇(0.41g)为黄色固体。m/z:[M+H] +209.0。 Step 3: Combine 2-chloro-3-methoxy-1-(2-methoxyethoxy)naphthalene (0.5g, 1.98mmol) and hydrogen chloride (4.0M 1,4-dioxane solution, 4.0mL) in dichloromethane (10mL) solution was stirred at room temperature for 1.5 hours, then, saturated aqueous sodium bicarbonate was added to adjust the pH to 7.0, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-Chloro-3-methoxynaphthalen-1-ol (0.41 g) is a yellow solid. m/z: [M+H] + 209.0.
步骤4：冰浴条件下，把三氟甲磺酸酐(0.7g，2.5mmol)加入到2-氯-3-甲氧基萘-1- 醇(0.4g，1.92mmol)和三乙胺(0.8mL，5.76mmol)的二氯甲烷(5mL)溶液中。反应液在0℃下搅拌2小时。加水淬灭反应，水相用乙酸乙酯萃取，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物经Flash柱层析(乙酸乙酯/石油醚＝0％-20％)纯化得2-氯-3-甲氧基萘-1-基三氟甲磺酸酯(0.17g)为白色固体。m/z:[M+H] +341.0。 Step 4: Under ice bath conditions, add trifluoromethanesulfonic anhydride (0.7g, 2.5mmol) to 2-chloro-3-methoxynaphthalene-1-ol (0.4g, 1.92mmol) and triethylamine (0.8 mL, 5.76 mmol) in dichloromethane (5 mL). The reaction solution was stirred at 0°C for 2 hours. The reaction was quenched by adding water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (ethyl acetate/petroleum ether=0%-20%). ) Purified to obtain 2-chloro-3-methoxynaphthalene-1-yl trifluoromethanesulfonate (0.17 g) as a white solid. m/z: [M+H] + 341.0.
硼酸和硼酸酯的合成Synthesis of Boric Acid and Boric Ester
硼酸通用合成方法：干冰丙酮浴下，将芳基或杂芳基的溴化物(1当量)的四氢呋喃(5～15mL/mmol溴化物)溶液用氮气置换，将正丁基锂(2.5M的正己烷溶液，0.9～1当量)滴加到上述溶液中，反应液在-78℃下搅拌1小时，加入硼酸三甲脂(1.5～2.5当量)，反应液继续在-78℃下搅拌4小时，加入水淬灭反应。混合物用乙酸乙酯稀释后用饱和食盐水洗，分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯)纯化得到相应的硼酸。General synthesis method for boric acid: Under dry ice acetone bath, replace the aryl or heteroaryl bromide (1 equivalent) in tetrahydrofuran (5-15mL/mmol bromide) solution with nitrogen, and replace the n-butyllithium (2.5M n-hexane) with nitrogen. Alkane solution, 0.9-1 equivalent) was added dropwise to the above solution, the reaction solution was stirred at -78°C for 1 hour, trimethyl borate (1.5 to 2.5 equivalents) was added, and the reaction solution continued to be stirred at -78°C for 4 hours. Water quenches the reaction. The mixture was diluted with ethyl acetate and washed with saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate) to obtain the corresponding boronic acid.
硼酸酯通用合成方法：将芳基或杂芳基的溴化物或三氟甲磺酸酯(1当量)、联硼酸频那醇酯(2～3当量)、乙酸钾(3～5当量)和PdCl 2dppf .CH 2Cl 2(0.1～0.15当量)的1,4-二氧六环(5～15mL/mmol溴化物)溶液用氮气置换，反应体系在80～120℃氮气氛下搅拌4～16小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯)纯化得到相应的硼酸酯。 General synthesis method of borate ester: the bromide or triflate of aryl or heteroaryl (1 equivalent), pinacol diborate (2~3 equivalent), potassium acetate (3~5 equivalent) And PdCl 2 dppf . CH 2 Cl 2 (0.1～0.15 equivalent) 1,4-dioxane (5～15mL/mmol bromide) solution was replaced with nitrogen, the reaction system was stirred at 80～120℃ under nitrogen atmosphere 4 ~16 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate) to obtain the corresponding borate.
表1Table 1
Figure PCTCN2020118772-appb-000071
Figure PCTCN2020118772-appb-000071
Figure PCTCN2020118772-appb-000072
Figure PCTCN2020118772-appb-000072
中间体5使用硼酸酯合成方法，得到相应的硼酸产物。Intermediate 5 uses boric acid ester synthesis method to obtain the corresponding boric acid product.
中间体32：(2-氨基-3,5-二氯-6-氟苯基)硼酸的合成Intermediate 32: Synthesis of (2-amino-3,5-dichloro-6-fluorophenyl)boronic acid
Figure PCTCN2020118772-appb-000073
Figure PCTCN2020118772-appb-000073
步骤1：冰浴条件下，向2,4-二氯-5-氟苯胺(2.62g，14.6mmol)和碳酸钠(2.65g，25mmol)的甲基叔丁基醚(60mL)溶液中加入三氟乙酸酐(3.78g，18mmol)，反应液室温搅拌12小时，用正己烷稀释后过滤，滤液减压浓缩。残留物用Flash柱层析(石油醚/乙酸乙酯＝19/1)纯化得N-(2,4-二氯-5-氟苯基)-2,2,2-三氟乙酰胺(3g)为灰色固体。Step 1: Under ice bath conditions, to 2,4-dichloro-5-fluoroaniline (2.62g, 14.6mmol) and sodium carbonate (2.65g, 25mmol) in methyl tert-butyl ether (60mL) solution was added three Fluoroacetic anhydride (3.78g, 18mmol), the reaction solution was stirred at room temperature for 12 hours, diluted with n-hexane and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=19/1) to obtain N-(2,4-dichloro-5-fluorophenyl)-2,2,2-trifluoroacetamide (3g ) Is a gray solid.
步骤2：-78℃，氮气保护下，向中N-(2,4-二氯-5-氟苯基)-2,2,2-三氟乙酰胺(3g，10.9mmol)的四氢呋喃(47mL)溶液中滴加正丁基锂(2.5M的正己烷溶液，8.7mL，22.7mmol)，反应体系在此温度下搅拌2小时，然后用硼酸三甲酯(2.47g，23.9mmol)淬灭反应，得到的混合物用乙酸乙酯稀释、有机相用饱和食盐水洗涤，分离有机相并浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得中间体32(850mg)为黄色油状物。m/z:[M+H] +224.0。 Step 2: -78℃, under nitrogen protection, add N-(2,4-dichloro-5-fluorophenyl)-2,2,2-trifluoroacetamide (3g, 10.9mmol) in tetrahydrofuran (47mL) ) Was added dropwise n-butyl lithium (2.5M n-hexane solution, 8.7 mL, 22.7 mmol) to the solution, the reaction system was stirred at this temperature for 2 hours, and then the reaction was quenched with trimethyl borate (2.47 g, 23.9 mmol) The resulting mixture was diluted with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was separated and concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain Intermediate 32 (850 mg ) Is yellow oil. m/z: [M+H] + 224.0.
中间体33：3,4-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯酚的合成Intermediate 33: Synthesis of 3,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
Figure PCTCN2020118772-appb-000074
Figure PCTCN2020118772-appb-000074
向中间体13(50mg，0.17mmol)的1,4-二氧六环(2mL)溶液中加入氯化氢(4M的1,4-二氧六环溶液，0.5mL)，得到的混合物在室温下搅拌3小时。然后直接减压浓缩 得中间体33(42mg)为黄色油状物。m/z:[M+H] +249.2。 To the 1,4-dioxane (2mL) solution of Intermediate 13 (50mg, 0.17mmol) was added hydrogen chloride (4M 1,4-dioxane solution, 0.5mL), and the resulting mixture was stirred at room temperature 3 hours. Then it was directly concentrated under reduced pressure to obtain Intermediate 33 (42 mg) as a yellow oil. m/z: [M+H] + 249.2.
中间体1-6：4-(4-溴呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-甲酸叔丁酯的合成Intermediate 1-6: Synthesis of tert-butyl 4-(4-bromofuro[2,3-f]quinazolin-9-yl)piperazine-1-carboxylate
Figure PCTCN2020118772-appb-000075
Figure PCTCN2020118772-appb-000075
步骤1：将4-溴-2,6-二氟苯腈(25g，0.11mol)，氨水(100mL)和异丙醇(60mL)加入封管，反应体系90℃下搅拌16小时。反应液冷却至室温后倒入水中，有大量固体析出，抽滤，滤饼真空干燥得中间体1-1(23.2g)为灰色固体。m/z:[M+H] +215.0。 Step 1: Add 4-bromo-2,6-difluorobenzonitrile (25g, 0.11mol), ammonia water (100mL) and isopropanol (60mL) into the sealed tube, and stir the reaction system at 90°C for 16 hours. After the reaction solution was cooled to room temperature, it was poured into water, a large amount of solids were precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 1-1 (23.2g) as a gray solid. m/z: [M+H] + 215.0.
步骤2：冰浴条件下，向2,2-二乙氧基乙醇(3.7g，27.9mmol)的DMF(60mL)溶液中分批加入钠氢(60％，1.1g，27.9mmol)，得到的混合物在0℃下搅拌1小时。接着把中间体1-1(5g，23.3mmol)加入到上述反应液中，50℃搅拌1小时。用冰水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得中间体1-2(4.8g，产率：63％)为灰色固体。m/z:[M+Na] +350.8。 Step 2: Under ice bath conditions, add sodium hydrogen (60%, 1.1g, 27.9mmol) to a solution of 2,2-diethoxyethanol (3.7g, 27.9mmol) in DMF (60mL) in batches to obtain The mixture was stirred at 0°C for 1 hour. Next, Intermediate 1-1 (5 g, 23.3 mmol) was added to the above reaction solution, and stirred at 50°C for 1 hour. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain Intermediate 1-2 ( 4.8 g, yield: 63%) is a gray solid. m/z: [M+Na] + 350.8.
步骤3：将多聚磷酸(16.9g，50.1mmol)的甲苯(150mL)混悬液升温到50℃。将中间体1-2(5.5g，16.7mmol)加入到上述溶液中，得到的混合物在50℃下搅拌2小时。冰水浴下，反应液用乙酸乙酯稀释，有机相用饱和的碳酸氢钠水溶液洗涤，分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝6/1)纯化得中间体1-3(1.1g)为灰色固体。m/z:[M+H] +237.0。 Step 3: The toluene (150 mL) suspension of polyphosphoric acid (16.9 g, 50.1 mmol) was heated to 50°C. Intermediate 1-2 (5.5 g, 16.7 mmol) was added to the above solution, and the resulting mixture was stirred at 50°C for 2 hours. Under ice-water bath, the reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate aqueous solution, the organic phase was separated and concentrated under reduced pressure, and the residue was chromatographed with Flash column (petroleum ether/ethyl acetate=6/1) The intermediate 1-3 (1.1 g) was purified as a gray solid. m/z: [M+H] + 237.0.
步骤4：将中间体1-3(0.33g，1.39mmol)的甲酸(12mL)和浓硫酸(0.3mL)混合溶液在100℃搅拌0.5小时。反应液冷却至室温后倒入水中，有大量固体析出，抽滤，滤饼真空干燥得中间体1-4(0.21g)为黄色固体。m/z:[M+H] +264.8。 Step 4: A mixed solution of intermediate 1-3 (0.33 g, 1.39 mmol) in formic acid (12 mL) and concentrated sulfuric acid (0.3 mL) was stirred at 100° C. for 0.5 hours. The reaction solution was cooled to room temperature and poured into water. A large amount of solids precipitated out, filtered off with suction, and the filter cake was vacuum dried to obtain Intermediate 1-4 (0.21 g) as a yellow solid. m/z: [M+H] + 264.8.
步骤5：向中间体1-4(350mg，1.32mmol)和N,N-二甲基苯胺(1.78g，14.7mmol)的1,4-二氧六环(16mL)溶液中加入三氯氧磷(1.6mL)，反应液110℃搅拌1小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩得中间体1-5(粗品)为黄色固体。m/z:[M+H] +282.8。 Step 5: To the 1,4-dioxane (16mL) solution of Intermediate 1-4 (350mg, 1.32mmol) and N,N-dimethylaniline (1.78g, 14.7mmol) was added phosphorus oxychloride (1.6 mL), the reaction solution was stirred at 110°C for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 1-5 (crude product) as a yellow solid. m/z: [M+H] + 282.8.
步骤6：向中间体1-5(粗品)和1-叔丁氧羰基哌嗪(0.37g，1.98mmol)的1,4-二氧六环(30mL)溶液中加入DIPEA(1.7g，13.2mmol)，反应液在50℃下搅拌21小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得中间体1-6(650mg)为黄色固体。m/z:[M+H] +433.0。 Step 6: To a solution of Intermediate 1-5 (crude) and 1-tert-butoxycarbonylpiperazine (0.37g, 1.98mmol) in 1,4-dioxane (30mL) was added DIPEA (1.7g, 13.2mmol) ), the reaction solution was stirred at 50°C for 21 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain Intermediate 1-6 (650 mg) It is a yellow solid. m/z: [M+H] + 433.0.
中间体2-4：4-(4-溴-7-氯呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-甲酸叔丁酯的合成Intermediate 2-4: Synthesis of tert-butyl 4-(4-bromo-7-chlorofuro[2,3-f]quinazolin-9-yl)piperazine-1-carboxylate
Figure PCTCN2020118772-appb-000076
Figure PCTCN2020118772-appb-000076
步骤1：向中间体1-3(0.43g，1.81mmol)的乙醇(15mL)溶液中加入氢氧化钾(0.41g，7.3mmol)的水(3mL)溶液，得到的混合物在90℃搅拌4小时。反应液冷却至室温后用水稀释，水相用二氯甲烷萃取、分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/3)纯化得中间体2-1(406mg)为灰色固体。m/z:[M+H] +254.8。 Step 1: To the ethanol (15mL) solution of Intermediate 1-3 (0.43g, 1.81mmol) was added potassium hydroxide (0.41g, 7.3mmol) in water (3mL), and the resulting mixture was stirred at 90°C for 4 hours . The reaction solution was cooled to room temperature and diluted with water. The aqueous phase was extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=2/3) to obtain Intermediate 2- 1 (406 mg) is a gray solid. m/z: [M+H] + 254.8.
步骤2：向中间体2-1(406mg，1.59mmol)的四氢呋喃(60mL)溶液中加入三光气(467mg，1.5mmol)的四氢呋喃(20mL)溶液，得到的混合物在60℃搅拌2小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝4/1)纯化得中间体2-2(325mg)为灰色固体。m/z:[M+H] +280.8。 Step 2: To a solution of Intermediate 2-1 (406 mg, 1.59 mmol) in tetrahydrofuran (60 mL) was added a solution of triphosgene (467 mg, 1.5 mmol) in tetrahydrofuran (20 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (dichloromethane/methanol=4/1) to obtain Intermediate 2-2 (325mg) as Gray solid. m/z: [M+H] + 280.8.
步骤3：向中间体2-2(100mg，0.36mmol)和N,N-二甲基苯胺(0.2mL)的1,4-二氧六环(5mL)溶液中加入三氯氧磷(2mL)，反应液在110℃搅拌2小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩得中间体2-3(粗品)为黄色固体。m/z:[M+H] +316.8。 Step 3: Add phosphorus oxychloride (2mL) to the solution of Intermediate 2-2 (100mg, 0.36mmol) and N,N-dimethylaniline (0.2mL) in 1,4-dioxane (5mL) The reaction solution was stirred at 110°C for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 2-3 (crude) as a yellow solid. m/z: [M+H] + 316.8.
步骤4：向中间体2-3(粗品)和DIPEA(0.78g，6.03mmol)的1,4-二氧六环(5mL)溶液中加入1-叔丁氧羰基哌嗪(100mg，0.53mmol)，反应液在50℃下搅拌2小时，用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩。残留物用Flash柱层析(石油醚/乙酸乙酯＝3/2)纯化得中间体2-4(100mg)为白色固体。m/z:[M+H] +466.6。 Step 4: To a solution of Intermediate 2-3 (crude) and DIPEA (0.78g, 6.03mmol) in 1,4-dioxane (5mL) was added 1-tert-butoxycarbonylpiperazine (100mg, 0.53mmol) The reaction solution was stirred at 50°C for 2 hours, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=3/2) to obtain Intermediate 2-4 (100 mg) as a white solid. m/z: [M+H] + 466.6.
中间体2-5～2-6的合成Synthesis of intermediates 2-5～2-6
利用中间体2-4的合成方法，将步骤4中的1-叔丁氧羰基哌嗪替换为2-叔丁氧羰基-2,7-二氮杂螺[3.5]壬烷或(S)-2-(氰甲基)哌嗪-1-甲酸苄酯得到中间体2-5～2-6：Using the synthetic method of intermediate 2-4, replace 1-tert-butoxycarbonylpiperazine in step 4 with 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane or (S)- Benzyl 2-(cyanomethyl)piperazine-1-carboxylate provides intermediates 2-5～2-6:
表2Table 2
Figure PCTCN2020118772-appb-000077
Figure PCTCN2020118772-appb-000077
中间体3-9：4-(4-溴-7-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-f]喹唑啉-9-基)哌嗪-1-甲酸叔丁酯的合成Intermediate 3-9: 4-(4-Bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-f]quinazoline-9 -Yl)piperazine-1-carboxylic acid tert-butyl ester synthesis
Figure PCTCN2020118772-appb-000078
Figure PCTCN2020118772-appb-000078
步骤1：将4-溴-6-硝基-1H-吲唑(9g，37.2mmol)，铁粉(10.4g，186mmol)，氯化铵(10g，186mmol)分别加入到水(30mL)和乙醇(130mL)的混合溶液中，得到的混合物在80℃下搅拌2小时。过滤，滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝1/1)纯化得中间体3-1(7.0g)为黄色固体。m/z:[M+H] +213.8。 Step 1: Add 4-bromo-6-nitro-1H-indazole (9g, 37.2mmol), iron powder (10.4g, 186mmol), ammonium chloride (10g, 186mmol) to water (30mL) and ethanol respectively (130 mL) of the mixed solution, the resulting mixture was stirred at 80°C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=1/1) to obtain Intermediate 3-1 (7.0 g) as a yellow solid. m/z: [M+H] + 213.8.
步骤2：向水合氯醛(3.9g，23.6mmol)，浓盐酸(5mL)，无水硫酸钠(13.4g，94.3mmol)的水(50mL)溶液中加入中间体3-1(2.5g，11.8mmol)的DMF(25mL)溶液。得到的混合物在90℃下搅拌30分钟后，加入盐酸羟胺(4.9g，70.7mmol)，继续在90℃下搅拌过夜。加入冰水淬灭反应，得到的混合物继续搅拌15分钟，过滤，滤饼用水洗后真空干燥得中间体3-2(2.9g)为黄色固体。m/z:[M+H] +284.5。 Step 2: To a solution of chloral hydrate (3.9g, 23.6mmol), concentrated hydrochloric acid (5mL), anhydrous sodium sulfate (13.4g, 94.3mmol) in water (50mL) was added Intermediate 3-1 (2.5g, 11.8) mmol) in DMF (25 mL). After the resulting mixture was stirred at 90°C for 30 minutes, hydroxylamine hydrochloride (4.9 g, 70.7 mmol) was added, and stirring was continued at 90°C overnight. The reaction was quenched by adding ice water, the resulting mixture was stirred for 15 minutes, filtered, and the filter cake was washed with water and dried in vacuo to obtain Intermediate 3-2 (2.9 g) as a yellow solid. m/z: [M+H] + 284.5.
步骤3：将中间体3-2(2.9g，10.2mmol)的浓硫酸(20mL)溶液在60℃搅拌1.5小时，然后小心地加入到冰水中，反应混合物过滤，滤饼用水洗涤后真空干燥后得中间体3-3(2.7g)为棕色固体。m/z:[M+H] +267.8。 Step 3: A solution of Intermediate 3-2 (2.9g, 10.2mmol) in concentrated sulfuric acid (20mL) was stirred at 60°C for 1.5 hours, then carefully added to ice water, the reaction mixture was filtered, the filter cake was washed with water and dried in vacuo The intermediate 3-3 (2.7g) was obtained as a brown solid. m/z: [M+H] + 267.8.
步骤4：冰浴条件下，向中间体3-3(2.7g，10.2mmol)的1,4-二氧六环(40mL)溶液中加入氢氧化钠(4.1g，102mmol)的水(5mL)溶液，然后逐滴加入30％双氧水(5.8g，50.7mmol)。加毕，反应液升至室温并搅拌1.5小时，用饱和的硫代硫酸钠水溶液(2mL)淬灭反应，混合物减压浓缩后经Flash柱层析(乙腈/10mmol/L碳酸氢铵水溶液＝20％)纯化得中间体3-4(2.0g)为黄色固体。m/z:[M+H] +257.8。 Step 4: Under ice bath conditions, add sodium hydroxide (4.1g, 102mmol) in water (5mL) to the 1,4-dioxane (40mL) solution of Intermediate 3-3 (2.7g, 10.2mmol) Solution, then add 30% hydrogen peroxide (5.8g, 50.7mmol) dropwise. After the addition, the reaction solution was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched with saturated sodium thiosulfate aqueous solution (2 mL). The mixture was concentrated under reduced pressure and then subjected to Flash column chromatography (acetonitrile/10mmol/L ammonium bicarbonate aqueous solution=20 %) The intermediate 3-4 (2.0g) was purified as a yellow solid. m/z: [M+H] + 257.8.
步骤5：冰浴条件下，向中间体3-4(1.6g，6.3mmol)，氯化铵(3.3g，62.5mmol)，DIPEA(2.4g，18.8mmol)的DMF(50mL)溶液中加入HATU(1.6g，6.3mmol)，得到的混合物在室温下搅拌2天，加水(10mL)淬灭反应，反应液经Flash柱层析(30％乙腈的碳酸氢铵水溶液)纯化得中间体3-5(630mg)为淡黄色固体。m/z:[M+H] +256.8。 Step 5: Under ice bath conditions, add HATU to a solution of Intermediate 3-4 (1.6g, 6.3mmol), ammonium chloride (3.3g, 62.5mmol), DIPEA (2.4g, 18.8mmol) in DMF (50mL) (1.6g, 6.3mmol), the resulting mixture was stirred at room temperature for 2 days, and water (10mL) was added to quench the reaction. The reaction solution was purified by Flash column chromatography (30% acetonitrile in ammonium bicarbonate aqueous solution) to obtain Intermediate 3-5 (630mg) is a pale yellow solid. m/z: [M+H] + 256.8.
步骤6：将中间体3-5(300mg，1.2mmol)和尿素(3.5g，58.8mmol)在180℃熔融下搅拌2小时后降温至80℃，加入水(15mL)搅拌5分钟，反应混合物过滤，滤饼 用水洗涤后真空干燥得中间体3-6(330mg)为淡黄色固体。m/z:[M+H] +280.8。 Step 6: Intermediate 3-5 (300mg, 1.2mmol) and urea (3.5g, 58.8mmol) were melted at 180°C and stirred for 2 hours, then cooled to 80°C, water (15mL) was added and stirred for 5 minutes, and the reaction mixture was filtered The filter cake was washed with water and dried in vacuo to obtain Intermediate 3-6 (330 mg) as a pale yellow solid. m/z: [M+H] + 280.8.
步骤7：冰浴条件下，向中间体3-6(330mg，1.2mmol)的三氯氧磷(35mL)溶液中加入N,N二甲基苯胺(3mL)，得到的混合物在100℃下搅拌过夜。反应液减压浓缩，残留物用乙酸乙酯稀释后用冰水洗涤，分离有机相并减压浓缩，残留物用Flash柱层析(乙酸乙酯/石油醚＝15/1)纯化后得中间体3-7(196mg)为淡黄色固体。m/z:[M+H] +319.0。 Step 7: Under ice bath conditions, N,N dimethylaniline (3 mL) was added to a solution of intermediate 3-6 (330 mg, 1.2 mmol) in phosphorus oxychloride (35 mL), and the resulting mixture was stirred at 100°C overnight. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with ice water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether=15/1) to obtain the intermediate Form 3-7 (196 mg) is a pale yellow solid. m/z: [M+H] + 319.0.
步骤8：将中间体3-7(196mg，0.6mmol)，DIPEA(239mg，1.9mmol)，1-叔丁氧羰基哌嗪(138mg，0.7mmol)的四氢呋喃(15mL)溶液在室温下搅拌30分钟，然后用水淬灭反应，水相用乙酸乙酯萃取，分离有机相并减压浓缩，残留物用Flash柱层析(乙酸乙酯/石油醚＝1/3)纯化得中间体3-8(226mg)为淡黄色固体。m/z:[M+H] +467.0。 Step 8: A solution of Intermediate 3-7 (196 mg, 0.6 mmol), DIPEA (239 mg, 1.9 mmol), 1-tert-butoxycarbonylpiperazine (138 mg, 0.7 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 30 minutes Then the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether = 1/3) to obtain Intermediate 3-8 ( 226mg) is a pale yellow solid. m/z: [M+H] + 467.0.
步骤9：向中间体3-8(226mg，0.5mmol)和对甲苯磺酸(9mg，0.05mmol)的四氢呋喃(5mL)溶液中加入3,4-二氢-2H-吡喃(61mg，0.7mmol)。反应液在室温下搅拌2小时后加入乙酸乙酯稀释，有机相用水洗涤，分离有机相并减压浓缩，残留物经Flash柱层析(乙酸乙酯/石油醚＝13/1)纯化得中间体3-9(230mg)为淡黄色固体。m/z:[M+H] +551.2。 Step 9: To the solution of intermediate 3-8 (226mg, 0.5mmol) and p-toluenesulfonic acid (9mg, 0.05mmol) in tetrahydrofuran (5mL) was added 3,4-dihydro-2H-pyran (61mg, 0.7mmol) ). The reaction solution was stirred at room temperature for 2 hours and then diluted with ethyl acetate. The organic phase was washed with water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether = 13/1) to obtain the intermediate Form 3-9 (230 mg) is a pale yellow solid. m/z: [M+H] + 551.2.
中间体4-5：2-((S)-1-丙烯酰基-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈的合成Intermediate 4-5: 2-((S)-1-acryloyl-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)furo Synthesis of [2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000079
Figure PCTCN2020118772-appb-000079
步骤1：向中间体2-3(1.1g，3.56mmol)和DIPEA(14.1g，109mmol)的1,4-二氧六环(60mL)溶液中加入(S)-2-(哌嗪-2-基)乙腈二盐酸盐(0.86g，4.43mmol)的乙腈(10mL)溶液。反应液在50℃下搅拌2小时，用水淬灭反应，水相用二氯甲烷萃取、分离有机相后减压浓缩得到中间体4-1(粗品)为黄色油状物。m/z:[M+H] +406.0。 Step 1: To a solution of Intermediate 2-3 (1.1g, 3.56mmol) and DIPEA (14.1g, 109mmol) in 1,4-dioxane (60mL) was added (S)-2-(piperazine-2 -Base) acetonitrile dihydrochloride (0.86 g, 4.43 mmol) in acetonitrile (10 mL). The reaction solution was stirred at 50° C. for 2 hours, and the reaction was quenched with water. The aqueous phase was extracted with dichloromethane, and the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 4-1 (crude) as a yellow oil. m/z: [M+H] + 406.0.
步骤2：向中间体4-1(粗品)的1,4-二氧六环(50mL)溶液中加入(Boc) 2O(3.9g，17.8mmol)。反应液室温搅拌12小时，用水淬灭反应，水相用乙酸乙酯萃取、分离有机相后减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得中间体4-2(810 mg)为黄色固体。m/z:[M+H] +506.0。 Step 2: To the 1,4-dioxane (50 mL) solution of Intermediate 4-1 (crude) was added (Boc) 2 O (3.9 g, 17.8 mmol). The reaction solution was stirred at room temperature for 12 hours, and the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and then concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the intermediate Form 4-2 (810 mg) is a yellow solid. m/z: [M+H] + 506.0.
步骤3：将中间体4-2(800mg，1.58mmol)，N-甲基-L-脯氨醇(1.63g，14.2mmol)，碳酸铯(2.32g，7.11mmol)和DIPEA(3.68g，28.5mmol)的1,4-二氧六环(15mL)混合物置于封管中，用氮气鼓泡2～3分钟，得到的混合物加热到130℃并搅拌2小时。反应液冷却至室温后用乙酸乙酯萃取、分离有机相后减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝9/1)纯化得中间体4-3(360mg)为黄色油状物。m/z:[M+H] +585.2。 Step 3: Combine Intermediate 4-2 (800mg, 1.58mmol), N-methyl-L-prolinol (1.63g, 14.2mmol), cesium carbonate (2.32g, 7.11mmol) and DIPEA (3.68g, 28.5 A mixture of 1,4-dioxane (15 mL) in mmol) was placed in a sealed tube, and nitrogen was bubbled for 2 to 3 minutes. The resulting mixture was heated to 130° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=9/1) to obtain Intermediate 4-3 (360mg) as yellow Oily substance. m/z: [M+H] + 585.2.
步骤4：将中间体4-3(110mg，0.19mmol)的二氯甲烷(5mL)和三氟乙酸(0.5mL)混合溶液在室温下搅拌3小时，然后减压浓缩得到中间体4-4(粗品)为黄色油状物。m/z:[M+H] +485.2。 Step 4: A mixed solution of Intermediate 4-3 (110 mg, 0.19 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to obtain Intermediate 4-4 ( Crude product) is yellow oil. m/z: [M+H] + 485.2.
步骤5：冰浴条件下，向中间体4-4(粗品)和DIPEA(0.5mL)的无水二氯甲烷(6mL)溶液中滴加丙烯酸酐(39mg，0.31mmol)的无水二氯甲烷(1mL)溶液。反应液在室温下搅拌6小时，用水淬灭反应，水相用乙酸乙酯萃取、分离有机相后减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝8/1)纯化得中间体4-5(70mg)为黄色油状物。m/z:[M+H] +539.2。 Step 5: Under ice bath conditions, add acrylic anhydride (39mg, 0.31mmol) in anhydrous dichloromethane to the solution of Intermediate 4-4 (crude) and DIPEA (0.5mL) in anhydrous dichloromethane (6mL) dropwise (1mL) solution. The reaction solution was stirred at room temperature for 6 hours, and the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and then concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=8/1). Intermediate 4-5 (70 mg) is a yellow oil. m/z: [M+H] + 539.2.
中间体4-7：1-((S)-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的合成Intermediate 4-7: 1-((S)-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)furo[2,3- f) Synthesis of quinazolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020118772-appb-000080
Figure PCTCN2020118772-appb-000080
步骤1：向中间体2-3(0.35g，1.06mmol)和(S)-3-甲基哌嗪-1-甲酸叔丁酯(0.32g，1.59mmol)的1,4-二氧六环(15mL)溶液中加入DIPEA(2.35g，18.2mmol)。反应液在50℃下搅拌3小时，用水淬灭反应，水相用乙酸乙酯萃取、分离有机相后减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得到中间体4-6(290mg)为黄色固体。m/z:[M+H] +481.0。 Step 1: To intermediate 2-3 (0.35g, 1.06mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.32g, 1.59mmol) in 1,4-dioxane (15 mL) DIPEA (2.35 g, 18.2 mmol) was added to the solution. The reaction solution was stirred at 50°C for 3 hours. The reaction was quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and then concentrated under reduced pressure. The residue was chromatographed with Flash column (petroleum ether/ethyl acetate=3/1) Purification gave Intermediate 4-6 (290 mg) as a yellow solid. m/z: [M+H] + 481.0.
步骤2～4：利用中间体4-5步骤3～5的合成方法，用中间体4-6反应得到4-7为黄色油状物。m/z:[M+H] +514.2。 Steps 2 to 4: Using the synthesis method of Steps 3 to 5 of Intermediate 4-5, react with Intermediate 4-6 to obtain 4-7 as a yellow oil. m/z: [M+H] + 514.2.
中间体4-8～4-15的合成Synthesis of intermediates 4-8～4-15
利用中间体4-5的合成方法，将步骤3中的N-甲基-L-脯氨醇分别替换为(R)-1-吗啉基丙-2-醇、(S)-(4,4-二氟-1-甲基吡咯烷-2-基)甲醇、((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇、(S)-(1-(2,2-二氟乙基)吡咯烷-2-基)甲醇、(S)-(1-(2-氟乙基)吡咯烷-2-基)甲醇、6-甲基吡啶-3-醇得到中间体4-8～4-13；将步骤5中的丙烯酸酐替换为甲基丙烯酸酐得到中间体4-14；将步骤1中的(S)-3-甲基哌嗪-1-甲酸叔丁酯替换为(3S,5S)-3,5-二甲基哌嗪-1-甲酸叔丁酯得到中间体4-15：Using the synthetic method of intermediate 4-5, the N-methyl-L-prolinol in step 3 was replaced with (R)-1-morpholin-2-ol, (S)-(4, 4-Difluoro-1-methylpyrrolidin-2-yl)methanol, ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol, (S)-(1-( 2,2-Difluoroethyl)pyrrolidin-2-yl)methanol, (S)-(1-(2-fluoroethyl)pyrrolidin-2-yl)methanol, 6-methylpyridin-3-ol Intermediates 4-8 to 4-13 are obtained; the acrylic anhydride in step 5 is replaced with methacrylic anhydride to obtain intermediate 4-14; the (S)-3-methylpiperazine-1-carboxylic acid in step 1 Replace tert-butyl ester with tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate to obtain intermediate 4-15:
表3table 3
Figure PCTCN2020118772-appb-000081
Figure PCTCN2020118772-appb-000081
中间体5-3：(S)-2-(1-丙烯酰基-4-(4-溴-7-(3-(二乙基氨基)氮杂环丁-1-基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈的合成Intermediate 5-3: (S)-2-(1-acryloyl-4-(4-bromo-7-(3-(diethylamino)azetidin-1-yl)furo[2, Synthesis of 3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000082
Figure PCTCN2020118772-appb-000082
步骤1：向中间体4-2(173mg，0.34mmol)的1,4-二氧六环(10mL)溶液中加入N,N-二乙基氮杂环丁-3-胺盐酸盐(137mg，0.68mmol)和DIPEA(0.2mL，1.02mmol)，反应液在120℃下微波反应1.5小时，然后将反应液冷却至室温后减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体5-1(142mg)为淡黄色固体。m/z:[M+H] +598.2。 Step 1: To a solution of Intermediate 4-2 (173mg, 0.34mmol) in 1,4-dioxane (10mL) was added N,N-diethylazetidin-3-amine hydrochloride (137mg , 0.68mmol) and DIPEA (0.2mL, 1.02mmol), the reaction solution was microwaved at 120°C for 1.5 hours, and then the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to Flash column chromatography (dichloromethane/methanol = 10/1) Intermediate 5-1 (142 mg) was purified as a pale yellow solid. m/z: [M+H] + 598.2.
步骤2&3：利用中间体4-5步骤4～5的合成方法，用中间体5-1反应得到5-3为褐色油状物。m/z:[M+H] +552.2。 Step 2&3: Using the synthesis method of Steps 4 to 5 of Intermediate 4-5, react with Intermediate 5-1 to obtain 5-3 as a brown oil. m/z: [M+H] + 552.2.
中间体6-1：2-((S)-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成Intermediate 6-1: 2-((S)-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)furo[2,3- f) Synthesis of quinazolin-9-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000083
Figure PCTCN2020118772-appb-000083
步骤1&2：同中间体4-5步骤3&4。Step 1&2: Same as Intermediate 4-5 Step 3&4.
步骤3：冰浴条件下，向中间体4-4(100mg，0.2mmol)的无水乙酸乙酯(3mL)溶液中分别加入三乙胺(0.23mL，1.6mmol)、2-氟丙烯酸(36mg，0.4mmol)和1-丙基磷酸酐(50％乙酸乙酯溶液，0.6mmol)。反应混合物在0℃下搅拌0.5小时后，加入饱和碳酸氢钠水溶液(20mL)淬灭反应，水相用二氯甲烷萃取，有机相用无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝20/1)纯化得到中间体6-1(90mg)为黄色固体。m/z:[M+H] +557.2。 Step 3: Under ice bath conditions, to a solution of Intermediate 4-4 (100mg, 0.2mmol) in anhydrous ethyl acetate (3mL) were added triethylamine (0.23mL, 1.6mmol) and 2-fluoroacrylic acid (36mg , 0.4 mmol) and 1-propyl phosphoric anhydride (50% ethyl acetate solution, 0.6 mmol). After the reaction mixture was stirred at 0°C for 0.5 hours, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, the aqueous phase was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by Flash column chromatography (dichloromethane/methanol=20/1) to obtain Intermediate 6-1 (90 mg) as a yellow solid. m/z: [M+H] + 557.2.
中间体6-2～6-16的合成Synthesis of Intermediate 6-2～6-16
利用中间体6-1的合成方法，将步骤1中的N-甲基-L-脯氨醇替换为(S)-(4,4-二氟-1-甲基吡咯烷-2-基)甲醇、(S)-(1-(2-氟乙基)吡咯烷-2-基)甲醇、((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇、((2S,4S)-4-氟-1-甲基吡咯烷-2-基)甲醇或(3R,5S)-5-(羟基甲基)-1-甲基吡咯烷-3-腈反应得到6-2、6-4、6-5、6-10或6-12；用中间体9-10为起始原料反应得到6-3；将步骤3中的2-氟丙烯酸替换为2-氯丙烯酸、2-(甲氧基甲基)丙烯酸、4-甲氧基巴豆酸或巴豆酸反应得到6-6～6-9；用中间体9-10和((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇、(R)-(4-甲基吗啉-3-基)甲醇或(4-甲基吗啉-2-基)甲醇为起始原料反应得到6-11、6-13或6-14；用中间体9-10为起始原料，将步骤3中的2-氟丙烯酸替换为4-甲氧基巴豆酸得到6-15；用中间体9-10和((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇为起始原料，将步骤3中的2-氟丙烯酸替换为4-甲氧基巴豆酸得到6-16：Using the synthesis method of Intermediate 6-1, replace N-methyl-L-prolinol in step 1 with (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl) Methanol, (S)-(1-(2-fluoroethyl)pyrrolidin-2-yl)methanol, ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol, ( (2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol or (3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidine-3-carbonitrile is reacted to obtain 6 -2, 6-4, 6-5, 6-10 or 6-12; use intermediate 9-10 as starting material to react to obtain 6-3; replace 2-fluoroacrylic acid in step 3 with 2-chloroacrylic acid , 2-(methoxymeth)acrylic acid, 4-methoxycrotonic acid or crotonic acid to obtain 6-6～6-9; using intermediate 9-10 and ((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methanol, (R)-(4-methylmorpholin-3-yl)methanol or (4-methylmorpholin-2-yl)methanol as starting materials 6-11, 6-13 or 6-14; Using intermediate 9-10 as the starting material, replace 2-fluoroacrylic acid in step 3 with 4-methoxycrotonic acid to obtain 6-15; use intermediate 9 -10 and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol as starting materials, replace the 2-fluoroacrylic acid in step 3 with 4-methoxycrotonic acid to obtain 6-16:
表4Table 4
Figure PCTCN2020118772-appb-000084
Figure PCTCN2020118772-appb-000084
Figure PCTCN2020118772-appb-000085
Figure PCTCN2020118772-appb-000085
中间体6-18：2-((S)-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)-1-((E)-4-吗啉基丁-2-烯酰基)哌嗪-2-基)乙腈的合成Intermediate 6-18: 2-((S)-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro Synthesis of furo[2,3-f]quinazolin-9-yl)-1-((E)-4-morpholinobut-2-enoyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000086
Figure PCTCN2020118772-appb-000086
步骤1：向(E)-4-溴丁-2-烯酸(170mg，1.03mmol)的二氯甲烷(5mL)溶液中加入草酰氯(1.5mL)，反应液在70℃下搅拌3小时后直接减压浓缩。残留物溶解在二氯甲烷(1mL)中，将上述溶液滴加至中间体9-12(210mg，0.43mmol)和吡啶(340mg，4.31mmol)的二氯甲烷(10mL)溶液中，得到的混合物在室温下搅拌1小时，加入冰水(20mL)淬灭反应，水相用二氯甲烷萃取，有机相用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥、过滤，滤液减压浓缩得中间体6-17(粗品)为棕色油状物。m/z:[M+H] +633.0。 Step 1: To (E)-4-bromobut-2-enoic acid (170mg, 1.03mmol) in dichloromethane (5mL) was added oxalyl chloride (1.5mL), the reaction solution was stirred at 70°C for 3 hours Concentrate directly under reduced pressure. The residue was dissolved in dichloromethane (1mL), and the above solution was added dropwise to a solution of Intermediate 9-12 (210mg, 0.43mmol) and pyridine (340mg, 4.31mmol) in dichloromethane (10mL) to obtain a mixture Stir at room temperature for 1 hour, add ice water (20 mL) to quench the reaction, extract the aqueous phase with dichloromethane, wash the organic phase with saturated brine, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Intermediate 6-17 (crude product) is a brown oil. m/z: [M+H] + 633.0.
步骤2：冰浴条件下，向中间体6-17(粗品)的二氯甲烷(10mL)溶液中加入吗啉(183mg，2.10mmol)，反应液室温搅拌0.5小时。将反应液直接减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝4/1)纯化得中间体6-18(130mg)为黄色油状物。m/z: [M+H] +640.2。 Step 2: Under ice bath conditions, morpholine (183 mg, 2.10 mmol) was added to the dichloromethane (10 mL) solution of Intermediate 6-17 (crude product), and the reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=4/1) to obtain Intermediate 6-18 (130 mg) as a yellow oil. m/z: [M+H] + 640.2.
中间体7-3：(S)-2-(4-(4-溴-7-(3-(乙基(2-氟乙基)氨基)氮杂环丁-1-基)呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成Intermediate 7-3: (S)-2-(4-(4-bromo-7-(3-(ethyl(2-fluoroethyl)amino)azetidin-1-yl)furo[2 Synthesis of ,3-f]quinazolin-9-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000087
Figure PCTCN2020118772-appb-000087
步骤1：利用中间体5-1的合成方法，用中间体4-2和N-乙基-N-(2-氟乙基)氮杂环丁-3-胺反应得到中间体7-1。m/z:[M+H] +616.2。 Step 1: Using the synthesis method of Intermediate 5-1, Intermediate 4-2 is reacted with N-ethyl-N-(2-fluoroethyl)azetidin-3-amine to obtain Intermediate 7-1. m/z: [M+H] + 616.2.
步骤2：冰浴条件下，向中间体7-1(150mg，0.24mmol)的无水1,4-二氧六环(4mL)溶液中滴加氯化氢(4M的1,4-二氧六环溶液，2mL)，加毕，将反应液在室温下搅拌2小时。反应液直接减压浓缩得中间体7-2(粗品)为淡黄色固体。m/z:[M+H] +516.2。 Step 2: Under ice bath conditions, add hydrogen chloride (4M 1,4-dioxane (4 mL) to the anhydrous 1,4-dioxane (4 mL) solution of Intermediate 7-1 (150 mg, 0.24 mmol) Solution, 2mL), after the addition, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain Intermediate 7-2 (crude product) as a pale yellow solid. m/z: [M+H] + 516.2.
步骤3：冰水浴下，向中间体7-2(粗品)和三乙胺(0.7mL，5.43mmol)的无水乙酸乙酯(10mL)溶液中加入2-氟丙烯酸(97.7mg，1.1mmol)和1-丙基磷酸酐(50％的乙酸乙酯溶液，1.63mmol)，加毕，反应体系升至室温，继续搅拌3小时。将反应液直接减压浓缩，残留物用prep-TLC(100％乙酸乙酯)纯化得到中间体7-3(80mg)为淡黄色固体。m/z:[M+H] +588.2。 Step 3: Under an ice-water bath, add 2-fluoroacrylic acid (97.7 mg, 1.1 mmol) to a solution of Intermediate 7-2 (crude) and triethylamine (0.7 mL, 5.43 mmol) in anhydrous ethyl acetate (10 mL) And 1-propyl phosphoric anhydride (50% ethyl acetate solution, 1.63 mmol), after the addition, the reaction system was raised to room temperature, and stirring was continued for 3 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by prep-TLC (100% ethyl acetate) to obtain Intermediate 7-3 (80 mg) as a pale yellow solid. m/z: [M+H] + 588.2.
中间体7-5：(S)-2-(4-(4-溴-7-(3-(二乙基氨基)氮杂环丁-1-基)呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成Intermediate 7-5: (S)-2-(4-(4-bromo-7-(3-(diethylamino)azetidin-1-yl)furo[2,3-f]quine Synthesis of oxazolin-9-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000088
Figure PCTCN2020118772-appb-000088
步骤1：冰浴条件下，向中间体4-1(397mg，0.98mmol)的无水乙酸乙酯(20mL)和三乙胺(1.35mL)混合溶液中分别加入2-氟丙烯酸(353mg，3.92mmol)和1-丙基磷酸酐(50％的乙酸乙酯溶液，6.0mmol)。反应混合物室温搅拌1.5小时，加冰水淬灭反应，水相用乙酸乙酯(30mL)萃取，分离有机相后减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝50/1)纯化得中间体7-4(332mg)为黄色固体。m/z:[M+H] +478.2。 Step 1: Under ice bath conditions, add 2-fluoroacrylic acid (353mg, 3.92) to the mixed solution of Intermediate 4-1 (397mg, 0.98mmol) in anhydrous ethyl acetate (20mL) and triethylamine (1.35mL). mmol) and 1-propyl phosphoric anhydride (50% ethyl acetate solution, 6.0 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by adding ice water. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was separated and concentrated under reduced pressure. The residue was subjected to Flash column chromatography (dichloromethane/methanol=50/1). ) Intermediate 7-4 (332mg) was purified as a yellow solid. m/z: [M+H] + 478.2.
步骤2：将中间体7-4(70mg，0.146mmol)，N,N-二乙基氨基氮杂环丁烷二盐酸盐 (59mg，0.292mmol)和DIPEA(189mg，1.46mmol)的乙腈(20mL)溶液在80℃搅拌2小时，反应液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝40/1)纯化得中间体7-5(65mg)为白色固体。m/z:[M+H] +570.2。 Step 2: Intermediate 7-4 (70mg, 0.146mmol), N,N-diethylaminoazetidine dihydrochloride (59mg, 0.292mmol) and DIPEA (189mg, 1.46mmol) in acetonitrile ( The 20mL) solution was stirred at 80°C for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=40/1) to obtain Intermediate 7-5 (65mg) as a white solid. m/z: [M+H] + 570.2.
中间体7-6的合成Synthesis of Intermediate 7-6
利用中间体7-4的合成方法，将步骤1中的N-乙基-N-(2-氟乙基)氮杂环丁-3-胺替换为N,N-二(2-氟乙基)氮杂环丁-3-胺得到中间体7-6：Using the synthesis method of Intermediate 7-4, the N-ethyl-N-(2-fluoroethyl)azetidin-3-amine in step 1 was replaced with N,N-bis(2-fluoroethyl) ) Azetidin-3-amine gives intermediate 7-6:
表5table 5
Figure PCTCN2020118772-appb-000089
Figure PCTCN2020118772-appb-000089
中间体8-5：2-((S)-1-丙烯酰基-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1H-吡唑并[3,4-f]喹唑啉-9-基)哌嗪-2-基)乙腈的合成Intermediate 8-5: 2-((S)-1-acryloyl-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H -Pyrazolo[3,4-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000090
Figure PCTCN2020118772-appb-000090
步骤1&2：将中间体3-7(350mg，1.09mmol)，DIPEA(427mg，3.3mmol)，(S)-2-(哌嗪-2-基)乙腈二盐酸盐(261mg，1.32mmol)的DMSO(15.0mL)溶液在室温下搅拌30分钟后，向上述反应液中加入(Boc) 2O(478mg，2.19mmol)，反应体系在室温下搅拌30分钟后加水(50mL)淬灭反应，水相用乙酸乙酯萃取，合并有机相并减压浓缩，残留物用Flash柱层析(乙酸乙酯/石油醚＝1/3)纯化得中间体8-2(380mg)为黄色固体。m/z:[M+H] +606.2。 Step 1&2: Intermediate 3-7 (350mg, 1.09mmol), DIPEA (427mg, 3.3mmol), (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (261mg, 1.32mmol) After the DMSO (15.0 mL) solution was stirred at room temperature for 30 minutes, (Boc) 2 O (478 mg, 2.19 mmol) was added to the above reaction solution. The reaction system was stirred at room temperature for 30 minutes and then water (50 mL) was added to quench the reaction. The phases were extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether = 1/3) to obtain Intermediate 8-2 (380 mg) as a yellow solid. m/z: [M+H] + 606.2.
步骤3：将中间体8-2(180mg，297μmol)，N-甲基-L-脯氨醇(171mg，1.48mmol)，DIPEA(192mg，1.48mmol)和碳酸铯(557mg，1.48mmol)的1,4二氧六环(5mL)混合物在封管中165℃下搅拌3小时。反应混合物过滤，滤液减压浓缩，残留物用Flash柱层析(甲醇/二氯甲烷＝1/3)纯化得中间体8-3(330mg)为淡黄色固体。m/z:[M+H] +587.2。 Step 3: Mix Intermediate 8-2 (180mg, 297μmol), N-methyl-L-prolinol (171mg, 1.48mmol), DIPEA (192mg, 1.48mmol) and cesium carbonate (557mg, 1.48mmol) in 1 The 4 dioxane (5 mL) mixture was stirred at 165°C for 3 hours in a sealed tube. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane = 1/3) to obtain Intermediate 8-3 (330 mg) as a pale yellow solid. m/z: [M+H] + 587.2.
步骤4：向中间体8-3(230mg，393μmol)的二氯甲烷(2.5mL)溶液中缓慢滴加三氟乙酸(0.5mL)。反应液室温搅拌2个小时后减压浓缩得中间体8-4(粗品)为棕色 固体。m/z:[M+H] +487.2。 Step 4: To a solution of Intermediate 8-3 (230 mg, 393 μmol) in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain Intermediate 8-4 (crude product) as a brown solid. m/z: [M+H] + 487.2.
步骤5：冰浴条件下，向中间体8-4(粗品)的二氯甲烷(10mL)溶液中分别加入DIPEA(151mg，1.17mmol)和丙烯酸酐(50mg，392μmol)。反应液室温搅拌5分钟后加入1滴氨水淬灭反应，然后直接减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝1:1)纯化得中间体8-5(200mg)为黄色固体。m/z:[M+H] +539.2。 Step 5: Under ice bath conditions, DIPEA (151 mg, 1.17 mmol) and acrylic anhydride (50 mg, 392 μmol) were added to the dichloromethane (10 mL) solution of Intermediate 8-4 (crude product). The reaction solution was stirred at room temperature for 5 minutes, and then 1 drop of ammonia was added to quench the reaction, and then it was directly concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=1:1) to obtain Intermediate 8-5 (200mg) as Yellow solid. m/z: [M+H] + 539.2.
中间体9-13：2-((S)-1-丙烯酰基-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈的合成Intermediate 9-13: 2-((S)-1-acryloyl-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2 Synthesis of ,3-Dihydrofuro[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000091
Figure PCTCN2020118772-appb-000091
步骤1：冰浴条件下，向丙烯醇(6.36mL，93mmol)的无水DMF(15mL)溶液中加入钠氢(60％，2.23g，93mmol)，反应液升至室温搅拌1.5小时。将2-氨基-4-溴-6-氟苯腈(10g，46.5mmol)的无水DMF(5mL)溶液滴加至上述反应液中，得到的混合物室温搅拌10小时，加水(500mL)淬灭反应，过滤，滤饼真空干燥得中间体9-1(11.7g)为黄色固体。m/z:[M+H] +253.0。 Step 1: Under ice bath conditions, sodium hydrogen (60%, 2.23 g, 93 mmol) was added to a solution of allyl alcohol (6.36 mL, 93 mmol) in anhydrous DMF (15 mL), and the reaction solution was raised to room temperature and stirred for 1.5 hours. A solution of 2-amino-4-bromo-6-fluorobenzonitrile (10g, 46.5mmol) in anhydrous DMF (5mL) was added dropwise to the above reaction solution, and the resulting mixture was stirred at room temperature for 10 hours, and quenched by adding water (500mL) Reaction, filtration, and vacuum drying of the filter cake gave Intermediate 9-1 (11.7 g) as a yellow solid. m/z: [M+H] + 253.0.
步骤2：将中间体9-1(11.7g，46.2mmol)加入到邻二氯苯(80mL)中，反应液在180℃下搅拌2.5小时后直接经Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化得中间体9-2(10g)为黄色固体。m/z:[M+H] +253.0； 1H NMR(400MHz,DMSO-d 6):δ6.63(s,1H),5.98-5.88(m,2H),5.20-5.14(m,2H),4.37(s,2H),3.53(d,J＝4.0Hz,2H)。 Step 2: Intermediate 9-1 (11.7g, 46.2mmol) was added to o-dichlorobenzene (80mL), the reaction solution was stirred at 180°C for 2.5 hours and then directly subjected to Flash column chromatography (petroleum ether/ethyl acetate) = 5/1) Intermediate 9-2 (10 g) was purified as a yellow solid. m/z: [M+H] + 253.0; 1 H NMR (400MHz, DMSO-d 6 ): δ6.63 (s, 1H), 5.98-5.88 (m, 2H), 5.20-5.14 (m, 2H) , 4.37 (s, 2H), 3.53 (d, J = 4.0 Hz, 2H).
步骤3：冰浴条件下，向中间体9-2(6.6g，26.1mmol)，4-二甲氨基吡啶(318mg，2.6mmol)和吡啶(20mL)的二氯甲烷(100mL)溶液中加入特戊酰氯(8.0mL，65.2mmol)，反应液缓慢升至室温并搅拌2小时。加水(100mL)淬灭反应，分离有机相后减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得中间体9-3(10g)为黄色固体。m/z:[M+H] +423.2。 Step 3: Under ice bath conditions, to intermediate 9-2 (6.6g, 26.1mmol), 4-dimethylaminopyridine (318mg, 2.6mmol) and pyridine (20mL) in dichloromethane (100mL) solution was added special Valeryl chloride (8.0 mL, 65.2 mmol), the reaction solution was slowly raised to room temperature and stirred for 2 hours. The reaction was quenched by adding water (100 mL), the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain Intermediate 9-3 (10 g) as a yellow solid. m/z: [M+H] + 423.2.
步骤4：-78℃下，向中间体9-3(10g，23.7mmol)的二氯甲烷(50mL)与甲醇(50mL)混合溶液中通15分钟的臭氧，然后将反应液内残留的臭氧排出后加入硼氢化钠(13.5g，356mmol)，反应液升至室温并搅拌30分钟。加水(100mL)淬灭反应，分离有机相后用稀盐酸(1M，20mL)洗涤后减压浓缩得中间体9-4(8.0g)为黄色固体。m/z:[M+H] +343.0。 Step 4: At -78°C, pass ozone in the mixed solution of intermediate 9-3 (10g, 23.7mmol) in dichloromethane (50mL) and methanol (50mL) for 15 minutes, and then discharge the remaining ozone in the reaction solution Then sodium borohydride (13.5 g, 356 mmol) was added, and the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding water (100 mL), the organic phase was separated, washed with dilute hydrochloric acid (1M, 20 mL), and concentrated under reduced pressure to obtain Intermediate 9-4 (8.0 g) as a yellow solid. m/z: [M+H] + 343.0.
步骤5：冰浴条件下，向中间体9-4(8.0g，23.4mmol)，三苯基膦(7.4g，28.1mmol)的四氢呋喃(150mL)溶液中缓慢加入DIAD(5.54mL，28.1mmol)。反应液在0℃搅拌15分钟。然后直接减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得中间体9-5(5g)为黄色固体。m/z:[M+H] +323.0。 Step 5: Under ice bath conditions, slowly add DIAD (5.54 mL, 28.1 mmol) to a solution of Intermediate 9-4 (8.0 g, 23.4 mmol), triphenylphosphine (7.4 g, 28.1 mmol) in tetrahydrofuran (150 mL) . The reaction solution was stirred at 0°C for 15 minutes. Then it was directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain Intermediate 9-5 (5g) as a yellow solid. m/z: [M+H] + 323.0.
步骤6：将中间体9-5(4.5g，13.9mmol)加入到浓硫酸(50mL)中，反应体系在50℃下搅拌24小时。冰浴条件下，反应液缓慢倾倒入冰水中，析出大量固体，固体过滤后分散在乙酸乙酯中(100mL)，加入氢氧化钠水溶液(10M，10mL)继续搅拌10分钟，固体过滤后经Flash柱层析(乙酸乙酯/石油醚/二氯甲烷/＝3/1/1)纯化得中间体9-6(2.1g)为淡黄色固体。m/z:[M+H] +257.0。 Step 6: Intermediate 9-5 (4.5 g, 13.9 mmol) was added to concentrated sulfuric acid (50 mL), and the reaction system was stirred at 50° C. for 24 hours. Under ice bath conditions, the reaction solution was slowly poured into ice water, and a large amount of solids precipitated. The solids were filtered and dispersed in ethyl acetate (100mL). Sodium hydroxide aqueous solution (10M, 10mL) was added and the mixture was stirred for 10 minutes. The solids were filtered and passed to Flash Purification by column chromatography (ethyl acetate/petroleum ether/dichloromethane/=3/1/1) gave Intermediate 9-6 (2.1g) as a pale yellow solid. m/z: [M+H] + 257.0.
步骤7：将中间体9-6(300mg，1.17mmol)和尿素(3.5g，58.5mmol)加热到180℃，熔融状态下搅拌2小时后降温至100℃，加入水(15mL)搅拌1小时，降温至0℃过滤，滤饼用水洗涤后真空干燥得中间体9-7(330mg)为淡黄色固体。m/z:[M+H] +283.0。 Step 7: Heat Intermediate 9-6 (300mg, 1.17mmol) and urea (3.5g, 58.5mmol) to 180°C, stir for 2 hours in a molten state, then cool to 100°C, add water (15mL) and stir for 1 hour. The temperature was lowered to 0°C and filtered. The filter cake was washed with water and dried in vacuo to obtain Intermediate 9-7 (330 mg) as a pale yellow solid. m/z: [M+H] + 283.0.
步骤8：将中间体9-7(330mg，1.17mmol)和N,N二甲基苯胺(0.5mL)加入到三氯氧磷(10mL)中，反应体系在110℃下搅拌2小时。然后直接减压浓缩，残留物用乙酸乙酯稀释后用冰水洗涤，分离有机相后并减压浓缩得到中间体9-8(粗品)为黄色固体。m/z:[M+H] +319.0。 Step 8: Intermediate 9-7 (330 mg, 1.17 mmol) and N,N dimethylaniline (0.5 mL) were added to phosphorus oxychloride (10 mL), and the reaction system was stirred at 110° C. for 2 hours. Then it was directly concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with ice water, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 9-8 (crude) as a yellow solid. m/z: [M+H] + 319.0.
步骤9～13：利用中间体4-5的合成方法，用中间体9-8反应得到中间体9-13为黄色固体。m/z:[M+H] +541.0。 Steps 9-13: Using the synthesis method of Intermediate 4-5, react with Intermediate 9-8 to obtain Intermediate 9-13 as a yellow solid. m/z: [M+H] + 541.0.
中间体9-14的合成Synthesis of Intermediate 9-14
利用中间体9-11的合成方法，将步骤9中的(S)-2-(哌嗪-2-基)乙腈替换为(S)-2-甲基哌嗪，步骤11中的N-甲基-L-脯氨醇替换为((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇得到中间体9-14：Using the synthesis method of Intermediate 9-11, (S)-2-(piperazin-2-yl)acetonitrile in step 9 was replaced with (S)-2-methylpiperazine, and N-methyl in step 11 Substitution of yl-L-prolinol with ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol gives intermediate 9-14:
表6Table 6
Figure PCTCN2020118772-appb-000092
Figure PCTCN2020118772-appb-000092
Figure PCTCN2020118772-appb-000093
Figure PCTCN2020118772-appb-000093
中间体10-13：(9-(4-丙烯酰基哌嗪-1-基)-4-溴-7-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-2-甲基)乙酸甲酯Intermediate 10-13: (9-(4-acryloylpiperazin-1-yl)-4-bromo-7-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl )Methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-2-methyl)acetate methyl
Figure PCTCN2020118772-appb-000094
Figure PCTCN2020118772-appb-000094
步骤1：冰浴条件下，向中间体9-3(9.2g，21.8mmol)的二氯甲烷(160mL)中分批加入间氯过氧苯甲酸(13.4g，65.5mmol)，反应体系缓慢升温至25℃并搅拌24小时。用二氯甲烷稀释反应液，有机相用饱和碳酸钠水溶液和水洗，分离有机相并浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝20/1)纯化得中间体10-1(8.1g)为淡黄色固体。m/z:[M+H] +437.2。 Step 1: Under ice bath conditions, m-chloroperoxybenzoic acid (13.4g, 65.5mmol) was added to the dichloromethane (160mL) of Intermediate 9-3 (9.2g, 21.8mmol) in batches, and the reaction system slowly heated up Bring to 25°C and stir for 24 hours. The reaction solution was diluted with dichloromethane, the organic phase was washed with saturated sodium carbonate aqueous solution and water, the organic phase was separated and concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=20/1) to obtain Intermediate 10-1 (8.1g) is a pale yellow solid. m/z: [M+H] + 437.2.
步骤2：向中间体10-1(8.1g，18.5mmol)的甲醇(150mL)溶液中加入碳酸钾固体(51.2g，370mmol)，反应体系在70℃下搅拌20小时。反应液冷却至室温后用二氯甲烷稀释，过滤，滤液浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得中间体10-2(4g)为白色固体。m/z:[M+H] +269.0； 1H NMR(400MHz,DMSO-d 6):δ6.41(s,1H),6.12(br.s,2H),5.09(br.s,1H),5.01-4.95(m,1H),3.66(dd,J＝3.6,12.0Hz,1H),3.54(dd,J＝3.6,12.0Hz,1H),3.05(dd,J＝7.2,15.2Hz,1H),2.87(dd,J＝7.2,15.2Hz,1H)。 Step 2: To the methanol (150 mL) solution of Intermediate 10-1 (8.1 g, 18.5 mmol) was added potassium carbonate solid (51.2 g, 370 mmol), and the reaction system was stirred at 70° C. for 20 hours. The reaction solution was cooled to room temperature and diluted with dichloromethane, filtered, and the filtrate was concentrated. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain Intermediate 10-2 (4g) as a white solid. m/z: [M+H] + 269.0; 1 H NMR (400MHz, DMSO-d 6 ): δ6.41(s,1H), 6.12(br.s,2H),5.09(br.s,1H) ,5.01-4.95(m,1H),3.66(dd,J=3.6,12.0Hz,1H),3.54(dd,J=3.6,12.0Hz,1H),3.05(dd,J=7.2,15.2Hz,1H ), 2.87 (dd, J=7.2, 15.2 Hz, 1H).
步骤3：将中间体10-2(1.2g，4.5mmol)和氢氧化钾水溶液(2M，22mL)加入到乙醇(30mL)中，反应液在90℃回流搅拌12小时。反应液冷却至0℃，用1M的盐酸调pH至5～6，水相用二氯甲烷萃取，分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体10-3(1.1g)为白色固体。m/z:[M+H] +287.0。 Step 3: Intermediate 10-2 (1.2 g, 4.5 mmol) and potassium hydroxide aqueous solution (2M, 22 mL) were added to ethanol (30 mL), and the reaction solution was refluxed and stirred at 90° C. for 12 hours. The reaction solution was cooled to 0°C, adjusted to pH 5-6 with 1M hydrochloric acid, the aqueous phase was extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure, and the residue was subjected to Flash column chromatography (dichloromethane/methanol=10/ 1) Intermediate 10-3 (1.1 g) was purified as a white solid. m/z: [M+H] + 287.0.
步骤4：将中间体10-3(800mg，2.8mmol)和尿素(8.4g，140mmol)混合均匀后加热至180℃搅拌1.5小时。反应液冷却至室温，加入水(15mL)，然后在100℃下 搅拌1小时，减压抽滤，滤液用乙酸乙酯/四氢呋喃混合溶剂(10/1)萃取，分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝5/1)纯化得中间体10-4(350mg)为白色固体。m/z:[M+H] +313.0。 Step 4: Intermediate 10-3 (800mg, 2.8mmol) and urea (8.4g, 140mmol) were mixed uniformly and heated to 180°C and stirred for 1.5 hours. The reaction solution was cooled to room temperature, water (15mL) was added, then stirred at 100°C for 1 hour, filtered under reduced pressure, the filtrate was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=5/1) to obtain Intermediate 10-4 (350 mg) as a white solid. m/z: [M+H] + 313.0.
步骤5：向中间体10-4(300mg，0.96mmol)的无水吡啶(5mL)溶液中加入醋酸酐(0.3mL，2.88mmol)，反应液在室温下搅拌5小时后直接减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝20/1)纯化后得中间体10-5(310mg)为白色固体。m/z:[M+H] +355.0。 Step 5: Add acetic anhydride (0.3mL, 2.88mmol) to the dry pyridine (5mL) solution of Intermediate 10-4 (300mg, 0.96mmol). The reaction solution was stirred at room temperature for 5 hours and then directly concentrated under reduced pressure. After purification by Flash column chromatography (dichloromethane/methanol=20/1), intermediate 10-5 (310 mg) was obtained as a white solid. m/z: [M+H] + 355.0.
步骤6&7：中间体10-5(310mg，0.87mmol)和三氯氧磷(10mL)的N,N-二甲苯胺(0.5mL)溶液中在110℃下搅拌2小时。减压浓缩。冰浴条件下，向残留物中加入乙酸乙酯(50mL)，然后用冰水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩得到的中间体10-6。冰浴条件下，向中间体10-6和1-叔丁氧羰基哌嗪(810mg，4.35mmol)的无水四氢呋喃(10mL)溶液中加入DIPEA(2mL)，反应液在此温度下搅拌10分钟。用冰水淬灭反应，水相用乙酸乙酯萃取，分离有机相并减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得中间体10-7(430mg)为黄色固体。m/z:[M+H] +541.0。 Step 6&7: Intermediate 10-5 (310 mg, 0.87 mmol) and phosphorus oxychloride (10 mL) in N,N-xylidine (0.5 mL) were stirred at 110°C for 2 hours. Concentrate under reduced pressure. Under ice bath conditions, ethyl acetate (50 mL) was added to the residue, then washed with ice water, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 10-6. Under ice bath conditions, DIPEA (2 mL) was added to the solution of Intermediate 10-6 and 1-tert-butoxycarbonylpiperazine (810 mg, 4.35 mmol) in anhydrous tetrahydrofuran (10 mL), and the reaction solution was stirred at this temperature for 10 minutes . The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain Intermediate 10-7 ( 430mg) is a yellow solid. m/z: [M+H] + 541.0.
步骤8：冰浴条件下，向中间体10-7(420mg，0.78mmol)的乙腈(10mL)溶液中加入氢氧化锂水溶液(1M，7.8mL)，反应液在此温度下搅拌2小时。水相用乙酸乙酯萃取，分离有机相并减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得中间体10-8(330mg)为黄色固体。m/z:[M+H] +499.0。 Step 8: Under ice bath conditions, lithium hydroxide aqueous solution (1M, 7.8 mL) was added to the acetonitrile (10 mL) solution of Intermediate 10-7 (420 mg, 0.78 mmol), and the reaction solution was stirred at this temperature for 2 hours. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain Intermediate 10-8 (330 mg) as a yellow solid. m/z: [M+H] + 499.0.
步骤9：将中间体10-8(330mg，0.66mmol)和咪唑(449mg，6.60mmol)溶解在无水吡啶中(10mL)，减压浓缩，重复两次。冰浴条件下，再次溶解在无水吡啶(10mL)中，然后滴加TBSCl的无水吡啶溶液(298mg，2mmol，2mL)，加毕，反应体系缓慢升至室温并搅拌过夜。反应液减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化得中间体10-9(380mg)为黄色固体。m/z:[M+H] +613.2。 Step 9: Intermediate 10-8 (330 mg, 0.66 mmol) and imidazole (449 mg, 6.60 mmol) were dissolved in anhydrous pyridine (10 mL), concentrated under reduced pressure, and repeated twice. Under ice bath conditions, it was dissolved in anhydrous pyridine (10 mL) again, and then an anhydrous pyridine solution of TBSCl (298 mg, 2 mmol, 2 mL) was added dropwise. After the addition, the reaction system was slowly raised to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain Intermediate 10-9 (380 mg) as a yellow solid. m/z: [M+H] + 613.2.
步骤10&11：冰浴条件下，将钠氢(26mg，0.65mmol)分散在无水DMF(5mL)溶液中，氮气保护下滴加((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇的DMF溶液(87mg，0.65mmol，0.5mL)，反应液在此温度下搅拌0.5小时，然后将中间体10-9的DMF溶液(80mg，0.13mmol，0.5mL)滴加到上述反应液中，加毕，冰浴下继续搅拌0.5小时得到包含中间体10-10的反应液。然后将反应液用乙酸乙酯稀释，用水淬灭反应，水相用乙酸乙酯萃取，分离有机相并减压浓缩，残留物经Flash柱层析(二氯甲烷/甲醇＝20/1)纯化得中间体10-11(83mg)为黄色固体。m/z:[M+H] +638.2。 Steps 10&11: Under ice bath conditions, disperse sodium hydrogen (26mg, 0.65mmol) in anhydrous DMF (5mL) solution, and add ((2S,4R)-4-fluoro-1-methylpyrrolidine dropwise under the protection of nitrogen -2-yl) methanol in DMF solution (87 mg, 0.65 mmol, 0.5 mL), the reaction solution was stirred at this temperature for 0.5 hours, and then the DMF solution of intermediate 10-9 (80 mg, 0.13 mmol, 0.5 mL) was added dropwise To the above reaction solution, after the addition, continue to stir for 0.5 hours in an ice bath to obtain a reaction solution containing intermediate 10-10. Then the reaction solution was diluted with ethyl acetate, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=20/1) The intermediate 10-11 (83 mg) was obtained as a yellow solid. m/z: [M+H] + 638.2.
步骤12&13：向中间体10-11(83mg，0.13mmol)的二氯甲烷(5mL)中滴加三氟乙酸(2mL)。反应液搅拌2个小时后减压浓缩得到中间体10-12。冰浴条件下，向中间体10-12和DIPEA(0.2mL)的无水二氯甲烷(2mL)溶液中缓慢加入丙烯酸酐的二 氯甲烷溶液(0.5M，0.3mL)。反应液在此温度下继续搅拌10分钟。加入1滴氨水淬灭反应，混合物直接减压浓缩，残留物经Flash柱层析(二氯甲烷/甲醇＝30/1)纯化得中间体10-13(50mg)为黄色固体。m/z:[M+H] +592.0。 Steps 12 & 13: To intermediate 10-11 (83 mg, 0.13 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction solution was stirred for 2 hours and then concentrated under reduced pressure to obtain Intermediate 10-12. Under ice bath conditions, to a solution of Intermediate 10-12 and DIPEA (0.2 mL) in anhydrous dichloromethane (2 mL) was slowly added a dichloromethane solution (0.5 M, 0.3 mL) of acrylic anhydride. The reaction solution was continuously stirred at this temperature for 10 minutes. The reaction was quenched by adding 1 drop of ammonia water, the mixture was directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=30/1) to obtain Intermediate 10-13 (50 mg) as a yellow solid. m/z: [M+H] + 592.0.
中间体11-1：2-((S)-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)-1-((E)-4-(二甲氨基)丁-2-烯酰基)哌嗪-2-基)乙腈Intermediate 11-1: 2-((S)-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)furo[2,3- f) Quinazolin-9-yl)-1-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000095
Figure PCTCN2020118772-appb-000095
步骤1&2：同中间体4-7步骤3&4。Step 1&2: Same as Step 3&4 of Intermediate 4-7.
步骤3：向中间体4-4(50mg，0.1mmol)的无水二氯甲烷(5mL)溶液中分别加入DIPEA(90μL，0.5mmol)、反式-4-二甲基胺基巴豆酸盐酸盐(33mg，0.2mmol)和HATU(57mg，0.15mmol)。反应混合物在室温下搅拌过夜，加入饱和碳酸氢钠水溶液(20mL)淬灭反应，水相用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝20/1)纯化得到中间体11-1(40mg)为黄色油状物。m/z:[M+H] +596.2。 Step 3: Add DIPEA (90μL, 0.5mmol) and trans-4-dimethylaminocrotonic acid to the solution of Intermediate 4-4 (50mg, 0.1mmol) in anhydrous dichloromethane (5mL). Salt (33 mg, 0.2 mmol) and HATU (57 mg, 0.15 mmol). The reaction mixture was stirred overnight at room temperature, and saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by chromatography (dichloromethane/methanol=20/1) gave Intermediate 11-1 (40mg) as a yellow oil. m/z: [M+H] + 596.2.
中间体11-2～11-3的合成Synthesis of intermediates 11-2～11-3
利用中间体11-1的合成方法，将步骤1中的N-甲基-L-脯氨醇替换为(S)-(4,4-二氟-1-甲基吡咯烷-2-基)甲醇或((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇得中间体11-2～11-3；Using the synthetic method of intermediate 11-1, replace N-methyl-L-prolinol in step 1 with (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl) Methanol or ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol gives intermediates 11-2～11-3;
表7Table 7
Figure PCTCN2020118772-appb-000096
Figure PCTCN2020118772-appb-000096
中间体12-1：2-((S)-4-(7-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成Intermediate 12-1: 2-((S)-4-(7-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl )-1-(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000097
Figure PCTCN2020118772-appb-000097
氮气保护下，将中间体6-11(100mg，0.17mmol)，联硼酸频那醇酯(86mg，0.34mmol)，醋酸钾(50mg，0.51mmol)和PdCl 2dppf .CH 2Cl 2(14mg，0.017mmol)的1,4-二氧六环(10mL)混合物在90℃下搅拌15小时。反应体系用乙酸乙酯稀释后，用水洗涤，分离有机相减压浓缩得到的中间体12-1(106mg)为黄色固体。m/z:[M+H] +625.4。 Under nitrogen protection, Intermediate 6-11 (100mg, 0.17mmol), pinacol diborate (86mg, 0.34mmol), potassium acetate (50mg, 0.51mmol) and PdCl 2 dppf . CH 2 Cl 2 (14mg, A mixture of 0.017 mmol) of 1,4-dioxane (10 mL) was stirred at 90°C for 15 hours. After the reaction system was diluted with ethyl acetate, it was washed with water, and the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 12-1 (106 mg) as a yellow solid. m/z: [M+H] + 625.4.
中间体12-2～12-3的合成Synthesis of intermediates 12-2～12-3
利用中间体12-1的合成方法，用中间体9-11或9-14反应得到12-2～12-3：Using the synthetic method of intermediate 12-1, react with intermediate 9-11 or 9-14 to obtain 12-2～12-3:
表8Table 8
Figure PCTCN2020118772-appb-000098
Figure PCTCN2020118772-appb-000098
中间体13-13：2-((S)-4-(4-溴-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)异噁唑并[5,4-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成Intermediate 13-13: 2-((S)-4-(4-bromo-7-(((S)-1-methylpyrrolidin-2-yl)methoxy)isoxazolo[5, Synthesis of 4-f]quinazolin-9-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
Figure PCTCN2020118772-appb-000099
Figure PCTCN2020118772-appb-000099
Figure PCTCN2020118772-appb-000100
Figure PCTCN2020118772-appb-000100
步骤1：向2-氨基-4-溴-6-氟苯腈(23.6g，110mmol)的无水乙腈(370mL)溶液中依次加入N-碘代丁二酰亚胺(27.2g，121mmol)和三氟乙酸(25g，220mmol)，反应体系在室温下避光搅拌1.5小时后减压浓缩。残留物溶解在乙酸乙酯中，依次用饱和亚硫酸氢钠水溶液、饱和碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物在0℃下用二氯甲烷打浆、过滤，滤饼真空干燥得中间体13-1(22.3g)为类白色固体。m/z:[M+H] +340.8。 Step 1: To a solution of 2-amino-4-bromo-6-fluorobenzonitrile (23.6g, 110mmol) in anhydrous acetonitrile (370mL) was added N-iodosuccinimide (27.2g, 121mmol) and Trifluoroacetic acid (25g, 220mmol), the reaction system was stirred at room temperature for 1.5 hours in the dark and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated sodium bisulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was slurried with dichloromethane at °C, filtered, and the filter cake was vacuum dried to obtain Intermediate 13-1 (22.3g) as an off-white solid. m/z: [M+H] + 340.8.
步骤2：将双三苯基磷二氯化钯(4.59g，6.54mmol)加入到中间体13-1(22.3g，65.4mmol)、(E)-苯乙烯基硼酸(14.5g，98.1mmol)和碳酸钾(18.1g，131mmol)的甲苯(200mL)和乙醇(50mL)混合溶液中，反应体系用氮气置换3次后在80℃下搅拌过夜，冷却后减压浓缩。残留物溶解在乙酸乙酯中，接着用水、饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物在冰浴条件下用二氯甲烷打浆、过滤，滤饼真空干燥得中间体13-2(6.92g)为黄色固体。m/z:[M+H] +317.0。 Step 2: Add bistriphenylphosphorus palladium dichloride (4.59g, 6.54mmol) to Intermediate 13-1 (22.3g, 65.4mmol), (E)-styrylboronic acid (14.5g, 98.1mmol) In a mixed solution of potassium carbonate (18.1 g, 131 mmol) in toluene (200 mL) and ethanol (50 mL), the reaction system was replaced with nitrogen three times and stirred overnight at 80° C., cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with water and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with dichloromethane under ice bath conditions, filtered, and filtered. The cake was dried under vacuum to obtain Intermediate 13-2 (6.92 g) as a yellow solid. m/z: [M+H] + 317.0.
步骤3：将双氧水(30％，9mL)滴加到中间体13-2(6.92g，21.8mmol)和碳酸钾(6.03g，43.6mmol)的DMSO(90mL)溶液中，反应体系室温搅拌1.5小时。然后将把反应液倒入冰水中，有大量固体析出，抽滤，滤饼真空干燥得中间体13-3(7.03g)为黄色固体。m/z:[M+H] +335.0。 Step 3: Add hydrogen peroxide (30%, 9mL) dropwise to intermediate 13-2 (6.92g, 21.8mmol) and potassium carbonate (6.03g, 43.6mmol) in DMSO (90mL) solution, and the reaction system is stirred at room temperature for 1.5 hours . Then the reaction solution was poured into ice water, a large amount of solids precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 13-3 (7.03 g) as a yellow solid. m/z: [M+H] + 335.0.
步骤4：向中间体13-3(7.03g，21mmol)的四氢呋喃(212mL)溶液中加入三光气(6.22g，21mmol)，反应体系室温搅拌过夜。减压浓缩后倒入冰水中，用饱和碳酸氢钠水溶液调pH至8，抽滤，滤饼用石油醚洗涤后真空干燥得中间体13-4(7.1g)为黄色固体。m/z:[M+H] +361.0。 Step 4: To a solution of Intermediate 13-3 (7.03 g, 21 mmol) in tetrahydrofuran (212 mL) was added triphosgene (6.22 g, 21 mmol), and the reaction system was stirred at room temperature overnight. After concentration under reduced pressure, it was poured into ice water, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, filtered with suction, the filter cake was washed with petroleum ether and dried in vacuo to obtain Intermediate 13-4 (7.1 g) as a yellow solid. m/z: [M+H] + 361.0.
步骤5：将中间体13-4(10.7g，29.5mmol)加入到三氯氧磷(106mL)中，然后加入N,N-二甲基苯胺(10.6mL)，反应体系在110℃搅拌2小时。减压浓缩除掉三氯氧磷，残留物倒入冰水中，用饱和碳酸氢钠水溶液调pH至8。水相用乙酸乙酯/四氢呋喃萃取，合并有机相用水、饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩得中间体13-5(11.7g)为黄色固体。m/z:[M+H] +397.0。 Step 5: Intermediate 13-4 (10.7g, 29.5mmol) was added to phosphorus oxychloride (106mL), and then N,N-dimethylaniline (10.6mL) was added, and the reaction system was stirred at 110°C for 2 hours . Phosphorus oxychloride was removed by concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate/tetrahydrofuran, the combined organic phases were washed with water and saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-5 (11.7g) as a yellow solid. m/z: [M+H] + 397.0.
步骤6：冰浴条件下，将(S)-2-(哌嗪-2-基)乙腈二盐酸盐(5.88g，29.7mmol)和DIPEA(10.5g，80.9mmol)的DMF(60mL)溶液用氮气置换，将中间体13-5(10.7g，27.0mmol)的DMF(100mL)溶液滴加到上述反应液中，接着加入(Boc) 2O(29.4g，135mmol)和DIPEA(25.6g，198mmol)，反应体系室温下搅拌过夜。加水淬灭反应，水相用乙酸乙 酯萃取，分离有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得中间体13-6(15.4g)为黄色固体。m/z:[M+H] +586.0。 Step 6: Under ice bath conditions, mix (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (5.88g, 29.7mmol) and DIPEA (10.5g, 80.9mmol) in DMF (60mL) Replace with nitrogen, add a solution of intermediate 13-5 (10.7g, 27.0mmol) in DMF (100mL) dropwise to the above reaction solution, and then add (Boc) 2 O (29.4g, 135mmol) and DIPEA (25.6g, 198mmol), and the reaction system was stirred overnight at room temperature. The reaction was quenched by adding water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain Intermediate 13-6 (15.4g) ) Is a yellow solid. m/z: [M+H] + 586.0.
步骤7：将中间体13-6(4.72g，8.04mmol)，N-甲基-L-脯氨醇(2.78g，24.1mmol)，碳酸铯(7.86g，24.1mmol)，DIPEA(5.2g，40.2mmol)和1,4-二氧六环(60mL)加入封管中，用氮气鼓泡2～3分钟，得到的混合物在150℃下搅拌3小时。反应液冷却至室温后过滤，滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体13-7(3.23g)为黄色固体。m/z:[M+H] +665.2。 Step 7: Intermediate 13-6 (4.72g, 8.04mmol), N-methyl-L-prolinol (2.78g, 24.1mmol), cesium carbonate (7.86g, 24.1mmol), DIPEA (5.2g, 40.2 mmol) and 1,4-dioxane (60 mL) were added to the sealed tube, and nitrogen gas was bubbled for 2 to 3 minutes, and the resulting mixture was stirred at 150°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=10/1) to obtain Intermediate 13-7 (3.23 g) as a yellow solid. m/z: [M+H] + 665.2.
步骤8：向中间体13-7(2.63g，3.95mmol)的二氯甲烷(36mL)和水(6mL)混合溶液中加入N-甲基-N-氧化吗啉(0.93g，7.9mmol)和二水合锇酸钾(0.15g，0.4mmol)，反应体系室温搅拌过夜。用10％硫代硫酸钠水溶液(6mL)淬灭反应，搅拌0.5小时，水相用二氯甲烷萃取，合并有机相后用饱和食盐水洗涤、无水硫酸钠干燥，过滤、滤液减压浓缩得中间体13-8(2.76g)为黄色固体。m/z:[M+H] +699.2。 Step 8: To the mixed solution of Intermediate 13-7 (2.63g, 3.95mmol) in dichloromethane (36mL) and water (6mL) was added N-methyl-N-morpholine oxide (0.93g, 7.9mmol) and Potassium osmate dihydrate (0.15 g, 0.4 mmol), and the reaction system was stirred at room temperature overnight. The reaction was quenched with 10% sodium thiosulfate aqueous solution (6 mL), stirred for 0.5 hours, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-8 (2.76 g) is a yellow solid. m/z: [M+H] + 699.2.
步骤9：向中间体13-8(2.76g，3.95mmol)的四氢呋喃(28mL)和水(21mL)混合溶液中加入高碘酸钠(2.03g，9.47mmol)。反应体系室温搅拌1小时。加水(14mL)淬灭反应，水相用二氯甲烷萃取，合并有机相后用饱和食盐水洗涤、无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体13-9(2.07g)为黄色固体。m/z:[M+H] +591.0。 Step 9: Add sodium periodate (2.03 g, 9.47 mmol) to a mixed solution of Intermediate 13-8 (2.76 g, 3.95 mmol) in tetrahydrofuran (28 mL) and water (21 mL). The reaction system was stirred at room temperature for 1 hour. The reaction was quenched by adding water (14 mL), the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (dichloromethane /Methanol=10/1) The intermediate 13-9 (2.07g) was purified as a yellow solid. m/z: [M+H] + 591.0.
步骤10：冰浴条件下，向中间体13-9(2.07g，3.5mmol)和盐酸羟胺(0.49g，7.0mmol)的乙醇(20mL)和水(10mL)混合溶液中滴加碳酸钠(0.37g，3.5mmol)的水溶液(10mL)，反应体系室温搅拌过夜。减压浓缩除去乙醇，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤、无水硫酸钠干燥，过滤、滤液减压浓缩得中间体13-10(2.02g)为黄色固体。m/z:[M+H] +606.2。 Step 10: Under ice bath conditions, add sodium carbonate (0.37 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol) in ethanol (20 mL) and water (10 mL) to a mixed solution of intermediate 13-9 (2.07 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol). g, 3.5 mmol) in water (10 mL), and the reaction system was stirred overnight at room temperature. The ethanol was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-10 (2.02g) as a yellow solid. m/z: [M+H] + 606.2.
步骤11：冰浴条件下，向中间体13-10(2.02g，3.3mmol)的四氢呋喃(100mL)溶液中加入叔丁醇钾(0.56g，5.0mmol)，反应体系在0℃下搅拌15分钟，接着升至室温搅拌1.5小时。加冰水淬灭反应，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤、无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体13-11(0.95g)为黄色固体。m/z:[M+H] +586.2； 1H NMR(400MHz,DMSO-d 6):δ6.25(s,1H),5.75(s,1H),4.63-4.35(m,4H),4.20-4.09(m,1H),3.92-3.65(m,4H),3.11-3.05(m,2H),2.88(s,3H),2.86-2.81(m,2H),2.24-2.14(m,1H),2.06-1.76(m,4H),1.43(s,9H)。 Step 11: Under ice bath conditions, add potassium tert-butoxide (0.56g, 5.0mmol) to a solution of Intermediate 13-10 (2.02g, 3.3mmol) in tetrahydrofuran (100mL), and stir the reaction system at 0°C for 15 minutes Then, it was raised to room temperature and stirred for 1.5 hours. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to Flash column chromatography (dichloromethane/methanol =10/1) Intermediate 13-11 (0.95g) was purified as a yellow solid. m/z: [M+H] + 586.2; 1 H NMR (400MHz, DMSO-d 6 ): δ6.25 (s, 1H), 5.75 (s, 1H), 4.63-4.35 (m, 4H), 4.20 -4.09(m,1H),3.92-3.65(m,4H),3.11-3.05(m,2H),2.88(s,3H),2.86-2.81(m,2H),2.24-2.14(m,1H) , 2.06-1.76 (m, 4H), 1.43 (s, 9H).
步骤12：冰浴条件下，向中间体13-11(170mg，290μmol)的二氯甲烷(5mL)溶液中滴加氯化氢的1,4-二氧六环溶液(4M，2.5mL)，反应体系在0℃下搅拌1小时。加冰水淬灭反应，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤、无水硫酸钠干燥，过滤、滤液减压浓缩得中间体13-12(200mg)为类白色固体。m/z:[M+H] +486.2。 Step 12: Under ice bath conditions, add 1,4-dioxane solution (4M, 2.5 mL) of hydrogen chloride dropwise to the solution of Intermediate 13-11 (170 mg, 290 μmol) in dichloromethane (5 mL), and the reaction system Stir at 0°C for 1 hour. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-12 (200 mg) as an off-white solid. m/z: [M+H] + 486.2.
步骤13：向中间体13-12(200mg，粗品)的无水DMF(5mL)溶液中分别加入DIPEA(0.5mL)、2-氟丙烯酸(99mg，0.6mmol)和HATU(171mg，0.45mmol)。反应混合物在室温下搅拌过夜，加入饱和碳酸氢钠水溶液淬灭反应，水相用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得中间体13-13(120mg)为黄色固体。m/z:[M+H] +558.0。 Step 13: DIPEA (0.5 mL), 2-fluoroacrylic acid (99 mg, 0.6 mmol) and HATU (171 mg, 0.45 mmol) were added to the solution of Intermediate 13-12 (200 mg, crude product) in anhydrous DMF (5 mL), respectively. The reaction mixture was stirred overnight at room temperature, and saturated aqueous sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed with Flash column ( Dichloromethane/methanol=10/1) was purified to obtain Intermediate 13-13 (120mg) as a yellow solid. m/z: [M+H] + 558.0.
中间体15-7：(S)-4-(4-溴-6-(2-异丙基苯基)-7-氧代-6,7-二氢呋喃并[2,3-f]喹唑啉-9-基)-3-甲基哌嗪-1-甲酸叔丁酯的合成Intermediate 15-7: (S)-4-(4-bromo-6-(2-isopropylphenyl)-7-oxo-6,7-dihydrofuro[2,3-f]quine Synthesis of tert-butyl oxazolin-9-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020118772-appb-000101
Figure PCTCN2020118772-appb-000101
步骤1：冰浴条件下，向2,2-乙氧基乙醇(2.8g，0.021mmol)的无水四氢呋喃(50mL)溶液中分批加入钠氢(60％，0.88g，0.022mol)，反应混合物在10℃下搅拌1小时。然后将4-溴-2,6-二氟苯甲酸甲酯(5g，0.02mol)的四氢呋喃溶液(10mL)缓慢滴加到上述反应混合物中。反应体系室温下搅拌2小时后，用冰水(20mL)淬灭反应，水相用乙酸乙酯萃取，分离有机相并用饱和食盐水洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝20/1)纯化得中间体15-1(4.1g)为无色油状物。m/z:[M+Na] +387.0。 Step 1: Under ice bath conditions, add sodium hydrogen (60%, 0.88g, 0.022mol) to 2,2-ethoxyethanol (2.8g, 0.021mmol) in anhydrous tetrahydrofuran (50mL) solution in batches, and react The mixture was stirred at 10°C for 1 hour. Then a tetrahydrofuran solution (10 mL) of methyl 4-bromo-2,6-difluorobenzoate (5 g, 0.02 mol) was slowly added dropwise to the above reaction mixture. After the reaction system was stirred at room temperature for 2 hours, the reaction was quenched with ice water (20 mL), the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to leave a residue The material was purified by Flash column chromatography (petroleum ether/ethyl acetate=20/1) to obtain Intermediate 15-1 (4.1 g) as a colorless oil. m/z: [M+Na] + 387.0.
步骤2：将多聚磷酸(11.4g，33.7mmol)的甲苯(80mL)悬浮液在60℃下搅拌30分钟。然后，将中间体15-1(4.1g，11.2mmol)的甲苯溶液(20mL)加入到上述悬浮液中，反应体系在60℃下搅拌1小时后减压浓缩，残留物用乙酸乙酯(50mL)稀释，有机相分别用水和饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得中间体15-2(2g)为黄色固体。m/z:[M+H] +273.0。 Step 2: A toluene (80 mL) suspension of polyphosphoric acid (11.4 g, 33.7 mmol) was stirred at 60° C. for 30 minutes. Then, a toluene solution (20 mL) of Intermediate 15-1 (4.1 g, 11.2 mmol) was added to the above suspension, the reaction system was stirred at 60°C for 1 hour and then concentrated under reduced pressure. The residue was washed with ethyl acetate (50 mL ) Diluted, the organic phase was washed with water and saturated sodium bicarbonate aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed with Flash column (petroleum ether/ethyl acetate=10/1) The intermediate 15-2 (2g) was purified as a yellow solid. m/z: [M+H] + 273.0.
步骤3：将中间体15-2(2.0g，7.32mmol)的氨甲醇(7M，10mL)溶液在封管中加热至100℃并搅拌过夜。反应液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/3)纯化得中间体15-3(1.15g)为白色固体。m/z:[M+H] +258.0。 Step 3: A solution of Intermediate 15-2 (2.0 g, 7.32 mmol) in ammonia methanol (7M, 10 mL) was heated to 100° C. in a sealed tube and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 1/3) to obtain Intermediate 15-3 (1.15 g) as a white solid. m/z: [M+H] + 258.0.
步骤4：向中间体15-3(630mg，2.44mmol)的无水1,2-二氯乙烷(20mL)溶液中滴加草酰氯(372mg，2.93mmol)，反应液在80℃下搅拌2小时。然后将反应液用冰 水浴冷却，再将2-异丙基苯胺(660mg，4.88mmol)的无水1,2-二氯乙烷(5mL)溶液缓慢滴加至上述反应液中。反应混合物室温搅拌1小时，用冰水(20mL)淬灭反应，分离有机相，水相用二氯甲烷(30mL)萃取，合并有机相后用无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得中间体15-4(820mg)为白色固体。m/z:[M+H] +419.0。 Step 4: Add oxalyl chloride (372 mg, 2.93 mmol) dropwise to the solution of Intermediate 15-3 (630 mg, 2.44 mmol) in anhydrous 1,2-dichloroethane (20 mL), and the reaction solution was stirred at 80°C for 2 hour. Then the reaction solution was cooled with an ice-water bath, and a solution of 2-isopropylaniline (660 mg, 4.88 mmol) in anhydrous 1,2-dichloroethane (5 mL) was slowly added dropwise to the above reaction solution. The reaction mixture was stirred at room temperature for 1 hour, the reaction was quenched with ice water (20 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate=3/1) to obtain Intermediate 15-4 (820 mg) as a white solid. m/z: [M+H] + 419.0.
步骤5：-20℃下，将LiHMDS(1M的四氢呋喃溶液，4.3mL)缓慢滴加到中间体15-4(0.82g，1.96mmol)的无水四氢呋喃(30mL)溶液中，得到的混合物缓慢升至室温继续搅拌1小时，然后用饱和氯化铵水溶液(20mL)淬灭反应，水相用乙酸乙酯萃取，分离有机相用无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用石油醚/乙酸乙酯混合溶剂(1/1，30mL)打浆，过滤，滤饼真空干燥得到中间体15-5(680mg)为白色固体。m/z:[M+H] +399.0。 Step 5: At -20°C, slowly add LiHMDS (1M tetrahydrofuran solution, 4.3 mL) to the intermediate 15-4 (0.82 g, 1.96 mmol) in anhydrous tetrahydrofuran (30 mL) solution, and the resulting mixture slowly rises Continue stirring at room temperature for 1 hour, then quench the reaction with saturated aqueous ammonium chloride solution (20 mL), extract the aqueous phase with ethyl acetate, separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use petroleum The ether/ethyl acetate mixed solvent (1/1, 30 mL) was slurried, filtered, and the filter cake was vacuum dried to obtain Intermediate 15-5 (680 mg) as a white solid. m/z: [M+H] + 399.0.
步骤6：向中间体15-5(0.3g，0.75mmol)的无水乙腈(30mL)溶液中依次加入三乙胺(455mg，4.5mmol)和三氯氧磷(691mg，4.5mmol)。反应混合物在80℃下搅拌2小时，然后直接减压浓缩得到中间体15-6(粗品)为黄色固体。Step 6: To a solution of Intermediate 15-5 (0.3 g, 0.75 mmol) in anhydrous acetonitrile (30 mL) were sequentially added triethylamine (455 mg, 4.5 mmol) and phosphorus oxychloride (691 mg, 4.5 mmol). The reaction mixture was stirred at 80°C for 2 hours, and then directly concentrated under reduced pressure to obtain Intermediate 15-6 (crude product) as a yellow solid.
步骤7：向中间体15-6(粗品)的乙腈(20mL)悬浮液中分别加入DIPEA(485mg，3.75mmol)和(S)-3-甲基哌嗪-1-甲酸叔丁酯(180mg，0.9mmol)。反应混合物在60℃下搅拌2小时，然后直接减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得中间体15-7(380mg)为淡黄色固体。m/z:[M+H] +581.2。 Step 7: To the suspension of Intermediate 15-6 (crude) in acetonitrile (20mL), DIPEA (485mg, 3.75mmol) and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (180mg, 0.9mmol). The reaction mixture was stirred at 60°C for 2 hours, and then directly concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain Intermediate 15-7 (380 mg) as a pale yellow solid. m/z: [M+H] + 581.2.
中间体15-8～15-10的合成Synthesis of Intermediate 15-8～15-10
利用中间体15-7的合成方法，步骤7中将(S)-3-甲基哌嗪-1-甲酸叔丁酯替换为(S)-2-(氰甲基)哌嗪-1-甲酸苄酯或2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯得到中间体15-8或15-10；Using the synthesis method of Intermediate 15-7, (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-2-(cyanomethyl)piperazine-1-carboxylic acid in step 7. Benzyl ester or tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain intermediate 15-8 or 15-10;
利用中间体15-7的合成方法，步骤4中将2-异丙基苯胺替换为2-异丙基-4-甲基吡啶-3-胺得到中间体15-9；Using the synthesis method of Intermediate 15-7, in step 4, 2-isopropylaniline is replaced with 2-isopropyl-4-methylpyridin-3-amine to obtain Intermediate 15-9;
表9Table 9
Figure PCTCN2020118772-appb-000102
Figure PCTCN2020118772-appb-000102
化合物的合成：Compound synthesis:
实施例1：1-(4-(4-(5-甲基-1H-吲唑-4-基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-基)丙-2-烯-1-酮(化合物1-1-1)的合成Example 1: 1-(4-(4-(5-methyl-1H-indazol-4-yl)furo[2,3-f]quinazolin-9-yl)piperazin-1-yl ) Synthesis of prop-2-en-1-one (compound 1-1-1)
Figure PCTCN2020118772-appb-000103
Figure PCTCN2020118772-appb-000103
步骤1：将中间体1-6(120mg，0.28mmol)，(5-甲基-1H-吲唑-4-基)硼酸(80mg，0.45mmol)，碳酸铯(92mg，0.28mmol)和PdCl 2dppf .CH 2Cl 2(15mg，0.02mmol)的1,4-二氧六环(12mL)和水(1mL)的混合物用氮气置换3次，反应体系在90℃搅拌12小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(100％乙酸乙酯)纯化得化合物1A(110mg，产率：56％)为黄色油状物。m/z:[M+H] +485.0。 Step 1: Intermediate 1-6 (120mg, 0.28mmol), (5-methyl-1H-indazol-4-yl)boronic acid (80mg, 0.45mmol), cesium carbonate (92mg, 0.28mmol) and PdCl 2 dppf . CH 2 Cl 2 (15 mg, 0.02 mmol), a mixture of 1,4-dioxane (12 mL) and water (1 mL) was replaced with nitrogen three times, and the reaction system was stirred at 90° C. for 12 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (100% ethyl acetate) to obtain compound 1A (110 mg, yield: 56%) as yellow Oily substance. m/z: [M+H] + 485.0.
步骤2：将化合物1A(110mg，0.23mmol)的二氯甲烷(10mL)和三氟乙酸(1mL)混合物在室温下搅拌1小时，减压浓缩得化合物1B(粗品)为黄色油状物。m/z:[M+H] +385.0。 Step 2: A mixture of compound 1A (110 mg, 0.23 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 1B (crude) as a yellow oil. m/z: [M+H] + 385.0.
步骤3：向化合物1B(粗品)和DIPEA(1mL)的二氯甲烷(20mL)溶液中滴加丙烯酰氯的二氯甲烷溶液(1M，25mg，0.28mL)，反应液在室温下搅拌30分钟。用水淬灭反应后减压浓缩，残留物经prep-HPLC(条件1)纯化得到化合物1-1-1(33.1mg，两步产率：32％)为黄色固体。m/z:[M+H] +439.0； 1H NMR(400MHz,DMSO-d 6):δ13.17(s,1H),8.77(s,1H),8.28(d,J＝2.0Hz,1H),7.70(s,1H),7.60(d,J＝8.4Hz,1H),7.51(s,1H),7.42(d,J＝8.4Hz,1H),6.94(d,J＝16.4,10.4Hz,1H),6.62(d,J＝2.0Hz,1H),6.21(d,J＝16.4,2.0Hz,1H),5.77(d,J＝10.4,2.4Hz,1H),3.90-3.85(m,4H),3.73-3.66(m,4H),2.23(s,3H)。 Step 3: To the dichloromethane (20 mL) solution of compound 1B (crude) and DIPEA (1 mL) was added dropwise a dichloromethane solution (1M, 25 mg, 0.28 mL) of acryloyl chloride, and the reaction solution was stirred at room temperature for 30 minutes. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 1) to obtain compound 1-1-1 (33.1 mg, two-step yield: 32%) as a yellow solid. m/z: [M+H] + 439.0; 1 H NMR (400MHz, DMSO-d 6 ): δ 13.17 (s, 1H), 8.77 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H ), 7.70 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 16.4, 10.4 Hz ,1H), 6.62 (d, J = 2.0Hz, 1H), 6.21 (d, J = 16.4, 2.0 Hz, 1H), 5.77 (d, J = 10.4, 2.4 Hz, 1H), 3.90-3.85 (m, 4H), 3.73-3.66 (m, 4H), 2.23 (s, 3H).
实施例2：(S)-2-(1-丙烯酰基-4-(4-(5-氨基-2-氯-3-氟苯基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-1-2)的合成Example 2: (S)-2-(1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)furo[2,3-f]quinazoline-9 -Yl)piperazin-2-yl)acetonitrile (compound 1-1-2)
Figure PCTCN2020118772-appb-000104
Figure PCTCN2020118772-appb-000104
步骤1：向中间体1-5(425mg，1.5mmol)和三乙胺(0.62ml，4.5mmol)的二氯甲烷(10mL)溶液中加入(S)-2-(1-丙烯酰基哌嗪-2-基)乙腈盐酸盐(480mg，2.7mmol)，反应液在室温下搅拌16小时。加入水淬灭反应，水相用二氯甲烷萃取，合并有机相并用无水硫酸钠干燥，过滤、浓缩。残留物经Flash柱层析(乙酸乙酯/石油醚＝0％-70％)纯化后得化合物3A(160mg，产率：26％)为浅黄色固体。m/z：[M+H] +426.0。 Step 1: To the solution of Intermediate 1-5 (425mg, 1.5mmol) and triethylamine (0.62ml, 4.5mmol) in dichloromethane (10mL) was added (S)-2-(1-acryloylpiperazine- 2-yl)acetonitrile hydrochloride (480 mg, 2.7 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether=0%-70%) to obtain compound 3A (160 mg, yield: 26%) as a pale yellow solid. m/z: [M+H] + 426.0.
步骤2：氮气保护下，将化合物3A(0.11g，0.26mmol)，中间体2(0.11g，0.38mmol)，PdCl 2dppf .CH 2Cl 2(32mg，0.04mmol)和碳酸钠(1.0M，0.78mL)的水(0.8mL)和1,4-二氧六环(7mL)的混合溶液在100℃微波条件下反应1小时，然后将反应体系冷却至室温，过滤除去不溶物，滤液减压浓缩后经prep-HPLC(条件2)纯化得化合物1-1-2(36mg，产率：28％)为类白色固体。m/z:[M+H] +491.2； 1H NMR(400MHz,DMSO-d 6):δ8.78(s,1H),8.37(s,1H),7.66(s,1H),7.00-6.80(m,2H),6.69-6.63(m,1H),6.57(s,1H),6.23(d,J＝16.6Hz,1H),5.86-5.76(m,3H),5.60-5.120(m,1H),4.90-4.00(m,4H),3.80-3.52(m,1H),3.22-2.99(m,3H)。 Step 2: Under the protection of nitrogen, compound 3A (0.11g, 0.26mmol), Intermediate 2 (0.11g, 0.38mmol), PdCl 2 dppf . CH 2 Cl 2 (32mg, 0.04mmol) and sodium carbonate (1.0M, A mixed solution of 0.78 mL) of water (0.8 mL) and 1,4-dioxane (7 mL) was reacted at 100°C under microwave conditions for 1 hour, then the reaction system was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was decompressed After concentration, it was purified by prep-HPLC (condition 2) to obtain compound 1-1-2 (36 mg, yield: 28%) as an off-white solid. m/z: [M+H] + 491.2; 1 H NMR (400MHz, DMSO-d 6 ): δ8.78 (s, 1H), 8.37 (s, 1H), 7.66 (s, 1H), 7.00-6.80 (m, 2H), 6.69-6.63 (m, 1H), 6.57 (s, 1H), 6.23 (d, J = 16.6 Hz, 1H), 5.86-5.76 (m, 3H), 5.60-5.120 (m, 1H) ), 4.90-4.00 (m, 4H), 3.80-3.52 (m, 1H), 3.22-2.99 (m, 3H).
实施例3：1-(4-(4-(5-甲基-1H-吲唑-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-基)丙-2-烯-1-酮(化合物1-2-1)的合成Example 3: 1-(4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methyl) Synthesis of furo[2,3-f]quinazolin-9-yl)piperazin-1-yl)prop-2-en-1-one (compound 1-2-1)
Figure PCTCN2020118772-appb-000105
Figure PCTCN2020118772-appb-000105
步骤1：冰浴条件下，向N-甲基-L-脯氨醇(159mg，1.38mmol)的DMF(12mL)溶液中分批加入钠氢(60％，56mg，1.38mmol)，反应体系在0℃下搅拌1小时后将中间体2-4(63.5mg，0.13mmol)加入到上述反应液中，得到的混合物在室温下搅拌2小时。用冰水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝4/1)纯化得化合物4A(29mg，产率：40％)为黄色油状物。m/z:[M+H] +545.8。 Step 1: Under ice bath conditions, add sodium hydrogen (60%, 56mg, 1.38mmol) to a solution of N-methyl-L-prolinol (159mg, 1.38mmol) in DMF (12mL) in batches. After stirring at 0°C for 1 hour, Intermediate 2-4 (63.5 mg, 0.13 mmol) was added to the above reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=4/1) to obtain compound 4A (29 mg, yield) : 40%) is a yellow oil. m/z: [M+H] + 545.8.
步骤2：将化合物4A(29mg，53.1μmol)，(5-甲基-1H-吲唑-4-基)硼酸(19mg，106μmol)，碳酸钠水溶液(0.26mL，1M)和PdCl 2dppf .CH 2Cl 2(4.5mg，5.31μmol)的1,4-二氧六环(4mL)混合物置于微波管内，反应体系用氮气置换后在100℃下微波反应1小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝1/1)纯化得化合物4B(17mg，产率：59％)为黄色油状物。 Step 2: Combine compound 4A (29mg, 53.1μmol), (5-methyl-1H-indazol-4-yl)boronic acid (19mg, 106μmol), sodium carbonate aqueous solution (0.26mL, 1M) and PdCl 2 dppf . CH A mixture of 2 Cl 2 (4.5 mg, 5.31 μmol) of 1,4-dioxane (4 mL) was placed in a microwave tube, and the reaction system was replaced with nitrogen and reacted in a microwave at 100° C. for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=1/1) to obtain compound 4B (17 mg, yield: 59). %) is a yellow oil.
步骤3：将化合物4B(17mg，28.5μmol)的二氯甲烷(5mL)和三氟乙酸(0.5mL)溶液在室温下搅拌2小时后减压浓缩得到化合物4C(粗品)为黄色油状物。m/z:[M+H] +497.8。 Step 3: A solution of compound 4B (17 mg, 28.5 μmol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain compound 4C (crude) as a yellow oil. m/z: [M+H] + 497.8.
步骤4：向化合物4C(粗品)和DIPEA(0.5mL)的二氯甲烷(5mL)溶液中滴加丙烯酰氯(2.8mg，31.3μmol)的二氯甲烷溶液(5mL)，反应液室温下搅拌10分钟。用水淬灭反应后直接减压浓缩，残留物经prep-HPLC(条件4)纯化得到化合物1-2-1(3.56mg，两步产率：23％)为白色固体。m/z:[M+H] +551.8； 1H NMR(400MHz,DMSO-d 6):δ13.14(s,1H),8.17(d,J＝2.0Hz,1H),7.58(d,J＝8.4Hz,1H),7.49(s,1H),7.46(s,1H),7.41(d,J＝8.4Hz,1H),6.92(dd,J＝16.4,10.4Hz,1H),6.53(d,J＝2.0Hz,1H),6.21(dd,J＝16.4,2.0Hz,1H),5.76(dd,J＝10.4,2.0Hz,1H),4.44-4.39(m,1H),4.24-4.19(m,1H),3.89-3.86(m,4H),3.61-3.72(m,4H),2.96-2.97(m,1H),2.57-2.65(m,1H),2.38(s,3H),2.23(s,3H),2.16-2.00(m,2H),1.66-1.72(m,3H)。 Step 4: Add acryloyl chloride (2.8 mg, 31.3 μmol) in dichloromethane (5 mL) dropwise to the dichloromethane (5 mL) solution of compound 4C (crude) and DIPEA (0.5 mL), and the reaction solution is stirred at room temperature for 10 minute. After quenching the reaction with water, it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 4) to obtain compound 1-2-1 (3.56 mg, two-step yield: 23%) as a white solid. m/z: [M+H] + 551.8; 1 H NMR (400MHz, DMSO-d 6 ): δ13.14 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.58 (d, J ＝8.4Hz,1H),7.49(s,1H),7.46(s,1H),7.41(d,J＝8.4Hz,1H),6.92(dd,J＝16.4,10.4Hz,1H),6.53(d ,J=2.0Hz,1H),6.21(dd,J=16.4,2.0Hz,1H), 5.76(dd,J=10.4,2.0Hz,1H),4.44-4.39(m,1H),4.24-4.19( m, 1H), 3.89-3.86 (m, 4H), 3.61-3.72 (m, 4H), 2.96-2.97 (m, 1H), 2.57-2.65 (m, 1H), 2.38 (s, 3H), 2.23 ( s, 3H), 2.16-2.00 (m, 2H), 1.66-1.72 (m, 3H).
实施例4：2-((2S)-1-丙烯酰基-4-(4-(5-甲基-1H-吲唑-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-2-2)的合成Example 4: 2-((2S)-1-acryloyl-4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrole) (Alk-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-2-2)
Figure PCTCN2020118772-appb-000106
Figure PCTCN2020118772-appb-000106
步骤1：将中间体2-6(100mg，0.18mmol)，N-甲基-L-脯氨醇(238mg，2.06mmol)，碳酸铯(268mg，0.82mmol)和DIPEA(505mg，3.91mmol)的1,4-二氧六环(15mL)混合物置于封管中，用氮气置换后在150℃下搅拌3小时。反应液冷却至室温，用乙酸乙酯稀释，有机相用水洗涤，分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝4/1)纯化得化合物6A(40mg，产率：36％)为黄色油状物。m/z:[M+H] +619.2。 Step 1: The intermediate 2-6 (100mg, 0.18mmol), N-methyl-L-prolinol (238mg, 2.06mmol), cesium carbonate (268mg, 0.82mmol) and DIPEA (505mg, 3.91mmol) The 1,4-dioxane (15 mL) mixture was placed in a sealed tube, replaced with nitrogen, and stirred at 150°C for 3 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=4/1) to obtain compound 6A (40mg, Yield: 36%) as yellow oil. m/z: [M+H] + 619.2.
步骤2：将化合物6A(40mg，64.6μmol)，(5-甲基-1H-吲唑-4-基)硼酸(57mg，323μmol)，碳酸钠水溶液(0.30mL，1M)和PdCl 2dppf .CH 2Cl 2(5.2mg，6.45μmol)的1,4-二氧六环(3mL)混合物置于微波管内，氮气置换后在110℃下微波反应1小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝4/1)纯化得化合物6B(35mg，产率：80％)为黄色固体。m/z:[M+H] +671.3。 Step 2: Compound 6A (40mg, 64.6μmol), (5-methyl-1H-indazol-4-yl)boronic acid (57mg, 323μmol), sodium carbonate aqueous solution (0.30mL, 1M) and PdCl 2 dppf . CH A mixture of 2 Cl 2 (5.2 mg, 6.45 μmol) of 1,4-dioxane (3 mL) was placed in a microwave tube, replaced with nitrogen, and reacted in a microwave at 110° C. for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (dichloromethane/methanol=4/1) to obtain compound 6B (35mg, yield: 80 %) is a yellow solid. m/z: [M+H] + 671.3.
步骤3：将化合物6B(45mg，67.1μmol)和10％的钯碳(45mg)的甲醇(20mL)混合物用氢气置换后在氢气氛下室温搅拌2.5小时。反应液用硅藻土过滤，滤液减压浓缩得化合物6C(粗品)为黄色固体。m/z:[M+H] +537.4。 Step 3: A mixture of compound 6B (45 mg, 67.1 μmol) and 10% palladium-carbon (45 mg) in methanol (20 mL) was replaced with hydrogen and stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain compound 6C (crude) as a yellow solid. m/z: [M+H] + 537.4.
步骤4：向化合物6C(粗品)和DIPEA(0.5mL)的二氯甲烷(8mL)溶液中滴加丙烯酸氯(6.1mg，67.1μmol)的二氯甲烷溶液(2mL)，反应液室温下搅拌3小时。用水淬灭反应后减压浓缩，残留物经prep-HPLC(条件2)纯化得到化合物1-2-2(6mg，两步产率：13％)为白色固体。m/z:[M+H] +591.2； 1H NMR(400MHz,DMSO-d 6):δ13.17(s,1H),8.23(s,1H),7.59(d,J＝8.8Hz,1H),7.48-7.51(m,2H),7.41(d,J＝8.8Hz,1H),6.93-6.90(m,1H),6.55(t,J＝2.0Hz,1H),6.25(d,J＝16.8,2.0Hz,1H),5.82(d,J＝10.8Hz,1H),5.19-4.93(m,1H),4.59-4.10(m,6H),3.22-2.96(m,6H),2.42(s,3H),2.30-2.20(m,4H),1.95-2.00(m,1H),1.62-1.78(m,3H)。 Step 4: To the dichloromethane (8mL) solution of compound 6C (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (2mL) of acrylic acid chloride (6.1mg, 67.1μmol), and the reaction mixture was stirred at room temperature for 3 hour. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 2) to obtain compound 1-2-2 (6 mg, two-step yield: 13%) as a white solid. m/z: [M+H] + 591.2; 1 H NMR (400MHz, DMSO-d 6 ): δ 13.17 (s, 1H), 8.23 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H ),7.48-7.51(m,2H),7.41(d,J=8.8Hz,1H), 6.93-6.90(m,1H), 6.55(t,J=2.0Hz,1H), 6.25(d,J= 16.8, 2.0 Hz, 1H), 5.82 (d, J = 10.8 Hz, 1H), 5.19-4.93 (m, 1H), 4.59-4.10 (m, 6H), 3.22-2.96 (m, 6H), 2.42 (s , 3H), 2.30-2.20 (m, 4H), 1.95-2.00 (m, 1H), 1.62-1.78 (m, 3H).
实施例5：2-((2S)-1-丙烯酰基-4-(4-(5-氯-6-氟-1H-吲唑-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈三氟乙酸盐(化合物1-2-3)的合成Example 5: 2-((2S)-1-acryloyl-4-(4-(5-chloro-6-fluoro-1H-indazol-4-yl)-7-(((S)-1- Methylpyrrolidin-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-2-3 )Synthesis
Figure PCTCN2020118772-appb-000107
Figure PCTCN2020118772-appb-000107
步骤1：将中间体4-3(100mg，0.17mmol)、中间体3(57mg，0.19mmol)、碳酸钠水溶液(0.85mL，0.85mmol)和PdCl 2dppf.CH 2Cl 2(14mg，0.017mmol)的1,4-二氧六环(5mL)的混合物用氮气置换3次，反应体系在110℃下微波反应1小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝9/1)纯化得化合物9A(粗品)为黄色固体。m/z:[M+H] +759.4。 Step 1: Combine Intermediate 4-3 (100mg, 0.17mmol), Intermediate 3 (57mg, 0.19mmol), aqueous sodium carbonate (0.85mL, 0.85mmol) and PdCl 2 dppf.CH 2 Cl 2 (14mg, 0.017mmol) The mixture of 1,4-dioxane (5 mL) in) was replaced with nitrogen three times, and the reaction system was microwaved at 110° C. for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=9/1) Compound 9A (crude product) is a yellow solid. m/z: [M+H] + 759.4.
步骤2：将化合物9A(粗品)的二氯甲烷(2mL)和三氟乙酸(0.5mL)混合溶液在室温下搅拌2小时后直接减压浓缩得化合物9B(粗品)为黄色油状物。m/z:[M+H] +575.4。 Step 2: A mixed solution of compound 9A (crude product) in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 9B (crude product) as a yellow oil. m/z: [M+H] + 575.4.
步骤3：向化合物9B(粗品)和DIPEA(0.5mL)的二氯甲烷(3mL)溶液中滴加丙烯酸酐的二氯甲烷溶液(0.1mL，0.25M)，反应液室温搅拌2小时。用水淬灭反应，得到的混合物直接减压浓缩，残留物用prep-HPLC(分离条件6)纯化得化合物1-2-3(1.65mg，三步产率：13％)为黄色固体。m/z:[M+H] +629.2； 1H NMR(400MHz,DMSO-d 6):δ13.13(s,1H),8.24-8.14(m,3H),7.75(s,1H),6.71(s,1H),6.17(dd,J＝2.0,16.4Hz,1H),5.75(d,J＝10.8Hz,1H),5.25(t,J＝4.8Hz,1H),4.79-4.44(m,3H),4.25-3.68(m,5H),3.14-2.94(m, 4H),2.94-2.85(m,4H),2.05-1.77(m,5H)。 Step 3: To the dichloromethane (3mL) solution of compound 9B (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (0.1mL, 0.25M) of acrylic anhydride, and the reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with water, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 6) to obtain compound 1-2-3 (1.65 mg, three-step yield: 13%) as a yellow solid. m/z: [M+H] + 629.2; 1 H NMR (400MHz, DMSO-d 6 ): δ 13.13 (s, 1H), 8.24-8.14 (m, 3H), 7.75 (s, 1H), 6.71 (s, 1H), 6.17 (dd, J = 2.0, 16.4 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H), 5.25 (t, J = 4.8 Hz, 1H), 4.79-4.44 (m, 3H), 4.25-3.68 (m, 5H), 3.14-2.94 (m, 4H), 2.94-2.85 (m, 4H), 2.05-1.77 (m, 5H).
实施例6：2-((2S)-1-丙烯酰基-4-(4-(2-氯-3-羟基萘-1-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-2-4)的合成Example 6: 2-((2S)-1-acryloyl-4-(4-(2-chloro-3-hydroxynaphthalen-1-yl)-7-(((S)-1-methylpyrrolidine) 2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-2-4)
Figure PCTCN2020118772-appb-000108
Figure PCTCN2020118772-appb-000108
步骤1：氮气保护下，将中间体4-3(26.6mg，0.08mmol)，中间体17(30mg，0.06mmol)，Pd(PPh 3) 4(6.5mg，0.006mmol)和碳酸钠水溶液(1.0M，0.17mL)的1,4-二氧六环(2.0mL)溶液用氮气置换后在120℃下微波反应0.5小时。然后将反应液冷却至室温，减压浓缩，残留物经Flash柱层析(甲醇/二氯甲烷＝0％-10％)纯化得化合物12A(24mg，产率：67％)为黄色固体。m/z:[M+H] +697.2。 Step 1: Under nitrogen protection, Intermediate 4-3 (26.6mg, 0.08mmol), Intermediate 17 (30mg, 0.06mmol), Pd(PPh 3 ) 4 (6.5mg, 0.006mmol) and sodium carbonate aqueous solution (1.0 M, 0.17 mL) of 1,4-dioxane (2.0 mL) solution was replaced with nitrogen and reacted in microwave at 120° C. for 0.5 hours. Then the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane=0%-10%) to obtain compound 12A (24 mg, yield: 67%) as a yellow solid. m/z: [M+H] + 697.2.
步骤2：在-40℃下，把三溴化硼(0.2mL)缓慢滴加到化合物12A(5mg，7.2μmol)的四氢呋喃(2mL)的溶液中，反应液缓慢升温至室温搅拌1个小时，将反应液降至0℃，加水淬灭反应，水相用乙酸乙酯萃取，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩得化合物12B(粗品)为黄色固体。m/z:[M+H] +583.2。 Step 2: At -40°C, slowly add boron tribromide (0.2 mL) dropwise to a solution of compound 12A (5 mg, 7.2 μmol) in tetrahydrofuran (2 mL), and the reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction solution was reduced to 0°C, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12B (crude) as a yellow solid. m/z: [M+H] + 583.2.
步骤3：冰浴条件下，向化合物12B(粗品)和三乙胺(0.05mL，0.36mmol)的二氯甲烷(1mL)溶液中加入丙烯酰氯的二氯甲烷溶液(0.85M，0.016mL)，反应体系在室温下搅拌0.5小时，减压浓缩除去溶剂，残留物溶于乙腈(2mL)，加入氨水(1mL)，得到的混合物在室温下搅拌0.5小时。将混合物直接用prep-HPLC(条件2)纯化得化合物1-2-4(0.42mg，两步产率：9％)为白色固体。m/z:[M+H] +637.3。 Step 3: Under ice bath conditions, add a dichloromethane solution (0.85M, 0.016mL) of acryloyl chloride to compound 12B (crude) and triethylamine (0.05mL, 0.36mmol) in dichloromethane (1mL), The reaction system was stirred at room temperature for 0.5 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in acetonitrile (2 mL), ammonia water (1 mL) was added, and the resulting mixture was stirred at room temperature for 0.5 hours. The mixture was directly purified by prep-HPLC (condition 2) to obtain compound 1-2-4 (0.42 mg, two-step yield: 9%) as a white solid. m/z: [M+H] + 637.3.
实施例7：2-((2S)-1-丙烯酰基-4-(4-(2-氟-6-羟基苯基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-2-5)的合成Example 7: 2-((2S)-1-acryloyl-4-(4-(2-fluoro-6-hydroxyphenyl)-7-(((S)-1-methylpyrrolidine-2- (Yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-2-5)
Figure PCTCN2020118772-appb-000109
Figure PCTCN2020118772-appb-000109
利用化合物1-2-2的合成方法，将步骤2中的(5-甲基-1H-吲唑-4-基)硼酸替换为(2-氟-6-羟基苯基)硼酸反应得到化合物1-2-5。m/z:[M+H] +571.2； 1H NMR(400MHz,DMSO-d 6):δ10.17(s,1H),9.81(br.s,1H),8.26(s,1H),7.54(s,1H),7.36(dd,J＝8.4,15.2Hz,1H),6.92(d,J＝8.4Hz,1H),6.85(t,J＝9.2Hz,1H),6.77(s,1H),6.24(dd,J＝2.0,16.4Hz,1H),5.83(d,J＝10.0Hz,1H),5.20-4.95(m,1H),4.82-4.53(m,2H),4.28-4.03(m,2H),3.94-3.57(m,2H),3.41-3.23(m,2H),3.23-3.02(m,4H),3.00(s,3H),2.36-2.26(m,1H),2.16-1.87(m,4H)。 Using the synthesis method of compound 1-2-2, the (5-methyl-1H-indazol-4-yl)boronic acid in step 2 was replaced with (2-fluoro-6-hydroxyphenyl)boronic acid to obtain compound 1 -2-5. m/z: [M+H] + 571.2; 1 H NMR (400MHz, DMSO-d 6 ): δ10.17 (s, 1H), 9.81 (br.s, 1H), 8.26 (s, 1H), 7.54 (s, 1H), 7.36 (dd, J = 8.4, 15.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.85 (t, J = 9.2 Hz, 1H), 6.77 (s, 1H) ,6.24(dd,J=2.0,16.4Hz,1H),5.83(d,J=10.0Hz,1H),5.20-4.95(m,1H),4.82-4.53(m,2H),4.28-4.03(m ,2H),3.94-3.57(m,2H),3.41-3.23(m,2H),3.23-3.02(m,4H),3.00(s,3H),2.36-2.26(m,1H),2.16-1.87 (m, 4H).
实施例8：2-((2S)-1-丙烯酰基-4-(4-(2,3-二氯-5-羟基苯基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈三氟乙酸盐(化合物1-2-6)的合成Example 8: 2-((2S)-1-acryloyl-4-(4-(2,3-dichloro-5-hydroxyphenyl)-7-(((S)-1-methylpyrrolidine) 2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-2-6)
Figure PCTCN2020118772-appb-000110
Figure PCTCN2020118772-appb-000110
利用化合物1-2-4的合成方法，用中间体4-3和19反应得到化合物1-2-6。m/z:[M+H] +621.2； 1H NMR(400MHz,DMSO-d 6):δ10.52(t,J＝5.2Hz,1H),9.83(s,1H),8.29(s,1H),7.49(s,1H),7.18-6.17(d,J＝2.8Hz,1H),6.87-6.83(m,2H),6.25-6.20(m,1H),5.83-5.80(d,J＝10.4Hz,1H),5.18(s,1H),4.93(s,1H),4.78-4.71(m,1H),4.64-4.55(m,2H),4.22-4.05(m,3H),3.89-3.85(m,4H),3.64-3.60(m,1H),3.39-3.36(m,1H),3.20-3.01(m,3H),2.38-1.88(m,4H)。 Using the synthetic method of compound 1-2-4, the reaction of intermediates 4-3 and 19 is used to obtain compound 1-2-6. m/z: [M+H] + 621.2; 1 H NMR (400MHz, DMSO-d 6 ): δ10.52(t,J=5.2Hz,1H), 9.83(s,1H), 8.29(s,1H ),7.49(s,1H),7.18-6.17(d,J=2.8Hz,1H),6.87-6.83(m,2H),6.25-6.20(m,1H),5.83-5.80(d,J=10.4 Hz, 1H), 5.18 (s, 1H), 4.93 (s, 1H), 4.78-4.71 (m, 1H), 4.64-4.55 (m, 2H), 4.22-4.05 (m, 3H), 3.89-3.85 ( m, 4H), 3.64-3.60 (m, 1H), 3.39-3.36 (m, 1H), 3.20-3.01 (m, 3H), 2.38-1.88 (m, 4H).
实施例9：2-((S)-1-丙烯酰基-4-(4-(3-羟基萘-1-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-3-1)的合成Example 9: 2-((S)-1-acryloyl-4-(4-(3-hydroxynaphthalen-1-yl)-7-(((S)-1-methylpyrrolidin-2-yl) )Methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-3-1)
Figure PCTCN2020118772-appb-000111
Figure PCTCN2020118772-appb-000111
步骤1：将中间体4-5(100mg，0.18mmol)，中间体1(70mg，0.22mmol)，碳酸钠水溶液(0.90mL，0.90mmol)和PdCl 2dppf .CH 2Cl 2(14.6mg，0.02mmol)的1,4-二氧六环(9mL)混合物用氮气置换3次，反应体系在110℃下微波反应1小时。用水淬灭反应，水相用乙酸乙酯萃取、分离有机相后减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝9/1)纯化得化合物8A(30mg，产率：51％)为黄色固体。m/z:[M+H] +647.2。 Step 1: Combine Intermediate 4-5 (100mg, 0.18mmol), Intermediate 1 (70mg, 0.22mmol), aqueous sodium carbonate (0.90mL, 0.90mmol) and PdCl 2 dppf . CH 2 Cl 2 (14.6mg, 0.02 The 1,4-dioxane (9 mL) mixture of mmol) was replaced with nitrogen three times, and the reaction system was microwaved at 110° C. for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=9/1) to obtain compound 8A (30 mg, yield: 51). %) is a yellow solid. m/z: [M+H] + 647.2.
步骤2：向化合物8A(30mg，46.4μmol)的1,4-二氧六环(2mL)溶液中加入氯化氢的1,4-二氧六环溶液(0.2mL，4M)，反应液室温搅拌1小时后减压浓缩，残留物经prep-HPLC(分离条件3)纯化得到化合物1-3-1(12.0mg，产率:43％)为黄色固体。 m/z:[M+H] +603.4； 1H NMR(400MHz,DMSO-d 6):δ10.00(s,1H),8.22(s,1H),7.84(d,J＝8.4Hz,1H),7.52-7.43(m,3H),7.29(d,J＝2.0Hz,1H),7.22-7.17(m,2H),6.96(br.s,1H),6.55(d,J＝2.0Hz,1H),6.25(dd,J＝2.0,2.4Hz,1H),5.82(d,J＝10.8Hz,1H),5.19-4.95(m,1H),4.58-4.40(m,2H),4.26-4.11(m,4H),3.86-3.81(m,1H),3.22-2.98(m,4H),2.69-2.61(m,1H),2.39(s,3H),2.22-2.18(m,1H),2.01-1.96(m,1H),1.73-1.65(m,3H)。 Step 2: To the 1,4-dioxane (2mL) solution of compound 8A (30mg, 46.4μmol) was added the 1,4-dioxane solution (0.2mL, 4M) of hydrogen chloride, and the reaction solution was stirred at room temperature for 1 After hours, it was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to obtain compound 1-3-1 (12.0 mg, yield: 43%) as a yellow solid. m/z: [M+H] + 603.4; 1 H NMR (400MHz, DMSO-d 6 ): δ10.00 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H ),7.52-7.43(m,3H),7.29(d,J=2.0Hz,1H),7.22-7.17(m,2H),6.96(br.s,1H),6.55(d,J=2.0Hz, 1H), 6.25 (dd, J = 2.0, 2.4 Hz, 1H), 5.82 (d, J = 10.8 Hz, 1H), 5.19-4.95 (m, 1H), 4.58-4.40 (m, 2H), 4.26-4.11 (m,4H),3.86-3.81(m,1H),3.22-2.98(m,4H),2.69-2.61(m,1H),2.39(s,3H),2.22-2.18(m,1H),2.01 -1.96 (m, 1H), 1.73-1.65 (m, 3H).
实施例10：2-((S)-1-丙烯酰基-4-(4-(2-氯-3-氟-5-羟基苯基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-3-2)的合成Example 10: 2-((S)-1-acryloyl-4-(4-(2-chloro-3-fluoro-5-hydroxyphenyl)-7-(((S)-1-methylpyrrole) (Alk-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-3-2)
Figure PCTCN2020118772-appb-000112
Figure PCTCN2020118772-appb-000112
利用化合物1-3-1的合成方法，将步骤1中的中间体1替换为中间体16反应得到化合物1-3-2。m/z:[M+H] +605.2； 1H NMR(400MHz,DMSO-d 6):δ10.45(s,1H),8.26(s,1H),7.46(s,1H),6.94-6.91(m,2H),6.83-6.82(m,1H),6.78-6.75(m,1H),6.24-6.19(m,1H),5.81-5.78(m,1H),4.42-4.38(m,1H),4.24-4.19(m,2H),4.17-4.12(m,1H),4.05-3.99(m,1H),3.03-2.94(m,3H),2.62-2.56(m,2H),2.38(s,3H),2.21-2.15(m,2H),2.02-1.92(m,2H),1.73-1.63(m,4H)。 Using the synthesis method of compound 1-3-1, the intermediate 1 in step 1 is replaced with intermediate 16 to obtain compound 1-3-2. m/z: [M+H] + 605.2; 1 H NMR (400MHz, DMSO-d 6 ): δ 10.45 (s, 1H), 8.26 (s, 1H), 7.46 (s, 1H), 6.94-6.91 (m,2H),6.83-6.82(m,1H),6.78-6.75(m,1H),6.24-6.19(m,1H),5.81-5.78(m,1H),4.42-4.38(m,1H) ,4.24-4.19(m,2H),4.17-4.12(m,1H),4.05-3.99(m,1H),3.03-2.94(m,3H),2.62-2.56(m,2H),2.38(s, 3H), 2.21-2.15 (m, 2H), 2.02-1.92 (m, 2H), 1.73-1.63 (m, 4H).
实施例11：2-((2S)-1-丙烯酰基-4-(4-(2-氨基-3,5-二氯-6-氟苯基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物1-4-1)的合成Example 11: 2-((2S)-1-acryloyl-4-(4-(2-amino-3,5-dichloro-6-fluorophenyl)-7-(((S)-1- Synthesis of methylpyrrolidin-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 1-4-1)
Figure PCTCN2020118772-appb-000113
Figure PCTCN2020118772-appb-000113
将中间体4-5(70mg，0.13mmol)、中间体32(58mg，0.26mmol)、碳酸钠水溶液(1M，0.65mL，0.5mmol)和PdCl 2dppf .CH 2Cl 2(11mg，0.013mmol)的1,4-二氧六环(5mL)混合物用氮气置换3次，反应体系在110℃微波反应1小时。用水淬灭反应，水相用乙酸乙酯萃取，分离有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，残留物经prep-HPLC(分离条件5)纯化得到化合物1-4-1(7.71mg，产率：10％)为类白色固体。m/z:[M+H] +638.2； 1H NMR(400MHz,DMSO-d 6):δ8.29(d,J＝14.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.57-7.49(m,1H),7.00(br.s,1H),6.77(s,1H),6.25(dd,J＝2.0,16.8Hz,1H),5.82(d,J＝11.2Hz,1H),5.36-5.31(m,2H),5.21-4.39(m,1H), 4.26-4.03(m,4H),3.13-2.93(m,5H),2.68-2.61(m,1H),2.39-2.31(m,4H),2.21-2.19(m,1H),2.03-1.91(m,2H),1.76-1.61(m,3H)。 Intermediate 4-5 (70mg, 0.13mmol), intermediate 32 (58mg, 0.26mmol), sodium carbonate aqueous solution (1M, 0.65mL, 0.5mmol) and PdCl 2 dppf . CH 2 Cl 2 (11mg, 0.013mmol) The 1,4-dioxane (5 mL) mixture was replaced with nitrogen three times, and the reaction system was microwaved at 110°C for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (separation condition 5) to obtain compound 1 -4-1 (7.71 mg, yield: 10%) is an off-white solid. m/z: [M+H] + 638.2; 1 H NMR (400MHz, DMSO-d 6 ): δ8.29 (d, J = 14.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57-7.49(m,1H),7.00(br.s,1H),6.77(s,1H), 6.25(dd,J=2.0,16.8Hz,1H), 5.82(d,J=11.2Hz,1H) ,5.36-5.31(m,2H),5.21-4.39(m,1H), 4.26-4.03(m,4H),3.13-2.93(m,5H),2.68-2.61(m,1H),2.39-2.31( m, 4H), 2.21-2.19 (m, 1H), 2.03-1.91 (m, 2H), 1.76-1.61 (m, 3H).
实施例12：(S)-2-(1-丙烯酰基-4-(4-(5-氨基-2-氯-3-氟苯基)-7-(3-(二乙基氨基)氮杂环丁-1-基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈三氟乙酸盐(化合物1-4-2)的合成Example 12: (S)-2-(1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)-7-(3-(diethylamino)aza Synthesis of Cyclobut-1-yl)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-4-2)
Figure PCTCN2020118772-appb-000114
Figure PCTCN2020118772-appb-000114
将中间体5-3(28mg，0.05mmol)、中间体2(27mg，0.10mmol)、碳酸钠水溶液(1M，0.15mL)和Pd(PPh 3) 4(5.8mg，0.005mmol)的1,4-二氧六环(5mL)混合物用氮气鼓泡1-2分钟，反应体系在120℃下微波反应0.5小时。用水淬灭反应，水相用乙酸乙酯萃取，分离有机相并用饱和食盐水洗，无水硫酸钠干燥，过滤、滤液减压浓缩，残留物经prep-HPLC(分离条件6)纯化得到化合物1-4-2(7.08mg，产率：24％)为类白色固体。m/z:[M+H] +617.2； 1H NMR(400MHz,DMSO-d 6):δ8.22(s,1H),7.36(s,1H),7.24-6.98(m,1H),6.98-6.91(m,1H),6.81(s,1H),6.66-6.62(s,1H),6.51(s,1H),6.24-6.60(d,J＝16.0Hz,1H),5.82-5.79(d,J＝12.0Hz,1H),4.47-4.38(m,4H),3.75(m,10H),3.21(m,5H),1.23-1.20(m,6H)。. Intermediate 5-3 (28mg, 0.05mmol), intermediate 2 (27mg, 0.10mmol), sodium carbonate aqueous solution (1M, 0.15mL) and Pd(PPh 3 ) 4 (5.8mg, 0.005mmol) in 1,4 The mixture of dioxane (5 mL) was bubbled with nitrogen for 1-2 minutes, and the reaction system was microwaved at 120° C. for 0.5 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (separation condition 6) to obtain compound 1- 4-2 (7.08 mg, yield: 24%) is an off-white solid. m/z: [M+H] + 617.2; 1 H NMR (400MHz, DMSO-d 6 ): δ8.22(s,1H),7.36(s,1H),7.24-6.98(m,1H),6.98 -6.91(m,1H),6.81(s,1H),6.66-6.62(s,1H),6.51(s,1H),6.24-6.60(d,J=16.0Hz,1H),5.82-5.79(d , J=12.0Hz, 1H), 4.47-4.38 (m, 4H), 3.75 (m, 10H), 3.21 (m, 5H), 1.23-1.20 (m, 6H). .
实施例13：化合物1-4-3～1-4-90的合成Example 13: Synthesis of Compounds 1-4-3～1-4-90
利用化合物1-4-1或1-4-2的合成方法，分别用中间体2、(3-氟-5-羟基苯基)硼酸、中间体4、5-氨基-2-甲基苯硼酸频那醇酯、中间体5、10、6、7、11、5-氨基-2-氟苯硼酸频哪醇酯、4-氨基-2-氯苯硼酸频那醇酯、中间体8、9、(2-氟-4-羟基苯基)硼酸、(2-氯-5-羟基苯基)硼酸、2-氟-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺、(2,3-二氟-4-羟基苯基)硼酸、(3-氯-4-羟基苯基)硼酸、(2-氯-4-羟基苯基)硼酸、中间体12、(5-氨基-2,3-二氟苯基)硼酸、中间体33、14、(2-氯-5-甲氧基苯基)硼酸、(2,3,5-三氯苯基)硼酸、中间体23、(5-氨基-2-氯苯基)硼酸、(3-氯-5-(三氟甲基)苯基)硼酸、(5-氯-2-甲基苯基)硼酸、(5-氟-2-甲基苯基)硼酸、中间体20、(2-氯-5-(三氟甲基)苯基)硼酸、中间体21、(2,5-二氯苯基)硼酸、中间体22、24、25或26和4-5反应得到化合物1-4-3～1-4-40；用中间体27和4-10反应得到化合物1-4-41；用中间体6-5和(2,3,5-三氯苯基)硼酸、中间体15或4-羟基-2-三氟甲基苯硼酸频哪醇酯反应得到化合物1-4-42～1-4-44；分别用中间体7-6、6-7、4-11、4-12、6-1、6-2、4-7、7-3、6-4、4-8、6-5、4-9、11-1、4-10、4-14、6-6或6-9和中间体2反应得到化合物1-4-45～1-4-61；分别用(2-氯-5-羟基苯基)硼酸、中间体6、33、8、15、20和中间体6-4反应得到化合物1-4-62～1-4-67；分别用中间体11-1、4-15、6-5、6-7、6-1、6-2、6-8、6-6、11-2、6-10、11-3、6-12、4-9或4-10和中间体20反应得到化 合物1-4-68～1-4-81；用中间体7-5、6-5或6-1和6反应得到化合物1-4-82～1-4-84；用中间体6-5和27或28反应得到化合物1-4-85～1-4-86；用中间体28和6-1或6-8反应得到化合物1-4-87～1-4-88；分别用中间体4-12或4-13和中间体15反应得到化合物1-4-89～1-4-90：Using the synthetic method of compound 1-4-1 or 1-4-2, intermediate 2, (3-fluoro-5-hydroxyphenyl)boronic acid, intermediate 4, 5-amino-2-methylphenylboronic acid Pinacol ester, intermediates 5, 10, 6, 7, 11, 5-amino-2-fluorophenylboronic acid pinacol ester, 4-amino-2-chlorophenylboronic acid pinacol ester, intermediates 8, 9 , (2-fluoro-4-hydroxyphenyl)boronic acid, (2-chloro-5-hydroxyphenyl)boronic acid, 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)aniline, (2,3-difluoro-4-hydroxyphenyl)boronic acid, (3-chloro-4-hydroxyphenyl)boronic acid, (2 -Chloro-4-hydroxyphenyl)boronic acid, intermediate 12, (5-amino-2,3-difluorophenyl)boronic acid, intermediate 33,14, (2-chloro-5-methoxyphenyl) Boric acid, (2,3,5-trichlorophenyl)boronic acid, intermediate 23, (5-amino-2-chlorophenyl)boronic acid, (3-chloro-5-(trifluoromethyl)phenyl)boronic acid , (5-chloro-2-methylphenyl)boronic acid, (5-fluoro-2-methylphenyl)boronic acid, intermediate 20, (2-chloro-5-(trifluoromethyl)phenyl)boronic acid , Intermediate 21, (2,5-dichlorophenyl)boronic acid, intermediates 22, 24, 25 or 26 and 4-5 are reacted to obtain compounds 1-4-3 to 1-4-40; Intermediate 27 and 4-10 reaction to obtain compound 1--4-41; using intermediate 6-5 and (2,3,5-trichlorophenyl)boronic acid, intermediate 15 or 4-hydroxy-2-trifluoromethylphenylboronic acid Naol ester reaction to obtain compounds 1--4-42～1-4-44; use intermediates 7-6, 6-7, 4-11, 4-12, 6-1, 6-2, 4-7, 7-3, 6-4, 4-8, 6-5, 4-9, 11-1, 4-10, 4-14, 6-6 or 6-9 react with intermediate 2 to obtain compound 1-4- 45～1-4-61; Respectively react with (2-chloro-5-hydroxyphenyl)boronic acid, intermediates 6, 33, 8, 15, 20 and intermediates 6-4 to obtain compound 1-4-52-1 -4-67; use intermediates 11-1, 4-15, 6-5, 6-7, 6-1, 6-2, 6-8, 6-6, 11-2, 6-10, 11 respectively -3, 6-12, 4-9 or 4-10 react with Intermediate 20 to obtain compound 1--4-68～1-4-81; react with Intermediate 7-5, 6-5 or 6-1 and 6 Compounds 1--4-82～1-4-84 are obtained; Compounds 1--4-85～1-4-86 are obtained by reaction with intermediates 6-5 and 27 or 28; Compounds 1--4-86 are obtained with intermediates 28 and 6-1 or 6 8 reaction to obtain compounds 1-4-87～1-4-88; reaction with intermediate 4-12 or 4-13 and intermediate 15 respectively to obtain compounds 1-4-89～1-4-90:
表10Table 10
Figure PCTCN2020118772-appb-000115
Figure PCTCN2020118772-appb-000115
Figure PCTCN2020118772-appb-000116
Figure PCTCN2020118772-appb-000116
Figure PCTCN2020118772-appb-000117
Figure PCTCN2020118772-appb-000117
Figure PCTCN2020118772-appb-000118
Figure PCTCN2020118772-appb-000118
Figure PCTCN2020118772-appb-000119
Figure PCTCN2020118772-appb-000119
Figure PCTCN2020118772-appb-000120
Figure PCTCN2020118772-appb-000120
Figure PCTCN2020118772-appb-000121
Figure PCTCN2020118772-appb-000121
Figure PCTCN2020118772-appb-000122
Figure PCTCN2020118772-appb-000122
Figure PCTCN2020118772-appb-000123
Figure PCTCN2020118772-appb-000123
Figure PCTCN2020118772-appb-000124
Figure PCTCN2020118772-appb-000124
Figure PCTCN2020118772-appb-000125
Figure PCTCN2020118772-appb-000125
Figure PCTCN2020118772-appb-000126
Figure PCTCN2020118772-appb-000126
Figure PCTCN2020118772-appb-000127
Figure PCTCN2020118772-appb-000127
Figure PCTCN2020118772-appb-000128
Figure PCTCN2020118772-appb-000128
Figure PCTCN2020118772-appb-000129
Figure PCTCN2020118772-appb-000129
Figure PCTCN2020118772-appb-000130
Figure PCTCN2020118772-appb-000130
Figure PCTCN2020118772-appb-000131
Figure PCTCN2020118772-appb-000131
Figure PCTCN2020118772-appb-000132
Figure PCTCN2020118772-appb-000132
实施例14：2-((S)-1-丙烯酰基-4-(4-(2-氨基-5-氯吡啶-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈三氟乙酸盐(化合物1-5-1)的合成Example 14: 2-((S)-1-acryloyl-4-(4-(2-amino-5-chloropyridin-4-yl)-7-(((S)-1-methylpyrrolidine) 2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-5-1)
Figure PCTCN2020118772-appb-000133
Figure PCTCN2020118772-appb-000133
利用化合物1-4-2的合成方法，用中间体4-5和18反应得到化合物13A。Using the synthetic method of compound 1-4-2, the reaction of intermediates 4-5 and 18 to obtain compound 13A.
向化合物13A(40mg，0.05mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(1mL)，反应液室温搅拌1小时。然后直接减压浓缩，残留物用prep-HPLC(条件8)纯化得到化合物1-5-1(5.95mg，产率：14％)为淡黄色固体。m/z:[M+H] +587.2。 Trifluoroacetic acid (1 mL) was added to a dichloromethane (3 mL) solution of compound 13A (40 mg, 0.05 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 8) to obtain compound 1-5-1 (5.95 mg, yield: 14%) as a pale yellow solid. m/z: [M+H] + 587.2.
实施例15：2-((S)-1-丙烯酰基-4-(4-(5-氨基-2-氯-3-氟苯基)-7-(((S)-4,4-二氟吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙基三氟乙酸盐(化合物1-5-2)的合成Example 15: 2-((S)-1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)-7-(((S)-4,4-di Fluoropyrrolidin-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)ethyl trifluoroacetate (compound 1-5-2 )Synthesis
Figure PCTCN2020118772-appb-000134
Figure PCTCN2020118772-appb-000134
步骤1：将中间体4-6(0.1g，0.2mmol)和三氟乙酸(1mL)的二氯甲烷(1mL)溶液在40℃下搅拌1小时。然后将反应液浓缩，残留物溶于二氯甲烷(5mL)，用三乙胺调pH至中性。将丙烯酰氯(0.8M的二氯甲烷溶液，0.5mL)加入到上述溶液中，得到的混合物在室温下搅拌1小时。减压浓缩后，残留物经Flash柱层析纯化(乙酸乙酯/ 石油醚＝0-60％)得化合物16A(80mg，产率：91％)为淡黄色固体。m/z:[M+H] +460.0。 Step 1: A solution of Intermediate 4-6 (0.1 g, 0.2 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was stirred at 40°C for 1 hour. Then the reaction solution was concentrated, the residue was dissolved in dichloromethane (5 mL), and the pH was adjusted to neutral with triethylamine. Acrylic chloride (0.8M dichloromethane solution, 0.5 mL) was added to the above solution, and the resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether=0-60%) to obtain compound 16A (80 mg, yield: 91%) as a pale yellow solid. m/z: [M+H] + 460.0.
步骤2：将化合物16A(50.0mg，0.11mmol)，(S)-4,4-二氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(116mg，0.50mmol)，DIPEA(40.7mg，0.33mmol)和碳酸铯(0.64g，1.98mmol)的1,4-二氧六环(1mL)溶液在110℃下搅拌2小时。然后将反应液浓缩，残留物经Flash柱层析(乙酸乙酯/石油醚＝0-70％)纯化得化合物16B(30mg，产率：42％)为黄色油状物。m/z:[M+H] +661.4。 Step 2: Compound 16A (50.0mg, 0.11mmol), (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (116mg, 0.50mmol), DIPEA ( A 1,4-dioxane (1 mL) solution of 40.7 mg, 0.33 mmol) and cesium carbonate (0.64 g, 1.98 mmol) was stirred at 110°C for 2 hours. Then the reaction solution was concentrated, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether=0-70%) to obtain compound 16B (30 mg, yield: 42%) as a yellow oil. m/z: [M+H] + 661.4.
步骤3：化合物16B(30mg，4.5μmol)，中间体2(18mg，0.06mmol)，Pd(PPh 3) 4(5.2mg，4.5μmol)和碳酸钠水溶液(1.0M，0.14mL)的1,4-二氧六环(1.5mL)溶液在120℃下微波反应0.5小时。将反应液冷却至室温后直接减压浓缩，残留物经Flash柱层析(甲醇/二氯甲烷＝0-10％)纯化得化合物16C(15mg，产率：45％)为黄色固体。m/z:[M+H] +726.4。 Step 3: Compound 16B (30mg, 4.5μmol), Intermediate 2 (18mg, 0.06mmol), Pd(PPh 3 ) 4 (5.2mg, 4.5μmol) and 1,4 of sodium carbonate aqueous solution (1.0M, 0.14mL) -Dioxane (1.5 mL) solution was microwaved at 120°C for 0.5 hours. The reaction solution was cooled to room temperature and directly concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol/dichloromethane=0-10%) to obtain compound 16C (15 mg, yield: 45%) as a yellow solid. m/z: [M+H] + 726.4.
步骤2：向化合物16C(15mg，0.02mmol)的二氯甲烷(1mL)溶液中加入三氟乙酸(1mL)，反应液室温搅拌1小时。然后直接减压浓缩，残留物用prep-HPLC(条件2)纯化得到化合物1-5-2(0.72mg，产率：6％)为淡黄色固体。m/z:[M+H] +626.2。 Step 2: Trifluoroacetic acid (1 mL) was added to the dichloromethane (1 mL) solution of compound 16C (15 mg, 0.02 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 1-5-2 (0.72 mg, yield: 6%) as a pale yellow solid. m/z: [M+H] + 626.2.
实施例16：化合物1-5-3～1-5-4的合成Example 16: Synthesis of Compounds 1-5-3～1-5-4
利用化合物1-5-2的合成方法，将步骤2中的(S)-4,4-二氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯替换为(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-甲酸叔丁酯或(S)-4-(二氟亚甲基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯得到化合物1-5-3～1-5-4：Using the synthesis method of compound 1-5-2, replace (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in step 2 with (2S,4R) Tert-Butyl-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate or (S)-4-(difluoromethylene)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Butyl esters give compounds 1-5-3～1-5-4:
表11Table 11
Figure PCTCN2020118772-appb-000135
Figure PCTCN2020118772-appb-000135
实施例17：1-(7-(4-(5-甲基-1H-吲唑-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(化合物1-6-1)的合成Example 17: 1-(7-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )Furo[2,3-f]quinazolin-9-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (compound 1- 6-1) Synthesis
Figure PCTCN2020118772-appb-000136
Figure PCTCN2020118772-appb-000136
利用化合物1-2-4的合成方法，用中间体2-5反应得到化合物1-6-1。m/z:[M+H] +592.4； 1H NMR(400MHz,DMSO-d 6):δ13.16(s,1H),8.15(s,1H),7.58(d,J＝8.4Hz,1H),7.51(s,1H),7.44(s,1H),7.40(d,J＝15.6Hz,1H),6.52(s,1H),6.39(dd,J＝17.2,10.4Hz,1H),6.15(d,J＝16.8Hz,1H),5.70(d,J＝10.8Hz,1H),4.43-4.38(m,1H),4.22-4.17(m,1H),4.06(s,2H),3.77(s,2H),3.52-3.65(m,4H),2.95-2.97(m,1H),2.57-2.60(m,1H),2.37(s,3H),2.23(s,3H),2.15-2.19(m,1H),1.92-1.99(m,5H),1.63-1.70(m,3H). Using the synthetic method of compound 1-2-4, react with intermediate 2-5 to obtain compound 1-6-1. m/z: [M+H] + 592.4; 1 H NMR (400MHz, DMSO-d 6 ): δ 13.16 (s, 1H), 8.15 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H ),7.51(s,1H),7.44(s,1H),7.40(d,J=15.6Hz,1H),6.52(s,1H),6.39(dd,J=17.2,10.4Hz,1H),6.15 (d,J=16.8Hz,1H), 5.70(d,J=10.8Hz,1H),4.43-4.38(m,1H),4.22-4.17(m,1H),4.06(s,2H),3.77( s, 2H), 3.52-3.65 (m, 4H), 2.95-2.97 (m, 1H), 2.57-2.60 (m, 1H), 2.37 (s, 3H), 2.23 (s, 3H), 2.15-2.19 ( m,1H),1.92-1.99(m,5H),1.63-1.70(m,3H).
实施例18：1-(4-(4-(3-羟基萘-1-基)-7-(6-甲基吡啶-3-基)呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-基)丙-2-烯-1-酮(化合物1-7-1)的合成Example 18: 1-(4-(4-(3-hydroxynaphthalen-1-yl)-7-(6-methylpyridin-3-yl)furo[2,3-f]quinazoline-9 -Yl)piperazin-1-yl)prop-2-en-1-one (compound 1-7-1) synthesis
Figure PCTCN2020118772-appb-000137
Figure PCTCN2020118772-appb-000137
步骤1：将中间体4-2(200mg，0.39mmol)，中间体1(118mg，0.37mmol)，碳酸钠水溶液(1.95mL，1M)和Pd(PPh 3) 4(45mg，0.04mmol)的1,4-二氧六环(20mL)混合物置于微波管中，反应体系用氮气置换后，90℃微波反应5小时。然后将反应液冷却至室温用水淬灭反应，水相用乙酸乙酯萃取、合并有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/2)纯化得化合物17A(240mg，产率：100％)为黄色固体。m/z:[M+H] +614.2。 Step 1: Mix Intermediate 4-2 (200mg, 0.39mmol), Intermediate 1 (118mg, 0.37mmol), sodium carbonate aqueous solution (1.95mL, 1M) and Pd(PPh 3 ) 4 (45mg, 0.04mmol) in 1 The mixture of ,4-dioxane (20 mL) was placed in a microwave tube, the reaction system was replaced with nitrogen, and the reaction was performed in a microwave at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 3/2) to obtain the compound 17A (240 mg, yield: 100%) is a yellow solid. m/z: [M+H] + 614.2.
步骤2：将化合物17A(220mg，0.36mmol)，(6-甲基吡啶-3-基)硼酸(128mg，0.93mmol)，碳酸钠水溶液(1.8mL，1M)和Pd(PPh 3) 4(86mg，0.09mmol)的1,4-二氧六环(20mL)混合物置于微波管中，反应体系用氮气置换后在90℃微波反应5小时。然后将反应液冷却至室温用水淬灭反应，水相用乙酸乙酯萃取、分离有机相并减压 浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得化合物17B(230mg，产率：87％)为黄色固体。m/z:[M+H] +671.2。 Step 2: Combine compound 17A (220mg, 0.36mmol), (6-methylpyridin-3-yl)boronic acid (128mg, 0.93mmol), aqueous sodium carbonate (1.8mL, 1M) and Pd(PPh 3 ) 4 (86mg , 0.09mmol) of 1,4-dioxane (20mL) mixture was placed in a microwave tube, the reaction system was replaced with nitrogen and then microwaved at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain the compound 17B (230 mg, yield: 87%) is a yellow solid. m/z: [M+H] + 671.2.
步骤3：将化合物17B(120mg，0.18mmol)的甲醇(10mL)和盐酸(1mL，1M)混合物在50℃下搅拌3小时后直接减压浓缩得到化合物17C(75mg，产率：79％)为黄色固体。m/z:[M+H] +527.2。 Step 3: A mixture of compound 17B (120mg, 0.18mmol) in methanol (10mL) and hydrochloric acid (1mL, 1M) was stirred at 50°C for 3 hours and then directly concentrated under reduced pressure to obtain compound 17C (75mg, yield: 79%) as Yellow solid. m/z: [M+H] + 527.2.
步骤4：向化合物17C(75mg，0.14mmol)和DIPEA(0.5mL)的二氯甲烷(5mL)溶液中滴加丙烯酰酐(0.6mL，0.5M的二氯甲烷溶液)，反应液室温下搅拌3小时。用氨水(5mL)淬灭反应，得到的混合物在室温下搅拌2小时，然后直接减压浓缩，残留物经prep-HPLC(条件5)纯化得到化合物1-7-1(7.12mg，产率：9％)为白色固体。m/z:[M+H] +581.2； 1H NMR(400MHz,DMSO-d 6):δ10.07(br.s,1H),9.54(d,J＝1.2Hz,1H),8.71(dd,J＝1.6,8.0Hz,1H),8.33(s,1H),7.86-7.82(m,2H),7.55-7.42(m,3H),7.31(d,J＝2.0Hz,1H),7.22-7.20(m,2H),6.96(dd,J＝2.4,14.0Hz,1H),6.63(d,J＝2.0Hz,1H),6.25(dd,J＝2.0,16.4Hz,1H),5.83(d,J＝10.4,1H),5.30-5.00(m,1H),4.62-4.18(m,3H),3.90-3.51(m,2H),3.29-3.06(m,3H),2.57(s,3H). Step 4: To compound 17C (75mg, 0.14mmol) and DIPEA (0.5mL) in dichloromethane (5mL) solution was added dropwise acryloyl anhydride (0.6mL, 0.5M dichloromethane solution), and the reaction mixture was stirred at room temperature 3 hours. The reaction was quenched with ammonia water (5 mL), the resulting mixture was stirred at room temperature for 2 hours, and then directly concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 5) to obtain compound 1-7-1 (7.12 mg, yield: 9%) is a white solid. m/z: [M+H] + 581.2; 1 H NMR (400MHz, DMSO-d 6 ): δ10.07 (br.s, 1H), 9.54 (d, J = 1.2 Hz, 1H), 8.71 (dd ,J=1.6,8.0Hz,1H),8.33(s,1H),7.86-7.82(m,2H),7.55-7.42(m,3H),7.31(d,J=2.0Hz,1H),7.22- 7.20 (m, 2H), 6.96 (dd, J = 2.4, 14.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.25 (dd, J = 2.0, 16.4 Hz, 1H), 5.83 (d ,J=10.4,1H),5.30-5.00(m,1H),4.62-4.18(m,3H),3.90-3.51(m,2H),3.29-3.06(m,3H),2.57(s,3H) .
实施例19：2-((S)-4-(4-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈三氟乙酸盐(化合物1-8-1)的合成Example 19: 2-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((S)-1 -Methylpyrrolidin-2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Synthesis of fluoroacetate (compound 1-8-1)
Figure PCTCN2020118772-appb-000138
Figure PCTCN2020118772-appb-000138
步骤1：氮气保护下，将中间体6-1(130mg，0.23mmol)、联硼酸频那醇酯(120mg，0.47mmol)、PdCl 2dppf .CH 2Cl 2(38mg，0.05mmol)和醋酸钾(68mg，0.69mmol)的1,4-二氧六环(5mL)溶液在100℃下搅拌16小时。反应体系冷却至室温后用乙酸乙酯(50mL)稀释，饱和食盐水洗涤，分离有机相并减压浓缩得到化合物18A(粗品)为黄色固体。m/z:[M+H] +605.2。 Step 1: Under the protection of nitrogen, the intermediate 6-1 (130mg, 0.23mmol), pinacol diborate (120mg, 0.47mmol), PdCl 2 dppf . CH 2 Cl 2 (38mg, 0.05mmol) and potassium acetate A solution of 1,4-dioxane (5 mL) (68 mg, 0.69 mmol) was stirred at 100°C for 16 hours. The reaction system was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with saturated brine, the organic phase was separated and concentrated under reduced pressure to obtain compound 18A (crude) as a yellow solid. m/z: [M+H] + 605.2.
步骤2：向化合物18A(粗品)的1,4-二氧六环(7mL)溶液中依次加入6-氯-4-甲基-5-(三氟甲基)吡啶-2-胺(70mg，0.33mmol)，Pd(PPh 3) 4(53mg，0.046mmol)和碳酸钠水溶液(1.0M，0.7mL)。反应体系鼓吹氮气2分钟，在120℃下微波反应0.5小时。反应体系冷却至室温后用乙酸乙酯(50mL)稀释，饱和食盐水洗涤，分离有机相并减压浓缩，残留物用prep-HPLC(条件6)纯化得化合物1-8-1(4.3mg，产率：3％)为白色固体。m/z:[M+H] +653.2； 1H NMR(400MHz,DMSO-d 6):δ8.22(d,J＝2.4Hz,1H),7.31(s,1H),6.77(s,2H),6.75(d,J＝2.0Hz,1H),6.49(s,1H),5.45-4.52(m,4H),4.41-4.37(m, 1H),4.23-4.13(m,3H),4.02-3.99(m,1H),3.13-3.06(m,2H),3.02-2.96(m,1H),2.65-2.56(m,1H),2.39(s,3H),2.39(s,3H),2.25-2.15(m,1H),2.03-1.93(m,1H),1.71-1.62(m,3H),1.28-1.23(m,2H)。 Step 2: Add 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine (70mg, 0.33 mmol), Pd(PPh 3 ) 4 (53 mg, 0.046 mmol) and aqueous sodium carbonate (1.0 M, 0.7 mL). The reaction system was blown with nitrogen for 2 minutes, and reacted in a microwave at 120°C for 0.5 hours. The reaction system was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with saturated brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 6) to obtain compound 1-8-1 (4.3 mg, Yield: 3%) is a white solid. m/z: [M+H] + 653.2; 1 H NMR (400MHz, DMSO-d 6 ): δ8.22(d,J=2.4Hz,1H),7.31(s,1H),6.77(s,2H ), 6.75(d,J=2.0Hz,1H),6.49(s,1H),5.45-4.52(m,4H),4.41-4.37(m, 1H),4.23-4.13(m,3H),4.02- 3.99(m,1H),3.13-3.06(m,2H),3.02-2.96(m,1H),2.65-2.56(m,1H), 2.39(s,3H), 2.39(s,3H), 2.25 2.15 (m, 1H), 2.03-1.93 (m, 1H), 1.71-1.62 (m, 3H), 1.28-1.23 (m, 2H).
实施例20：化合物1-8-2～1-8-5的合成Example 20: Synthesis of Compounds 1-8-2～1-8-5
利用化合物1-8-1合成方法，分别用中间体6-1、6-10或6-8和相应的胺反应得到化合物1-8-2～1-8-5：Using the synthetic method of compound 1-8-1, the intermediates 6-1, 6-10 or 6-8 are reacted with the corresponding amines to obtain compounds 1-8-2～1-8-5:
表12Table 12
Figure PCTCN2020118772-appb-000139
Figure PCTCN2020118772-appb-000139
实施例21：1-(4-(4-(5-甲基-1H-吲唑-4-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1H-吡 唑并[3,4-f]喹唑啉-9-基)哌嗪-1-基)丙-2-烯-1-酮(化合物2-1-1)的合成Example 21: 1-(4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )-1H-pyrazolo[3,4-f]quinazolin-9-yl)piperazin-1-yl)prop-2-en-1-one (Compound 2-1-1)
Figure PCTCN2020118772-appb-000140
Figure PCTCN2020118772-appb-000140
步骤1：将中间体3-9(106mg，0.2mmol)，N-甲基-L-脯氨醇(111mg，0.8mmol)，DIPEA(250mg，0.4mmol)和碳酸铯(188mg，0.5mmol)的1,4二氧六环(2.5mL)溶液在封管中170℃搅拌3小时。反应混合物过滤，滤液减压浓缩，残留物经Flash柱层析(甲醇/二氯甲烷＝1/3)纯化得化合物7A(115mg，产率：95％)为淡黄色固体。m/z:[M+H] +632.3。 Step 1: The intermediate 3-9 (106mg, 0.2mmol), N-methyl-L-prolinol (111mg, 0.8mmol), DIPEA (250mg, 0.4mmol) and cesium carbonate (188mg, 0.5mmol) The 1,4 dioxane (2.5 mL) solution was stirred at 170°C for 3 hours in a sealed tube. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane = 1/3) to obtain compound 7A (115 mg, yield: 95%) as a pale yellow solid. m/z: [M+H] + 632.3.
步骤2：将化合物7A(46.8mg，74.2μmol)，5-甲基-1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吲唑(30.5mg，89.1μmol)，PdCl 2dppf .CH 2Cl 2(6mg，7.3μmol)，碳酸钠水溶液(1M，222μmol)的1,4二氧六环(25mL)混合物用氮气置换3次。反应体系在100℃下搅拌3小时，然后冷却至室温，过滤，滤液减压浓缩，残留物用Flash柱层析(甲醇/二氯甲烷＝1/6)纯化得到化合物7B(40.3mg，产率:71％)为淡黄色固体。 Step 2: The compound 7A (46.8mg, 74.2μmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxoboran-2-yl)-1H-indazole (30.5mg, 89.1μmol), PdCl 2 dppf . CH 2 Cl 2 (6mg, 7.3μmol), sodium carbonate aqueous solution (1M, 222μmol) ) 1,4 dioxane (25 mL) mixture was replaced with nitrogen 3 times. The reaction system was stirred at 100°C for 3 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol/dichloromethane=1/6) to obtain compound 7B (40.3 mg, yield : 71%) is a pale yellow solid.
步骤3：向化合物7B(40.3mg,52.6μmol)的二氯甲烷(5mL)溶液中滴加三氟醋酸(1mL)。反应液室温搅拌5小时后减压浓缩得化合物7C(粗品)为棕色固体。m/z:[M+H] +498.3。 Step 3: Add trifluoroacetic acid (1 mL) dropwise to a solution of compound 7B (40.3 mg, 52.6 μmol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature for 5 hours and then concentrated under reduced pressure to obtain compound 7C (crude product) as a brown solid. m/z: [M+H] + 498.3.
步骤4：冰水浴下，向化合物7C(粗品)的二氯甲烷(3mL)溶液中分别加入DIPEA(17.1mg，133μmol)和丙烯酸酐(5.6mg，44.2μmol)。反应液室温搅拌5分钟后加入1滴氨水淬灭反应，得到的混合物减压浓缩后经prep-HPLC(条件2)纯化得化合物2-1-1(3.01mg，两步产率：12％)为白色固体。m/z:[M+H] +552.3； 1H NMR(400MHz,DMSO-d 6):δ13.28(s,1H),13.16(s,1H),7.64(s,1H),7.58(d,J＝8.8Hz,1H),7.51(s,1H),7.41(d,J＝8.8Hz,1H),7.26(s,1H),6.91-6.85(m,1H),6.19(dd,J＝16.4,2.0Hz,1H),5.77-5.73(m,1H),4.47-4.44(m,2H),3.89-3.84(m,4H),3.69-3.59(m,4H),3.31(s,3H),2.26(s,3H),1.74-1.65(m,4H),1.26-1.22(m,3H)。 Step 4: Under an ice water bath, DIPEA (17.1 mg, 133 μmol) and acrylic anhydride (5.6 mg, 44.2 μmol) were added to the dichloromethane (3 mL) solution of compound 7C (crude product), respectively. The reaction solution was stirred at room temperature for 5 minutes, and 1 drop of ammonia was added to quench the reaction. The resulting mixture was concentrated under reduced pressure and purified by prep-HPLC (condition 2) to obtain compound 2-1-1 (3.01 mg, two-step yield: 12%) It is a white solid. m/z: [M+H] + 552.3; 1 H NMR (400MHz, DMSO-d 6 ): δ 13.28 (s, 1H), 13.16 (s, 1H), 7.64 (s, 1H), 7.58 (d ,J=8.8Hz,1H),7.51(s,1H),7.41(d,J=8.8Hz,1H),7.26(s,1H),6.91-6.85(m,1H),6.19(dd,J= 16.4, 2.0Hz, 1H), 5.77-5.73 (m, 1H), 4.47-4.44 (m, 2H), 3.89-3.84 (m, 4H), 3.69-3.59 (m, 4H), 3.31 (s, 3H) , 2.26 (s, 3H), 1.74-1.65 (m, 4H), 1.26-1.22 (m, 3H).
实施例22：2-((S)-1-丙烯酰基-4-(4-(5-氨基-2-氯-3-氟苯基)-7-(((S)-1-甲基吡咯烷-2-基) 甲氧基)-1H-吡唑并[3,4-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物2-1-2)的合成Example 22: 2-((S)-1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)-7-(((S)-1-methylpyrrole) (Alk-2-yl)methoxy)-1H-pyrazolo[3,4-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 2-1-2)
Figure PCTCN2020118772-appb-000141
Figure PCTCN2020118772-appb-000141
将中间体8-5(30mg，55.6μmol)，中间体2(30mg，111μmol)，Pd(PPh 3) 4(5mg，5.5μmol)，碳酸钠水溶液(1M，17.7mg，167μmol)分别加入到1,4二氧六环(25mL)中。反应混合物用氮气置换后130℃下微波反应0.5小时，将反应液冷却至室温后过滤，滤液减压浓缩，残留物经prep-HPLC(条件2)纯化得化合物2-1-2(1.18mg，产率：3％)为白色固体。m/z:[M+H] +604.3； 1H NMR(400MHz,DMSO-d 6):δ9.73(s,1H),7.84-7.77(m,2H),7.63-7.56(m,1H),7.22-7.20(m,1H),6.89(s,2H),6.65-6.58(m,2H),6.24-6.20(m,1H),5.81-5.73(m,1H),4.25-4.20(m,4H),3.30(s,3H),3.31(s,3H),2.13-2.09(m,4H),2.03-1.91(m,4H),1.26-1.22(m,2H)。 Intermediate 8-5 (30mg, 55.6μmol), Intermediate 2 (30mg, 111μmol), Pd(PPh 3 ) 4 (5mg, 5.5μmol), sodium carbonate aqueous solution (1M, 17.7mg, 167μmol) were added to 1 , 4 in dioxane (25mL). The reaction mixture was replaced with nitrogen and reacted in a microwave at 130°C for 0.5 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 2) to obtain compound 2-1-2 (1.18 mg, Yield: 3%) is a white solid. m/z: [M+H] + 604.3; 1 H NMR (400MHz, DMSO-d 6 ): δ9.73 (s, 1H), 7.84-7.77 (m, 2H), 7.63-7.56 (m, 1H) , 7.22-7.20 (m, 1H), 6.89 (s, 2H), 6.65-6.58 (m, 2H), 6.24-6.20 (m, 1H), 5.81-5.73 (m, 1H), 4.25-4.20 (m, 4H), 3.30 (s, 3H), 3.31 (s, 3H), 2.13-2.09 (m, 4H), 2.03-1.91 (m, 4H), 1.26-1.22 (m, 2H).
实施例23：2-((S)-1-丙烯酰基-4-(4-(5-氨基-2-氯-3-氟苯基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[3,4-f]喹唑啉-9-基)哌嗪-2-基)乙腈(化合物3-1-1)的合成Example 23: 2-((S)-1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)-7-(((S)-1-methylpyrrole) (Alk-2-yl)methoxy)-2,3-dihydrofuro[3,4-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile (compound 3-1-1) Synthesis
Figure PCTCN2020118772-appb-000142
Figure PCTCN2020118772-appb-000142
将中间体9-9(40mg，74.2μmol)，中间体2(25mg，89μmol)，PdCl 2dppf .CH 2Cl 2(6mg，7.4μmol)，碳酸钠水溶液(1M，0.5mL)分别加入到1,4二氧六环(4mL)中。反应混合物用氮气置换后120℃下微波反应1小时，将反应液冷却至室温后过滤，滤液减压浓缩，残留物经prep-HPLC(条件5)纯化得化合物3-1-1(3mg，产率：12％)为淡黄色固体。m/z:[M+H] +606.3； 1H NMR(400MHz,DMSO-d 6):δ6.95(s,1H),6.93-6.83(m,2H),6.58(dd,J＝2.0,12.0Hz,1H),6.43(s,1H),6.21(dd,J＝2.0,12.0Hz,1H),5.80(d,J＝10.8Hz,1H),5.74(s,1H),4.81(t,J＝8.4Hz,2H),4.39-4.33(m,1H),4.30-4.06(m,2H),4.01-3.90(m,1H),3.13-3.02(m,3H),2.98-2.92(m,1H),2.45-2.37(m,3H),2.06-1.95(m,2H),1.80-1.59(m,3H),1.55-0.82(m,7H)。 Intermediate 9-9 (40mg, 74.2μmol), intermediate 2 (25mg, 89μmol), PdCl 2 dppf . CH 2 Cl 2 (6mg, 7.4μmol), sodium carbonate aqueous solution (1M, 0.5mL) were added to 1 , 4 Dioxane (4mL). The reaction mixture was replaced with nitrogen and reacted in a microwave at 120°C for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Condition 5) to obtain compound 3-1-1 (3 mg, product). Rate: 12%) is a pale yellow solid. m/z:[M+H] + 606.3; 1 H NMR(400MHz,DMSO-d 6 ):δ6.95(s,1H),6.93-6.83(m,2H),6.58(dd,J=2.0, 12.0Hz, 1H), 6.43 (s, 1H), 6.21 (dd, J = 2.0, 12.0 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 5.74 (s, 1H), 4.81 (t, J = 8.4Hz, 2H), 4.39-4.33 (m, 1H), 4.30-4.06 (m, 2H), 4.01-3.90 (m, 1H), 3.13-3.02 (m, 3H), 2.98-2.92 (m, 1H), 2.45-2.37 (m, 3H), 2.06-1.95 (m, 2H), 1.80-1.59 (m, 3H), 1.55-0.82 (m, 7H).
实施例24：化合物3-1-2～3-1-16的合成Example 24: Synthesis of Compounds 3-1-2～3-1-16
利用化合物3-1-1或1-4-2的合成方法，分别用中间体2、20、28、27或(5-氯异喹啉-4-基)硼酸和中间体6-3反应得到化合物3-1-2～3-1-6；用中间体6-11和中间体20、28或 625反应得到化合物3-1-7～3-1-9；用中间体6-13、6-14、6-15、6-16或6-18和中间体20反应得到化合物3-1-10～3-1-14；用中间体6-15和中间体28或27反应得到化合物3-1-15～3-1-16：Using the synthetic method of compound 3-1-1 or 1-4-2, reacting with intermediate 2, 20, 28, 27 or (5-chloroisoquinolin-4-yl)boronic acid and intermediate 6-3, respectively Compounds 3-1-2～3-1-6; react with intermediate 6-11 and intermediates 20, 28 or 625 to obtain compounds 3-1-7～3-1-9; use intermediates 6-13, 6 -14, 6-15, 6-16 or 6-18 react with intermediate 20 to obtain compound 3-1-10～3-1-14; react with intermediate 6-15 and intermediate 28 or 27 to obtain compound 3- 1-15～3-1-16:
表13Table 13
Figure PCTCN2020118772-appb-000143
Figure PCTCN2020118772-appb-000143
Figure PCTCN2020118772-appb-000144
Figure PCTCN2020118772-appb-000144
Figure PCTCN2020118772-appb-000145
Figure PCTCN2020118772-appb-000145
Figure PCTCN2020118772-appb-000146
Figure PCTCN2020118772-appb-000146
实施例25：1-(4-(4-(5-氨基-2-(三氟甲基)苯基)-7-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2-(羟甲基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)哌嗪-1-基)丙-2-烯-1-酮(化合物3-2-1)的合成Example 25: 1-(4-(4-(5-amino-2-(trifluoromethyl)phenyl)-7-(((2S,4R)-4-fluoro-1-methylpyrrolidine- 2-yl)methoxy)-2-(hydroxymethyl)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)piperazin-1-yl)propan-2 -En-1-one (Compound 3-2-1) Synthesis
Figure PCTCN2020118772-appb-000147
Figure PCTCN2020118772-appb-000147
步骤1：将中间体10-13(50mg，0.09mmol)，中间体20(22mg，0.09mmol)，Pd(PPh 3) 4(9mg，0.0,1mmol)，碳酸钠水溶液(0.3mL，1M)加入到1,4二氧六环(4mL)中。反应体系在氮气保护下110℃搅拌1个小时后过滤，滤液减压浓缩，残留物经Flash柱层析(二氯甲烷/甲醇＝20/1)纯化得化合物20A(40mg，产率：70％)为黄色固体。m/z:[M+H] +673.2。 Step 1: Add Intermediate 10-13 (50mg, 0.09mmol), Intermediate 20 (22mg, 0.09mmol), Pd(PPh 3 ) 4 (9mg, 0.0, 1mmol), sodium carbonate aqueous solution (0.3mL, 1M) Into 1,4 dioxane (4mL). The reaction system was stirred at 110°C under nitrogen protection for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=20/1) to obtain compound 20A (40mg, yield: 70%) ) Is a yellow solid. m/z: [M+H] + 673.2.
步骤2：冰浴条件下，将化合物20A(40mg，0.06mmol)溶解在乙腈中(5mL)，加入氢氧化锂水溶液(1M，0.6mL)，反应体系在此温度下搅拌1小时。然后用乙酸乙酯/四氢呋喃混合溶剂(10/1)萃取，分离有机相并浓缩，残留物经prep-HPLC(条件5)纯化得化合物3-2-1(3.9mg，产率：11％)为白色固体。m/z:[M+H] +631.3； 1H NMR(400MHz,DMSO-d 6):δ7.44(d,J＝8.8Hz,1H),6.88-6.82(m,2H),6.67(d,J＝8.4Hz,1H),6.45(d,J＝8.4Hz,1H),6.16(dd,J＝2.0,16.4Hz,1H),5.94(br.s,2H),5.73(dd,J＝2.0,10.4Hz,1H),5.26(br.s,1H),5.11-5.00(m,2H),4.39-4.21(m,2H),3.84-3.75(m,3H),3.64-3.42(m,4H),3.04-2.86(m,3H),2.77-2.70(m,1H),2.39(s,3H),2.18-1.24(m,6H)。 Step 2: Under ice bath conditions, dissolve compound 20A (40 mg, 0.06 mmol) in acetonitrile (5 mL), add aqueous lithium hydroxide solution (1M, 0.6 mL), and stir the reaction system at this temperature for 1 hour. Then it was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated, and the residue was purified by prep-HPLC (condition 5) to obtain compound 3-2-1 (3.9 mg, yield: 11%) It is a white solid. m/z: [M+H] + 631.3; 1 H NMR (400MHz, DMSO-d 6 ): δ7.44 (d, J = 8.8Hz, 1H), 6.88-6.82 (m, 2H), 6.67 (d ,J=8.4Hz,1H), 6.45(d,J=8.4Hz,1H), 6.16(dd,J=2.0,16.4Hz,1H), 5.94(br.s,2H), 5.73(dd,J= 2.0, 10.4 Hz, 1H), 5.26 (br.s, 1H), 5.11-5.00 (m, 2H), 4.39-4.21 (m, 2H), 3.84-3.75 (m, 3H), 3.64-3.42 (m, 4H), 3.04-2.86 (m, 3H), 2.77-2.70 (m, 1H), 2.39 (s, 3H), 2.18-1.24 (m, 6H).
实施例26：2-((S)-4-(4-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-7-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈三氟乙酸盐(化合物3-3-1)的合成Example 26: 2-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-1-(2- Synthesis of fluoroacryloyl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 3-3-1)
Figure PCTCN2020118772-appb-000148
Figure PCTCN2020118772-appb-000148
将化合物12-1(106mg，0.17mmol)，6-氯-4-甲基-5-(三氟甲基)吡啶-2-胺(36mg，0.17mmol)，碳酸钠水溶液(1.0M，0.5mL)和Pd(PPh 3) 4(20mg，0.017mmol)加入到1,4-二氧六环中(2mL)，反应混合物氮气置换后，在120℃下微波反应1小时，然后直接减压浓缩，残留物用prep-HPLC(条件6)纯化得化合物3-3-1(22mg，产率：19％)为黄色固体。m/z:[M+H] +673.2；1H NMR(400MHz,DMSO-d 6):δ10.30(br.s,2H),6.91(s,1H),6.87-6.67(m,2H),6.45(s,1H),5.57-5.52(m,1H),5.45-5.37(m,2H),5.27-5.22(m,1H),4.84-4.75(m,3H),4.63-4.58(m,1H),4.28-4.19(m,2H),4.16-4.08(m,2H),4.05-3.94(m,2H),3.38-3.28(m,2H),3.24-3.10(m,3H),3.04(s,3H),2.36-2.35(m,3H),2.33-2.32(m,2H)。 Compound 12-1 (106mg, 0.17mmol), 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine (36mg, 0.17mmol), sodium carbonate aqueous solution (1.0M, 0.5mL ) And Pd(PPh 3 ) 4 (20 mg, 0.017 mmol) were added to 1,4-dioxane (2 mL), the reaction mixture was replaced with nitrogen, reacted in microwave at 120°C for 1 hour, and then directly concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 6) to obtain compound 3-3-1 (22 mg, yield: 19%) as a yellow solid. m/z: [M+H] + 673.2; 1H NMR (400MHz, DMSO-d 6 ): δ10.30 (br.s, 2H), 6.91 (s, 1H), 6.87-6.67 (m, 2H), 6.45 (s, 1H), 5.57-5.52 (m, 1H), 5.45-5.37 (m, 2H), 5.27-5.22 (m, 1H), 4.84-4.75 (m, 3H), 4.63-4.58 (m, 1H) ), 4.28-4.19 (m, 2H), 4.16-4.08 (m, 2H), 4.05-3.94 (m, 2H), 3.38-3.28 (m, 2H), 3.24-3.10 (m, 3H), 3.04 (s ,3H),2.36-2.35(m,3H),2.33-2.32(m,2H).
实施例27：6-氨基-2-(9-((S)-3-(氰基甲基)-4-(2-氟丙烯酰基)哌嗪-1-基)-7-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-4-基)-3-(三氟甲基)异烟腈三氟乙酸盐(化合物3-3-2)的合成Example 27: 6-Amino-2-(9-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-7-(((S )-1-Methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-4-yl)-3-(trifluoromethyl) Synthesis of isonicotinonitrile trifluoroacetate (compound 3-3-2)
Figure PCTCN2020118772-appb-000149
Figure PCTCN2020118772-appb-000149
步骤1：氮气保护下，将6-(二(4-甲氧基苄基)氨基)-2-氯-3-(三氟甲基)异烟腈(130mg，0.28mmol)，12-2(120mg，0.19mmol)、PdCl 2dppf .CH 2Cl 2(30mg，0.04mmol)和氟化钾(120mg，2.07mmol)的1,4-二氧六环和水(6.6mL/3.0mL)混合溶液在120℃下微波反应0.5小时。反应混合物冷却至室温，减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得化合物19A(100mg，产率：56％)为黄色固体。m/z:[M+H] +934.7。 Step 1: Under the protection of nitrogen, 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-(trifluoromethyl)isonicotinonitrile (130mg, 0.28mmol), 12-2( 120mg, 0.19mmol), PdCl 2 dppf . CH 2 Cl 2 (30mg, 0.04mmol) and potassium fluoride (120mg, 2.07mmol) in 1,4-dioxane and water (6.6mL/3.0mL) mixed solution Microwave reaction at 120°C for 0.5 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol=10/1) to obtain compound 19A (100 mg, yield: 56%) as a yellow solid. m/z: [M+H] + 934.7.
步骤2：氮气保护下，将化合物19A(90mg，0.09mmol)的三氟乙酸(5.0mL)溶液在50℃下搅拌4小时。反应混合物冷却至室温，减压浓缩，残留物用饱和碳酸氢钠水溶液调pH到8，水相用二氯甲烷萃取，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩， 残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得化合物19B(80mg，粗品)为黑色油状物。m/z:[M+H] +594.0。 Step 2: Under the protection of nitrogen, a solution of compound 19A (90 mg, 0.09 mmol) in trifluoroacetic acid (5.0 mL) was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purified by Flash column chromatography (dichloromethane/methanol=10/1) to obtain compound 19B (80 mg, crude product) as a black oil. m/z: [M+H] + 594.0.
步骤3：冰浴条件下，向化合物19B(70mg，0.12mmol)，1-丙基磷酸酐(50％乙酸乙酯溶液，2.40mmol)和DIPEA(774mg，6.0mmol)的无水乙酸乙酯/二氯甲烷(10.0mL/2.0mL)溶液中加入2-氟丙烯酸(53mg，0.59mmol)，反应液在室温下搅拌1小时。用二氯甲烷(100mL)稀释，有机相用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得化合物3-3-2(10.1mg，两步产率：13％)为白色固体。m/z:[M+H] +666.3； 1H NMR(400MHz,DMSO-d 6):δ9.71(s,1H),7.55(s,1H),7.05(s,1H),5.45-5.24(m,2H),4.84-4.80(m,1H),4.69-4.51(m,1H),4.21-4.17(m,1H),3.98-3.95(m,1H),3.84-3.76(m,1H),3.60-3.57(m,2H),3.54-3.46(m,4H),3.31-3.27(m,3H),3.13-3.08(m,4H),2.96(s,3H),2.34-2.33(m,1H),2.28-2.24(m,1H),2.07-1.87(m,3H)。 Step 3: Under ice bath conditions, add compound 19B (70 mg, 0.12 mmol), 1-propyl phosphoric anhydride (50% ethyl acetate solution, 2.40 mmol) and DIPEA (774 mg, 6.0 mmol) in anhydrous ethyl acetate/ 2-Fluoroacrylic acid (53 mg, 0.59 mmol) was added to the dichloromethane (10.0 mL/2.0 mL) solution, and the reaction solution was stirred at room temperature for 1 hour. Dilute with dichloromethane (100 mL), wash the organic phase with saturated brine, separate the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use Flash column chromatography (dichloromethane/methanol=10/ 1) Purified compound 3-3-2 (10.1 mg, two-step yield: 13%) as a white solid. m/z: [M+H] + 666.3; 1 H NMR(400MHz,DMSO-d 6 ): δ9.71(s,1H),7.55(s,1H),7.05(s,1H),5.45-5.24 (m,2H),4.84-4.80(m,1H),4.69-4.51(m,1H),4.21-4.17(m,1H),3.98-3.95(m,1H),3.84-3.76(m,1H) , 3.60-3.57(m,2H),3.54-3.46(m,4H),3.31-3.27(m,3H),3.13-3.08(m,4H),2.96(s,3H),2.34-2.33(m, 1H), 2.28-2.24 (m, 1H), 2.07-1.87 (m, 3H).
实施例28：化合物3-3-3～3-3-9的合成Example 28: Synthesis of Compounds 3-3-3～3-3-9
利用化合物3-3-1的合成方法，用6-氯-5-(三氟甲基)吡啶-2-胺和中间体6-11反应得到化合物3-3-3；利用化合物3-3-2的合成方法，分别用中间体12-2和6-氯-N,N-二(4-甲氧基苄基)-5-(三氟甲基)吡嗪-2-胺、6-氯-4-甲氧基-5-(三氟甲基)吡啶-2-胺、6-氯-4-甲基-5-(三氟甲基)吡啶-2-胺或6-氯-5-(三氟甲基)吡啶-2-胺反应得到化合物3-3-4～3-3-7；用中间体9-11和20为起始原料，步骤3中的2-氟丙烯酸替换为(E)-4-氟丁-2-烯酸得到化合物3-3-8；用中间体12-2和6-氯-4-甲基-5-(三氟甲基)吡啶-2-胺为起始原料，将步骤3中的2-氟丙烯酸替换为(E)-4-甲氧基丁-2-烯酸反应得到化合物3-3-9：Using the synthetic method of compound 3-3-1, 6-chloro-5-(trifluoromethyl)pyridine-2-amine and intermediate 6-11 are used to react to obtain compound 3-3-3; compound 3-3- 2 synthesis method, respectively using intermediate 12-2 and 6-chloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyrazine-2-amine, 6-chloro -4-Methoxy-5-(trifluoromethyl)pyridin-2-amine, 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine or 6-chloro-5- (Trifluoromethyl)pyridine-2-amine is reacted to obtain compounds 3-3-4～3-3-7; Intermediates 9-11 and 20 are used as starting materials, and 2-fluoroacrylic acid in step 3 is replaced by ( E)-4-fluorobut-2-enoic acid to obtain compound 3-3-8; using intermediate 12-2 and 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine as Starting material, replace the 2-fluoroacrylic acid in step 3 with (E)-4-methoxybut-2-enoic acid, and react to obtain compound 3-3-9:
表14Table 14
Figure PCTCN2020118772-appb-000150
Figure PCTCN2020118772-appb-000150
Figure PCTCN2020118772-appb-000151
Figure PCTCN2020118772-appb-000151
实施例29：1-((S)-4-(4-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-7-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3-二氢呋喃并[2,3-f]喹唑啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮(化合物3-3-10)的合成Example 29: 1-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-3-methylpiper Synthesis of azin-1-yl)prop-2-en-1-one (compound 3-3-10)
Figure PCTCN2020118772-appb-000152
Figure PCTCN2020118772-appb-000152
向化合物19C(利用化合物19B的合成方法，用中间体12-3和6-氯-4-甲氧基-5-(三氟甲基)吡啶-2-胺反应得到)(120mg，0.2mmol)的二氯甲烷(5mL)溶液中滴加丙烯酰氯(0.8M的二氯甲烷溶液，0.5mL)，得到的混合物在室温搅拌1小时。减压浓缩后，残留物经prep-HPLC纯化(条件5)得化合物3-3-10(42mg，产率：32％)为白色固体。m/z:[M+H] +630.4； 1H NMR(400MHz,DMSO-d 6):δ6.98-6.80(m,2H),6.77-6.67(m,2H),6.42(s,1H),6.20-6.14(m,1H),5.75(dd,J＝2.0,10.4Hz,1H),5.25-5.11(m,1H),4.78(t,J＝8.8Hz,2H),4.50-4.29(m,3H),4.25-4.20(m,1H),4.15-3.95(m,1H),3.81-3.78(m,1H),3.55-3.45(m,1H),3.36-3.26(m,2H),3.14-2.86(m,4H),2.48-2.42(m,1H),2.39(s,3H),2.36(s,3H),2.18-1.11(m,5H)。 To compound 19C (using the synthetic method of compound 19B, reacting with intermediate 12-3 and 6-chloro-4-methoxy-5-(trifluoromethyl)pyridin-2-amine) (120mg, 0.2mmol) Acrylic acid chloride (0.8M dichloromethane solution, 0.5 mL) was added dropwise to the dichloromethane (5 mL) solution of the resulting mixture, and the resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by prep-HPLC (condition 5) to obtain compound 3-3-10 (42 mg, yield: 32%) as a white solid. m/z: [M+H] + 630.4; 1 H NMR (400MHz, DMSO-d 6 ): δ 6.98-6.80 (m, 2H), 6.77-6.67 (m, 2H), 6.42 (s, 1H) ,6.20-6.14(m,1H),5.75(dd,J=2.0,10.4Hz,1H),5.25-5.11(m,1H),4.78(t,J=8.8Hz,2H),4.50-4.29(m ,3H),4.25-4.20(m,1H),4.15-3.95(m,1H),3.81-3.78(m,1H),3.55-3.45(m,1H),3.36-3.26(m,2H),3.14 -2.86(m,4H), 2.48-2.42(m,1H), 2.39(s,3H), 2.36(s,3H), 2.18-1.11(m,5H).
实施例30：9-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-6-(2-异丙基苯基)-4-(5-甲基-1H-吲唑-4-基)呋喃并[2,3-f]喹唑啉-7(6H)-酮(化合物4-1-1)的合成Example 30: 9-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-(2-isopropylphenyl)-4-(5-methyl-1H- Synthesis of indazol-4-yl)furo[2,3-f]quinazolin-7(6H)-one (Compound 4-1-1)
Figure PCTCN2020118772-appb-000153
Figure PCTCN2020118772-appb-000153
步骤1：向中间体15-7(95mg，0.16mmol)的1,4-二氧六环(5mL)溶液中分别加入(5-甲基-1H-吲唑-4-基)硼酸(58mg，0.33mmol)，Pd(PPh 3) 4(19mg，0.016mmol)和碳酸钠水溶液(0.48mL，0.48mmol)。反应混合物氮气鼓泡1-2分钟后，在微波条件下160℃反应0.5小时，然后将反应液冷却至室温后减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/4)纯化得化合物10A(79mg，产率：76％)为淡黄色固体。m/z:[M+H] +633.3。 Step 1: To a solution of Intermediate 15-7 (95mg, 0.16mmol) in 1,4-dioxane (5mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (58mg, 0.33 mmol), Pd(PPh 3 ) 4 (19 mg, 0.016 mmol) and aqueous sodium carbonate (0.48 mL, 0.48 mmol). After bubbling the reaction mixture with nitrogen for 1-2 minutes, it was reacted at 160°C for 0.5 hours under microwave conditions, and then the reaction solution was cooled to room temperature and concentrated under reduced pressure. 4) Purified compound 10A (79 mg, yield: 76%) as a pale yellow solid. m/z: [M+H] + 633.3.
步骤2：将化合物10A(79mg，0.12mmol)的二氯甲烷(10mL)和三氟乙酸(1mL)混合溶液在室温搅拌2小时后直接减压浓缩得到化合物10B(粗品)为黄色固体。m/z:[M+H] +533.3。 Step 2: A mixed solution of compound 10A (79 mg, 0.12 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 10B (crude product) as a yellow solid. m/z: [M+H] + 533.3.
步骤3：冰水浴下，向化合物10B(粗品)的无水二氯甲烷(10mL)溶液中分别加入DIPEA(78mg，0.60mmol)和丙烯酸酐的二氯甲烷溶液(0.25M，0.59mL，0.15mmol)。反应混合物在此温度下搅拌1小时后，加入氨水(0.05mL)淬灭反应，得到的混合物直 接减压浓缩，残留物用prep-HPLC(条件2)纯化得到化合物4-1-1(24.3mg，产率：34％)为白色固体。m/z:[M+H] +587.2； 1H NMR(400MHz,DMSO-d 6):δ13.14(s,1H),8.20-8.17(m,1H),7.52-7.21(m,7H),6.99-6.83(m,1H),6.58-6.46(m,1H),6.28-6.17(m,2H),5.81-5.73(m,1H),4.74-4.06(m,3H),3.97-3.86(m,1H),3.76-3.44(m,2H),3.31-3.06(m,2H),2.12-2.02(m,3H),1.38-1.26(m,3H),1.16-1.06(m,3H),1.00-0.88(m,3H)。 Step 3: Under an ice-water bath, add DIPEA (78mg, 0.60mmol) and acrylic anhydride in dichloromethane (0.25M, 0.59mL, 0.15mmol) to a solution of compound 10B (crude) in anhydrous dichloromethane (10mL). ). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 4-1-1 (24.3 mg , Yield: 34%) is a white solid. m/z: [M+H] + 587.2; 1 H NMR (400MHz, DMSO-d 6 ): δ13.14(s,1H), 8.20-8.17(m,1H),7.52-7.21(m,7H) ,6.99-6.83(m,1H),6.58-6.46(m,1H),6.28-6.17(m,2H),5.81-5.73(m,1H),4.74-4.06(m,3H),3.97-3.86( m,1H),3.76-3.44(m,2H),3.31-3.06(m,2H),2.12-2.02(m,3H),1.38-1.26(m,3H),1.16-1.06(m,3H), 1.00-0.88 (m, 3H).
实施例31：2-((2S)-1-丙烯酰基-4-(6-(2-异丙基苯基)-4-(5-甲基-1H-吲唑-4-基)-7-氧代-6,7-二氢呋喃并[2,3-f]喹唑啉-9-基)哌嗪-2-基)乙腈三氟乙酸盐(化合物4-1-2)的合成Example 31: 2-((2S)-1-acryloyl-4-(6-(2-isopropylphenyl)-4-(5-methyl-1H-indazol-4-yl)-7 Synthesis of -oxo-6,7-dihydrofuro[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 4-1-2)
Figure PCTCN2020118772-appb-000154
Figure PCTCN2020118772-appb-000154
步骤1：利用化合物10A的合成方法，用中间体15-8和(5-甲基-1H-吲唑-4-基)硼酸反应得到化合物11A为白色固体。m/z:[M+H] +692.2。 Step 1: Using the synthetic method of compound 10A, intermediate 15-8 is reacted with (5-methyl-1H-indazol-4-yl)boronic acid to obtain compound 11A as a white solid. m/z: [M+H] + 692.2.
步骤2：向化合物11A(100mg，0.14mmol)的甲醇(30mL)溶液中加入钯碳(10％，60mg)，反应体系用氢气置换3次，然后在氢气氛下室温搅拌1.5小时。反应混合物用硅藻土过滤，滤液减压浓缩后得到化合物11B(75mg，产率：92％)为白色固体。m/z:[M+H] +558.3。 Step 2: To a methanol (30 mL) solution of compound 11A (100 mg, 0.14 mmol) was added palladium on carbon (10%, 60 mg), the reaction system was replaced with hydrogen 3 times, and then stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 11B (75 mg, yield: 92%) as a white solid. m/z: [M+H] + 558.3.
步骤3：冰浴条件下，向化合物11B(75mg，0.13mmol)的无水二氯甲烷(15mL)溶液中分别加入DIPEA(50mg，0.39mmol)和丙烯酸酐的二氯甲烷溶液(0.3M，0.54mL，0.16mmol)。反应混合物在此温度下搅拌5小时后，加入氨水(0.05mL)淬灭反应，得到的混合物直接减压浓缩，残留物用prep-HPLC(,条件7)纯化得到化合物4-1-2(4.1mg，产率：5％)为白色固体。m/z:[M+H] +612.3； 1H NMR(400MHz,DMSO-d 6):δ13.17(s,1H),8.23(s,1H),7.55-7.29(m,7H),7.24(s,0.57H),7.11(s,0.30H),6.98(s,0.42H),6.58(d,J＝2.0Hz,0.50H),6.54(d,J＝2.0Hz,0.25H),6.50(d,J＝2.0Hz,0.17H),6.31-6.21(m,2H),5.84(d,J＝11.2Hz,1H),5.28-4.95(m,1H),4.30-4.03(m,5H),3.54-3.34(m,2H),3.13-2.94(m,2H),2.12-2.04(m,3H),1.17-1.08(m,3H),1.07-0.90(m,3H)。 Step 3: Under ice bath conditions, add DIPEA (50mg, 0.39mmol) and acrylic anhydride in dichloromethane (0.3M, 0.54 mL, 0.16 mmol). After the reaction mixture was stirred at this temperature for 5 hours, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (, condition 7) to obtain compound 4-1-2 (4.1 mg, yield: 5%) is a white solid. m/z: [M+H] + 612.3; 1 H NMR (400MHz, DMSO-d 6 ): δ13.17(s,1H), 8.23(s,1H), 7.55-7.29(m,7H), 7.24 (s,0.57H),7.11(s,0.30H),6.98(s,0.42H),6.58(d,J=2.0Hz,0.50H),6.54(d,J=2.0Hz,0.25H),6.50 (d,J=2.0Hz,0.17H),6.31-6.21(m,2H),5.84(d,J=11.2Hz,1H),5.28-4.95(m,1H),4.30-4.03(m,5H) ,3.54-3.34(m,2H),3.13-2.94(m,2H),2.12-2.04(m,3H),1.17-1.08(m,3H),1.07-0.90(m,3H).
实施例32：9-((S)-4-丙烯酰基-2-甲基哌嗪-1-基)-4-(2-氟-6-羟基苯基)-6-(2-异丙基苯基)-呋喃并[2,3-f]喹唑啉-7(6H)-酮(化合物4-1-3)的合成Example 32: 9-((S)-4-acryloyl-2-methylpiperazin-1-yl)-4-(2-fluoro-6-hydroxyphenyl)-6-(2-isopropyl) Synthesis of phenyl)-furo[2,3-f]quinazolin-7(6H)-one (Compound 4-1-3)
Figure PCTCN2020118772-appb-000155
Figure PCTCN2020118772-appb-000155
步骤1：利用化合物10A的合成方法，用中间体15-7和4-氟-6-甲氧基苯硼酸反应得到化合物15A为淡黄色固体。m/z:[M+H] +627.4。 Step 1: Using the synthetic method of compound 10A, the intermediate 15-7 is reacted with 4-fluoro-6-methoxyphenylboronic acid to obtain compound 15A as a pale yellow solid. m/z: [M+H] + 627.4.
步骤2：将化合物15A(100mg，0.16mmol)溶解在无水二氯甲烷(7.0mL)中，-20℃下缓慢滴加三溴化硼的二氯甲烷溶液(0.30mol/L,3.2mL，0.96mmol)。反应混合溶液室温搅拌过夜后，加入甲醇(5mL)继续搅拌30分钟后直接减压浓缩，残留物用Flash柱层析(乙腈/0.1％的三氟乙酸水溶液＝0％～50％)纯化得化合物15B(97mg，产率：100％)为淡黄色固体。m/z:[M+H] +513.3。 Step 2: Dissolve compound 15A (100mg, 0.16mmol) in anhydrous dichloromethane (7.0mL), slowly add boron tribromide in dichloromethane solution (0.30mol/L, 3.2mL, 0.96mmol). After the reaction mixture was stirred at room temperature overnight, methanol (5 mL) was added and the stirring was continued for 30 minutes, and then it was directly concentrated under reduced pressure. The residue was purified by Flash column chromatography (acetonitrile/0.1% trifluoroacetic acid aqueous solution=0%-50%) to obtain the compound 15B (97 mg, yield: 100%) is a pale yellow solid. m/z: [M+H] + 513.3.
步骤3：冰浴条件下，向化合物15B(130mg，0.21mmol)的无水二氯甲烷(10mL)溶液中分别加入DIPEA(260mg，2.10mmol)和丙烯酸酐的二氯甲烷溶液(0.30M，0.85mL，0.26mmol)。反应混合物在此温度下搅拌1小时后，加入氨水(2.5mL)淬灭反应，然后继续搅拌2小时后得到的混合物直接减压浓缩，残留物用prep-HPLC(条件5)纯化得到化合物4-1-3(30.9mg，产率：26％)为白色固体。m/z:[M+H] +567.2； 1H NMR(400MHz,DMSO-d 6):δ10.06(s,1H),8.15(s,1H),7.57(d,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.36(t,J＝7.2Hz,1H),7.27-7.22(m,2H),6.99-6.82(m,1H),6.78-6.67(m,3H),6.30-6.18(m,2H),5.76(dd,J＝2.0,10.0Hz,1H),4.66-4.38(m,2H),4.24-4.09(m,1H),3.95-3.81(m,2H),3.23-3.03(m,2H),1.30-1.24(m,3H),1.11(d,J＝6.8Hz,3H),1.03-0.99(m,3H). Step 3: Under ice bath conditions, add DIPEA (260 mg, 2.10 mmol) and acrylic anhydride in dichloromethane (0.30M, 0.85) to a solution of compound 15B (130 mg, 0.21 mmol) in anhydrous dichloromethane (10 mL). mL, 0.26 mmol). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (2.5 mL) was added to quench the reaction, and then the stirring was continued for 2 hours. The resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to obtain compound 4- 1-3 (30.9 mg, yield: 26%) is a white solid. m/z: [M+H] + 567.2; 1 H NMR (400MHz, DMSO-d 6 ): δ10.06 (s, 1H), 8.15 (s, 1H), 7.57 (d, J = 7.2Hz, 1H ),7.48(t,J=7.2Hz,1H),7.36(t,J=7.2Hz,1H),7.27-7.22(m,2H),6.99-6.82(m,1H),6.78-6.67(m, 3H), 6.30-6.18 (m, 2H), 5.76 (dd, J = 2.0, 10.0 Hz, 1H), 4.66-4.38 (m, 2H), 4.24-4.09 (m, 1H), 3.95-3.81 (m, 2H),3.23-3.03(m,2H),1.30-1.24(m,3H), 1.11(d,J=6.8Hz,3H), 1.03-0.99(m,3H).
实施例33：(S)-9-(-4-丙烯酰基-2-甲基哌嗪-1-基)-4-(5-氨基-2-氯-3-氟苯基)-6-(2-异丙基-4-甲基吡啶-3-基)-呋喃并[2,3-f]喹唑啉-7(6H)-酮三氟乙酸盐(化合物4-1-4)的合成Example 33: (S)-9-(-4-acryloyl-2-methylpiperazin-1-yl)-4-(5-amino-2-chloro-3-fluorophenyl)-6-( 2-isopropyl-4-methylpyridin-3-yl)-furo[2,3-f]quinazolin-7(6H)-one trifluoroacetate (compound 4-1-4) synthesis
Figure PCTCN2020118772-appb-000156
Figure PCTCN2020118772-appb-000156
步骤1：将化合物15-9(350mg，0.59mmol)的二氯甲烷(16mL)和三氟乙酸(2mL)混合物在室温下搅拌2小时，减压浓缩得化合物14A(粗品)为黄色油状物。m/z:[M+H] +497.2。 Step 1: A mixture of compound 15-9 (350 mg, 0.59 mmol) in dichloromethane (16 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain compound 14A (crude product) as a yellow oil. m/z: [M+H] + 497.2.
步骤2：向化合物14A(粗品)和DIPEA(381mg，2.95mmol)的二氯甲烷(20mL)溶液中滴加丙烯酸酐的二氯甲烷(0.5M，1.3mL，0.65mmol)溶液，反应液室温搅拌1小时。用氨水淬灭反应后减压浓缩，残留物经Flash柱层析(二氯甲烷/甲醇＝30/1)纯化得到化合物14B(400mg，两步产率：100％)为黄色固体。Step 2: To the dichloromethane (20mL) solution of compound 14A (crude product) and DIPEA (381mg, 2.95mmol) was added dropwise a solution of acrylic anhydride in dichloromethane (0.5M, 1.3mL, 0.65mmol), the reaction solution was stirred at room temperature 1 hour. The reaction was quenched with ammonia water and concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane/methanol=30/1) to obtain compound 14B (400 mg, two-step yield: 100%) as a yellow solid.
步骤3：化合物14B(55mg，0.10mmol)，中间体2(54mg，0.20mmol)，碳酸钠水溶液(1M，0.30mL)和Pd(PPh 3) 4(12mg，0.01mmol)的1,4-二氧六环(2mL)混合物加入到微波管中，氮气鼓泡1-2分钟后，反应体系130℃下微波反应0.5小时。反应混合物减压浓缩，残留物用prep-HPLC(条件7)纯化得到化合物4-1-4(16.6mg，产 率：27％)为白色固体。m/z:[M+H] +615.2； 1H NMR(400MHz,DMSO-d 6):δ8.61(d,J＝4.8Hz,1H),8.23(d,J＝2.0Hz,1H),7.48-7.47(m,1H),6.98-6.83(m,1H),6.80(t,J＝1.6Hz,1H),6.56(dd,J＝2.4,12.0Hz,1H),6.33(s,1H),6.23-6.16(m,2H),5.76(dd,J＝2.4,10.8Hz,1H),4.65-3.39(m,2H),4.26-3.89(m,2H),3.72-3.46(m,2H),3.30-3.06(m,1H),2.79-2.73(m,1H),2.02(s,1.5H),2.01(s,1.5H),1.33-1.21(m,3H),1.12(d,J＝6.0Hz,3H),1.03(d,J＝6.0Hz,3H). Step 3: Compound 14B (55mg, 0.10mmol), Intermediate 2 (54mg, 0.20mmol), sodium carbonate aqueous solution (1M, 0.30mL) and Pd(PPh 3 ) 4 (12mg, 0.01mmol) 1,4-bis The oxane (2 mL) mixture was added to the microwave tube, and after nitrogen bubbling for 1-2 minutes, the reaction system was reacted in a microwave at 130° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 7) to obtain compound 4-1-4 (16.6 mg, yield: 27%) as a white solid. m/z: [M+H] + 615.2; 1 H NMR (400MHz, DMSO-d 6 ): δ8.61(d,J=4.8Hz,1H), 8.23(d,J=2.0Hz,1H), 7.48-7.47(m,1H), 6.98-6.83(m,1H), 6.80(t,J=1.6Hz,1H), 6.56(dd,J=2.4,12.0Hz,1H), 6.33(s,1H) ,6.23-6.16(m,2H),5.76(dd,J=2.4,10.8Hz,1H),4.65-3.39(m,2H),4.26-3.89(m,2H),3.72-3.46(m,2H) ,3.30-3.06(m,1H),2.79-2.73(m,1H),2.02(s,1.5H),2.01(s,1.5H),1.33-1.21(m,3H),1.12(d,J= 6.0Hz,3H),1.03(d,J=6.0Hz,3H).
实施例34：化合物4-1-5～4-1-12的合成Example 34: Synthesis of Compounds 4-1-5～4-1-12
利用化合物4-1-1的合成方法，用中间体15-9和(5-甲基-1H-吲唑-4-基)硼酸反应得到化合物4-1-5；Utilizing the synthetic method of compound 4-1-1, reacting intermediate 15-9 with (5-methyl-1H-indazol-4-yl)boronic acid to obtain compound 4-1-5;
利用化合物4-1-3合成方法，用中间体15-9或15-10和2-氯-5-甲氧基苯硼酸片那醇酯反应得到化合物4-1-9、4-1-12；利用化合物4-1-4的合成方法，用中间体15-7或15-10为起始原料反应得到化合物4-1-6、4-1-11；将步骤3中的中间体2替换为中间体32反应得到化合物4-1-7；用中间体15-7为起始原料，将步骤3中的中间体2分别替换为中间体32、2,3-二氯苯硼酸反应得到化合物4-1-8、4-1-10；Using compound 4-1-3 synthesis method, using intermediate 15-9 or 15-10 and 2-chloro-5-methoxyphenylboronic acid lenacol ester to react to obtain compound 4-1-9, 4-1-12 ; Using the synthetic method of compound 4-1-4, using intermediate 15-7 or 15-10 as the starting material to react to obtain compound 4-1-6, 4-1-11; replace intermediate 2 in step 3 Intermediate 32 is reacted to obtain compound 4-1-7; Intermediate 15-7 is used as starting material, and Intermediate 2 in step 3 is replaced with Intermediate 32 and 2,3-dichlorophenylboronic acid to obtain compound 4-1-8, 4-1-10;
表15Table 15
Figure PCTCN2020118772-appb-000157
Figure PCTCN2020118772-appb-000157
Figure PCTCN2020118772-appb-000158
Figure PCTCN2020118772-appb-000158
Figure PCTCN2020118772-appb-000159
Figure PCTCN2020118772-appb-000159
实施例35：化合物5-1-1的合成Example 35: Synthesis of Compound 5-1-1
利用通用方法1反应得到化合物5-1-1：Use general method 1 to obtain compound 5-1-1:
表16Table 16
Figure PCTCN2020118772-appb-000160
Figure PCTCN2020118772-appb-000160
生物实施例：Biological embodiment:
实施例1：pERK细胞水平测试Example 1: pERK cell level test
本实验使用PHOSPHO-ERK1/2(THR202/TYR 204)(Cisibo，64ERKPEH)试剂盒来检测人胰腺癌细胞Mia Paca-2中ERK1/2的磷酸化水平，通过ERK1/2的磷酸化水平来研究化合物对KRAS的抑制作用。In this experiment, the Phospho-ERK1/2 (THR202/TYR 204) (Cisibo, 64ERKPEH) kit was used to detect the phosphorylation level of ERK1/2 in human pancreatic cancer cells Mia Paca-2, and the phosphorylation level of ERK1/2 was used to study The inhibitory effect of the compound on KRAS.
该实验是根据制造商的实验方案进行的。第一天将MIA PaCa-2细胞(ATCC)悬液的密度调整为2.1×10 5细胞/mL，按95ul/孔铺在96孔板里，则每孔细胞数为2×10 4，将细胞培养板放在37℃、5％CO 2的培养箱中过夜培养。第二天将化合物用100％DMSO梯度稀释，再用完全培养基(DMDM+10％FBS+1％P/S)进一步稀释为化合物工作液，按5ul/孔加入96孔细胞培养板，在37℃、5％CO 2培养箱中孵育4小时。孵育结束，吸弃培养基，50ul/孔加入1x lysis buffer，室温振荡30分钟。取16ul裂解液加入白色浅孔384孔板中，再加4ul预配制的抗体混合液，用封板膜封板，室温过夜孵育。第三天在TECAN M1000 Pro读板仪上使用HTRF设置进行检测，并计算得到化合物的IC 50值。结果如下表17所示： The experiment was carried out according to the manufacturer's experimental protocol. On the first day, adjust the density of the MIA PaCa-2 cell (ATCC) suspension to 2.1×10 5 cells/mL, and spread it in a 96-well plate at 95ul/well, then the number of cells per well will be 2×10 4. The culture plate was placed in an incubator at 37°C and 5% CO 2 for overnight culture. On the next day, the compound was diluted with 100% DMSO gradient, and then further diluted with complete medium (DMDM+10%FBS+1%P/S) to become the compound working solution, and 5ul/well was added to 96-well cell culture plate at 37 Incubate in a 5% CO 2 incubator for 4 hours. At the end of the incubation, aspirate and discard the medium, add 1x lysis buffer to 50ul/well, and shake at room temperature for 30 minutes. Take 16ul of the lysate and add it to a white shallow 384-well plate, then add 4ul of the pre-prepared antibody mixture, seal the plate with a sealing film, and incubate overnight at room temperature. On the third day, the HTRF setting was used on the TECAN M1000 Pro plate reader for detection, and the IC 50 value of the compound was calculated. The results are shown in Table 17 below:
表17Table 17
化合物编号Compound number IC 50(μM) IC 50 (μM) 化合物编号Compound number IC 50(μM) IC 50 (μM)
1-1-11-1-1 11.93011.930 1-4-661-4-66 0.00690.0069
1-1-21-1-2 0.52010.5201 1-4-671-4-67 0.00450.0045
1-2-11-2-1 0.63610.6361 1-4-681-4-68 0.00040.0004
1-2-21-2-2 0.06650.0665 1-4-691-4-69 0.10300.1030
1-2-31-2-3 0.12290.1229 1-4-701-4-70 0.00190.0019
1-2-41-2-4 0.00900.0090 1-4-711-4-71 >1>1
1-2-51-2-5 0.60050.6005 1-4-721-4-72 0.00970.0097
1-2-61-2-6 0.00690.0069 1-4-731-4-73 0.00640.0064
1-3-11-3-1 0.00170.0017 1-4-741-4-74 0.00120.0012
1-3-21-3-2 0.01630.0163 1-4-751-4-75 0.00570.0057
1-4-11-4-1 0.08940.0894 1-4-761-4-76 0.00400.0040
1-4-21-4-2 0.02250.0225 1-4-771-4-77 0.01060.0106
1-4-31-4-3 0.00220.0022 1-4-781-4-78 0.00480.0048
1-4-41-4-4 0.42960.4296 1-4-791-4-79 0.00840.0084
1-4-51-4-5 1.4141.414 1-4-801-4-80 0.00120.0012
1-4-61-4-6 0.02470.0247 1-4-811-4-81 0.00050.0005
1-4-71-4-7 0.08940.0894 1-4-821-4-82 0.13510.1351
1-4-81-4-8 0.01980.0198 1-4-831-4-83 0.00330.0033
1-4-91-4-9 0.00430.0043 1-4-841-4-84 0.02070.0207
1-4-101-4-10 0.01800.0180 1-4-851-4-85 0.00690.0069
1-4-111-4-11 >1>1 1-4-861-4-86 0.00160.0016
1-4-121-4-12 2.0312.031 1-4-871-4-87 0.00050.0005
1-4-131-4-13 0.57130.5713 1-4-881-4-88 0.00070.0007
1-4-141-4-14 0.00180.0018 1-4-891-4-89 0.00200.0020
1-4-151-4-15 0.09190.0919 1-4-901-4-90 0.09180.0918
1-4-161-4-16 5.7715.771 1-5-11-5-1 0.19080.1908
1-4-171-4-17 0.00380.0038 1-5-21-5-2 0.02870.0287
1-4-181-4-18 0.04590.0459 1-5-31-5-3 0.02320.0232
1-4-191-4-19 2.6052.605 1-5-41-5-4 0.00710.0071
1-4-201-4-20 1.6121.612 1-6-11-6-1 0.87700.8770
1-4-211-4-21 0.07470.0747 1-7-11-7-1 >1>1
1-4-221-4-22 0.01010.0101 1-8-11-8-1 0.01230.0123
1-4-231-4-23 2.6632.663 1-8-21-8-2 0.01310.0131
1-4-241-4-24 0.00170.0017 1-8-31-8-3 0.08770.0877
1-4-251-4-25 1.3671.367 1-8-41-8-4 0.06210.0621
1-4-261-4-26 0.68940.6894 1-8-51-8-5 0.01030.0103
1-4-271-4-27 0.00540.0054 2-1-12-1-1 1.2911.291
1-4-281-4-28 0.00090.0009 2-1-22-1-2 0.00600.0060
1-4-291-4-29 0.03120.0312 3-1-13-1-1 0.00470.0047
1-4-301-4-30 0.54800.5480 3-1-23-1-2 0.08860.0886
1-4-311-4-31 0.05510.0551 3-1-33-1-3 0.01910.0191
1-4-321-4-32 0.17250.1725 3-1-43-1-4 0.00570.0057
1-4-331-4-33 0.00080.0008 3-1-53-1-5 0.13320.1332
1-4-341-4-34 0.38370.3837 3-1-63-1-6 0.05370.0537
1-4-351-4-35 0.16380.1638 3-1-73-1-7 0.00290.0029
1-4-361-4-36 0.01040.0104 3-1-83-1-8 0.00130.0013
1-4-371-4-37 0.01220.0122 3-1-93-1-9 0.02850.0285
1-4-381-4-38 0.01500.0150 3-1-103-1-10 0.13600.1360
1-4-391-4-39 0.00050.0005 3-1-113-1-11 0.08640.0864
1-4-401-4-40 0.00910.0091 3-1-123-1-12 0.00500.0050
1-4-411-4-41 0.00060.0006 3-1-133-1-13 0.00850.0085
1-4-421-4-42 >1>1 3-1-143-1-14 0.02440.0244
1-4-431-4-43 0.00300.0030 3-1-153-1-15 0.00200.0020
1-4-441-4-44 0.01390.0139 3-1-163-1-16 0.01200.0120
1-4-451-4-45 >1>1 3-2-13-2-1 0.06200.0620
1-4-461-4-46 0.09990.0999 3-3-13-3-1 0.02040.0204
1-4-471-4-47 0.07270.0727 3-3-23-3-2 0.19370.1937
1-4-481-4-48 0.01280.0128 3-3-33-3-3 0.07860.0786
1-4-491-4-49 0.04220.0422 3-3-63-3-6 0.03130.0313
1-4-501-4-50 0.52780.5278 3-3-73-3-7 0.37540.3754
1-4-511-4-51 0.31690.3169 3-3-83-3-8 0.00130.0013
1-4-521-4-52 >1>1 3-3-93-3-9 0.07000.0700
1-4-531-4-53 0.10500.1050 3-3-103-3-10 0.16190.1619
1-4-541-4-54 1.5351.535 4-1-14-1-1 0.16920.1692
1-4-551-4-55 0.05860.0586 4-1-24-1-2 0.37820.3782
1-4-561-4-56 0.02270.0227 4-1-34-1-3 0.47010.4701
1-4-571-4-57 0.00890.0089 4-1-44-1-4 1.0051.005
1-4-581-4-58 0.00190.0019 4-1-54-1-5 0.44800.4480
1-4-591-4-59 0.16840.1684 4-1-64-1-6 1.2091.209
1-4-601-4-60 0.02020.0202 4-1-74-1-7 1.0461.046
1-4-611-4-61 0.02560.0256 4-1-84-1-8 1.8691.869
1-4-621-4-62 0.11960.1196 4-1-94-1-9 0.71370.7137
1-4-631-4-63 0.16450.1645 4-1-104-1-10 0.52520.5252
1-4-641-4-64 0.04600.0460 4-1-114-1-11 >1>1
1-4-651-4-65 0.00960.0096 4-1-124-1-12 >1>1
实施例2：细胞增殖试验Example 2: Cell Proliferation Test
本发明中，运用细胞增殖实验的方法来评价化合物的生物活性。In the present invention, the method of cell proliferation experiment is used to evaluate the biological activity of the compound.
1)将3000个Miapaca-2人胰腺癌细胞(南京科佰)种植于96孔板中，细胞培养于Dulbecco’s Modified Eagle’s基质及10％胎牛血清中，培养环境为37℃及5％CO 2。第二天，将待测化合物的储备液溶入DMSO中并加入至指示浓度的培养基中，孵化72小时，待测化合物浓度范围为1.5nM～100μM。阴性对照细胞仅用vehicle进行处理。在产品说明书的指示下运用Cell Titer-Glo检测试剂盒(Cell Titer-glo，Promega)来评价细胞活性。运用Graphpad软件对数据进行分析，并得到IC 50值及化合物拟合曲线(结果见表18)。 1) 3000 Miapaca-2 human pancreatic cancer cells (Nanjing Kebai) were planted in 96-well plates, and the cells were cultured in Dulbecco's Modified Eagle's matrix and 10% fetal bovine serum. The culture environment was 37°C and 5% CO 2 . On the second day, the stock solution of the test compound is dissolved in DMSO and added to the medium of the indicated concentration, and incubated for 72 hours. The concentration of the test compound ranges from 1.5 nM to 100 μM. Negative control cells were treated with vehicle only. Use the Cell Titer-Glo test kit (Cell Titer-glo, Promega) to evaluate cell viability under the instructions of the product manual. Use Graphpad software to analyze the data, and obtain IC 50 values and compound fitting curves (see Table 18 for the results).
2)将3000个NCI-H358人非小细胞肺癌细胞(南京科佰)种植于96孔板中，细胞培养于RPMI-1640及10％胎牛血清中，培养环境为37℃及5％CO2。第二天，将待测化合物的储备液溶入10％DMSO中并加入96孔板至指示浓度，孵化72小时，待测化合物浓度范围为4.5nM～30μM。阴性对照细胞仅用vehicle进行处理。在产品说明书的指示下运用Cell Titer-Glo检测试剂盒(Cell Titer-glo，Promega)来评价细胞活性。运用Graphpad软件对数据进行分析，并得到IC 50值及化合物拟合曲线(结果见表19)。 2) 3000 NCI-H358 human non-small cell lung cancer cells (Nanjing Kebai) were planted in a 96-well plate, and the cells were cultured in RPMI-1640 and 10% fetal bovine serum. The culture environment was 37°C and 5% CO2. On the second day, the stock solution of the test compound was dissolved in 10% DMSO and added to a 96-well plate to the indicated concentration, and incubated for 72 hours. The concentration range of the test compound was 4.5 nM-30 μM. Negative control cells were treated with vehicle only. Use the Cell Titer-Glo test kit (Cell Titer-glo, Promega) to evaluate cell viability under the instructions of the product manual. Use Graphpad software to analyze the data, and obtain IC 50 values and compound fitting curves (see Table 19 for the results).
表18Table 18
化合物编号Compound number IC 50(μM) IC 50 (μM) 化合物编号Compound number IC 50(μM) IC 50 (μM)
1-2-11-2-1 0.5690.569 1-4-601-4-60 0.1010.101
1-2-21-2-2 0.1770.177 1-4-611-4-61 0.3550.355
1-2-31-2-3 0.5050.505 1-4-631-4-63 0.1990.199
1-2-41-2-4 0.0900.090 1-4-651-4-65 0.2380.238
1-2-51-2-5 0.2940.294 1-4-661-4-66 0.0610.061
1-2-61-2-6 0.0190.019 1-4-671-4-67 0.0860.086
1-3-11-3-1 0.0110.011 1-4-681-4-68 0.0390.039
1-3-21-3-2 0.0530.053 1-4-701-4-70 0.0260.026
1-4-11-4-1 0.4380.438 1-4-721-4-72 0.0200.020
1-4-21-4-2 0.3960.396 1-4-731-4-73 0.2400.240
1-4-31-4-3 0.0310.031 1-4-741-4-74 0.0410.041
1-4-61-4-6 0.3560.356 1-4-751-4-75 0.0790.079
1-4-71-4-7 0.2520.252 1-4-761-4-76 0.0140.014
1-4-81-4-8 0.0370.037 1-4-771-4-77 0.0430.043
1-4-91-4-9 0.0050.005 1-4-781-4-78 0.0080.008
1-4-101-4-10 0.1560.156 1-4-791-4-79 0.1160.116
1-4-141-4-14 0.0180.018 1-4-801-4-80 0.1820.182
1-4-171-4-17 0.0650.065 1-4-811-4-81 0.0050.005
1-4-181-4-18 0.3650.365 1-4-831-4-83 0.1290.129
1-4-221-4-22 0.3940.394 1-4-841-4-84 0.0290.029
1-4-241-4-24 0.0290.029 1-4-851-4-85 0.1070.107
1-4-291-4-29 0.1240.124 1-4-861-4-86 0.0080.008
1-4-301-4-30 0.4840.484 1-4-871-4-87 0.0130.013
1-4-311-4-31 0.1910.191 1-4-881-4-88 0.0370.037
1-4-321-4-32 0.4180.418 1-4-891-4-89 0.0140.014
1-4-331-4-33 0.0010.001 1-8-11-8-1 0.2600.260
1-4-351-4-35 0.1250.125 1-8-21-8-2 0.3280.328
1-4-361-4-36 0.5030.503 1-8-51-8-5 0.1710.171
1-4-371-4-37 0.1980.198 2-1-22-1-2 0.0370.037
1-4-381-4-38 0.2660.266 3-1-13-1-1 0.0350.035
1-4-391-4-39 0.0310.031 3-1-23-1-2 0.3730.373
1-4-401-4-40 0.3190.319 3-1-33-1-3 0.0480.048
1-4-411-4-41 0.0160.016 3-1-43-1-4 0.0070.007
1-4-431-4-43 0.0190.019 3-1-73-1-7 0.0190.019
1-4-441-4-44 0.3720.372 3-1-83-1-8 0.0180.018
1-4-481-4-48 0.1410.141 3-1-93-1-9 0.0940.094
1-4-491-4-49 0.1930.193 3-1-123-1-12 0.1200.120
1-4-531-4-53 0.4580.458 3-1-133-1-13 0.0890.089
1-4-551-4-55 0.2460.246 3-1-143-1-14 0.2510.251
1-4-561-4-56 0.1910.191 3-1-153-1-15 0.0610.061
1-4-571-4-57 0.1250.125 3-3-63-3-6 0.1950.195
1-4-581-4-58 0.0270.027 4-1-14-1-1 0.1580.158
表19Table 19
Figure PCTCN2020118772-appb-000161
Figure PCTCN2020118772-appb-000161
Figure PCTCN2020118772-appb-000162
Figure PCTCN2020118772-appb-000162

Claims (22)

  1. 一种如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐；A compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts;
    Figure PCTCN2020118772-appb-100001
    Figure PCTCN2020118772-appb-100001
    其中，among them,
    α和β键分别为单键或双键；The α and β bonds are single bonds or double bonds, respectively;
    X为N或CR 2； X is N or CR 2 ;
    β键为单键时，Y为C(O)，Z为NR 3；β键为双键时，Y和Z分别独立地为N或CR 2； When the β bond is a single bond, Y is C(O) and Z is NR 3 ; when the β bond is a double bond, Y and Z are independently N or CR 2 respectively ;
    α键为单键时，W为N，V为CH 2或C(O)；α键为双键时，W为C，V为CR 4或N； When the α bond is a single bond, W is N and V is CH 2 or C(O); when the α bond is a double bond, W is C and V is CR 4 or N;
    U和M分别独立地为N、C或CH；U and M are each independently N, C or CH;
    A环为苯基、3-8元环烷基、5-6元杂芳基或4-8元杂环烷基；所述A环为未取代，或者选择性地被1～3个R 5基团取代在任意位置； The A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
    B环为5-10元杂环烷基；所述B环为未取代，或者选择性被1～3个R 6基团取代在任意位置； The B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
    R为C 6-10芳基、5-10元杂芳基或9-14元稠合杂环烷基；所述R为未取代或者选择性被1个或多个R 7基团取代在任意位置； R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
    R 1为C 2-4烯基、C 2-4炔基或部分不饱和的C 4-6环烷基；所述R 1为未取代或者选择性被1～3个R 8基团取代在任意位置； R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
    R 2为氢、羟基、卤素、氰基、氨基、-R A、-NR AR B、-OR A或-SR A； R 2 is hydrogen, hydroxy, halo, cyano, amino, -R A, -NR A R B , -OR A , or -SR A;
    R 3为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基或5-10杂芳基-C 1-4烷基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、氧代基、卤代C 1-6烷基、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、4-6元杂环烷基或4-6元杂环烷基-C 1-4烷基的取代基 取代在任意位置； R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
    R 4为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基或C 3-8环烷基； R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
    R 5为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、酰基、C 3-8元环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基或-B(OR”) 2； R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
    R 6为氢、氧代基、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(O)OR’或-C(O)NR’ 2；R 6中，所述C 1-6烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR'2; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
    R 7为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、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 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基、5-10元杂芳基-C 1-4烷基、-NH-C 3-6环烷基、-(CH 2) nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”) 2、-OC(O)R”、-OC(O)N(R”) 2或-B(OR”) 2；R 7中，所述C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基或5-10元杂芳基-C 1-4烷基为未取代或者选择性被1～3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置； R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR', -NHC(O)R", -C(O)R", -C(O)N(R") 2 ,- OC (O) R ", - OC (O) N (R") 2 or -B (oR ") 2; R 7 , said C 3-8 cycloalkyl, C 3-8 cycloalkyl -C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkane Group, 5-10 membered heteroaryl or 5-10 membered heteroaryl-C 1-4 alkyl is unsubstituted or optionally selected from 1 to 3 halogen, hydroxy, amino, carboxy, cyano, C 1 Substituents of -4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
    R 8为氢、氘、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基；其中，所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代，或者选择性被1～3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置； R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 alkyl are substituted at any position;
    R A为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基、3-10元杂环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基或5-10元杂芳基-C 1-6烷基；所述R A为未取代或者选择性被一个或多个R c取代在任意位置； R A is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3 -10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 membered heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl group or a 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
    R B为氢、氰基、羟基或C 1-6烷基； R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl;
    或者，R A和R B相互连接形成4-8杂环烷基；所述杂环烷基为未取代或者选择性被 1～3个选自羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、酰基、C 1-4烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基和5-10元杂芳基-C 1-4烷基的取代基取代在任意位置； Alternatively, R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1- The substituents of 4- alkyl, C 6-10 aryl-C 1-4 alkyl and 5-10 membered heteroaryl-C 1-4 alkyl are substituted at any position;
    R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-6烷基、C 1-4烷氧基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷氨基-C 1-6烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基、-(CH 2) n-N(CN)R’、-(CH 2) n-C(O)R’、-(CH 2) n-C(O)N(R’) 2、-(CH 2) n-S(O) 2N(R’) 2、-(CH 2) n-NR”C(O)R’、-(CH 2) n-NR”S(O) 2R’或-(CH 2) n-B(OR”) 2；R c中，所述C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基为未取代或者选择性被1-3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、C 1-4烷氨基和C 1-4烷基的取代基取代在任意位置； R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1 -6 alkylamino-C 1-6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 ring Alkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1 -4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C(O)R', -(CH 2 ) n -C(O)N(R') 2 , -(CH 2 ) n -S(O) 2 N(R') 2 , -(CH 2 ) n -NR”C(O)R', -(CH 2 ) n -NR”S(O) 2 R'or -(CH 2 ) n -B(OR") 2 ; in R c , the C 1-4 alkylene group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 Membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycle Alkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl are unsubstituted or optionally selected from 1-3 Substituents from halogen, hydroxy, amino, cyano, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 alkyl are substituted at any position;
    R’为氢、C 1-4烷基、卤代C 1-4烷基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、6-10元杂芳基、C 6-10芳基-C 1-4烷基或6-10元杂芳基-C 1-4烷基； R'is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
    R”为氢或C 1-6烷基； R" is hydrogen or C 1-6 alkyl;
    n为0到4的整数；n is an integer from 0 to 4;
    并且，排除以下情况：A环为苯基或1,3-二氧杂环戊烯基时，R 2为氢。 In addition, the following cases are excluded: when the A ring is a phenyl group or a 1,3-dioxolyl group, R 2 is hydrogen.
  2. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，A环为
    Figure PCTCN2020118772-appb-100002
    Figure PCTCN2020118772-appb-100003
    The compound represented by formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein the A ring is
    Figure PCTCN2020118772-appb-100002
    Figure PCTCN2020118772-appb-100003
    Figure PCTCN2020118772-appb-100004
    Figure PCTCN2020118772-appb-100005
    所述A环为未取代，或者选择性被1～3个R 5取代在任意位置；
    Figure PCTCN2020118772-appb-100004
    Figure PCTCN2020118772-appb-100005
    The A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position;
    和/或，B环为
    Figure PCTCN2020118772-appb-100006
    Figure PCTCN2020118772-appb-100007
    所述B环为未取代，或者选择性被1～3的R 6取代在任意位置。     And/or, the B ring is
    Figure PCTCN2020118772-appb-100006
    Figure PCTCN2020118772-appb-100007
    The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 at any position.
  3. 如权利要求2所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 5为H或-CH 2OH； The compound of formula (I) according to claim 2, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R 5 is H or -CH 2 OH;
    和/或，R 6为H、-CH 3、-CF 3、-CHF 2、-CH 2CN、-CH 2OH、-CH 2CH 2OH 、-CH 2CH 2OCH 3或-CH 2OCH 3。 And/or, R 6 is H, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CN, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 OCH 3 or -CH 2 OCH 3 .
  4. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，A环为吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基或2,3-二氢呋喃基；The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, characterized in that the A ring is pyridyl, pyrimidinyl, pyrazine Group, pyridazinyl, furanyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazole, 1 , 2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl or 2,3-dihydrofuranyl;
    和/或，B环为
    Figure PCTCN2020118772-appb-100008
    Figure PCTCN2020118772-appb-100009
    And/or, the B ring is
    Figure PCTCN2020118772-appb-100008
    Figure PCTCN2020118772-appb-100009
  5. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R为苯基、萘基、吡啶基、吡嗪基、哒嗪基、喹啉基、 异喹啉基、2,3-二氢苯并呋喃基、1H-苯并[d]咪唑-2(3H)-酮基、1H-吲唑基、酞嗪基、1-羟基-1,3-二氢苯并[c][1,2]氧杂硼戊环基、3-羟基-1,3-二氢萘并[2,1-c][1,2]氧杂硼戊环基或1-羟基-1,3-二氢萘并[2,3-c][1,2]氧杂硼戊环基；所述R为未取代或者选择性被1～5个R 7取代在任意位置； The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R is phenyl, naphthyl, pyridyl, Pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 1H-benzo[d]imidazole-2(3H)-keto, 1H-indazolyl , Phthalazinyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl, 3-hydroxy-1,3-dihydronaphtho[2,1-c ][1,2]oxaborolanyl or 1-hydroxy-1,3-dihydronaphtho[2,3-c][1,2]oxaborolanyl; the R is unsubstituted Or optionally substituted by 1 to 5 R 7 at any position;
    和/或，R 7为氢、卤素、羟基、氨基、氰基、C 1-4烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-6烷氨基、C 3-6环烷基、3-6元杂环烷基或-B(OH) 2；所述C 3-6环烷基或3-6元杂环烷基为未取代或者选择性被1～3个选自羟基、氨基、氟、氯、甲基、三氟甲基和三氟甲氧基的取代基取代在任意位置。 And/or, R 7 is hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy Group, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -B(OH) 2 ; the C 3-6 cycloalkyl or 3-6 membered heterocycloalkane The group is unsubstituted or optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, amino, fluorine, chlorine, methyl, trifluoromethyl and trifluoromethoxy in any position.
  6. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R为
    Figure PCTCN2020118772-appb-100010
    Figure PCTCN2020118772-appb-100011
    The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R is
    Figure PCTCN2020118772-appb-100010
    Figure PCTCN2020118772-appb-100011
    Figure PCTCN2020118772-appb-100012
    Figure PCTCN2020118772-appb-100012
    Figure PCTCN2020118772-appb-100013
    Figure PCTCN2020118772-appb-100013
  7. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或 药学上可接受的盐，其特征在于，R 1为
    Figure PCTCN2020118772-appb-100014
    其中，R 8a为H、D、卤素或C 1-3烷氧基-C 1-4烷基；R 8b和R 8c分别独立地为H、D、卤素、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-4烷基、C 1-3烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基；其中，所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代，或者选择性被1～3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置；     The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R 1 is
    Figure PCTCN2020118772-appb-100014
    Wherein, R 8a is H, D, halogen or C 1-3 alkoxy-C 1-4 alkyl; R 8b and R 8c are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1- 4- alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; Wherein, the C 1-6 alkylamino-C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or is optionally substituted by 1 to 3 A substituent selected from halogen, hydroxy, amino, cyano, C 1-4 alkoxy, oxo and C 1-4 alkyl is substituted at any position;
    或，R 1为
    Figure PCTCN2020118772-appb-100015
    Or, R 1 is
    Figure PCTCN2020118772-appb-100015
  8. 如权利要求1～7任一项所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，α和β键分别为双键；X为N；W为C，V为CR 4或N；Y为CR 2；Z为N。 The compound of formula (I) according to any one of claims 1 to 7, its isomer, stable isotope derivative or pharmaceutically acceptable salt, characterized in that the α and β bonds are respectively Double bond; X is N; W is C, V is CR 4 or N; Y is CR 2 ; Z is N.
  9. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 2为-OR A、-NR AR B、5-10元杂芳基或3-10元杂环烷基；所述5-10元杂芳基或3-10元杂环烷基为未取代或者选择性被一个或多个R c取代在任意位置； The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R 2 is -OR A , -NR A R B. 5-10 membered heteroaryl group or 3-10 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted by one or more R c Replace in any position;
    和/或，R 4为氢、卤素、C 2-4烯基、C 1-4烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基或C 3-6环烷基。 And/or, R 4 is hydrogen, halogen, C 2-4 alkenyl, C 1-4 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy Group or C 3-6 cycloalkyl.
  10. 如权利要求1所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 2为
    Figure PCTCN2020118772-appb-100016
    Figure PCTCN2020118772-appb-100017
    The compound of formula (I) according to claim 1, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R 2 is
    Figure PCTCN2020118772-appb-100016
    Figure PCTCN2020118772-appb-100017
    Figure PCTCN2020118772-appb-100018
    Figure PCTCN2020118772-appb-100018
    Figure PCTCN2020118772-appb-100019
    Figure PCTCN2020118772-appb-100019
    Figure PCTCN2020118772-appb-100020
    Figure PCTCN2020118772-appb-100020
    和/或，R 4为氢。 And/or, R 4 is hydrogen.
  11. 如权利要求1～10任一项所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，其为式(II)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，The compound of formula (I) according to any one of claims 1 to 10, its isomer, stable isotope derivative or pharmaceutically acceptable salt, characterized in that it is of formula (II) The shown compound, its isomer, stable isotope derivative or pharmaceutically acceptable salt,
    Figure PCTCN2020118772-appb-100021
    Figure PCTCN2020118772-appb-100021
    其中，A环、B环、X、U、M、R、R 1、R 2和R 4的定义如权利要求1～10任一项所述。 Wherein, ring A, ring B, X, U, M, R, R 1 , R 2 and R 4 are as defined in any one of claims 1-10.
  12. 如权利要求11所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，X为N；U和M分别独立地为N、C；The compound of formula (I) according to claim 11, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein X is N; U and M are each independently N, C;
    A环为5-6元杂芳基或5-6元杂环烷基；Ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl;
    B环为
    Figure PCTCN2020118772-appb-100022
    所述B环为未取代，或者选择性被1～3个R 6基团取代在任意位置；     Ring B is
    Figure PCTCN2020118772-appb-100022
    The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
    R为C 6-10芳基或5-10元杂芳基；所述R为未取代或者选择性被1～4个R 7基团取代在任意位置； R is a C 6-10 aryl group or a 5-10 membered heteroaryl group; said R is unsubstituted or optionally substituted by 1 to 4 R 7 groups in any position;
    R 1为C 2-4烯基；所述R 1为未取代或者选择性被1～3个R 8基团取代在任意位置； R 1 is a C 2-4 alkenyl group; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups at any position;
    R 2为-OR A； R 2 is -OR A ;
    R 4为H； R 4 is H;
    R 6为氢、C 1-6烷基或C 1-6烷氧基；R 6中，所述C 1-6烷基为未取代或者选择性被1～3个选自卤素、羟基、氰基和C 1-4烷氧基的取代基取代在任意位置； R 6 is hydrogen, a C 1-6 alkyl group or a C 1-6 alkoxy group; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, and cyano groups. The substituents of the C 1-4 alkoxy group and the C 1-4 alkoxy group are substituted at any position;
    R 7为氢、羟基、卤素、氰基、氨基、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、C 3-8环烷基或3-8元杂环烷基； R 7 is hydrogen, hydroxy, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 3 -8 cycloalkyl or 3-8 membered heterocycloalkyl;
    R 8为氢、氘、卤素、C 1-6烷基、C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基或C 1-6烷氨基-C 1-4烷基； R 8 is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino- C 1-4 alkyl or C 1-6 alkylamino-C 1-4 alkyl;
    R A为C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基或3-10杂环烷基-C 1-6烷基；所述R A为未取代或者选择性被一个或多个R c取代在任意位置； R A is C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or -C 1-6 alkyl heterocycloalkyl 3-10 - C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c at an arbitrary position;
    R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。 R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl or halogenated C 1-4 alkoxy.
  13. 如权利要求1～10任一项所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，其为式(IIA)、(IIB)、(IIC)或(IID)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，The compound of formula (I) according to any one of claims 1 to 10, its isomer, stable isotope derivative or pharmaceutically acceptable salt, characterized in that it is of formula (IIA) , (IIB), (IIC) or (IID), its isomers, stable isotope derivatives or pharmaceutically acceptable salts,
    Figure PCTCN2020118772-appb-100023
    Figure PCTCN2020118772-appb-100023
    Figure PCTCN2020118772-appb-100024
    Figure PCTCN2020118772-appb-100024
    其中，B环、R、R A、R 1和R 5的定义如权利要求1～10任一项所述。 Wherein the definition of Ring B, R, R A, R 1 and R 5 is 1 to 10 according to any one of claims.
  14. 如权利要求1～7任一项所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，α键为双键；β键为单键；X为N；W为C，V为CR 4或N；Y为C(O)，Z为NR 3； The compound of formula (I) according to any one of claims 1 to 7, its isomer, stable isotope derivative or pharmaceutically acceptable salt, characterized in that the α bond is a double bond; β bond is a single bond; X is N; W is C, V is CR 4 or N; Y is C(O), Z is NR 3 ;
    和/或，R 3为环己基、环丙基甲基、苯基、吡啶基、嘧啶基、噻唑或1H-吡唑基；所述R 3为未取代或者选择性被1～3个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 3-6环烷基的取代基取代在任意位置； And/or, R 3 is cyclohexyl, cyclopropylmethyl, phenyl, pyridyl, pyrimidinyl, thiazole or 1H-pyrazolyl; said R 3 is unsubstituted or is optionally selected from 1 to 3 The substituents of halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl are substituted at any position;
    和/或，R 4为氢。 And/or, R 4 is hydrogen.
  15. 如权利要求14所述的如式(I)所示的化合物，其异构体、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 3为
    Figure PCTCN2020118772-appb-100025
    Figure PCTCN2020118772-appb-100026
    The compound of formula (I) according to claim 14, its isomer, stable isotope derivative or pharmaceutically acceptable salt, wherein R 3 is
    Figure PCTCN2020118772-appb-100025
    Figure PCTCN2020118772-appb-100026
  16. 如权利要求1所述的如式(I)所示的化合物为以下任一结构：The compound represented by formula (I) according to claim 1 has any of the following structures:
    Figure PCTCN2020118772-appb-100027
    Figure PCTCN2020118772-appb-100027
    Figure PCTCN2020118772-appb-100028
    Figure PCTCN2020118772-appb-100028
    Figure PCTCN2020118772-appb-100029
    Figure PCTCN2020118772-appb-100029
    Figure PCTCN2020118772-appb-100030
    Figure PCTCN2020118772-appb-100030
    Figure PCTCN2020118772-appb-100031
    Figure PCTCN2020118772-appb-100031
    Figure PCTCN2020118772-appb-100032
    Figure PCTCN2020118772-appb-100032
    Figure PCTCN2020118772-appb-100033
    Figure PCTCN2020118772-appb-100033
    Figure PCTCN2020118772-appb-100034
    Figure PCTCN2020118772-appb-100034
    Figure PCTCN2020118772-appb-100035
    Figure PCTCN2020118772-appb-100035
    Figure PCTCN2020118772-appb-100036
    Figure PCTCN2020118772-appb-100036
    Figure PCTCN2020118772-appb-100037
    Figure PCTCN2020118772-appb-100037
    Figure PCTCN2020118772-appb-100038
    Figure PCTCN2020118772-appb-100038
    Figure PCTCN2020118772-appb-100039
    Figure PCTCN2020118772-appb-100039
    Figure PCTCN2020118772-appb-100040
    Figure PCTCN2020118772-appb-100040
  17. 一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如权利要求1～16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐。A pharmaceutical composition comprising a therapeutically effective amount of active components and pharmaceutically acceptable auxiliary materials; the active components include the compound represented by formula (I) according to any one of claims 1-16, Its isomers, stable isotope derivatives or pharmaceutically acceptable salts.
  18. 一种如权利要求1～16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17所述药物组合物在制备KRAS G12C抑制剂药物中的应用。A compound of formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts according to any one of claims 1-16, or the pharmaceutical combination according to claim 17 The application of the drug in the preparation of KRAS G12C inhibitor drugs.
  19. 一种如权利要求1～16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17所述药物组合物在制备治疗和/或缓解与KRAS G12C相关疾病的药物中的应用。A compound of formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts according to any one of claims 1-16, or the pharmaceutical combination according to claim 17 The application in the preparation of drugs for the treatment and/or alleviation of KRAS G12C-related diseases.
  20. 如权利要求19所述的应用，其特征在于：所述的KRAS G12C相关疾病为癌症。The application according to claim 19, wherein the KRAS G12C related disease is cancer.
  21. 一种如权利要求1～16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17所述药物组合物在制备治疗癌症的药物中的应用。A compound of formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts according to any one of claims 1-16, or the pharmaceutical combination according to claim 17 In the preparation of medicines for the treatment of cancer.
  22. 一种联合制剂，包括如权利要求1～16任一项所述如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17所述所述药物组合物和其它种类的用于治疗癌症的治疗剂合用。A combined preparation comprising the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts as claimed in any one of claims 1-16, or as claimed in claim 17. The said pharmaceutical composition is used in combination with other kinds of therapeutic agents for the treatment of cancer.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022105859A1 (en) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022152233A1 (en) * 2021-01-15 2022-07-21 Beigene, Ltd. Kras g12c inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023056421A1 (en) * 2021-10-01 2023-04-06 Incyte Corporation Pyrazoloquinoline kras inhibitors
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
US11964989B2 (en) 2022-07-20 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988135B (en) * 2019-04-04 2022-10-28 宜昌市第一人民医院（三峡大学人民医院） Small molecule inhibitor AZIN19 and application thereof in pharmacy
CN114621244B (en) * 2020-12-14 2023-08-18 成都百裕制药股份有限公司 Pyridine derivative and application thereof in medicine
WO2022184178A1 (en) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
CN115181106B (en) * 2021-04-07 2024-04-05 药雅科技(上海)有限公司 Quinazoline KRAS G12D Preparation and application of mutant protein inhibitor
WO2022216762A1 (en) * 2021-04-08 2022-10-13 Genentech, Inc. Oxazepine compounds and uses thereof in the treatment of cancer
CA3217694A1 (en) * 2021-05-24 2022-12-01 Zusheng XU Nitrogen-containing heterocyclic compound, method for preparing same and use of same
WO2024032702A1 (en) * 2022-08-11 2024-02-15 Beigene, Ltd. Heterocyclic compounds, compositions thereof, and methods of treatment therewith
CN116120315B (en) * 2023-04-19 2023-06-09 山东绿叶制药有限公司 KRAS G12C inhibitor and application thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488910A (en) * 2013-10-10 2017-03-08 亚瑞克西斯制药公司 Inhibitors of kras g12c
CN107849022A (en) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 Substituted quinazoline compound and its application method
CN108779097A (en) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 Include the quinazoline compound and its application method of the 2- substitutions of substituted heterocycle
WO2018206539A1 (en) * 2017-05-11 2018-11-15 Astrazeneca Ab Heteroaryl compounds that inhibit g12c mutant ras proteins
WO2018218070A2 (en) * 2017-05-25 2018-11-29 Araxes Pharma Llc Covalent inhibitors of kras
US20190177338A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Chemical compounds
CN110036010A (en) * 2016-09-29 2019-07-19 亚瑞克西斯制药公司 The inhibitor of KRAS G12C mutain
CN110256421A (en) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 KRAS-G12C inhibitor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2473054B1 (en) * 2009-09-04 2017-06-14 The Regents of the University of Michigan Compositions and methods for treatment of leukemia
US10822312B2 (en) * 2016-03-30 2020-11-03 Araxes Pharma Llc Substituted quinazoline compounds and methods of use
US11639346B2 (en) * 2017-05-25 2023-05-02 Araxes Pharma Llc Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488910A (en) * 2013-10-10 2017-03-08 亚瑞克西斯制药公司 Inhibitors of kras g12c
CN107849022A (en) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 Substituted quinazoline compound and its application method
CN108779097A (en) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 Include the quinazoline compound and its application method of the 2- substitutions of substituted heterocycle
CN110036010A (en) * 2016-09-29 2019-07-19 亚瑞克西斯制药公司 The inhibitor of KRAS G12C mutain
WO2018206539A1 (en) * 2017-05-11 2018-11-15 Astrazeneca Ab Heteroaryl compounds that inhibit g12c mutant ras proteins
WO2018218070A2 (en) * 2017-05-25 2018-11-29 Araxes Pharma Llc Covalent inhibitors of kras
US20190177338A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Chemical compounds
CN110256421A (en) * 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 KRAS-G12C inhibitor

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2022105859A1 (en) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Kras g12d inhibitors
WO2022152233A1 (en) * 2021-01-15 2022-07-21 Beigene, Ltd. Kras g12c inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2023056421A1 (en) * 2021-10-01 2023-04-06 Incyte Corporation Pyrazoloquinoline kras inhibitors
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS
US11964989B2 (en) 2022-07-20 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors

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