WO2022111513A1 - Aromatic compound, and preparation method therefor and use thereof - Google Patents

Aromatic compound, and preparation method therefor and use thereof Download PDF

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Publication number
WO2022111513A1
WO2022111513A1 PCT/CN2021/132725 CN2021132725W WO2022111513A1 WO 2022111513 A1 WO2022111513 A1 WO 2022111513A1 CN 2021132725 W CN2021132725 W CN 2021132725W WO 2022111513 A1 WO2022111513 A1 WO 2022111513A1
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substituted
heteroatoms
alkyl
unsubstituted
alkoxy
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PCT/CN2021/132725
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French (fr)
Chinese (zh)
Inventor
向少云
王苏月
吕志坚
杨帅
方琪
黄焘
杨瑞
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杭州多域生物技术有限公司
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Priority to CN202180066528.7A priority Critical patent/CN116390915A/en
Publication of WO2022111513A1 publication Critical patent/WO2022111513A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an aromatic compound, its preparation method and application.
  • KRAS is one of the main members of the RAS gene family. Among the members of the RAS family, oncogenic mutations are most commonly found in KRAS (85%), of which KRAS G12C is the most common type of KRAS mutation, while HRAS and NRAS are less common. Mutations in the KRAS gene are found in one in seven of all metastatic human cancers, making it the most frequently mutated oncogene: more than 30% in lung adenocarcinoma, more than 40% in colorectal cancer, and more than 40% in pancreatic cancer. Cancer has a mutation rate of over 90%. KRAS gene mutation is called "the most difficult mutation to deal with". After years of efforts, KRAS inhibitors have entered clinical phase I trials abroad. The present invention focuses on the invention of novel KRAS inhibitors and KRAS degraders. It is hoped that this will provide tumor patients with a new treatment method, solve the usual drug resistance problem, and increase the effective use cycle of drugs.
  • the invention provides an aromatic compound, its preparation method and application.
  • the aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.
  • the present invention provides a compound of formula A or a pharmaceutically acceptable salt thereof,
  • Z is O or NR 5 ;
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 ,
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently hydrogen, R 5-1a substituted or unsubstituted C 1 -C 6 alkanes group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-2a ;
  • R 5-5 is cyano or halogen
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 5-2a is C 1 -C 6 alkyl, cyano or halogen
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is OR 2-1 , a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , or a "heteroatom substituted or unsubstituted by R 2-3 selected from one of N, O and S" or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 , R 2-3 and R 2-1a are independently hydroxy, halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
  • R 2-2a and R 2-2b are independently C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 ;
  • R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a ;
  • R 2-2a-1a is C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
  • a terminal is connected to R 3-1a
  • the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
  • n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;
  • n1 and m2 are independently 0, 1, 2, 3, 4 or 5;
  • Ring D is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
  • R 3-1a is the ligand of E3 ligase, and its structure can be, for example,
  • R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl,
  • Ring A can be a 5-6 membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B can be a C 6 -C 10 aromatic ring
  • Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
  • R a , R b , R c , R d and R e independently can be hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 can independently be 0, 1, 2, 3 or 4;
  • R 4 is halogen, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 are independently 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a -1 , R 2-2a-1a , R 3-1 and R 3-2 are independently the same or different.
  • the compound shown in the formula A is the compound shown in the formula I or the formula I',
  • the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms; the definitions of R 1 , R 2 , R 3 , R 4 and Z are as shown above.
  • the definitions of certain groups are as follows, and the undefined groups are as described above (hereinafter referred to as a certain scheme): when R 5 is a C 1 -C 6 alkyl group, the The C 1 -C 6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • R 1 is C 1 -C 6 alkyl
  • R 5 when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the number of the R 5-5 can be 1, 2 or 3.
  • the C 2 -C 6 alkenyl when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl may be a C 2 -C 4 alkenyl , preferably
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently substituted or unsubstituted by R 5-1a
  • the number of R 5-1a can be independently 1, 2 or 3.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C substituted or unsubstituted by R 5-1a
  • the C1 - C6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl , preferably methyl, ethyl or tert-butyl.
  • R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a
  • the number of said R 5-2a can be 1, 2 or 3.
  • R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a
  • the alkenyl can be C 2 -C 4 alkenyl, preferably vinyl.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl
  • the C 2 -C 6 alkynyl group can be a C 2 -C 4 alkynyl group, preferably an ethynyl group.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy group can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy, preferably methoxy.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1
  • the number of R 4-1a-1 can be 1, 2 or 3 indivual.
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1
  • the C 1 -C 6 alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 5-2a is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 1 when R 1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • R 2 when R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , the number of R 2-2 can be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the number of R 2-3 can be 1, 2, 3 or 4.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the 5-15-membered heteroaryl group is "heteroaryl”
  • the “heteroatom is selected from one or more of N, O and S
  • the number of heteroatoms is 1, 2, 3 or 4"
  • the 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as ), or "hetero atoms are selected from N, the number of hetero atoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as
  • R 2-1 when R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a , the number of R 2-1a may be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group may be a C 6 -C 10 aryl group , preferably phenyl or naphthyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 2-2 when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 2-2 when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 2-1a when R 2-1a is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 2-1a is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 2-2a when R 2-2a is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
  • R 2-2a when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1
  • the number of R 2-2a-1 can be 1, 2 or 3 .
  • R 2-2b is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1
  • the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • R 2-2a-1 when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a -1a , the number of R 2-2a-1a can be 1 or 2 or 3.
  • R 2-2a-1 when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy may be methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
  • R 2-2a-1a is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 3 when R 3 is C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , the number of R 3-1 can be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the number of R 3-2 can be 1, 2, 3 or 4.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the 5-15-membered heteroaryl group is "heteroaryl”
  • the “heteroatom is selected from one or more of N, O and S
  • the number of heteroatoms is 1, 2, 3 or 4"
  • the 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as ).
  • R 3-1 when R 3-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
  • the C 1 -C 6 alkyl can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 3-2 when R 3-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
  • R 3-2 when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • the C 3 -C 6 cycloalkyl can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane alkyl( for example ).
  • ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"
  • the said A 3-10-membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatoms selected from one or more of N, O and S" one or more, the number of heteroatoms is 1-3" 3-6 membered heterocycle, preferably tetrahydrofuran ( for example ), piperidine ( for example ) or piperazine ( for example ).
  • the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example ).
  • ring D is a 5-10-membered heteroaromatic ring with “heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"
  • the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatom is selected from N, O and S”.
  • One or more of the heteroatoms, the number of heteroatoms is 1-3 "5-6 membered heteroaromatic rings, preferably pyridine rings ( for example ) or pyrazine ring ( for example ).
  • R 3-1a-1 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • R 3-1a-2 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl It can be a 5-6 membered heterocycloalkyl group with “heteroatoms selected from N, and the number of heteroatoms is 1-2", preferably a tetrahydropyrrolyl group ( for example ).
  • the C 6 -C 10 aromatic ring in ring B, can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example ).
  • the 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be It is a 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3".
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" is preferably a 5-10-membered monocyclic heteroaromatic ring "hetero atoms are selected from N and S" One or more of, the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, more preferably thiazole ring ( for example ).
  • R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl
  • the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 5 may be
  • R1 can be hydrogen or methyl.
  • R2-2 and R2-1a can independently be -OH, -F, -Cl, -NH2 or -OMe.
  • R 2-1 can be
  • R 2 may be
  • R 3-1a may be
  • R 3-1 and R 3-2 independently can be OH, Me, Et, CN,
  • R 3 can be any organic compound
  • the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase promoting complex (APC), UBR5 (EDD1), SOCS/BC - box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 , PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin
  • R4 is F.
  • R 3 is
  • Z can be NR5.
  • R 5 may be
  • R 5 may be
  • R 5 may be
  • R 5-1 can be C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a .
  • R 5-1 can be C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a .
  • R 5-1 can be C 2 -C 6 alkenyl.
  • R 5-2 can be C 1 -C 6 alkyl.
  • R 5-3 and R 5-4 can independently be hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
  • R1 can be hydrogen
  • R 2 can be C 6 -C 15 aryl substituted or unsubstituted by R 2-2 .
  • R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
  • R 2-2 can be hydroxy, halogen, amino or C 1 -C 6 alkoxy.
  • R 2-2 can be hydroxy, halo or amino.
  • R 2-2 can be hydroxy or halo.
  • R 2-1a can be halogen.
  • R 3 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 .
  • R 3-1 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 .
  • One or more a 5-15-membered heteroaryl group with 1, 2, 3 or 4" heteroatoms.
  • R 3 can be substituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl.
  • R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl or -LR 3-1a .
  • R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl.
  • R 3-1 and R 3-2 independently can be methyl or isopropyl.
  • -L- can be The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl groups are connected.
  • n1 can be 0, 1, 2, 3, 4, 5 or 6.
  • m1 may be 0, 1, 2 or 3.
  • R 3-1a may be
  • R 3-1a-1 and R 3-1a-2 can independently be hydrogen or
  • the number of R 3-1 and R 3-2 can be 2, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • R 5-2 is C 1 -C 6 alkyl
  • R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a ;
  • a terminal is connected to R 3-1a
  • the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
  • n1 0, 1, 2, 3, 4, 5 or 6;
  • n1 0, 1, 2 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen or
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a ;
  • R 5-2 is C 1 -C 6 alkyl
  • R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen or amino
  • R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl
  • R 3-1 and R 3-2 are two, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
  • R 3-1 and R 3-2 are independently methyl or isopropyl
  • R 3-1 and R 3-2 are two, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is a 5-15-membered heteroaryl group substituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";
  • R 3-2 is C 1 -C 6 alkyl.
  • the compound shown in the formula I' can be any of the following structures,
  • the present invention provides a method for preparing the above-mentioned compound represented by formula A, which is method one, method two, method three or method four,
  • the first method includes the following steps: in a solvent, in the presence of a base, the compound represented by the formula II-1A and the compound represented by the formula II-2 are subjected to the following reaction to obtain the compound represented by the formula A. ,
  • method 1 includes the following steps: in a solvent, in the presence of a base, the compound represented by formula II-1 and the compound represented by formula II-2 are subjected to the following reaction to obtain The described compound shown in formula I,
  • the second method includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1A and the compound shown in formula III-2 or III-3 are subjected to the following reaction to obtain the described Compounds of formula A,
  • method 2 includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula III-1 and the compound represented by formula III-2 or III-3 are carried out as follows The reaction shown, obtains the described compound shown in formula I,
  • Z is NR 5
  • R 5 is
  • the third method includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1A and the compound shown in IV-2 are subjected to the reaction shown below to obtain the compound shown in formula A,
  • method 3 includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1 and the compound shown in IV-2 are subjected to the following reaction to obtain the The compound shown in formula I,
  • Z is NR 5
  • R 5 is
  • Method 4 includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula V-1A and the compound represented by formula V-2 or V-3 are subjected to the following reaction to obtain the described Compounds of formula A,
  • method four includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula V-1 and the compound represented by formula V-2 or V-3 are carried out as follows The reaction shown, obtains the described compound shown in formula I,
  • Z is O or NR 5 , and R 5 is C 1 -C 6 alkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5-1 , R 5-3 and R 5-4 are defined as above.
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.
  • the compound represented by formula A or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
  • the pharmaceutical excipients may include pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical composition can exist in the form of conventional dosage forms in the art, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably liquid, Suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.
  • any of the excipients 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, etc.
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated Oils
  • adsorption promoters such as lactose, white sugar,
  • any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.
  • binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient 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 and the like .
  • the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection of isotonic pressure with blood.
  • any carrier commonly used in the art can also be used.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, and the like can also be used.
  • usual solubilizers, buffers, pain relievers and the like may be added.
  • the content of the compound in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5-95% by mass, preferably 30-80% by mass .
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or mixed with injection delivery solutions (such as glucose solutions and amino acid solutions) for intravenous injection; suppositories are administered medicine to the rectum.
  • the present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a KRAS inhibitor, the KRAS inhibitor is preferably a KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro.
  • the present invention provides a kind of application of the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a KRAS inhibitor, the KRAS inhibitor is preferably KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro.
  • the present invention provides the use of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a medicine for preventing and/or treating KRAS-related diseases.
  • the KRAS is preferably KRAS G12C.
  • the present invention provides a kind of application of the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicine for preventing and/or treating KRAS-related diseases .
  • the KRAS is preferably KRAS G12C.
  • the KRAS-related disease may be a cancer characterized by KRAS mutation, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.
  • the present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament, the medicament being a medicament for preventing and/or treating cancer .
  • the present invention provides a kind of application of above-mentioned compound shown in formula I or its pharmaceutically acceptable salt or above-mentioned pharmaceutical composition in preparing medicine, and described medicine is used for prevention and/or or drugs to treat cancer.
  • the cancer may be a cancer characterized by KRAS mutations, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.
  • the present invention provides a compound represented by formula A, its pharmaceutically acceptable salts, its stereoisomers, its tautomers, its isotopic compounds, its nitrogen oxides, its metabolites, and its prodrugs , its crystalline form, or its solvate,
  • Z is O or NR 5 ;
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 ,
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently hydrogen, R 5-1a substituted or unsubstituted C 1 -C 6 alkanes group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-2a ;
  • R 5-5 is cyano or halogen
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 5-2a is C 1 -C 6 alkyl, cyano or halogen
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is OR 2-1 , a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , or a "heteroatom substituted or unsubstituted by R 2-3 selected from one of N, O and S" or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 , R 2-3 and R 2-1a are independently hydroxy, halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
  • R 2-2a and R 2-2b are independently C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 ;
  • R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a ;
  • R 2-2a-1a is C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
  • a terminal is connected to R 3-1a
  • the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
  • n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;
  • n1 and m2 are independently 0, 1, 2, 3, 4 or 5;
  • Ring D is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
  • R 3-1a is the ligand of E3 ligase, and its structure can be, for example,
  • R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl,
  • Ring A can be a 5-6 membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B can be a C 6 -C 10 aromatic ring
  • Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
  • R a , R b , R c , R d and R e independently can be hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 can independently be 0, 1, 2, 3 or 4;
  • R 4 is halogen, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 are independently 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a -1 , R 2-2a-1a , R 3-1 and R 3-2 are independently the same or different.
  • the compound shown in the formula A is the compound shown in the formula I or the formula I',
  • R 1 , R 2 , R 3 , R 4 , Z and * are defined as above.
  • the definitions of certain groups are as follows, and the undefined groups are as described above (hereinafter referred to as a certain scheme): when R 5 is a C 1 -C 6 alkyl group, the The C 1 -C 6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • R 5 when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the number of the R 5-5 can be 1, 2 or 3.
  • the C 2 -C 6 alkenyl when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl may be a C 2 -C 4 alkenyl , preferably
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently substituted or unsubstituted by R 5-1a
  • the number of R 5-1a can be independently 1, 2 or 3.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C substituted or unsubstituted by R 5-1a
  • the C1 - C6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl , preferably methyl, ethyl or tert-butyl.
  • R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a
  • the number of said R 5-2a can be 1, 2 or 3.
  • R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a
  • the alkenyl can be C 2 -C 4 alkenyl, preferably vinyl.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl
  • the C 2 -C 6 alkynyl group can be a C 2 -C 4 alkynyl group, preferably an ethynyl group.
  • R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy group can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy, preferably methoxy.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1
  • the number of R 4-1a-1 can be 1, 2 or 3 indivual.
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1
  • the C 1 -C 6 alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 5-2a is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 1 when R 1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • R 2 when R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , the number of R 2-2 can be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the number of R 2-3 can be 1, 2, 3 or 4.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the 5-15-membered heteroaryl group is "heteroaryl”
  • the “heteroatom is selected from one or more of N, O and S
  • the number of heteroatoms is 1, 2, 3 or 4"
  • the 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as ), or "hetero atoms are selected from N, the number of hetero atoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as
  • R 2-1 when R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a , the number of R 2-1a can be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group may be a C 6 -C 10 aryl group , preferably phenyl or naphthyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 2-2 when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 2-2 when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 2-1a when R 2-1a is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 2-1a is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 2-2a when R 2-2a is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
  • R 2-2a when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1
  • the number of R 2-2a-1 can be 1, 2 or 3 .
  • R 2-2b is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1
  • the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • R 2-2a-1 when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a -1a , the number of R 2-2a-1a can be 1 or 2 or 3.
  • R 2-2a-1 when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy may be methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
  • R 2-2a-1a is C 1 -C 6 alkoxy
  • the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 3 when R 3 is C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , the number of R 3-1 can be 1, 2, 3 or 4.
  • the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the number of R 3-2 can be 1, 2, 3 or 4.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4
  • the 5-15-membered heteroaryl group is "heteroaryl”
  • the “heteroatom is selected from one or more of N, O and S
  • the number of heteroatoms is 1, 2, 3 or 4"
  • the 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as ).
  • R 3-1 when R 3-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
  • the C 1 -C 6 alkyl can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • R 3-2 when R 3-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
  • R 3-2 when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
  • the C 3 -C 6 cycloalkane can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane ( for example ).
  • ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"
  • the said A 3-10-membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatoms selected from one or more of N, O and S"
  • the number of heteroatoms is 1-3" 3-6 membered heterocycle, preferably tetrahydrofuran ( for example ), piperidine ( for example ) or piperazine ( for example ).
  • the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example ).
  • ring D is a 5-10-membered heteroaromatic ring with “heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"
  • the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatom is selected from N, O and S”.
  • One or more of the heteroatoms, the number of heteroatoms is 1-3 "5-6 membered heteroaromatic rings, preferably pyridine rings ( for example ) or pyrazine ring ( for example ).
  • R 3-1a-1 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • R 3-1a-2 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl It can be a 5-6 membered heterocycloalkyl group with “heteroatoms selected from N, and the number of heteroatoms is 1-2", preferably a tetrahydropyrrolyl group ( for example ).
  • the C 6 -C 10 aromatic ring in ring B, can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example ).
  • the 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be It is a 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3".
  • hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" is preferably a 5-10-membered monocyclic heteroaromatic ring "hetero atoms are selected from N and S" One or more of, the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, more preferably thiazole ring ( for example ).
  • R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl
  • the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R 5 may be
  • R1 can be hydrogen or methyl.
  • R2-2 and R2-1a can independently be -OH, -F, -Cl, -NH2 or -OMe.
  • R 2-1 can be
  • R 2 may be
  • R 3-1a may be
  • R 3-1 and R 3-2 independently can be OH, Me, Et, CN,
  • R 3 can be any organic compound
  • the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase promoting complex (APC), UBR5 (EDD1), SOCS/BC -box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 , PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin
  • R4 is F.
  • R 3 is
  • Z can be NR5.
  • R 5 may be
  • R 5 may be
  • R 5 may be
  • R 5-1 can be C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a .
  • R 5-1 can be C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a .
  • R 5-1 can be C 2 -C 6 alkenyl.
  • R 5-2 can be C 1 -C 6 alkyl.
  • R 5-3 and R 5-4 can independently be hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
  • R1 can be hydrogen
  • R 2 can be C 6 -C 15 aryl substituted or unsubstituted by R 2-2 .
  • R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
  • R 2-2 can be hydroxy, halogen, amino or C 1 -C 6 alkoxy.
  • R 2-2 can be hydroxy, halo or amino.
  • R 2-2 can be hydroxy or halo.
  • R 2-1a can be halogen.
  • R 3 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 .
  • R 3-1 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 .
  • One or more a 5-15-membered heteroaryl group with 1, 2, 3 or 4" heteroatoms.
  • R 3 can be substituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl.
  • R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl or -LR 3-1a .
  • R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl.
  • R 3-1 and R 3-2 independently can be methyl or isopropyl.
  • -L- can be The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl groups are connected.
  • n1 can be 0, 1, 2, 3, 4, 5 or 6.
  • m1 may be 0, 1, 2 or 3.
  • R 3-1a may be
  • R 3-1a-1 and R 3-1a-2 can independently be hydrogen or
  • the number of R 3-1 and R 3-2 can be 2, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • R 5-2 is C 1 -C 6 alkyl
  • R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a ;
  • a terminal is connected to R 3-1a
  • the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
  • n1 0, 1, 2, 3, 4, 5 or 6;
  • n1 0, 1, 2 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen or
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a ;
  • R 5-2 is C 1 -C 6 alkyl
  • R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
  • R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
  • R 5-1a-1 is C 1 -C 6 alkoxy
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy
  • R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl, halogen or amino
  • R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
  • R 3-1 and R 3-2 are independently C 1 -C 6 alkyl
  • R 3-1 and R 3-2 are two, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
  • R 3-1 and R 3-2 are independently methyl or isopropyl
  • R 3-1 and R 3-2 are two, and R 3-1 and R 3-2 are different.
  • R 4 is F
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is a 5-15-membered heteroaryl group substituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";
  • R 3-2 is C 1 -C 6 alkyl.
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients; the compound represented by formula A or a pharmaceutically acceptable salt thereof Can be a therapeutically effective amount.
  • the present invention provides a kind of pharmaceutical composition, it comprises the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, Its nitrogen oxides, its metabolites, its prodrugs, its crystal forms, or its solvates, and pharmaceutical excipients.
  • the compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystal form, or a solvate thereof may be a therapeutically effective amount.
  • the pharmaceutical excipients may include pharmaceutically acceptable carriers, diluents and/or excipients.
  • the present invention provides the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its former Use of the drug, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator.
  • the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its Use of the metabolite, its prodrug, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator.
  • the kinase modulator can be a kinase inhibitor or a kinase agonist.
  • the kinase can be KRAS, such as KRAS G12C. Said KRAS inhibitor is used in vitro.
  • the present invention provides the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its former Use of a medicine, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a medicine.
  • the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its Use of metabolites, their prodrugs, their crystal forms, or their solvates, or the above-mentioned pharmaceutical compositions in the preparation of medicines.
  • the medicament may be a medicament for preventing and/or treating KRAS-related diseases or a medicament for preventing and/or treating cancer.
  • the KRAS is preferably KRAS G12C.
  • the KRAS-related disease may be cancer.
  • the cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer.
  • the cancer may be a cancer characterized by KRAS mutations.
  • the present invention also provides a method for treating KRAS-related diseases, comprising administering to a patient a therapeutically effective amount of the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer body, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition.
  • the present invention also provides a method for the treatment of KRAS-related diseases, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, Its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition.
  • the KRAS is preferably KRAS G12C.
  • the KRAS-related disease may be cancer.
  • the cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer.
  • the cancer may be a cancer characterized by KRAS mutations.
  • KRAS mutations have also been identified in hematological malignancies (eg, cancers affecting the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments relate to administering the disclosed compounds (eg, in the form of pharmaceutical compositions) to patients in need of treatment of hematological malignancies.
  • malignancies include, but are not limited to, leukemias and lymphomas.
  • the presently disclosed compounds can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL) and/or other leukemias.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • CML chronic myeloid leukemia
  • AoL acute monocytic leukemia
  • the compounds are useful in the treatment of lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.
  • the compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom'
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • Stereoisomers may exist as single stereoisomers or as mixtures thereof (eg, racemates).
  • stereoisomer refers to a cis-trans isomer or an optical isomer.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • “Pharmaceutically acceptable salts” according to the present invention are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and have It will be apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion and the like.
  • the compound of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those 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, Heptanoate, Oxalate, Malonate, Succinate, Suberate, Benzoate, methylbenzoate, phthalate, maleate, mesylate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-Malic acid, fumaric acid, succin
  • its pharmaceutically acceptable salts may also include: alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as zinc, calcium or magnesium salts; organic base salts such as and ammonia, alkylamines (including but not limited to: methylamine, triethylamine), hydroxyalkylamines, amino acids (including but not limited to: lysine, arginine), N-methylglucamine the salt formed.
  • alkali metal salts such as lithium, sodium or potassium salts
  • alkaline earth metal salts such as zinc, calcium or magnesium salts
  • organic base salts such as and ammonia, alkylamines (including but not limited to: methylamine, triethylamine), hydroxyalkylamines, amino acids (including but not limited to: lysine, arginine), N-methylglucamine the salt formed.
  • tautomer in the present invention refers to a functional group isomer produced by the rapid movement of a certain atom in two positions in a molecule, such as an enol tautomer and a keto tautomer.
  • isotopic compound means that one or more atoms in the compound exist in the form of their unnatural abundance.
  • its unnaturally abundant form means that about 95% of it is deuterium.
  • solvate in the present invention refers to the substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • metabolic refers to a substance produced by the metabolic activity of microorganisms.
  • prodrug refers to a chemical derivative of a compound of the present invention which, if chemically reacted in vivo, converts to a compound of general formula I.
  • crystal form means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
  • amorphous means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.
  • alkoxy refers to the group -O-RX, wherein RX is an alkyl group as defined above.
  • alkenyl refers to a straight or branched chain unsaturated non-aromatic hydrocarbon or cycloalkenyl group having one or more carbon-carbon double bonds, preferably a C2 - C6 alkenyl group.
  • alkenyl groups include Cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.
  • alkynyl refers to a straight or branched chain unsaturated non-aromatic hydrocarbon group having one or more carbon-carbon triple bonds, preferably a C 2 -C 6 alkynyl group, such as ethynyl, propynyl and the like.
  • amino refers to NH2 .
  • cycloalkyl refers to a straight or branched chain saturated alkyl group having the indicated number of carbon atoms. It can be monocyclic, bicyclic or polycyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyl refers to a saturated monocyclic group having a heteroatom, preferably a 3-10 membered saturated monocyclic group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. ring, preferably a 3-7 membered saturated monocycle, more preferably a 5-6 membered saturated monocycle.
  • heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like.
  • Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4 -base.
  • the "heterocycle” in the present invention loses one hydrogen atom, which is a heterocycloalkyl group. Therefore, the ring obtained after the heterocycloalkyl group in the present invention obtains one hydrogen atom is the heterocycle of the present invention. Similarly, the ring obtained after the aryl group, heteroaryl group and cycloalkyl group in the present invention obtains a hydrogen atom is the aromatic ring, heteroaromatic ring and cycloalkane of the present invention.
  • C 3 -C 6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl refers to phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur,
  • furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl , thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, benzisoxazolyl, quinoline base, isoquinolyl, etc.
  • the ligand of E3 ligase can be the group after the compound of formula A loses one atom or atomic group;
  • Q 1 , Q 3 , M 1 , M 2 and M 3 are independently C(R q1 )(R q2 ), N(R q3 ), O or S, and Q 2 is C(R q4 ) or N;
  • R m1 , R m2 , R m5 , R m13 and R m14 are independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R m3 is H or C 1 -C 6 alkyl
  • R m4 is halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NR m5 C 1 -C 6 alkyl, C 6 -C 15 aryl, "heteroatom One or more selected from N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, C 3 -C 6 cycloalkyl, "heteroatom” One or more selected from N, O and S, the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
  • R m6 is one of halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , C 6 -C 15 aryl, heteroatom selected from N, O and S or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl or "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
  • R m7 is a C 6 -C 15 aryl group, a heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group Or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
  • Ring N is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
  • R m8 and R m9 are independently H, OH or CN;
  • R m10 is C 1 -C 6 alkyl, -NH 2 , -NR m5 C 1 -C 6 alkyl, -NR m5 (CH 2 ) q8 C 6 -C 15 aryl, -NR m5 C 6 -C 15 Aryl, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, "heteroatoms are selected from N, One or more of O and S, the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
  • R m11 is -NH 2 , -NR m5 -C 1 -C 6 alkyl or -C 1 -C 6 alkyl;
  • R m15 and R m16 are independently H, deuterium, C 1 -C 6 alkyl, cyano-substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 15 aryl, one or more heteroatoms selected from N, O and S, the number of heteroatoms is 1, 2, 3 Or 4" 5-15-membered heteroaryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10-membered heterocycloalkyl ; or R m15 and R m16 together with the N atom they are connected to form a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15 yuan Heteroaryl or 3-10-membered heterocyclo
  • q1, q6, q9, q10 are independently 0, 1, 2, 3, 4, 5 or 6;
  • q2, q3, q4, q5, q7, q8, q11, q12, q13, q15, q16 are independently 1, 2, 3, 4, 5 or 6;
  • q14 is 0 or 1.
  • the ligand of E3 ligase can be, for example, a group after the compounds of formula A-1 to formula A-4 lose one atom or atomic group;
  • Q 3 , M 1 , M 2 and M 3 are independently C(R q1 )(R q2 ), N(R q3 ), O or S, and Q 2 is C(R q4 ) or N;
  • halogen eg F, Cl, Br or I
  • the ligand of E3 ligase can be, for example, a group after the following compound loses one atom or atomic group;
  • the ligand of E3 ligase can be, for example, any of the following groups;
  • ligand is a biological field concept that refers to a molecule or group capable of binding to a target protein.
  • modulator refers to a compound that increases or decreases the level of a target molecule or the function of a target molecule relative to a standard control (eg, such as the absence of a modulator).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.
  • Step A Dissolve 2-bromo-1-fluoro-4-iodobenzene (8.4 g, 27.92 mmol) in dry toluene (100 mL), then add 2-isopropyl-6-methylaniline (5.0 g, 33.50 mmol), Pd(OAC) 2 (palladium acetate, 0.627 g, 2.792 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.738 g, 2.792 mmol) and cesium carbonate (13.64 g, 41.88 mmol). The reaction solution was refluxed overnight under nitrogen protection.
  • Step B Combine N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methylaniline (6.068 g, 18.897 mmol) and 3-chloro-3-oxopropane Methyl acid (15.48 g, 113.38 mmol) was dissolved in dichloromethane (200 mL), then triethylamine (11.47 g, 113.38 mmol) was slowly added dropwise at room temperature over 2 hours and stirred for 10 minutes. After the liquid phase mass spectrometry monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added.
  • Step C Sodium hydroxide (5.034 g, 125.86 mmol) dissolved in 30 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2- isopropyl-6-methylphenyl)amino)-3-carbonylpropionic acid methyl ester (5.3 g, 12.586 mmol) solution was stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid.
  • Step D 3-((3-Bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropionic acid (4.846 g, 11.90 mmol ) was dissolved in Eatons Reagent (40 mL) and stirred at 55°C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step E 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (4.51 g, 11.5938 mmol) Dissolve in phosphorus oxychloride (30 mL) and stir at 90°C for 2 hours. After LC mass spectrometry showed the disappearance of the starting material, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution.
  • Step F Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (0.705 g, 1.732 mmol) in 2 oxane (10 mL), then add piperazine-1-carboxylate tert-butyl ester (1.613 g, 8.661 mmol) and N,N-diisopropylethylamine (2.239 g, 17.32 mmol) and stir at 110 °C 2 days.
  • Step G 4-(7-Bromo-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinoline-4 -yl)piperazine-1-carboxylate tert-butyl ester (0.400g, 0.7179mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.234g, 1.4358mmol), potassium orthophosphate (305mg, 1.4358mmol ) and Pd dba 3 (tris(dibenzylideneacetone)dipalladium, 0.099 g, 0.1077 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxy Hetero-6-phosphoryladamantane, 0.063 g, 0.2154 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (8 mL/2 mL) in which the air was replaced with arg
  • Step H 4-(6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-2-carbonyl- 1,2-Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.200 g, 0.339 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and allowed to stand at room temperature The mixture was stirred for 1 hour under low pressure.
  • Step I 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-4-(piperazine-1 -yl)quinolin-2(1H)-one (0.166 g, 0.339 mmol) was dissolved in dichloromethane (13 mL) and DIPEA (N,N-diisopropylethylamine) (0.219 g, 1.695 mmol) was added and acryloyl chloride (0.031 g, 0.339 mmol) and stirred at room temperature for 2 hours.
  • DIPEA N,N-diisopropylethylamine
  • Step A 2-bromo-1-fluoro-4-iodobenzene (5.0g, 16.62mmol), 2-ethyl-6-methylaniline (2.25g, 16.62mmol), palladium acetate (0.373 g, 1.7 mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.03 g, 1.7 mmol) and cesium carbonate (8.12 g, 24.93 mmol) were put into a 250 mL single-necked vial , anhydrous toluene (100 mL) was added, and it was replaced with nitrogen three times, and then heated at 100 degrees for 16 hours.
  • Step B N-(3-bromo-4-fluorophenyl)-2-ethyl-6-methylaniline (5.0 g, 16.22 mmol), 3-chloro-3-oxopropionic acid Methyl ester (13.29 g, 97.34 mmol) was put into a 250 mL single-necked bottle together, anhydrous dichloromethane (150 mL) was added, cooled to 0 degrees, and triethylamine (16.77 g, 130 mmol) was slowly added. It was then stirred at room temperature for another hour.
  • Step C methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionate (5.0 g, 12.25 g mmol) and sodium hydroxide (2.45 g, 61.23 mmol) were put into a 250 mL single-neck flask, and tetrahydrofuran (100 mL) and water (20 mL) were added. Stir at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 3 with 1 molar hydrochloric acid.
  • Step D 3-((3-Bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionic acid (4.2 g, 10.65 mmol) Put it into a 100mL single-neck bottle together with Eaton's reagent (15mL), and then heat it to 90 degrees to react for 16 hours.
  • Step E Put 7-bromo-1-(2-ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione into a 100 mL single-port In the bottle, 20 mL of phosphorus oxychloride was added, and then heated to 80 degrees to react for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with ethyl acetate (100 mL ⁇ 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result.
  • Step F 7-Bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (1.0 g, 2.53 mmol ), piperazine-1-carboxylate tert-butyl ester (2.36g, 12.7mmol) and DIPEA (N,N-diisopropylethylamine, 1.36g, 12.7mmol) were put into the single-necked bottle of 50mL together, and 5mL 1 , 4-dioxane, and then heated to 110 degrees for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly.
  • Step G 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.4g, 0.73mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.229g, 1.47mmol), 1,3,5,7-tetramethyl-6 - Phenyl-2,4,8-trioxa-6-phosphoryladamantane (44 mg, 0.14 mmol), potassium phosphate (312 mg, 1.47 mmol) and Pd 2 dba 3 (tris(dibenzylideneacetone)di Palladium, 67 mg, 0.07 mmol) were put into a 50 mL single-necked bottle together, added solvent tetrahydrofuran (10 mL) and water (2.5 mL), replaced with nitrogen three times, heated to 60 degrees and re
  • Step H 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (0.2 g, 0.28 mmol) was dissolved in 5 mL of dichloromethane and trifluoroacetic acid (0.272 g, 2.8 mmol) was added.
  • Step 1 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.2 g, 73% purity, 0.255 mmol) and triethylamine (77 mg, 0.75 mmol) were dissolved in 5 mL of dichloromethane , cooled to 0 degrees, and allyl chloride (23 mg, 0.255 mmol) was added. The reaction was carried out at room temperature for 2 hours.
  • Step A Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC) 2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs 2 CO 3 (Cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection.
  • Step B N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise at room temperature over 3 hours and stirred for 10 minutes. After the liquid phase mass spectrometry showed that the raw materials disappeared, dichloromethane (200 mL) was added to dilute the reaction solution and water (2 ⁇ 200 mL) was added.
  • Step C A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2) dissolved in methanol (240 mL). , 6-dimethylphenyl)amino)-3-carbonylpropionic acid methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid.
  • Step D Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) in Eatons Reagent (40 mL) and stirred overnight at 55°C. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step E 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25g, 17.31mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After LC-MS monitoring showed the disappearance of the raw materials, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution.
  • Step F 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (0.65 g, 1.71 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (1.59 g, 8.55 mmol) and N,N-diisopropylethylamine (2.21 g, 17.1 mmol) and stirred at 110 °C for 2 days.
  • Step G 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) tert-Butyl piperazine-1-carboxylate (0.711 g, 1.34 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.419 g, 2.688 mmol), potassium orthophosphate (570 mg, 2.688 mmol) and Pd 2 dba 3 ( (tris(dibenzylideneacetone)dipalladium, 0.184 g, 0.21 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa- 6-Phosphoryladamantane, 0.177 g, 0.4 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (15 mL, 4/1) replaced with argon for 15 minutes, and replaced with
  • Step H 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.251 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (4.2 mL) was added and stirred at room temperature After 1 hour, LC-MS monitoring showed the disappearance of the raw materials, concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and added dichloromethane (10 mL) and concentrated again under reduced pressure until dichloromethane and trifluoroacetic acid were completely removed to obtain 1.
  • Step I 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.206 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and DIEA (N,N-diisopropylethylamine) (0.289 g, 2.235 mmol) and acryloyl chloride were added (0.041 g, 0.447 mmol) and stirred at room temperature for 2 hours.
  • DIEA N,N-diisopropylethylamine
  • Step A 2-bromo-1-fluoro-4-iodobenzene (10.0 g, 33.23 mmol), 2-isopropyl-4-methyl-3-aminopyridine (4.99 g, 33.23 mmol) ), palladium acetate (0.746g, 3.32mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07g, 3.32mmol) and cesium carbonate (16.24g, 49.85mmol) were put together Into a 500 mL single-necked bottle, anhydrous toluene (200 mL) was added, and the mixture was replaced with nitrogen for 3 times, and then heated at 100 degrees to react for 16 hours.
  • anhydrous toluene 200 mL
  • Step B N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methyl-3-aminopyridine (7.9g, 24.44mmol), 3-chloro- Methyl 3-oxopropionate (10.01g, 73.33mmol) was put into a 250mL single-necked bottle together, anhydrous dichloromethane (150mL) was added, cooled to 0 degrees, and triethylamine (12.3g, 122mmol) was slowly added . It was then stirred at room temperature for another hour.
  • Step C methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionate ( 3.5 g, 8.27 mmol) and sodium hydroxide (1.65 g, 41.34 mmol) were put into a 250 mL single-neck flask, and tetrahydrofuran (100 mL) and water (20 mL) were added. Stir at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 7 with 1 molar hydrochloric acid.
  • Step D 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionic acid (3.2g , 7.82mmol) and Eaton's reagent (15mL) were put into a 100mL single-neck bottle, and then heated to 90 degrees for 16 hours of reaction.
  • Step E 7-Bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)-dione ( 2.6g, 6.65mmol) into a 100mL single-neck bottle, add 20mL phosphorus oxychloride, and then heat to 80 degrees to react for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with dichloromethane (100 mL ⁇ 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result.
  • Step F 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one (0.4 g, 0.98 mmol), piperazine-1-carboxylate tert-butyl ester (909 mg, 4.88 mmol) and DIPEA (N, N-diisopropylethylamine, 631 mg, 4.88 mmol) were put into a 50 mL single-necked bottle together, added 3mL of 1,4-dioxane, then heated to 110 degrees and reacted for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly.
  • Step G 4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinoline Lin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.35g, 0.63mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.195g, 1.26mmol), potassium orthophosphate (267mg, 1.26mmol) and Pd 2 dba 3 ((tris(dibenzylideneacetone)dipalladium, 0.027 g, 0.03 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4, 8-Trioxa-6-phosphoryladamantane, 0.030 g, 0.06 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (10 mL, 4/1) in which the air was replaced with argon
  • Step H 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.25g, 0.423mmol) was dissolved in 5mL of dichloromethane, trifluoroacetic acid (0.482g, 4.23 mmol). The reaction was carried out at room temperature for 2 hours, and the reaction of the raw materials was detected by liquid phase mass spectrometry.
  • Step 1 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(piperidine)
  • Azin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.25 g, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) were dissolved in 5 mL of dichloromethane , cooled to 0 degrees, and acryloyl chloride (36 mg, 0.4 mmol) was added. The reaction was carried out at room temperature for 2 hours.
  • Step A 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.3g, 0.55mmol), (2-amino-6-chlorophenyl)boronic acid (0.142g, 0.83mmol), 1,3,5,7-tetramethyl yl-6-phenyl-2,4,8-trioxa-6-phosphoramantane (32 mg, 0.11 mmol), potassium phosphate (233 mg, 1.1 mmol) and Pd 2 dba 3 ((tris(dibenzylidene) (base acetone) dipalladium, 55mg, 0.06mmol) put into the single-necked bottle of 50mL together, add solvent tetrahydrofuran (8mL) and water (2mL), replace three times with nitrogen, be heated to 60 degrees and
  • Step B 4-(7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (30 mg, 0.06 mmol) was dissolved in 2 mL of dichloromethane and trifluoroacetic acid (63 mg, 0.6 mmol) was added. The reaction was carried out at room temperature for 2 hours.
  • Step C 7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-4-(piperazine-1- yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (33 mg, 0.061 mmol) and triethylamine (12 mg, 1.2 mmol) were dissolved in 2 mL of dichloromethane and cooled to 0 degree, allyl chloride (5.5 mg, 0.061 mmol) was added. The reaction was carried out at room temperature for 2 hours.
  • Example 7 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxybenzene yl)quinolin-2(1H)-one
  • Step A Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC) 2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs 2 CO 3 (Cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection.
  • Step B N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise at room temperature over 3 hours and stirred for 10 minutes. After the liquid phase mass spectrometry showed that the raw materials disappeared, dichloromethane (200 mL) was added to dilute the reaction solution and water (2 ⁇ 200 mL) was added.
  • Step C A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2) dissolved in methanol (240 mL). , 6-dimethylphenyl)amino)-3-carbonylpropionic acid methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid.
  • Step D Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) in Eatons Reagent (40 mL) and stirred overnight at 55°C. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step E 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25g, 17.31mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After LC-MS monitoring showed the disappearance of the raw materials, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution.
  • Step F 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (300 mg, 0.78 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (725 mg, 3.9 mmol) and N,N-diisopropylethylamine (603.0 mg, 4.68 mmol) and stirred at 110 °C for 2 days.
  • Step G 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) tert-Butyl piperazine-1-carboxylate (60 mg, 0.11 mmol), 2-fluoro-4-methoxyphenylboronic acid (96 mg, 0.56 mmol), potassium acetate (89 mg, 0.91 mmol) and Pacl2 (pddf) (8 mg , 0.01 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (1 mL, 4/1) in which the air was replaced with argon for 15 minutes, the air was replaced with argon again, and stirred at 60 °C for 3 days .
  • Step H 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline
  • Step I 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.084 mmol) was dissolved in dichloromethane (1 mL) and DIPEA (N,N-diisopropylethylamine) (21.67 g, 0.168 mmol) and propylene were added Acyl chloride (15 mg, 0.168 mmol) was stirred at room temperature for 2 hours.
  • DIPEA N,N-diisopropylethylamine
  • Step A 2-Methoxyethylamine (100 mg, 1.33 mmol) was dissolved in DCM (1.5 mL) and DIPEA (344 mg, 2.67 mmol) was added and stirred at room temperature for 0.5 h, p-nitrobenzene was added Ethyl chloroformate (320 mg, 1.60 mml) was reacted at room temperature for 1 h.
  • Step B 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-
  • Step B 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-
  • Step A Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (110 mL), then add 2-isopropylaniline (5.39 g, 39.86 mmol) ), Pd(OAC) 2 (palladium acetate, 0.75g, 3.34mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07g, 3.34mmol) and cesium carbonate (16.24g) , 49.72 mmol). The reaction solution was refluxed overnight under nitrogen protection.
  • Step B N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, 31.15 mmol) and methyl 3-chloro-3-oxopropionate (8.5 g, 62.26 mmol) was dissolved in dichloromethane (100 mL), then triethylamine (6.3 g, 62.26 mmol) was slowly added dropwise over 1 hour at room temperature and stirred for 30 minutes. After the liquid phase mass spectrometry monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added.
  • Step C 56 mL of 2N sodium hydroxide was added to 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3 dissolved in methanol (110 mL) - methyl carbonylpropionate (11.2 g, 27.47 mmol) solution, stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid.
  • Step D Dissolve 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionic acid (9.8 g, 24.86 mmol) in Eatons Reagent (Eaton's reagent) (70 mL) and stirred at 70 °C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Eatons Reagent Eaton's reagent
  • Step E 7-Bromo-6-fluoro-1-(2-isopropylphenyl)quinoline-2,4(1H,3H)-dione (7.3 g, 19.40 mmol) was dissolved in Phosphorus oxychloride (45 mL) and stirred at 80°C for 6 hours. After LC mass spectrometry showed the disappearance of the starting material, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution.
  • Step F Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (2.4 g, 6.08 mmol) in two oxane (20 mL), then add piperazine-1-carboxylate tert-butyl ester (5.65 g, 30.38 mmol) and N,N-diisopropylethylamine (4.72 g, 36.52 mmol) and stir at 110 °C 2 days.
  • Step G 4-(7-Bromo-6-fluoro-1-(2-isopropylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine - 1-Carboxylic acid tert-butyl ester (0.500g, 0.918mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.624g, 3.6717mmol), potassium acetate (0.54g, 3.923mmol ) and PdCl (dppf) 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, 0.134 g, 0.183 mmol) was dissolved in a mixed solution of 1,4-dioxane and water in which the air was replaced with argon for 15 minutes (8mL/2mL), the air was replaced with argon again, and stirred at 90°C for 48h.
  • Step H 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, 0.577 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperaz
  • Step I 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.281 g, 0.574 mmol) was dissolved in dichloromethane (10 mL) and DIPEA (N,N-diisopropylethylamine) (0.371 g, 2.87 mmol) and acryloyl chloride were added (0.104 g, 1.15 mmol) and stirred at room temperature for 2 hours.
  • DIPEA N,N-diisopropylethylamine
  • Step A 2-Methoxyethylamine (0.2 g, 2.66 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) (0.688 g, 5.32 mmol) was added ) under an ice bath and stirred for 10 minutes, slowly added 4-nitrophenylcarbonyl chloride (0.805g, 3.99mmol) and naturally raised to room temperature and stirred for 2h.
  • DIPEA N,N-diisopropylethylamine
  • Step B 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazine-1-car
  • Step C 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl(2-methoxyethyl)carbamate (0.243 g, 1.01 mmol), slowly add 1M KHMDS (2 ml) under ice bath, remove the ice bath and stir at 65°C for 12 h. After monitoring by liquid phase mass spectrometry shows the disappearance of the raw materials, concentrate under reduced pressure to remove the solvent to prepare 4-(6-fluoro).
  • Step A 2-(2-Methoxyethoxy)ethylamine (0.2 g, 1.68 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) was added ) (434g, 3.36mmol) was stirred under ice bath for 10 minutes, 4-nitrophenylcarbonyl chloride (0.507g, 2.51mmol) was slowly added to room temperature and stirred for 2h. Concentrated to remove the solvent to prepare 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)carbamate (0.419 g, yellow oil, yield 88.2%) MS (ESI) M /Z: 284.3[M+H] + .
  • Step B 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazine-1-car
  • Step C 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)amino was added Formate (0.216g, 0.76mmol), slowly add 1M KHMDS (2ml) under an ice bath, remove the ice bath and stir at 65°C for 12h.
  • Step B 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazine-1-car
  • Step C 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.228 g, 0.466 mmol) was dissolved in dichloromethane (4 mL) and 3-(2-methoxyethoxy)propionic acid (0.103 g, 0.695 mmol) and trichloromethane were added Ethylamine (0.118 g, 1.15 mmol), then BOP reagent (0.226 g, 0.512 mmol) was added and stirred at room temperature for 12 h.
  • Step A 2-isopropyl-4-methyl-pyridin-3-amine (2g, 13.3mmol), palladium acetate (147.8mg, 0.66mmol), BINAP (808mg, 1.3mmol) and carbonic acid Cesium (8.6g, 26.6mmol) was added to toluene (30ml) to replace nitrogen three times and stirred overnight at 110°C. After the reaction was completed by mass spectrometry, the solvent was spin-dried and purified by column chromatography to obtain N-(3-bromo-4-fluorobenzene yl)-2-isopropyl-4-methylpyridin-3-amine (2.8 g, 8.7 mmol yield: 65%). MS (ESI) M/Z: 323.3 [M+H]+.
  • Step B N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8g, 8.7mmol) was dissolved in dichloroethane (30ml) ) was dissolved, and methyl 3-chloro-3-oxopropionate (2.4 g. 17.4) was added dropwise to the solution, stirred at 70 degrees Celsius overnight, cooled to room temperature, washed with saturated sodium carbonate solution, extracted with ethyl acetate, and dried.
  • Step C 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid methyl ester ( 3g, 7mmol) dissolve with methanol (5ml), add dropwise 2M sodium hydroxide solution (10ml) to the solution and stir for 1 hour TLC monitoring, after the reaction is complete, adjust the pH to neutrality with 2M hydrochloric acid solution, spin dry the solvent, use flash ( acetonitrile/water) to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2 g, 5 mmol ).
  • Step D 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2g , 5mmol) was dissolved in 5ml of Eaton's reagent, stirred at 80°C for 1 hour, cooled to room temperature, added to ice water and adjusted to neutrality with 2M sodium hydroxide solution, extracted with ethyl acetate, and the solvent was spin-dried to obtain 7-bromo- 6-Fluoro-1-(2-isopropyl-6-methyl-pyridyl)quinoline-2,4-dione (2 g crude).
  • Step E 7-Bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinoline-2,4-dione (1 g crude) was treated with trichloro Phosphorus oxide (8ml) was dissolved, stirred at 80°C for 2 hours, the solvent was spin-dried, the pH was adjusted to neutral with 2M sodium hydroxide solution, extracted with dichloromethane, the organic phase was spin-dried, and purified by column chromatography (PE/EA0 ⁇ 100%) to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol)
  • Step F 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol ) was dissolved in DMF, added N,N-diisopropylethylamine (260mg, 2mmol) and (S)-1-N-Boc-2-methylpiperazine (200mg, 1mmol) and stirred at 60°C for two hours , after confirming that the reaction was complete by mass spectrometry, it was purified by flash (acetonitrile/water 0-100%) to obtain tert-butyl (2S)-4-[7-bromo-6-fluoro-1-(2-isopropyl-4-methyl] (404 mg, 0.7 mmol, 80% yield). MS(ESI) M/Z: 573.1[M+H]
  • Step G tert-Butyl(2S)-4-[7-bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo- 4-Quinolinyl]-2-methyl-piperazine-1-carboxylate (200 mg, 0.348 mmol) was dissolved in 1,4 dioxane, and 1,3,5,7-tetramethyl was added to the system yl-6-phenyl-2,4,8-trioxa-6-phosphoadamantane (10.16 mg, 0.0348), potassium phosphate (148 mg, 0.7 mmol) 2-fluoro-6-hydroxyphenylboronic acid (108 mg, 0.7 ) and tris(dibenzylideneacetone)dipalladium (31 mg, 0.0348 mmol) replaced nitrogen three times, then stirred at 60°C overnight, spin-dried the solvent, and purified with flash (acetonitrile/water 0-100%) to obtain tert-but
  • Step H tert-Butyl(2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3 -pyridyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-1-carboxylate (55mg) 0.09mmol) was dissolved in dichloromethane (1ml) trifluoroacetic acid (0.5ml) was added ml) stirred at room temperature for 1 hour, spin-dried, then added dichloromethane (2ml) and N,N-diisopropylethylamine (64mg, 0.5mmol) and added acryloyl chloride (8Fmg, 0.09mmol) during stirring to react half After one hour, mass spectrometry confirmed that the reaction was complete, the solvent was spun dry, and purified by flash (acetonitrile/water) to obtain 6-fluoro-7-(2-fluoro-6
  • SOS1 exchange domain (564-1049) protein (Cytoskeleton, Inc., Cat. No. GE02-XL)
  • Compounds with a 400-fold final concentration such as the final detection concentration of 25 ⁇ M, are prepared to a 400-fold concentration, that is, 10 mM.
  • the compound was serially diluted to the set number of concentration points using an automatic micropipette.
  • reaction buffer containing 50 mM Tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.1% BSA, 14 mM MgCl2 , 0.01% Tween-20, 1 mM DTT.
  • the fluorescence signal value (Ex580/Em620) was continuously read within 2 hours (read every 5 minutes) with a microplate reader SpectraMax Paradigm.
  • Inhibition rate (%) (maximum value-sample value)/(maximum value-minimum value) ⁇ 100%.
  • Table 1 shows the inhibition rate and IC50 of the compounds of the present invention on KRAS G12C at 1 ⁇ M and 10 ⁇ M.
  • test compound in DMSO to prepare a stock solution with a concentration of 10 mM.
  • the stock solution was first diluted with DMSO to 2 mM, 10 concentrations, 3-fold serial dilution. Then dilute to 30 ⁇ M with growth medium. Add 50 ⁇ L/well to the 96-well plate seeded with cells.
  • test compound in DMSO to prepare a stock solution with a concentration of 10 mM.
  • the stock solutions were first diluted with DMSO to 3 mM, 2 mM, 1 mM, and then diluted with growth medium to 150 ⁇ M, 100 ⁇ M, and 50 ⁇ M, respectively.
  • the 6-well plate medium was discarded and 200 ⁇ l of diluted compound was added to bring the 6-well plate volume to 2 ml. Incubate in a 37°C, 5% CO 2 incubator for 8 hours, 24 hours, and 48 hours, respectively.
  • Secondary antibody incubation Dilute the antibody at a ratio of 1:3000 and incubate at room temperature for 1 hour.

Abstract

Provided are an aromatic compound represented by formula A or a pharmaceutically acceptable salt thereof, and a preparation method therefor and the use thereof. The aromatic compound has a good inhibitory effect on KRAS, especially KRAS G12C.

Description

一种芳香化合物、其制备方法及应用A kind of aromatic compound, its preparation method and application
本申请要求申请日为2020/11/24的中国专利申请2020113346910的优先权；要求申请日为2021/11/16的中国专利申请2021113580344的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2020113346910 with the filing date of 2020/11/24; the priority of Chinese patent application 2021113580344 with the filing date of 2021/11/16. This application cites the full text of the above Chinese patent application.
技术领域technical field
本发明涉及一种芳香化合物、其制备方法及应用。The present invention relates to an aromatic compound, its preparation method and application.
背景技术Background technique
KRAS属于RAS基因家族主要成员之一，在RAS家族成员中，致癌突变最常见于KRAS(85％)，其中KRAS G12C是最常见的KRAS突变类型，而HRAS与NRAS则较为少见。在人类所有转移性癌症中，有七分之一存在KRAS基因突变，使其成为最常见的致癌突变基因：在肺腺癌中的突变率超过30％，大肠癌的突变率超过40％，胰腺癌的突变率超过90％。KRAS基因突变被称为“最难对付的突变”，经过多年的努力，国外已有KRAS抑制剂进入临床一期实验。本发明着重在全新的KRAS抑制剂和KRAS降解剂的发明。希望由此给肿瘤患者提供一种新的治疗手段，解决通常的耐药性问题，增加药物的有效使用周期。KRAS is one of the main members of the RAS gene family. Among the members of the RAS family, oncogenic mutations are most commonly found in KRAS (85%), of which KRAS G12C is the most common type of KRAS mutation, while HRAS and NRAS are less common. Mutations in the KRAS gene are found in one in seven of all metastatic human cancers, making it the most frequently mutated oncogene: more than 30% in lung adenocarcinoma, more than 40% in colorectal cancer, and more than 40% in pancreatic cancer. Cancer has a mutation rate of over 90%. KRAS gene mutation is called "the most difficult mutation to deal with". After years of efforts, KRAS inhibitors have entered clinical phase I trials abroad. The present invention focuses on the invention of novel KRAS inhibitors and KRAS degraders. It is hoped that this will provide tumor patients with a new treatment method, solve the usual drug resistance problem, and increase the effective use cycle of drugs.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种芳香化合物、其制备方法及应用。本发明的芳香化合物对KRAS尤其是KRAS G12C具有良好的抑制作用。The invention provides an aromatic compound, its preparation method and application. The aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.
本发明提供了一种如式A所示化合物或其药学上可接受的盐，The present invention provides a compound of formula A or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021132725-appb-000001
Figure PCTCN2021132725-appb-000001
其中，in,
Z为O或NR 5； Z is O or NR 5 ;
R 5为C 1-C 6烷基、
Figure PCTCN2021132725-appb-000002
被R 5-5取代或未取代的C 2-C 6烯基、
Figure PCTCN2021132725-appb-000003
R 5 is C 1 -C 6 alkyl,
Figure PCTCN2021132725-appb-000002
C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 ,
Figure PCTCN2021132725-appb-000003
R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为氢、被R 5-1a取代或未取代的C 1-C 6烷基、被R 5-2a取代或未取代的C 2-C 6烯基、C 2-C 6炔基或C 1-C 6烷氧基； R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently hydrogen, R 5-1a substituted or unsubstituted C 1 -C 6 alkanes group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-2a ;
R 5-5为氰基或卤素； R 5-5 is cyano or halogen;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 5-2a为C 1-C 6烷基、氰基或卤素； R 5-2a is C 1 -C 6 alkyl, cyano or halogen;
R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
R 2为OR 2-1、被R 2-2取代或未取代的C 6-C 15芳基或被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 2 is OR 2-1 , a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , or a "heteroatom substituted or unsubstituted by R 2-3 selected from one of N, O and S" or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基； R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
R 2-2、R 2-3和R 2-1a独立地为羟基、卤素、氨基、C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2021132725-appb-000004
Figure PCTCN2021132725-appb-000005
R 2-2 , R 2-3 and R 2-1a are independently hydroxy, halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
Figure PCTCN2021132725-appb-000004
Figure PCTCN2021132725-appb-000005
R 2-2a和R 2-2b独立地为被R 2-2a-1取代或未取代的C 1-C 6烷基； R 2-2a and R 2-2b are independently C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 ;
R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基； R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a ;
R 2-2a-1a为C 1-C 6烷氧基； R 2-2a-1a is C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为羟基、氰基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-L-R 3-1a； R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
-L-为
Figure PCTCN2021132725-appb-000006
Figure PCTCN2021132725-appb-000007
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂 原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接； -L- for
Figure PCTCN2021132725-appb-000006
Figure PCTCN2021132725-appb-000007
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
n1、n2、n3、n4、n5、n6和n7独立地为0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;
m1和m2独立地为0、1、2、3、4或5；m1 and m2 are independently 0, 1, 2, 3, 4 or 5;
环D为C 3-C 6环烷烃、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环、C 6-C 10芳环或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环； Ring D is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
R 3-1a为E3连接酶的配体，其结构例如可为
Figure PCTCN2021132725-appb-000008
R 3-1a is the ligand of E3 ligase, and its structure can be, for example,
Figure PCTCN2021132725-appb-000008
R 3-1a-1和R 3-1a-2独立地可为氢、C 1-C 6烷基、
Figure PCTCN2021132725-appb-000009
Figure PCTCN2021132725-appb-000010
R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl,
Figure PCTCN2021132725-appb-000009
Figure PCTCN2021132725-appb-000010
环A可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环；Ring A can be a 5-6 membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
环B可为C 6-C 10芳环； Ring B can be a C 6 -C 10 aromatic ring;
环C可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环；Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
R a、R b、R c、R d和R e独立地可为氢、羟基或C 1-C 6烷基； R a , R b , R c , R d and R e independently can be hydrogen, hydroxy or C 1 -C 6 alkyl;
o1、o2和o3独立地可为0、1、2、3或4；o1, o2 and o3 can independently be 0, 1, 2, 3 or 4;
R 4为卤素、OCH 3、OH、CN、CONH 2或COOH； R 4 is halogen, OCH 3 , OH, CN, CONH 2 or COOH;
R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2的个数独立地为1、2、3、4或5个，当为2、3、4或5个时，R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2独立地相同或不同。 The numbers of R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 are independently 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a -1 , R 2-2a-1a , R 3-1 and R 3-2 are independently the same or different.
在本发明的某一方案中，所述的如式A所示化合物为如式I或式I’所示的化合物，In a certain scheme of the present invention, the compound shown in the formula A is the compound shown in the formula I or the formula I',
Figure PCTCN2021132725-appb-000011
Figure PCTCN2021132725-appb-000011
其中，标“*”的碳原子为S构型碳原子、R构型碳原子或非手性碳原子；R 1、R 2、R 3、R 4和Z的定义如上所示。 Wherein, the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms; the definitions of R 1 , R 2 , R 3 , R 4 and Z are as shown above.
在本发明某一方案中，某些基团的定义如下，未定义的基团同前所述(以下简称在某一方案中)：当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme of the present invention, the definitions of certain groups are as follows, and the undefined groups are as described above (hereinafter referred to as a certain scheme): when R 5 is a C 1 -C 6 alkyl group, the The C 1 -C 6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
在本发明某一方案中：
Figure PCTCN2021132725-appb-000012
为
Figure PCTCN2021132725-appb-000013
R 1为C 1-C 6烷基；例如
Figure PCTCN2021132725-appb-000014
Figure PCTCN2021132725-appb-000015
In a certain scheme of the present invention:
Figure PCTCN2021132725-appb-000012
for
Figure PCTCN2021132725-appb-000013
R 1 is C 1 -C 6 alkyl; for example
Figure PCTCN2021132725-appb-000014
Figure PCTCN2021132725-appb-000015
在本发明某一方案中：当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的R 5-5的个数可为1、2或3个。 In a certain scheme of the present invention: when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the number of the R 5-5 can be 1, 2 or 3.
在本发明某一方案中：当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的C 2-C 6烯基可为C 2-C 4烯基，优选
Figure PCTCN2021132725-appb-000016
In a certain scheme of the present invention: when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl may be a C 2 -C 4 alkenyl , preferably
Figure PCTCN2021132725-appb-000016
在本发明某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，R 5-1a的个数可独立地为1、2或3个。 In a certain scheme of the present invention: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently substituted or unsubstituted by R 5-1a In the case of the C 1 -C 6 alkyl group, the number of R 5-1a can be independently 1, 2 or 3.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或叔丁基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C substituted or unsubstituted by R 5-1a When 1 - C6 alkyl, the C1 - C6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl , preferably methyl, ethyl or tert-butyl.
在某一方案中：当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的R 5-2a的个数可为1、2或3个。 In a certain scheme: when R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the number of said R 5-2a can be 1, 2 or 3.
在某一方案中：当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的烯基可为C 2- C 4烯基，优选乙烯基。 In a certain scheme: when R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the alkenyl can be C 2 -C 4 alkenyl, preferably vinyl.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 2-C 6炔基时，所述的C 2-C 6炔基可为C 2-C 4炔基，优选乙炔基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl , the C 2 -C 6 alkynyl group can be a C 2 -C 4 alkynyl group, preferably an ethynyl group.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可独立地为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy , the C 1 -C 6 alkoxy group can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy, preferably methoxy.
在某一方案中：当R 5-5为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R 5-5 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，R 4-1a-1的个数可为1、2或3个。 In a certain scheme: when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1, the number of R 4-1a-1 can be 1, 2 or 3 indivual.
在某一方案中：当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基。 In a certain scheme: when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 , the C 1 -C 6 alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
在某一方案中：当R 5-1a-1为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 5-1a-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 5-2a为C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme: when R 5-2a is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, preferably methyl.
在某一方案中：当R 5-2a为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R 5-2a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：当R 1为C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme: when R 1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
在某一方案中：当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，R 2-2的个数可为1、2、3或4个。 In a certain scheme: when R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , the number of R 2-2 can be 1, 2, 3 or 4.
在某一方案中：当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 2 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-2 , the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
在某一方案中：当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 2-3的个数可为1、2、3或4个。 In a certain scheme: when R 2 is substituted or unsubstituted by R 2-3 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "a", the number of R 2-3 can be 1, 2, 3 or 4.
在某一方案中：当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基。 In a certain scheme: when R 2 is substituted or unsubstituted by R 2-3 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "heteroaryl", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5- The 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基优选“杂原子选自N，杂原子个数为1、2或个”的5-6元单环杂芳基，更优选吡啶基(例如
Figure PCTCN2021132725-appb-000017
)，或“杂原子选自N，杂原子个数为1-2个”的8-10元双环杂芳基，优选吲唑基，例如
Figure PCTCN2021132725-appb-000018
Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as
Figure PCTCN2021132725-appb-000017
), or "hetero atoms are selected from N, the number of hetero atoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as
Figure PCTCN2021132725-appb-000018
在某一方案中：当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，R 2-1a的个数可为1、2、3或4个。 In a certain scheme: when R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a , the number of R 2-1a may be 1, 2, 3 or 4.
在某一方案中：当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 2-1 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-1a , the C 6 -C 15 aryl group may be a C 6 -C 10 aryl group , preferably phenyl or naphthyl.
在某一方案中：当R 2-2为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟或氯。 In a certain scheme: when R 2-2 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：当R 2-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 2-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 2-1a为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟或氯。 In a certain scheme: when R 2-1a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：当R 2-1a为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 2-1a is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 2-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数可为1、2或3个。 In a certain scheme: when R 2-2a is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
在某一方案中：当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。 In a certain scheme: when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
在某一方案中：当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数可为1、2或3个。 In a certain scheme: when R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
在某一方案中：当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。 In a certain scheme: when R 2-2b is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
在某一方案中：当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，R 2-2a-1a的个数可为1、2或3个。 In a certain scheme: when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a -1a , the number of R 2-2a-1a can be 1 or 2 or 3.
在某一方案中：当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基。 In a certain scheme: when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy may be methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
在某一方案中：当R 2-2a-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-2a-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，R 3-1的个数可为1、2、3或4个。 In a certain scheme: when R 3 is C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , the number of R 3-1 can be 1, 2, 3 or 4.
在某一方案中：当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 3 is a C 6 -C 15 aryl group substituted or unsubstituted by R 3-1 , the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
在某一方案中：当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 3-2的个数可为1、2、3或4个。 In a certain scheme: when R 3 is substituted or unsubstituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 In the case of a 5-15-membered heteroaryl group with "a", the number of R 3-2 can be 1, 2, 3 or 4.
在某一方案中：当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基。 In a certain scheme: when R 3 is substituted or unsubstituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "heteroaryl", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5- The 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基优选“杂原子选自N，杂原子个数为1、2或个”的5-6元单环杂芳基，更优选吡啶基(例如
Figure PCTCN2021132725-appb-000019
)。 Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as
Figure PCTCN2021132725-appb-000019
).
在某一方案中：当R 3-1为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或异丙基。 In a certain scheme: when R 3-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
在某一方案中：当R 3-1为C 1-C 6烷氧基时，所述的C 1-C 6烷基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 3-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkyl can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 3-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或异丙基。 In a certain scheme: when R 3-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
在某一方案中：当R 3-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当环D为C 3-C 6环烷烃时，所述的C 3-C 6环烷基可为环丙烷、环丁 烷、环戊烷或环己烷，优选环己烷(
Figure PCTCN2021132725-appb-000020
例如为
Figure PCTCN2021132725-appb-000021
)。 In a certain scheme: when ring D is C 3 -C 6 cycloalkane, the C 3 -C 6 cycloalkyl can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane alkyl(
Figure PCTCN2021132725-appb-000020
for example
Figure PCTCN2021132725-appb-000021
).
在某一方案中：当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-6元杂环，优选四氢呋喃(
Figure PCTCN2021132725-appb-000022
例如为
Figure PCTCN2021132725-appb-000023
)、哌啶(
Figure PCTCN2021132725-appb-000024
例如为
Figure PCTCN2021132725-appb-000025
)或哌嗪(
Figure PCTCN2021132725-appb-000026
例如为
Figure PCTCN2021132725-appb-000027
)。 In a certain scheme: when ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the said A 3-10-membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatoms selected from one or more of N, O and S" one or more, the number of heteroatoms is 1-3" 3-6 membered heterocycle, preferably tetrahydrofuran (
Figure PCTCN2021132725-appb-000022
for example
Figure PCTCN2021132725-appb-000023
), piperidine (
Figure PCTCN2021132725-appb-000024
for example
Figure PCTCN2021132725-appb-000025
) or piperazine (
Figure PCTCN2021132725-appb-000026
for example
Figure PCTCN2021132725-appb-000027
).
在某一方案中：当环D为C 6-C 10芳环时，所述的C 6-C 10芳环可为苯环或萘环，优选苯环(
Figure PCTCN2021132725-appb-000028
例如为
Figure PCTCN2021132725-appb-000029
)。 In a certain scheme: when ring D is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (
Figure PCTCN2021132725-appb-000028
for example
Figure PCTCN2021132725-appb-000029
).
在某一方案中：当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-6元杂芳环，优选吡啶环(
Figure PCTCN2021132725-appb-000030
例如为
Figure PCTCN2021132725-appb-000031
)或吡嗪环(
Figure PCTCN2021132725-appb-000032
例如为
Figure PCTCN2021132725-appb-000033
)。 In a certain scheme: when ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the The "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatom is selected from N, O and S". One or more of the heteroatoms, the number of heteroatoms is 1-3 "5-6 membered heteroaromatic rings, preferably pyridine rings (
Figure PCTCN2021132725-appb-000030
for example
Figure PCTCN2021132725-appb-000031
) or pyrazine ring (
Figure PCTCN2021132725-appb-000032
for example
Figure PCTCN2021132725-appb-000033
).
在某一方案中：当R 3-1a-1为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 3-1a-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 3-1a-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 3-1a-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在某一方案中：环A中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环烷基可为“杂原子选自N，杂原子个数为1-2个”的5-6元杂环烷基，优选四氢吡咯基(
Figure PCTCN2021132725-appb-000034
例如为
Figure PCTCN2021132725-appb-000035
)。 In a certain scheme: in Ring A, the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl It can be a 5-6 membered heterocycloalkyl group with "heteroatoms selected from N, and the number of heteroatoms is 1-2", preferably a tetrahydropyrrolyl group (
Figure PCTCN2021132725-appb-000034
for example
Figure PCTCN2021132725-appb-000035
).
在某一方案中：环B中，所述的C 6-C 10芳环可为苯环或萘环，优选苯环(
Figure PCTCN2021132725-appb-000036
例如为
Figure PCTCN2021132725-appb-000037
)。 In a certain scheme: in ring B, the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (
Figure PCTCN2021132725-appb-000036
for example
Figure PCTCN2021132725-appb-000037
).
在某一方案中：环C中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环或双环杂芳环。In a certain scheme: in ring C, the 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be It is a 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3".
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环优选“杂原子选自N和S中的一种或多种，杂原子个数为1-2个”的5-6元单环杂芳环，更优选噻唑环(
Figure PCTCN2021132725-appb-000038
例如为
Figure PCTCN2021132725-appb-000039
)。 Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" is preferably a 5-10-membered monocyclic heteroaromatic ring "hetero atoms are selected from N and S" One or more of, the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, more preferably thiazole ring (
Figure PCTCN2021132725-appb-000038
for example
Figure PCTCN2021132725-appb-000039
).
在某一方案中：当R a、R b、R c、R d和R e独立地为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或叔丁基。 In a certain scheme: when R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
在某一方案中：当R 4为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R4 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000040
Figure PCTCN2021132725-appb-000041
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000040
Figure PCTCN2021132725-appb-000041
在某一方案中：R 1可为氢或甲基。 In a certain scheme: R1 can be hydrogen or methyl.
在某一方案中：
Figure PCTCN2021132725-appb-000042
可为
Figure PCTCN2021132725-appb-000043
Figure PCTCN2021132725-appb-000044
Figure PCTCN2021132725-appb-000045
In a scheme:
Figure PCTCN2021132725-appb-000042
can be
Figure PCTCN2021132725-appb-000043
Figure PCTCN2021132725-appb-000044
Figure PCTCN2021132725-appb-000045
在某一方案中：
Figure PCTCN2021132725-appb-000046
可为
Figure PCTCN2021132725-appb-000047
In a scheme:
Figure PCTCN2021132725-appb-000046
can be
Figure PCTCN2021132725-appb-000047
在某一方案中：
Figure PCTCN2021132725-appb-000048
可为
Figure PCTCN2021132725-appb-000049
Figure PCTCN2021132725-appb-000050
In a scheme:
Figure PCTCN2021132725-appb-000048
can be
Figure PCTCN2021132725-appb-000049
Figure PCTCN2021132725-appb-000050
在某一方案中：R 2-2和R 2-1a独立地可为-OH、-F、-Cl、-NH 2或-OMe。 In a certain scheme: R2-2 and R2-1a can independently be -OH, -F, -Cl, -NH2 or -OMe.
在某一方案中：R 2-1可为
Figure PCTCN2021132725-appb-000051
In one scheme: R 2-1 can be
Figure PCTCN2021132725-appb-000051
在某一方案中：R 2可为
Figure PCTCN2021132725-appb-000052
Figure PCTCN2021132725-appb-000053
In one scheme: R 2 may be
Figure PCTCN2021132725-appb-000052
Figure PCTCN2021132725-appb-000053
在某一方案中：-L-可为
Figure PCTCN2021132725-appb-000054
Figure PCTCN2021132725-appb-000055
In a scheme: -L- can be
Figure PCTCN2021132725-appb-000054
Figure PCTCN2021132725-appb-000055
在某一方案中：R 3-1a可为
Figure PCTCN2021132725-appb-000056
In one scheme: R 3-1a may be
Figure PCTCN2021132725-appb-000056
在某一方案中：R 3-1和R 3-2独立地可为OH、Me、Et、CN、
Figure PCTCN2021132725-appb-000057
Figure PCTCN2021132725-appb-000058
Figure PCTCN2021132725-appb-000059
In a certain scheme: R 3-1 and R 3-2 independently can be OH, Me, Et, CN,
Figure PCTCN2021132725-appb-000057
Figure PCTCN2021132725-appb-000058
Figure PCTCN2021132725-appb-000059
在某一方案中：R 3可为
Figure PCTCN2021132725-appb-000060
Figure PCTCN2021132725-appb-000061
In one scheme: R 3 can be
Figure PCTCN2021132725-appb-000060
Figure PCTCN2021132725-appb-000061
在某一方案中：所述的E3连接酶可为von Hippel-Lindau(VHL)、CRBN、MDM2、cIAP、Cereblon、XIAP、E3A、后期促进复合物(APC)、UBR5(EDD1)、SOCS/BC- box/eloBC/CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box蛋白15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、Mind Bomb 1/MIB1、Mind Bomb 2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5或ZNRF3，优选VHL、CRBN、MDM2或cIAP。In a certain scheme: the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase promoting complex (APC), UBR5 (EDD1), SOCS/BC - box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 , PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54 , β-TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-box protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP -2/HIAP-1, cIAP(pan), ITCH/AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, preferably VHL, CRBN, MDM2 or cIAP.
在某一方案中：当R 1为C 1-C 6烷基时，与R 1相连的C原子的构型为S构型。 In a certain scheme: when R 1 is a C 1 -C 6 alkyl group, the configuration of the C atom to which R 1 is attached is the S configuration.
在某一方案中：R 4为F。 In one aspect: R4 is F.
在某一方案中：R 3为
Figure PCTCN2021132725-appb-000062
Figure PCTCN2021132725-appb-000063
In one scheme: R 3 is
Figure PCTCN2021132725-appb-000062
Figure PCTCN2021132725-appb-000063
在某一方案中：Z可为NR 5。 In one aspect: Z can be NR5.
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000064
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000064
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000065
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000065
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000066
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000066
在某一方案中：R 5-1可为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基。 In a certain scheme: R 5-1 can be C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a .
在某一方案中：R 5-1可为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基。 In a certain scheme: R 5-1 can be C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 5-1可为C 2-C 6烯基。 In a certain scheme: R 5-1 can be C 2 -C 6 alkenyl.
在某一方案中：R 5-2可为C 1-C 6烷基。 In a certain scheme: R 5-2 can be C 1 -C 6 alkyl.
在某一方案中：R 5-3和R 5-4独立地可为氢、或被R 5-1a取代或未取代的C 1-C 6烷基。 In a certain scheme: R 5-3 and R 5-4 can independently be hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 1可为氢。 In one aspect: R1 can be hydrogen.
在某一方案中：R 2可为被R 2-2取代或未取代的C 6-C 15芳基。 In a certain scheme: R 2 can be C 6 -C 15 aryl substituted or unsubstituted by R 2-2 .
在某一方案中：R 2可为被R 2-2取代的C 6-C 15芳基。 In a certain scheme: R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
在某一方案中：R 2-2可为羟基、卤素、氨基或C 1-C 6烷氧基。 In a certain scheme: R 2-2 can be hydroxy, halogen, amino or C 1 -C 6 alkoxy.
在某一方案中：R 2-2可为羟基、卤素或氨基。 In a certain scheme: R 2-2 can be hydroxy, halo or amino.
在某一方案中：R 2-2可为羟基或卤素。 In a certain scheme: R 2-2 can be hydroxy or halo.
在某一方案中：R 2-1a可为卤素。 In one aspect: R 2-1a can be halogen.
在某一方案中：R 3可为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基。 In a certain scheme: R 3 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 . One or more , a 5-15-membered heteroaryl group with 1, 2, 3 or 4" heteroatoms.
在某一方案中：R 3可为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基。 In a certain scheme: R 3 can be substituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl.
在某一方案中：R 3-1和R 3-2独立地可为C 1-C 6烷基或-L-R 3-1a。 In one embodiment: R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl or -LR 3-1a .
在某一方案中：R 3-1和R 3-2独立地可为C 1-C 6烷基。 In a certain scheme: R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl.
在某一方案中：R 3-1和R 3-2独立地可为甲基或异丙基。 In a certain scheme: R 3-1 and R 3-2 independently can be methyl or isopropyl.
在某一方案中：-L-可为
Figure PCTCN2021132725-appb-000067
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接。 In a scheme: -L- can be
Figure PCTCN2021132725-appb-000067
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl groups are connected.
在某一方案中：n1可为0、1、2、3、4、5或6。In a certain scheme: n1 can be 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：m1可为0、1、2或3。In a certain scheme: m1 may be 0, 1, 2 or 3.
在某一方案中：R 3-1a可为
Figure PCTCN2021132725-appb-000068
In one scheme: R 3-1a may be
Figure PCTCN2021132725-appb-000068
在某一方案中：R 3-1a-1和R 3-1a-2独立地可为氢或
Figure PCTCN2021132725-appb-000069
In a certain scheme: R 3-1a-1 and R 3-1a-2 can independently be hydrogen or
Figure PCTCN2021132725-appb-000069
在某一方案中：R 3-1和R 3-2的个数可为2个，且R 3-1和R 3-2不同。 In a certain scheme: the number of R 3-1 and R 3-2 can be 2, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000070
 R5 is
Figure PCTCN2021132725-appb-000070
R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基； R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
R 2为被R 2-2取代或未取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为C 1-C 6烷基或-L-R 3-1a； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a ;
-L-为
Figure PCTCN2021132725-appb-000071
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接； -L- for
Figure PCTCN2021132725-appb-000071
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
n1为0、1、2、3、4、5或6；n1 is 0, 1, 2, 3, 4, 5 or 6;
m1为0、1、2或3；m1 is 0, 1, 2 or 3;
R 3-1a为
Figure PCTCN2021132725-appb-000072
R 3-1a is
Figure PCTCN2021132725-appb-000072
R 3-1a-1和R 3-1a-2独立地为氢或
Figure PCTCN2021132725-appb-000073
R 3-1a-1 and R 3-1a-2 are independently hydrogen or
Figure PCTCN2021132725-appb-000073
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000074
 R5 is
Figure PCTCN2021132725-appb-000074
R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基； R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a ;
R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为C 1-C 6烷基。 R 3-1 and R 3-2 are independently C 1 -C 6 alkyl.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000075
 R5 is
Figure PCTCN2021132725-appb-000075
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基、卤素或氨基； R 2-2 is hydroxyl, halogen or amino;
R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
R 3-1和R 3-2独立地为C 1-C 6烷基； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl;
R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同。 The number of R 3-1 and R 3-2 is two, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000076
 R5 is
Figure PCTCN2021132725-appb-000076
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
R 3-1和R 3-2独立地为甲基或异丙基； R 3-1 and R 3-2 are independently methyl or isopropyl;
R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同。 The number of R 3-1 and R 3-2 is two, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000077
 R5 is
Figure PCTCN2021132725-appb-000077
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
R 3为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a 5-15-membered heteroaryl group substituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";
R 3-2为C 1-C 6烷基。 R 3-2 is C 1 -C 6 alkyl.
本发明中，所述的如式I所示化合物可为如下任一结构，In the present invention, the described compound shown in formula I can be any of the following structures,
Figure PCTCN2021132725-appb-000078
Figure PCTCN2021132725-appb-000078
本发明中，所述的如式I’所示化合物可为如下任一结构，In the present invention, the compound shown in the formula I' can be any of the following structures,
Figure PCTCN2021132725-appb-000079
Figure PCTCN2021132725-appb-000079
本发明提供了一种上述的如式A所示化合物的制备方法，其为方法一、方法二、方法三或方法四，The present invention provides a method for preparing the above-mentioned compound represented by formula A, which is method one, method two, method three or method four,
方法一包括以下步骤：溶剂中，在碱的存在下，将如式II-1A所示化合物和如式II-2所示化合物进行如下所示的反应，得所述的如式A所示化合物，The first method includes the following steps: in a solvent, in the presence of a base, the compound represented by the formula II-1A and the compound represented by the formula II-2 are subjected to the following reaction to obtain the compound represented by the formula A. ,
Figure PCTCN2021132725-appb-000080
Figure PCTCN2021132725-appb-000080
例如，式A为式I时，方法一包括以下步骤：溶剂中，在碱的存在下，将如式II-1所示化合物和如式II-2所示化合物进行如下所示的反应，得所述的如式I所示化合物，For example, when formula A is formula I, method 1 includes the following steps: in a solvent, in the presence of a base, the compound represented by formula II-1 and the compound represented by formula II-2 are subjected to the following reaction to obtain The described compound shown in formula I,
Figure PCTCN2021132725-appb-000081
Figure PCTCN2021132725-appb-000081
方法二包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式III-1A所示化合物和如式III-2或III-3所示化合物进行如下所示的反应，得所述的如式A所示化合物，The second method includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1A and the compound shown in formula III-2 or III-3 are subjected to the following reaction to obtain the described Compounds of formula A,
Figure PCTCN2021132725-appb-000082
Figure PCTCN2021132725-appb-000082
例如，式A为式I时，方法二包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式III-1所示化合物和如式III-2或III-3所示化合物进行如下所示的反应，得所述的如式I所示化合物，For example, when formula A is formula I, method 2 includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula III-1 and the compound represented by formula III-2 or III-3 are carried out as follows The reaction shown, obtains the described compound shown in formula I,
Figure PCTCN2021132725-appb-000083
Figure PCTCN2021132725-appb-000083
方法一或方法二中，Z为NR 5，R 5为
Figure PCTCN2021132725-appb-000084
In the first method or the second method, Z is NR 5 , and R 5 is
Figure PCTCN2021132725-appb-000084
方法三包括以下步骤：溶剂中，在碱的存在下，将如式IV-1A所示化合物和IV-2所示化合物进行如下所示的反应，得所述的如式A所示化合物，The third method includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1A and the compound shown in IV-2 are subjected to the reaction shown below to obtain the compound shown in formula A,
Figure PCTCN2021132725-appb-000085
Figure PCTCN2021132725-appb-000085
例如，式A为式I时，方法三包括以下步骤：溶剂中，在碱的存在下，将如式IV-1所示化合物和IV-2所示化合物进行如下所示的反应，得所述的如式I所示化合物，For example, when formula A is formula I, method 3 includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1 and the compound shown in IV-2 are subjected to the following reaction to obtain the The compound shown in formula I,
Figure PCTCN2021132725-appb-000086
Figure PCTCN2021132725-appb-000086
方法三中，Z为NR 5，R 5为
Figure PCTCN2021132725-appb-000087
In the third method, Z is NR 5 , and R 5 is
Figure PCTCN2021132725-appb-000087
方法四包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式V-1A所示化合物和如式V-2或V-3所示化合物进行如下所示的反应，得所述的如式A所示化合物，Method 4 includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula V-1A and the compound represented by formula V-2 or V-3 are subjected to the following reaction to obtain the described Compounds of formula A,
Figure PCTCN2021132725-appb-000088
Figure PCTCN2021132725-appb-000088
例如，式A为式I时，方法四包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式V-1所示化合物和如式V-2或V-3所示化合物进行如下所示的反应，得所述的如式I所示化合物，For example, when formula A is formula I, method four includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula V-1 and the compound represented by formula V-2 or V-3 are carried out as follows The reaction shown, obtains the described compound shown in formula I,
Figure PCTCN2021132725-appb-000089
Figure PCTCN2021132725-appb-000089
方法四中，Z为O或NR 5，R 5为C 1-C 6烷基； In method four, Z is O or NR 5 , and R 5 is C 1 -C 6 alkyl;
其中，R 1、R 2、R 3、R 4、R 5-1、R 5-3和R 5-4的定义同上所述。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5-1 , R 5-3 and R 5-4 are defined as above.
在某一方案中，方法一、方法二、方法三或方法四中，所述的反应的条件和操作与本 领域该类反应常规的条件和操作相同。In a certain scheme, in Method 1, Method 2, Method 3 or Method 4, the conditions and operations of the described reaction are the same as the conventional conditions and operations of this type of reaction in the art.
本发明提供了一种药物组合物，其包括上述如式A所示化合物或其药学上可接受的盐，和药用辅料。所述的如式A所示化合物或其药学上可接受的盐可为治疗有效量。The present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients. The compound represented by formula A or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
某一方案中，本发明提供了一种药物组合物，其包括上述如式I所示化合物或其药学上可接受的盐，和药用辅料。所述的如式I所示化合物或其药学上可接受的盐可为治疗有效量。In a certain aspect, the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient. The compound represented by formula I or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
所述药物组合物中，所述药用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 pharmaceutical excipients may include pharmaceutically acceptable carriers, diluents and/or excipients.
根据治疗目的，药物组合物可以本领域常规的剂型形式存在，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 exist in the form of conventional dosage forms in the art, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably liquid, Suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.
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 tablet form, any of the excipients 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, etc.; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.; disintegration inhibitors, such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated Oils; adsorption promoters, such as quaternary amine bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerol, 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. The usual coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered film tablets and multi-layered tablets as required.
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 pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, 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 a suppository, any excipient 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 and the like .
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 glycerol, etc.) to prepare an injection of isotonic pressure with blood. In the preparation of injections, any carrier 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 solubilizers, buffers, pain relievers and the like may be added.
本发明中，所述的化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 compound in the pharmaceutical composition is not particularly limited, and can be selected within 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 administration method of the pharmaceutical composition is not particularly limited. Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or mixed with injection delivery solutions (such as glucose solutions and amino acid solutions) for intravenous injection; suppositories are administered medicine to the rectum.
本发明提供了一种上述如式A所示化合物或其药学上可接受的盐、或上述的药物组合物在制备KRAS抑制剂的应用，所述的KRAS抑制剂优选KRAS G12C抑制剂。所述的KRAS抑制剂在体外使用。某一方案中，本发明提供了一种上述如式I所示化合物或其药学上可接受的盐、或上述的药物组合物在制备KRAS抑制剂的应用，所述的KRAS抑制剂优选KRAS G12C抑制剂。所述的KRAS抑制剂在体外使用。本发明提供了一种上述如式A所示化合物或其药学上可接受的盐、或上述的药物组合物在制备用于预防和/或治疗KRAS相关疾病的药物中的应用。所述的KRAS优选KRAS G12C。某一方案中，本发明提供了一种上述如式I所示化合物或其药学上可接受的盐、或上述的药物组合物在制备用于预防和/或治疗KRAS相关疾病的药物中的应用。所述的KRAS优选KRAS G12C。所述的KRAS相关疾病可为以KRAS突变为特征的癌症，例如胰腺癌、大肠癌或肺腺癌。The present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a KRAS inhibitor, the KRAS inhibitor is preferably a KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro. In a certain scheme, the present invention provides a kind of application of the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a KRAS inhibitor, the KRAS inhibitor is preferably KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro. The present invention provides the use of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a medicine for preventing and/or treating KRAS-related diseases. The KRAS is preferably KRAS G12C. In a certain scheme, the present invention provides a kind of application of the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicine for preventing and/or treating KRAS-related diseases . The KRAS is preferably KRAS G12C. The KRAS-related disease may be a cancer characterized by KRAS mutation, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.
本发明提供了一种上述如式A所示化合物或其药学上可接受的盐、或上述的药物组合物在制备药物中的应用，所述的药物为用于预防和/或治疗癌症的药物。某一方案中，本发明提供了一种上述如式I所示化合物或其药学上可接受的盐、或上述的药物组合物在制备药物中的应用，所述的药物为用于预防和/或治疗癌症的药物。所述的癌症可为以KRAS突变为特征的癌症，例如胰腺癌、大肠癌或肺腺癌。The present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament, the medicament being a medicament for preventing and/or treating cancer . In a certain scheme, the present invention provides a kind of application of above-mentioned compound shown in formula I or its pharmaceutically acceptable salt or above-mentioned pharmaceutical composition in preparing medicine, and described medicine is used for prevention and/or or drugs to treat cancer. The cancer may be a cancer characterized by KRAS mutations, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.
本发明提供了一种如式A所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物，The present invention provides a compound represented by formula A, its pharmaceutically acceptable salts, its stereoisomers, its tautomers, its isotopic compounds, its nitrogen oxides, its metabolites, and its prodrugs , its crystalline form, or its solvate,
Figure PCTCN2021132725-appb-000090
Figure PCTCN2021132725-appb-000090
其中，in,
Z为O或NR 5； Z is O or NR 5 ;
R 5为C 1-C 6烷基、
Figure PCTCN2021132725-appb-000091
被R 5-5取代或未取代的C 2-C 6烯基、
Figure PCTCN2021132725-appb-000092
R 5 is C 1 -C 6 alkyl,
Figure PCTCN2021132725-appb-000091
C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 ,
Figure PCTCN2021132725-appb-000092
R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为氢、被R 5-1a取代或未取代的C 1-C 6烷基、被R 5-2a取代或未取代的C 2-C 6烯基、C 2-C 6炔基或C 1-C 6烷氧基； R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently hydrogen, R 5-1a substituted or unsubstituted C 1 -C 6 alkanes group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-2a ;
R 5-5为氰基或卤素； R 5-5 is cyano or halogen;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 5-2a为C 1-C 6烷基、氰基或卤素； R 5-2a is C 1 -C 6 alkyl, cyano or halogen;
R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
R 2为OR 2-1、被R 2-2取代或未取代的C 6-C 15芳基或被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 2 is OR 2-1 , a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , or a "heteroatom substituted or unsubstituted by R 2-3 selected from one of N, O and S" or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基； R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
R 2-2、R 2-3和R 2-1a独立地为羟基、卤素、氨基、C 1-C 6烷基、C 1-C 6烷氧基、
Figure PCTCN2021132725-appb-000093
Figure PCTCN2021132725-appb-000094
R 2-2 , R 2-3 and R 2-1a are independently hydroxy, halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
Figure PCTCN2021132725-appb-000093
Figure PCTCN2021132725-appb-000094
R 2-2a和R 2-2b独立地为被R 2-2a-1取代或未取代的C 1-C 6烷基； R 2-2a and R 2-2b are independently C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 ;
R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基； R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a ;
R 2-2a-1a为C 1-C 6烷氧基； R 2-2a-1a is C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为羟基、氰基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-L-R 3-1a； R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
-L-为
Figure PCTCN2021132725-appb-000095
Figure PCTCN2021132725-appb-000096
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂 原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接； -L- for
Figure PCTCN2021132725-appb-000095
Figure PCTCN2021132725-appb-000096
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
n1、n2、n3、n4、n5、n6和n7独立地为0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;
m1和m2独立地为0、1、2、3、4或5；m1 and m2 are independently 0, 1, 2, 3, 4 or 5;
环D为C 3-C 6环烷烃、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环、C 6-C 10芳环或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环； Ring D is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
R 3-1a为E3连接酶的配体，其结构例如可为
Figure PCTCN2021132725-appb-000097
R 3-1a is the ligand of E3 ligase, and its structure can be, for example,
Figure PCTCN2021132725-appb-000097
R 3-1a-1和R 3-1a-2独立地可为氢、C 1-C 6烷基、
Figure PCTCN2021132725-appb-000098
Figure PCTCN2021132725-appb-000099
R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl,
Figure PCTCN2021132725-appb-000098
Figure PCTCN2021132725-appb-000099
环A可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环；Ring A can be a 5-6 membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
环B可为C 6-C 10芳环； Ring B can be a C 6 -C 10 aromatic ring;
环C可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环；Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
R a、R b、R c、R d和R e独立地可为氢、羟基或C 1-C 6烷基； R a , R b , R c , R d and R e independently can be hydrogen, hydroxy or C 1 -C 6 alkyl;
o1、o2和o3独立地可为0、1、2、3或4；o1, o2 and o3 can independently be 0, 1, 2, 3 or 4;
R 4为卤素、OCH 3、OH、CN、CONH 2或COOH； R 4 is halogen, OCH 3 , OH, CN, CONH 2 or COOH;
R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2的个数独立地为1、2、3、4或5个，当为2、3、4或5个时，R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2独立地相同或不同。 The numbers of R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 are independently 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a -1 , R 2-2a-1a , R 3-1 and R 3-2 are independently the same or different.
在本发明的某一方案中，所述的如式A所示化合物为如式I或式I’所示的化合物，In a certain scheme of the present invention, the compound shown in the formula A is the compound shown in the formula I or the formula I',
Figure PCTCN2021132725-appb-000100
Figure PCTCN2021132725-appb-000100
其中，R 1、R 2、R 3、R 4、Z和*的定义如上所示。 Here, R 1 , R 2 , R 3 , R 4 , Z and * are defined as above.
在本发明某一方案中，某些基团的定义如下，未定义的基团同前所述(以下简称在某一方案中)：当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme of the present invention, the definitions of certain groups are as follows, and the undefined groups are as described above (hereinafter referred to as a certain scheme): when R 5 is a C 1 -C 6 alkyl group, the The C 1 -C 6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
在本发明某一方案中：当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的R 5-5的个数可为1、2或3个。 In a certain scheme of the present invention: when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the number of the R 5-5 can be 1, 2 or 3.
在本发明某一方案中：当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的C 2-C 6烯基可为C 2-C 4烯基，优选
Figure PCTCN2021132725-appb-000101
In a certain scheme of the present invention: when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl may be a C 2 -C 4 alkenyl , preferably
Figure PCTCN2021132725-appb-000101
在本发明某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，R 5-1a的个数可独立地为1、2或3个。 In a certain scheme of the present invention: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently substituted or unsubstituted by R 5-1a In the case of the C 1 -C 6 alkyl group, the number of R 5-1a can be independently 1, 2 or 3.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或叔丁基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C substituted or unsubstituted by R 5-1a When 1 - C6 alkyl, the C1 - C6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl , preferably methyl, ethyl or tert-butyl.
在某一方案中：当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的R 5-2a的个数可为1、2或3个。 In a certain scheme: when R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the number of said R 5-2a can be 1, 2 or 3.
在某一方案中：当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的烯基可为C 2-C 4烯基，优选乙烯基。 In a certain scheme: when R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the alkenyl can be C 2 -C 4 alkenyl, preferably vinyl.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 2-C 6炔基时，所述的C 2-C 6炔基可为C 2-C 4炔基，优选乙炔基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl , the C 2 -C 6 alkynyl group can be a C 2 -C 4 alkynyl group, preferably an ethynyl group.
在某一方案中：当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可独立地为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy , the C 1 -C 6 alkoxy group can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy, preferably methoxy.
在某一方案中：当R 5-5为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R 5-5 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，R 4-1a-1的个数可 为1、2或3个。 In a certain scheme: when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1, the number of R 4-1a-1 can be 1, 2 or 3 indivual.
在某一方案中：当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基。 In a certain scheme: when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 , the C 1 -C 6 alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
在某一方案中：当R 5-1a-1为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 5-1a-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 5-2a为C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme: when R 5-2a is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, preferably methyl.
在某一方案中：当R 5-2a为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R 5-2a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：当R 1为C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。 In a certain scheme: when R 1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
在某一方案中：当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，R 2-2的个数可为1、2、3或4个。 In a certain scheme: when R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , the number of R 2-2 can be 1, 2, 3 or 4.
在某一方案中：当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 2 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-2 , the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
在某一方案中：当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 2-3的个数可为1、2、3或4个。 In a certain scheme: when R 2 is substituted or unsubstituted by R 2-3 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "a", the number of R 2-3 can be 1, 2, 3 or 4.
在某一方案中：当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基。 In a certain scheme: when R 2 is substituted or unsubstituted by R 2-3 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "heteroaryl", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5- The 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基优选“杂原子选自N，杂原子个数为1、2或个”的5-6元单环杂芳基，更优选吡啶基(例如
Figure PCTCN2021132725-appb-000102
)，或“杂原子选自N，杂原子个数为1-2个”的8-10元双环杂芳基，优选吲唑基，例如
Figure PCTCN2021132725-appb-000103
Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as
Figure PCTCN2021132725-appb-000102
), or "hetero atoms are selected from N, the number of hetero atoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as
Figure PCTCN2021132725-appb-000103
在某一方案中：当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，R 2-1a的个数可为1、 2、3或4个。 In a certain scheme: when R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a , the number of R 2-1a can be 1, 2, 3 or 4.
在某一方案中：当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 2-1 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-1a , the C 6 -C 15 aryl group may be a C 6 -C 10 aryl group , preferably phenyl or naphthyl.
在某一方案中：当R 2-2为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟或氯。 In a certain scheme: when R 2-2 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：当R 2-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 2-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 2-1a为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟或氯。 In a certain scheme: when R 2-1a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：当R 2-1a为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 2-1a is C 1 -C 6 alkyl, the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 2-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数可为1、2或3个。 In a certain scheme: when R 2-2a is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
在某一方案中：当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。 In a certain scheme: when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
在某一方案中：当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数可为1、2或3个。 In a certain scheme: when R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 can be 1, 2 or 3 .
在某一方案中：当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。 In a certain scheme: when R 2-2b is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
在某一方案中：当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，R 2-2a-1a的个数可为1、2或3个。 In a certain scheme: when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a -1a , the number of R 2-2a-1a can be 1 or 2 or 3.
在某一方案中：当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基。 In a certain scheme: when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy may be methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.
在某一方案中：当R 2-2a-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 2-2a-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，R 3-1的个数可为1、2、3或4个。 In a certain scheme: when R 3 is C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , the number of R 3-1 can be 1, 2, 3 or 4.
在某一方案中：当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基可 为C 6-C 10芳基，优选苯基或萘基。 In a certain scheme: when R 3 is a C 6 -C 15 aryl group substituted or unsubstituted by R 3-1 , the C 6 -C 15 aryl group can be a C 6 -C 10 aryl group, preferably phenyl or naphthyl.
在某一方案中：当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 3-2的个数可为1、2、3或4个。 In a certain scheme: when R 3 is substituted or unsubstituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 In the case of a 5-15-membered heteroaryl group with "a", the number of R 3-2 can be 1, 2, 3 or 4.
在某一方案中：当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基。 In a certain scheme: when R 3 is substituted or unsubstituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4 When the 5-15-membered heteroaryl group is "heteroaryl", the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5- The 15-membered heteroaryl group can be a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" or Bicyclic heteroaryl.
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基优选“杂原子选自N，杂原子个数为1、2或个”的5-6元单环杂芳基，更优选吡啶基(例如
Figure PCTCN2021132725-appb-000104
)。 Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl groups are preferably "hetero atoms are selected from From N, the number of heteroatoms is 1, 2 or "" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as
Figure PCTCN2021132725-appb-000104
).
在某一方案中：当R 3-1为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或异丙基。 In a certain scheme: when R 3-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
在某一方案中：当R 3-1为C 1-C 6烷氧基时，所述的C 1-C 6烷基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 3-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkyl can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当R 3-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基或异丙基。 In a certain scheme: when R 3-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.
在某一方案中：当R 3-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基。 In a certain scheme: when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
在某一方案中：当环D为C 3-C 6环烷烃时，所述的C 3-C 6环烷烃可为环丙烷、环丁烷、环戊烷或环己烷，优选环己烷(
Figure PCTCN2021132725-appb-000105
例如为
Figure PCTCN2021132725-appb-000106
)。 In a certain scheme: when ring D is C 3 -C 6 cycloalkane, the C 3 -C 6 cycloalkane can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane (
Figure PCTCN2021132725-appb-000105
for example
Figure PCTCN2021132725-appb-000106
).
在某一方案中：当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-6元杂环，优选四氢呋喃(
Figure PCTCN2021132725-appb-000107
例如为
Figure PCTCN2021132725-appb-000108
)、哌啶(
Figure PCTCN2021132725-appb-000109
例如为
Figure PCTCN2021132725-appb-000110
)或哌嗪(
Figure PCTCN2021132725-appb-000111
例如为
Figure PCTCN2021132725-appb-000112
)。 In a certain scheme: when ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the said A 3-10-membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatoms selected from one or more of N, O and S" One or more, the number of heteroatoms is 1-3" 3-6 membered heterocycle, preferably tetrahydrofuran (
Figure PCTCN2021132725-appb-000107
for example
Figure PCTCN2021132725-appb-000108
), piperidine (
Figure PCTCN2021132725-appb-000109
for example
Figure PCTCN2021132725-appb-000110
) or piperazine (
Figure PCTCN2021132725-appb-000111
for example
Figure PCTCN2021132725-appb-000112
).
在某一方案中：当环D为C 6-C 10芳环时，所述的C 6-C 10芳环可为苯环或萘环，优选苯环(
Figure PCTCN2021132725-appb-000113
例如为
Figure PCTCN2021132725-appb-000114
)。 In a certain scheme: when ring D is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (
Figure PCTCN2021132725-appb-000113
for example
Figure PCTCN2021132725-appb-000114
).
在某一方案中：当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-6元杂芳环，优选吡啶环(
Figure PCTCN2021132725-appb-000115
例如为
Figure PCTCN2021132725-appb-000116
)或吡嗪环(
Figure PCTCN2021132725-appb-000117
例如为例如
Figure PCTCN2021132725-appb-000118
)。 In a certain scheme: when ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the The "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be "heteroatom is selected from N, O and S". One or more of the heteroatoms, the number of heteroatoms is 1-3 "5-6 membered heteroaromatic rings, preferably pyridine rings (
Figure PCTCN2021132725-appb-000115
for example
Figure PCTCN2021132725-appb-000116
) or pyrazine ring (
Figure PCTCN2021132725-appb-000117
for example
Figure PCTCN2021132725-appb-000118
).
在某一方案中：当R 3-1a-1为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 3-1a-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在某一方案中：当R 3-1a-2为C 1-C 6烷基时，所述的C 1-C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain scheme: when R 3-1a-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在某一方案中：环A中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环烷基可为“杂原子选自N，杂原子个数为1-2个”的5-6元杂环烷基，优选四氢吡咯基(
Figure PCTCN2021132725-appb-000119
例如为
Figure PCTCN2021132725-appb-000120
)。 In a certain scheme: in Ring A, the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl It can be a 5-6 membered heterocycloalkyl group with "heteroatoms selected from N, and the number of heteroatoms is 1-2", preferably a tetrahydropyrrolyl group (
Figure PCTCN2021132725-appb-000119
for example
Figure PCTCN2021132725-appb-000120
).
在某一方案中：环B中，所述的C 6-C 10芳环可为苯环或萘环，优选苯环(
Figure PCTCN2021132725-appb-000121
例如为
Figure PCTCN2021132725-appb-000122
)。 In a certain scheme: in ring B, the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (
Figure PCTCN2021132725-appb-000121
for example
Figure PCTCN2021132725-appb-000122
).
在某一方案中：环C中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环或双环杂芳环。In a certain scheme: in ring C, the 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be It is a 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3".
所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环优选“杂原子选自N和S中的一种或多种，杂原子个数为1-2个”的5-6元单环杂芳环，更优选噻唑环(
Figure PCTCN2021132725-appb-000123
例如为
Figure PCTCN2021132725-appb-000124
)。 Said "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" is preferably a 5-10-membered monocyclic heteroaromatic ring "hetero atoms are selected from N and S" One or more of, the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, more preferably thiazole ring (
Figure PCTCN2021132725-appb-000123
for example
Figure PCTCN2021132725-appb-000124
).
在某一方案中：当R a、R b、R c、R d和R e独立地为C 1-C 6烷基时，所述的C 1-C 6烷基 可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或叔丁基。 In a certain scheme: when R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
在某一方案中：当R 4为卤素时，所述的卤素可为氟、氯、溴或碘，优选氟。 In a certain scheme: when R4 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000125
Figure PCTCN2021132725-appb-000126
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000125
Figure PCTCN2021132725-appb-000126
在某一方案中：R 1可为氢或甲基。 In a certain scheme: R1 can be hydrogen or methyl.
在某一方案中：
Figure PCTCN2021132725-appb-000127
可为
Figure PCTCN2021132725-appb-000128
Figure PCTCN2021132725-appb-000129
In a scheme:
Figure PCTCN2021132725-appb-000127
can be
Figure PCTCN2021132725-appb-000128
Figure PCTCN2021132725-appb-000129
在某一方案中：
Figure PCTCN2021132725-appb-000130
可为
Figure PCTCN2021132725-appb-000131
In a scheme:
Figure PCTCN2021132725-appb-000130
can be
Figure PCTCN2021132725-appb-000131
在某一方案中：
Figure PCTCN2021132725-appb-000132
可为
Figure PCTCN2021132725-appb-000133
Figure PCTCN2021132725-appb-000134
In a scheme:
Figure PCTCN2021132725-appb-000132
can be
Figure PCTCN2021132725-appb-000133
Figure PCTCN2021132725-appb-000134
在某一方案中：R 2-2和R 2-1a独立地可为-OH、-F、-Cl、-NH 2或-OMe。 In a certain scheme: R2-2 and R2-1a can independently be -OH, -F, -Cl, -NH2 or -OMe.
在某一方案中：R 2-1可为
Figure PCTCN2021132725-appb-000135
In one scheme: R 2-1 can be
Figure PCTCN2021132725-appb-000135
在某一方案中：R 2可为
Figure PCTCN2021132725-appb-000136
Figure PCTCN2021132725-appb-000137
In one scheme: R 2 may be
Figure PCTCN2021132725-appb-000136
Figure PCTCN2021132725-appb-000137
在某一方案中：-L-可为
Figure PCTCN2021132725-appb-000138
Figure PCTCN2021132725-appb-000139
In a scheme: -L- can be
Figure PCTCN2021132725-appb-000138
Figure PCTCN2021132725-appb-000139
在某一方案中：R 3-1a可为
Figure PCTCN2021132725-appb-000140
In one scheme: R 3-1a may be
Figure PCTCN2021132725-appb-000140
在某一方案中：R 3-1和R 3-2独立地可为OH、Me、Et、CN、
Figure PCTCN2021132725-appb-000141
Figure PCTCN2021132725-appb-000142
In a certain scheme: R 3-1 and R 3-2 independently can be OH, Me, Et, CN,
Figure PCTCN2021132725-appb-000141
Figure PCTCN2021132725-appb-000142
在某一方案中：R 3可为
Figure PCTCN2021132725-appb-000143
Figure PCTCN2021132725-appb-000144
Figure PCTCN2021132725-appb-000145
In one scheme: R 3 can be
Figure PCTCN2021132725-appb-000143
Figure PCTCN2021132725-appb-000144
Figure PCTCN2021132725-appb-000145
在某一方案中：所述的E3连接酶可为von Hippel-Lindau(VHL)、CRBN、MDM2、cIAP、Cereblon、XIAP、E3A、后期促进复合物(APC)、UBR5(EDD1)、SOCS/BC-box/eloBC/CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box蛋白15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、Mind Bomb 1/MIB1、Mind Bomb 2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、 SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5或ZNRF3，优选VHL、CRBN、MDM2或cIAP。In a certain scheme: the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase promoting complex (APC), UBR5 (EDD1), SOCS/BC -box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 , PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54 , β-TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-box protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP -2/HIAP-1, cIAP(pan), ITCH/AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, preferably VHL, CRBN, MDM2 or cIAP.
在某一方案中：当R 1为C 1-C 6烷基时，与R 1相连的C原子的构型为S构型。 In a certain scheme: when R 1 is a C 1 -C 6 alkyl group, the configuration of the C atom to which R 1 is attached is the S configuration.
在某一方案中：R 4为F。 In one aspect: R4 is F.
在某一方案中：R 3为
Figure PCTCN2021132725-appb-000146
Figure PCTCN2021132725-appb-000147
In one scheme: R 3 is
Figure PCTCN2021132725-appb-000146
Figure PCTCN2021132725-appb-000147
在某一方案中：Z可为NR 5。 In one aspect: Z can be NR5.
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000148
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000148
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000149
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000149
在某一方案中：R 5可为
Figure PCTCN2021132725-appb-000150
In one scheme: R 5 may be
Figure PCTCN2021132725-appb-000150
在某一方案中：R 5-1可为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基。 In a certain scheme: R 5-1 can be C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a .
在某一方案中：R 5-1可为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基。 In a certain scheme: R 5-1 can be C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 5-1可为C 2-C 6烯基。 In a certain scheme: R 5-1 can be C 2 -C 6 alkenyl.
在某一方案中：R 5-2可为C 1-C 6烷基。 In a certain scheme: R 5-2 can be C 1 -C 6 alkyl.
在某一方案中：R 5-3和R 5-4独立地可为氢、或被R 5-1a取代或未取代的C 1-C 6烷基。 In a certain scheme: R 5-3 and R 5-4 can independently be hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 1可为氢。 In one aspect: R1 can be hydrogen.
在某一方案中：R 2可为被R 2-2取代或未取代的C 6-C 15芳基。 In a certain scheme: R 2 can be C 6 -C 15 aryl substituted or unsubstituted by R 2-2 .
在某一方案中：R 2可为被R 2-2取代的C 6-C 15芳基。 In a certain scheme: R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
在某一方案中：R 2-2可为羟基、卤素、氨基或C 1-C 6烷氧基。 In a certain scheme: R 2-2 can be hydroxy, halogen, amino or C 1 -C 6 alkoxy.
在某一方案中：R 2-2可为羟基、卤素或氨基。 In a certain scheme: R 2-2 can be hydroxy, halo or amino.
在某一方案中：R 2-2可为羟基或卤素。 In a certain scheme: R 2-2 can be hydroxy or halo.
在某一方案中：R 2-1a可为卤素。 In one aspect: R 2-1a can be halogen.
在某一方案中：R 3可为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基。 In a certain scheme: R 3 may be C 6 -C 15 aryl substituted by R 3-1 , or "heteroatom selected from N, O, and S" substituted by R 3-2 . One or more , a 5-15-membered heteroaryl group with 1, 2, 3 or 4" heteroatoms.
在某一方案中：R 3可为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基。 In a certain scheme: R 3 can be substituted by R 3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl.
在某一方案中：R 3-1和R 3-2独立地可为C 1-C 6烷基或-L-R 3-1a。 In one embodiment: R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl or -LR 3-1a .
在某一方案中：R 3-1和R 3-2独立地可为C 1-C 6烷基。 In a certain scheme: R 3-1 and R 3-2 independently can be C 1 -C 6 alkyl.
在某一方案中：R 3-1和R 3-2独立地可为甲基或异丙基。 In a certain scheme: R 3-1 and R 3-2 independently can be methyl or isopropyl.
在某一方案中：-L-可为
Figure PCTCN2021132725-appb-000151
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接。 In a scheme: -L- can be
Figure PCTCN2021132725-appb-000151
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl groups are connected.
在某一方案中：n1可为0、1、2、3、4、5或6。In a certain scheme: n1 can be 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：m1可为0、1、2或3。In a certain scheme: m1 may be 0, 1, 2 or 3.
在某一方案中：R 3-1a可为
Figure PCTCN2021132725-appb-000152
In one scheme: R 3-1a may be
Figure PCTCN2021132725-appb-000152
在某一方案中：R 3-1a-1和R 3-1a-2独立地可为氢或
Figure PCTCN2021132725-appb-000153
In a certain scheme: R 3-1a-1 and R 3-1a-2 can independently be hydrogen or
Figure PCTCN2021132725-appb-000153
在某一方案中：R 3-1和R 3-2的个数可为2个，且R 3-1和R 3-2不同。 In a certain scheme: the number of R 3-1 and R 3-2 can be 2, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000154
 R5 is
Figure PCTCN2021132725-appb-000154
R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基； R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
R 2为被R 2-2取代或未取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为C 1-C 6烷基或-L-R 3-1a； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a ;
-L-为
Figure PCTCN2021132725-appb-000155
a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接； -L- for
Figure PCTCN2021132725-appb-000155
The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
n1为0、1、2、3、4、5或6；n1 is 0, 1, 2, 3, 4, 5 or 6;
m1为0、1、2或3；m1 is 0, 1, 2 or 3;
R 3-1a为
Figure PCTCN2021132725-appb-000156
R 3-1a is
Figure PCTCN2021132725-appb-000156
R 3-1a-1和R 3-1a-2独立地为氢或
Figure PCTCN2021132725-appb-000157
R 3-1a-1 and R 3-1a-2 are independently hydrogen or
Figure PCTCN2021132725-appb-000157
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000158
 R5 is
Figure PCTCN2021132725-appb-000158
R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基； R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a ;
R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
R 3-1和R 3-2独立地为C 1-C 6烷基。 R 3-1 and R 3-2 are independently C 1 -C 6 alkyl.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000159
 R5 is
Figure PCTCN2021132725-appb-000159
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基、卤素或氨基； R 2-2 is hydroxyl, halogen or amino;
R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
R 3-1和R 3-2独立地为C 1-C 6烷基； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl;
R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同。 The number of R 3-1 and R 3-2 is two, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000160
 R5 is
Figure PCTCN2021132725-appb-000160
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
R 3-1和R 3-2独立地为甲基或异丙基； R 3-1 and R 3-2 are independently methyl or isopropyl;
R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同。 The number of R 3-1 and R 3-2 is two, and R 3-1 and R 3-2 are different.
在某一方案中：In a scheme:
R 4为F； R 4 is F;
Z为NR 5； Z is NR 5 ;
R 5为
Figure PCTCN2021132725-appb-000161
 R5 is
Figure PCTCN2021132725-appb-000161
R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
R 1为氢； R 1 is hydrogen;
R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
R 3为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a 5-15-membered heteroaryl group substituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";
R 3-2为C 1-C 6烷基。 R 3-2 is C 1 -C 6 alkyl.
本发明提供了一种药物组合物，其包括上述如式A所示化合物或其药学上可接受的盐，和药用辅料；所述的如式A所示化合物或其药学上可接受的盐可为治疗有效量。The present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients; the compound represented by formula A or a pharmaceutically acceptable salt thereof Can be a therapeutically effective amount.
某一方案中，本发明提供了一种药物组合物，其包括上述如式I所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物，和药用辅料。所述的如式I所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物可为治疗有效量。In a certain scheme, the present invention provides a kind of pharmaceutical composition, it comprises the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, Its nitrogen oxides, its metabolites, its prodrugs, its crystal forms, or its solvates, and pharmaceutical excipients. The compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystal form, or a solvate thereof, may be a therapeutically effective amount.
所述药物组合物中，所述药用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 pharmaceutical excipients may include pharmaceutically acceptable carriers, diluents and/or excipients.
本发明提供了一种上述如式A所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物在制备激酶调节剂的应用。某一方案中，本发明提供了一种上述如式I所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物在制备激酶调节剂的应用。所述的激酶调节剂可为激酶抑制剂或激酶激动剂。所述的 激酶可为KRAS，例如KRAS G12C。所述的KRAS抑制剂在体外使用。The present invention provides the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its former Use of the drug, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator. In a certain scheme, the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its Use of the metabolite, its prodrug, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator. The kinase modulator can be a kinase inhibitor or a kinase agonist. The kinase can be KRAS, such as KRAS G12C. Said KRAS inhibitor is used in vitro.
本发明提供了一种上述如式A所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物在制备药物中的应用。某一方案中，本发明提供了一种上述如式I所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物在制备药物中的应用。所述的药物可为预防和/或治疗KRAS相关疾病的药物或用于预防和/或治疗癌症的药物。所述的KRAS优选KRAS G12C。所述的KRAS相关疾病可为癌症。所述的癌症可为肺癌、胰腺癌、胰腺导管癌、大肠癌、结肠癌、直肠癌、阑尾癌、食管鳞癌、头颈鳞癌或乳腺癌。所述的癌症可为以KRAS突变为特征的癌症。The present invention provides the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its former Use of a medicine, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a medicine. In a certain scheme, the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its Use of metabolites, their prodrugs, their crystal forms, or their solvates, or the above-mentioned pharmaceutical compositions in the preparation of medicines. The medicament may be a medicament for preventing and/or treating KRAS-related diseases or a medicament for preventing and/or treating cancer. The KRAS is preferably KRAS G12C. The KRAS-related disease may be cancer. The cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer. The cancer may be a cancer characterized by KRAS mutations.
本发明还提供了一种治疗KRAS相关疾病的方法，其包括向患者施用治疗有效量的上述如式A所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物。某一方案中，本发明还提供了一种治疗KRAS相关疾病的方法，其包括向患者施用治疗有效量的上述如式I所示化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其氮氧化物、其代谢产物、其前药、其晶型、或其溶剂化物、或上述的药物组合物。所述的KRAS优选KRAS G12C。所述的KRAS相关疾病可为癌症。所述的癌症可为肺癌、胰腺癌、胰腺导管癌、大肠癌、结肠癌、直肠癌、阑尾癌、食管鳞癌、头颈鳞癌或乳腺癌。所述的癌症可为以KRAS突变为特征的癌症。The present invention also provides a method for treating KRAS-related diseases, comprising administering to a patient a therapeutically effective amount of the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer body, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition. In a certain scheme, the present invention also provides a method for the treatment of KRAS-related diseases, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, Its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition. The KRAS is preferably KRAS G12C. The KRAS-related disease may be cancer. The cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer. The cancer may be a cancer characterized by KRAS mutations.
还已经在血液恶性肿瘤(例如，影响血液、骨髓和/或***的癌症)中鉴别出KRAS突变。因此，某些实施例涉及将所披露化合物(例如，呈药物组合物形式)施用需要治疗血液恶性肿瘤的患者。此类恶性肿瘤包括但不限于白血病和淋巴瘤。例如，当前所披露的化合物可以用于治疗诸如以下等疾病：急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、慢性髓性白血病(CML)、急性单核细胞白血病(AMoL)和/或其他白血病。在其他实施例中，这些化合物可用于治疗淋巴瘤，例如所有亚型的霍奇金淋巴瘤或非霍奇金淋巴瘤。在各个实施例中，这些化合物可用于治疗浆细胞恶性肿瘤，例如多发性骨髓瘤、套细胞淋巴瘤和华氏巨球蛋白血症。KRAS mutations have also been identified in hematological malignancies (eg, cancers affecting the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments relate to administering the disclosed compounds (eg, in the form of pharmaceutical compositions) to patients in need of treatment of hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL) and/or other leukemias. In other embodiments, the compounds are useful in the treatment of lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, the compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.
如无特别说明，本发明所用术语具有如下含义：Unless otherwise specified, the terms used in the present invention have the following meanings:
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.
本发明“化合物”、“药学上可接受的盐”、“互变异构体”、“同位素化合物”或“溶剂化 物”中的取代基R 1、R 2、R 3和R 4中如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。 Substituents R 1 , R 2 , R 3 and R 4 in the "compounds", "pharmaceutically acceptable salts", "tautomers", "isotopic compounds" or "solvates" of the present invention are as present in Stereoisomers may exist as single stereoisomers or as mixtures thereof (eg, racemates). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
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，例如锂、钠或钾盐；碱土金属盐，例如锌、钙或镁盐；有机碱盐，例如和氨、烷基氨类(包括但不限于：甲胺、三乙胺)、羟基烷基氨类、氨基酸(包括但不限于：赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。"Pharmaceutically acceptable salts" according to the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and have It will be apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion and the like. The compound of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those 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, Heptanoate, Oxalate, Malonate, Succinate, Suberate, Benzoate, methylbenzoate, phthalate, maleate, mesylate, 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 salts, ascorbates, salicylates. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salts may also include: alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as zinc, calcium or magnesium salts; organic base salts such as and ammonia, alkylamines (including but not limited to: methylamine, triethylamine), hydroxyalkylamines, amino acids (including but not limited to: lysine, arginine), N-methylglucamine the salt formed.
本发明所述的“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，例如烯醇式和酮式互变异构体。The "tautomer" in the present invention refers to a functional group isomer produced by the rapid movement of a certain atom in two positions in a molecule, such as an enol tautomer and a keto tautomer.
本发明所述的“同位素化合物”是指化合物中的一个或多个原子以其非天然丰度的形式存在。以氢原子为例，其非天然丰度的形式是指其中约95％为氘。The term "isotopic compound" as used in the present invention means that one or more atoms in the compound exist in the form of their unnatural abundance. In the case of the hydrogen atom, its unnaturally abundant form means that about 95% of it is deuterium.
本发明所述的“溶剂化物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The "solvate" in the present invention refers to the substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.
术语“代谢产物”是指通过微生物新陈代谢活动中所产生的物质。The term "metabolite" refers to a substance produced by the metabolic activity of microorganisms.
术语“前药”表示作为本发明的化合物的化学衍生物，该衍生物在体内如果发生化学反应转化成通式I所示的化合物。The term "prodrug" refers to a chemical derivative of a compound of the present invention which, if chemically reacted in vivo, converts to a compound of general formula I.
术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。The term "crystal form" means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.
术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的烷基。The term "alkoxy" refers to the group -O-RX, wherein RX is an alkyl group as defined above.
术语“烯基”是指具有一个或多个碳碳双键的直链或支链不饱和非芳香烃基或环烯基，优选C 2-C 6烯基。烯基的实例包括
Figure PCTCN2021132725-appb-000162
Figure PCTCN2021132725-appb-000163
环丙烯、环丁烯、环戊烯、环己烯等。 The term "alkenyl" refers to a straight or branched chain unsaturated non-aromatic hydrocarbon or cycloalkenyl group having one or more carbon-carbon double bonds, preferably a C2 - C6 alkenyl group. Examples of alkenyl groups include
Figure PCTCN2021132725-appb-000162
Figure PCTCN2021132725-appb-000163
Cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.
术语“炔基”是指具有一个或多个碳碳三键的直链或支链不饱和非芳香烃基，优选C 2-C 6炔基，例如乙炔基、丙炔基等。 The term "alkynyl" refers to a straight or branched chain unsaturated non-aromatic hydrocarbon group having one or more carbon-carbon triple bonds, preferably a C 2 -C 6 alkynyl group, such as ethynyl, propynyl and the like.
术语“氨基”是指NH 2。 The term "amino" refers to NH2 .
术语“羧基”是指COOH。The term "carboxy" refers to COOH.
术语“环烷基”是指具有指定的碳原子数的直链或支链饱和烷基。其可为单环、双环或多环。环烷基的实例包括环丙基、环丁基、环戊基或环己基。The term "cycloalkyl" refers to a straight or branched chain saturated alkyl group having the indicated number of carbon atoms. It can be monocyclic, bicyclic or polycyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
术语“杂环烷基”是指具有杂原子的饱和的单环基团，优选含有1个、2个或3个独立选自N、O和S的环杂原子的3-10元饱和的单环，优选3-7元饱和的单环，更优选5-6元饱和的单环。杂环烷基的示例为：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。优选的杂环基为吗啉-4-基、哌啶-1-基、吡咯烷-1-基、硫代吗啉-4-基和1,1-二氧代-硫代吗啉-4-基。The term "heterocycloalkyl" refers to a saturated monocyclic group having a heteroatom, preferably a 3-10 membered saturated monocyclic group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. ring, preferably a 3-7 membered saturated monocycle, more preferably a 5-6 membered saturated monocycle. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4 -base.
本发明中的“杂环”失去一个氢原子后的基团即为杂环烷基。因此，本发明中的杂环烷基得到一个氢原子后得到的环即为本发明的杂环。同样地，本发明中的芳基、杂芳基、环烷基得到一个氢原子后得到的环即为本发明的芳环、杂芳环、环烷烃。The "heterocycle" in the present invention loses one hydrogen atom, which is a heterocycloalkyl group. Therefore, the ring obtained after the heterocycloalkyl group in the present invention obtains one hydrogen atom is the heterocycle of the present invention. Similarly, the ring obtained after the aryl group, heteroaryl group and cycloalkyl group in the present invention obtains a hydrogen atom is the aromatic ring, heteroaromatic ring and cycloalkane of the present invention.
本发明中，C 3-C 6环烷基是指环丙基、环丁基、环戊基或环已基。 In the present invention, C 3 -C 6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
术语“芳基”是指苯基或萘基。The term "aryl" refers to phenyl or naphthyl.
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环或9-10元双环，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, For example furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl , thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, benzisoxazolyl, quinoline base, isoquinolyl, etc.
本发明中，E3连接酶的配体可以为式A化合物失去一个原子或原子团后的基团；In the present invention, the ligand of E3 ligase can be the group after the compound of formula A loses one atom or atomic group;
Figure PCTCN2021132725-appb-000164
Figure PCTCN2021132725-appb-000164
式A化合物中，Q 1、Q 3、M 1、M 2和M 3独立地为C(R q1)(R q2)、N(R q3)、O或S，Q 2为C(R q4)或N；R q1、R q2、R q3和R q4独立地为H、氘、卤素、CN、NO 2、OH、氧代(＝O)、NH 2、羧基、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基； In the compound of formula A, Q 1 , Q 3 , M 1 , M 2 and M 3 are independently C(R q1 )(R q2 ), N(R q3 ), O or S, and Q 2 is C(R q4 ) or N; R q1 , R q2 , R q3 and R q4 are independently H, deuterium, halogen, CN, NO 2 , OH, oxo (=O), NH 2 , carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl;
R 1’和R 2’独立地为H、D、卤素(例如F、Cl、Br或I)、CN、OH、NO 2、(CR m1R m2) q1COOR m3、氧代(＝O)、C 1-C 10烷基、R m4取代的C 1-C 10烷基、C 1-C 6烷氧基、R m6取代的C 1-C 6烷氧基、-OR m7、NH 2、O(CH 2) q2(CH 2) q3NH 2、(CH 2) q4(NR m5)(CH 2) q5NH 2、
Figure PCTCN2021132725-appb-000165
(CR m8R m9) q7NH 2、-S-C 1-C 6烷基、-COR m10、C 3-C 6环烷基、C 3-C 6环烯基、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基、C 6-C 15芳基、杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基、(CH 2) q9SO 2R m11、(CH 2) q10NR m5SO 2C 1-C 6烷基、-NR m5SO 2C 1-C 6烷基、-NR m5COC 1-C 6烷基、-NR m5(CH 2) q11CONR m5C 1-C 6烷基、(CH 2) q12NR m5(CH 2) q13(NR m5) q14SO 2R m12、-(CR m5R m13) q15COOR m14、(CH 2) q16CONR m15R m16； R 1 ' and R 2 ' are independently H, D, halogen (eg F, Cl, Br or I), CN, OH, NO 2 , (CR m1 R m2 ) q1 COOR m3 , oxo (=O), C 1 -C 10 alkyl, R m4 substituted C 1 -C 10 alkyl, C 1 -C 6 alkoxy, R m6 substituted C 1 -C 6 alkoxy, -OR m7 , NH 2 , O (CH 2 ) q2 (CH 2 ) q3 NH 2 , (CH 2 ) q4 (NR m5 )(CH 2 ) q5 NH 2 ,
Figure PCTCN2021132725-appb-000165
(CR m8 R m9 ) q7 NH 2 , -SC 1 -C 6 alkyl, -COR m10 , C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, "heteroatom selected from N, O and One or more of S, 3-10-membered heterocycloalkyl with 1-3" heteroatoms, C 6 -C 15 aryl, a heteroatom selected from one of N, O and S or more, 5-15-membered heteroaryl with 1, 2, 3 or 4" heteroatoms, (CH 2 ) q9 SO 2 R m11 , (CH 2 ) q10 NR m5 SO 2 C 1 -C 6 alkyl, -NR m5 SO 2 C 1 -C 6 alkyl, -NR m5 COC 1 -C 6 alkyl, -NR m5 (CH 2 ) q11 CONR m5 C 1 -C 6 alkyl, (CH 2 ) q12 NR m5 (CH 2 ) q13 (NR m5 ) q14 SO 2 R m12 , -(CR m5 R m13 ) q15 COOR m14 , (CH 2 ) q16 CONR m15 R m16 ;
R m1、R m2、R m5、R m13和R m14独立地为H、氘、C 1-C 6烷基、C 2-C 6烯基或C 2-C 6炔基； R m1 , R m2 , R m5 , R m13 and R m14 are independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R m3为H或C 1-C 6烷基； R m3 is H or C 1 -C 6 alkyl;
R m4为卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷氧基、NH 2、NR m5C 1-C 6烷基、C 6-C 15芳基、“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基、C 3-C 6环烷基、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基； R m4 is halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , NR m5 C 1 -C 6 alkyl, C 6 -C 15 aryl, "heteroatom One or more selected from N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, C 3 -C 6 cycloalkyl, "heteroatom" One or more selected from N, O and S, the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
R m6为卤素、OH、CN、C 1-C 6烷基、C 1-C 6烷氧基、NH 2、C 6-C 15芳基、杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基或“杂原子 选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基； R m6 is one of halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , C 6 -C 15 aryl, heteroatom selected from N, O and S or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl or "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
R m7为C 6-C 15芳基、杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基； R m7 is a C 6 -C 15 aryl group, a heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group Or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
环N为C 3-C 6环烷烃、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环、C 6-C 10芳环或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环； Ring N is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
R m8和R m9独立地为H、OH或CN； R m8 and R m9 are independently H, OH or CN;
R m10为C 1-C 6烷基、-NH 2、-NR m5C 1-C 6烷基、-NR m5(CH 2) q8C 6-C 15芳基、-NR m5C 6-C 15芳基、杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基； R m10 is C 1 -C 6 alkyl, -NH 2 , -NR m5 C 1 -C 6 alkyl, -NR m5 (CH 2 ) q8 C 6 -C 15 aryl, -NR m5 C 6 -C 15 Aryl, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, "heteroatoms are selected from N, One or more of O and S, the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl;
R m11为-NH 2、-NR m5-C 1-C 6烷基或-C 1-C 6烷基； R m11 is -NH 2 , -NR m5 -C 1 -C 6 alkyl or -C 1 -C 6 alkyl;
R m15和R m16独立地为H、氘、C 1-C 6烷基、氰基取代的C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基C 1-C 6烷基、C 3-C 6环烷基、C 6-C 15芳基、杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基；或R m15和R m16与其相连的N原子一起形成杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环烷基； R m15 and R m16 are independently H, deuterium, C 1 -C 6 alkyl, cyano-substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 15 aryl, one or more heteroatoms selected from N, O and S, the number of heteroatoms is 1, 2, 3 Or 4" 5-15-membered heteroaryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 3-10-membered heterocycloalkyl ; or R m15 and R m16 together with the N atom they are connected to form a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15 yuan Heteroaryl or 3-10-membered heterocycloalkyl with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
q1、q6、q9、q10独立地为0、1、2、3、4、5或6；q1, q6, q9, q10 are independently 0, 1, 2, 3, 4, 5 or 6;
q2、q3、q4、q5、q7、q8、q11、q12、q13、q15、q16独立地为1、2、3、4、5或6；q2, q3, q4, q5, q7, q8, q11, q12, q13, q15, q16 are independently 1, 2, 3, 4, 5 or 6;
q14为0或1。q14 is 0 or 1.
本发明中，E3连接酶的配体例如可为式A-1至式A-4化合物失去一个原子或原子团后的基团；In the present invention, the ligand of E3 ligase can be, for example, a group after the compounds of formula A-1 to formula A-4 lose one atom or atomic group;
Figure PCTCN2021132725-appb-000166
Figure PCTCN2021132725-appb-000166
其中，Q 3、M 1、M 2和M 3独立地为C(R q1)(R q2)、N(R q3)、O或S，Q 2为C(R q4)或N；R q1、R q2、R q3和R q4独立地为H、氘、卤素、CN、NO 2、OH、氧代(＝O)、NH 2、羧基、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基； wherein, Q 3 , M 1 , M 2 and M 3 are independently C(R q1 )(R q2 ), N(R q3 ), O or S, and Q 2 is C(R q4 ) or N; R q1 , R q2 , R q3 and R q4 are independently H, deuterium, halogen, CN, NO 2 , OH, oxo (=O), NH 2 , carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkane oxy or C 1 -C 6 haloalkyl;
R 1’和R 2’独立地为H、D、卤素(例如F、Cl、Br或I)、CN、OH、NO 2、NH 2、COOH、氧代(＝O)或C 1-C 4烷基。 R 1 ' and R 2 ' are independently H, D, halogen (eg F, Cl, Br or I), CN, OH, NO 2 , NH 2 , COOH, oxo (=O) or C 1 -C 4 alkyl.
本发明中，E3连接酶的配体例如可为下列化合物失去一个原子或原子团后的基团；In the present invention, the ligand of E3 ligase can be, for example, a group after the following compound loses one atom or atomic group;
Figure PCTCN2021132725-appb-000167
Figure PCTCN2021132725-appb-000167
本发明中，E3连接酶的配体例如可为以下任意基团；In the present invention, the ligand of E3 ligase can be, for example, any of the following groups;
Figure PCTCN2021132725-appb-000168
Figure PCTCN2021132725-appb-000168
术语“配体”是一个生物领域概念，指能与目标蛋白结合的分子或基团。The term "ligand" is a biological field concept that refers to a molecule or group capable of binding to a target protein.
术语“调节剂”是指相对于标准对照(例如像不存在调节剂)，使靶标分子的水平或靶标分子的功能增加或降低的化合物。The term "modulator" refers to a compound that increases or decreases the level of a target molecule or the function of a target molecule relative to a standard control (eg, such as the absence of a modulator).
在符合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 conforming to common knowledge in the art, the above 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.
本发明的积极进步效果在于：本发明的芳香化合物对KRAS尤其是KRAS G12C具有良好的抑制作用。The positive improvement effect of the present invention is that the aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
实施例1：合成4-(4-丙烯酰哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)喹啉-2(1H)-酮Example 1: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methyl) phenyl)quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000169
Figure PCTCN2021132725-appb-000169
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000170
Figure PCTCN2021132725-appb-000170
步骤A(Step A)：将2-溴-1-氟-4-碘苯(8.4g,27.92mmol)溶解在无水甲苯(100mL)中，然后加入2-异丙基-6-甲基苯胺(5.0g,33.50mmol)、Pd(OAC) 2(醋酸钯，0.627g，2.792mmol)、BINAP(1,1'-联萘-2,2'-双二苯膦，1.738g,2.792mmol)和碳酸铯(13.64g,41.88mmol)。反应液在氮气保护下回流过夜。液相质谱显示原料消失后，用乙酸乙酯洗涤反应溶液，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到N-(3- 溴-4-氟苯基)-2-异丙基-6-甲基苯胺(6.068g，橙色固体，收率67.68％)。MS(ESI)M/Z：324.1[M+H+]。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (8.4 g, 27.92 mmol) in dry toluene (100 mL), then add 2-isopropyl-6-methylaniline (5.0 g, 33.50 mmol), Pd(OAC) 2 (palladium acetate, 0.627 g, 2.792 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.738 g, 2.792 mmol) and cesium carbonate (13.64 g, 41.88 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methyl Aniline (6.068 g, orange solid, 67.68% yield). MS (ESI) M/Z: 324.1 [M+H+].
步骤B(Step B)：将N-(3-溴-4-氟苯基)-2-异丙基-6-甲基苯胺(6.068g,18.897mmol)和3-氯-3-氧代丙酸甲酯(15.48g,113.38mmol)溶解在二氯甲烷(200mL)中,然后在室温下2小时内缓慢的滴加三乙胺(11.47g,113.38mmol)并搅拌10分钟。液相质谱监测显示原料消失后，加入二氯甲烷(100mL)稀释反应液并加入水(100mL),混合液用二氯甲烷(80mL×3次)萃取，合并有机相，有机相先用饱和食盐水(80mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到3-((3-溴-4-氟苯基)(2-异丙基-6-甲基苯基)氨基)-3-羰基丙酸甲酯(5.3g,淡黄色固体，收率66.6％)。MS(ESI)M/Z：424.1.1[M+H +]。 Step B (Step B): Combine N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methylaniline (6.068 g, 18.897 mmol) and 3-chloro-3-oxopropane Methyl acid (15.48 g, 113.38 mmol) was dissolved in dichloromethane (200 mL), then triethylamine (11.47 g, 113.38 mmol) was slowly added dropwise at room temperature over 2 hours and stirred for 10 minutes. After the liquid phase mass spectrometry monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added. The mixture was extracted with dichloromethane (80 mL × 3 times), and the organic phases were combined, and the organic phase was first used with saturated salt Washed with water (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methyl) (5.3 g, pale yellow solid, 66.6% yield). MS (ESI) M/Z: 424.1.1 [M+H + ].
步骤C(Step C)：将溶解在30mL水中的氢氧化钠(5.034g,125.86mmol)加入到溶解在甲醇(120mL)中的3-((3-溴-4-氟苯基)(2-异丙基-6-甲基苯基)氨基)-3-羰基丙酸甲酯(5.3g,12.586mmol)溶液中，室温条件下搅拌1小时。LCMS监测显示原料消失后，混合溶液用水(100mL)稀释，然后用稀盐酸调节水相pH为2。用乙酸乙酯(2×100mL)萃取两次，有机层用盐水清洗，Na 2SO 4干燥，过滤，最后减压浓缩。得到3-((3-溴-4-氟苯基)(2-异丙基-6-甲基苯基)氨基)-3-氧丙酸(4.846g，淡黄色固体，收率94.57％)。MS(ESI)M/Z：408.0[M+H +]。 Step C (Step C): Sodium hydroxide (5.034 g, 125.86 mmol) dissolved in 30 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2- isopropyl-6-methylphenyl)amino)-3-carbonylpropionic acid methyl ester (5.3 g, 12.586 mmol) solution was stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2 x 100 mL), the organic layer was washed with brine, dried over Na2SO4 , filtered, and finally concentrated under reduced pressure. Obtained 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropionic acid (4.846 g, pale yellow solid, yield 94.57%) . MS (ESI) M/Z: 408.0 [M+H + ].
步骤D(Step D)：将3-((3-溴-4-氟苯基)(2-异丙基-6-甲基苯基)氨基)-3-氧丙酸(4.846g，11.90mmol)溶解在Eatons Reagent(伊顿试剂)(40mL)中并在55℃下搅拌过夜。液相质谱监测显示原料消失后，向饱和的碳酸氢钠溶液中逐滴缓慢加入反应液并用饱和碳酸氢钠溶液调节pH为7-8。用二氯甲烷(2×100mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(4.51g,白色固体，收率97.42％)。MS(ESI)M/Z：392.1[M+H +]。 Step D (Step D): 3-((3-Bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropionic acid (4.846 g, 11.90 mmol ) was dissolved in Eatons Reagent (40 mL) and stirred at 55°C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (4.51 g, white solid, 97.42% yield) was obtained. MS (ESI) M/Z: 392.1 [M+H + ].
步骤E(Step E)：将7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(4.51g,11.5938mmol)溶解在三氯氧磷(30mL)中并在90℃下搅拌2小时。液相质谱显示原料消失后，减压蒸馏除去三氯氧磷，缓慢加入水(40mL)并用饱和碳酸氢钠溶液调节溶液pH为7-8。用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到固体用N,N-二甲基甲酰胺溶解并制备得到7-溴-4-氯-6-氟-1-(2-异丙基苯基)喹啉-2(1H)-酮(0.705g,黄色固体，收率14.94％)。MS(ESI)M/Z：408.1[M+H +]。 Step E (Step E): 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (4.51 g, 11.5938 mmol) Dissolve in phosphorus oxychloride (30 mL) and stir at 90°C for 2 hours. After LC mass spectrometry showed the disappearance of the starting material, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained solid was dissolved with N,N-dimethylformamide and prepared to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (0.705 g, yellow solid, yield 14.94%). MS (ESI) M/Z: 408.1 [M+H + ].
步骤F(Step F)：将7-溴-4-氯-6-氟-1-(2-异丙基苯基)喹啉-2(1H)-酮(0.705g,1.732mmol)溶解在二氧六环(10mL)中，然后加入哌嗪-1-甲酸叔丁酯(1.613g,8.661mmol) 和N,N-二异丙基乙胺(2.239g,17.32mmol)并在110℃下搅拌2天。液相质谱显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/2)得到4-(7-溴-6-氟-1-(2-异丙基-6-甲基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.832g，白色固体，收率86.21％)。MS(ESI)M/Z：558.1[M+H +]。 Step F (Step F): Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (0.705 g, 1.732 mmol) in 2 oxane (10 mL), then add piperazine-1-carboxylate tert-butyl ester (1.613 g, 8.661 mmol) and N,N-diisopropylethylamine (2.239 g, 17.32 mmol) and stir at 110 °C 2 days. After the disappearance of the starting material was shown by liquid phase mass spectrometry, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-6-fluoro). -1-(2-Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.832g, white solid, yield 86.21%). MS (ESI) M/Z: 558.1 [M+H + ].
1H NMR(400MHz,CDCl3)δ7.58–7.51(m,1H),7.46–7.35(m,2H),7.25(s,1H),6.74–6.53(m,1H),6.32(d,J＝4.7Hz,1H),3.70(s,4H),3.13(s,4H),2.47–2.38(m,1H),1.95(s,3H),1.51(s,9H),1.15(d,J＝6.8Hz,3H),1.03(d,J＝6.9Hz,3H).1H NMR(400MHz, CDCl3)δ7.58-7.51(m,1H),7.46-7.35(m,2H),7.25(s,1H),6.74-6.53(m,1H),6.32(d,J=4.7 Hz, 1H), 3.70(s, 4H), 3.13(s, 4H), 2.47–2.38(m, 1H), 1.95(s, 3H), 1.51(s, 9H), 1.15(d, J=6.8Hz ,3H),1.03(d,J＝6.9Hz,3H).
步骤G(Step G)：将4-(7-溴-6-氟-1-(2-异丙基-6-甲基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.400g,0.7179mmol),2-氟-6-羟基苯硼酸(0.234g,1.4358mmol),正磷酸钾(305mg,1.4358mmol)和Pd 2dba 3(三(二亚苄基丙酮)二钯，0.099g,0.1077mmol)以及PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷，0.063g,0.2154mmol)混合物溶解在用氩气置换空气15分钟的1,4-二氧六环和水混合溶液(8mL/2mL)中，再次用氩气置换空气，并在60℃下搅拌3天，液相质谱显示原料消失后，用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.340g,淡黄色固体，收率80.3％)。 Step G (Step G): 4-(7-Bromo-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinoline-4 -yl)piperazine-1-carboxylate tert-butyl ester (0.400g, 0.7179mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.234g, 1.4358mmol), potassium orthophosphate (305mg, 1.4358mmol ) and Pd dba 3 (tris(dibenzylideneacetone)dipalladium, 0.099 g, 0.1077 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxy Hetero-6-phosphoryladamantane, 0.063 g, 0.2154 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (8 mL/2 mL) in which the air was replaced with argon for 15 minutes, and was replaced with argon again. air, and stirred at 60 °C for 3 days. After the liquid phase mass spectrometry showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-( 2-Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, pale yellow solid, received rate 80.3%).
MS(ESI)M/Z：590.2[M+H +]。 MS (ESI) M/Z: 590.2 [M+H + ].
步骤H(Step H)：将4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.200g,0.339mmol)溶解在二氯甲烷(6mL)中并加入三氟乙酸(3mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.166g，棕色固体，收率100％)。MS(ESI)M/Z：490.2[M+H +]。 Step H (Step H): 4-(6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-2-carbonyl- 1,2-Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.200 g, 0.339 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and allowed to stand at room temperature The mixture was stirred for 1 hour under low pressure. After monitoring by liquid chromatography and mass spectrometry showed the disappearance of the raw materials, dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed. 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-4-(piperazin-1-yl)quinoline-2 was obtained (1H)-ketone (0.166 g, brown solid, 100% yield). MS (ESI) M/Z: 490.2 [M+H + ].
步骤I(Step I)：将6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.166g,0.339mmol)溶解在二氯甲烷(13mL)中并加入DIPEA(N,N-二异丙基乙胺)(0.219g，1.695mmol)和丙烯酰氯(0.031g，0.339mmol)并在室温下搅拌2小时，LCMS监测显示原料消失后，减压浓缩除去溶剂并将所得固体溶解在N,N-二甲基甲酰胺(5mL)中送制备得到4-(4-丙烯酰哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)喹啉-2(1H)-酮(0.0329g,白色固体，收率17.85％)。MS(ESI)M/Z：544.2[M+H +]。 Step I (Step I): 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-4-(piperazine-1 -yl)quinolin-2(1H)-one (0.166 g, 0.339 mmol) was dissolved in dichloromethane (13 mL) and DIPEA (N,N-diisopropylethylamine) (0.219 g, 1.695 mmol) was added and acryloyl chloride (0.031 g, 0.339 mmol) and stirred at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL). Preparation of 4-(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl) ) quinolin-2(1H)-one (0.0329 g, white solid, 17.85% yield). MS (ESI) M/Z: 544.2 [M+H + ].
1H NMR(400MHz,DMSO)δ10.08(s,1H),7.71(d,J＝10.2Hz,1H),7.42-7.32(m,2H), 7.28-7.14(m,2H),6.95-6.81(m,1H),6.77-6.63(m,2H),6.40-6.31(m,1H),6.24(s,1H),6.23-6.15(m,1H),5.80-5.71(m,1H),3.86(s,4H),3.20(s,4H),2.47-2.32(m,1H),1.84(d,J＝20.9Hz,3H),1.11-0.88(m,6H)。 1 H NMR (400MHz, DMSO) δ 10.08(s, 1H), 7.71(d, J=10.2Hz, 1H), 7.42-7.32(m, 2H), 7.28-7.14(m, 2H), 6.95-6.81 (m,1H),6.77-6.63(m,2H),6.40-6.31(m,1H),6.24(s,1H),6.23-6.15(m,1H),5.80-5.71(m,1H),3.86 (s, 4H), 3.20 (s, 4H), 2.47-2.32 (m, 1H), 1.84 (d, J=20.9Hz, 3H), 1.11-0.88 (m, 6H).
实施例2：合成4-(4-丙烯酰哌嗪-1-基)-1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)喹啉-2(1H)-酮Example 2: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyl Phenyl)quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000171
Figure PCTCN2021132725-appb-000171
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000172
Figure PCTCN2021132725-appb-000172
步骤A(Step A):将2-溴-1-氟-4-碘苯(5.0g,16.62mmol)，2-乙基-6-甲基苯胺(2.25g，16.62mmol)，醋酸钯(0.373g，1.7mmol)，BIANP(1,1'-联萘-2,2'-双二苯膦，1.03g，1.7mmol)和碳酸铯(8.12g，24.93mmol)一起放进250mL的单口瓶中，加入无水甲苯(100mL)，再用氮气置换3次，之后加热100度反应16小时。冷却过滤，滤饼用乙酸乙酯洗涤。滤液浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得到N-(3-溴-4-氟苯基)-2-乙基-6-甲基苯胺(4.2g，棕黑色油状物，收率82％)。MS(ESI)M/Z：308[M+H +]。 Step A (Step A): 2-bromo-1-fluoro-4-iodobenzene (5.0g, 16.62mmol), 2-ethyl-6-methylaniline (2.25g, 16.62mmol), palladium acetate (0.373 g, 1.7 mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.03 g, 1.7 mmol) and cesium carbonate (8.12 g, 24.93 mmol) were put into a 250 mL single-necked vial , anhydrous toluene (100 mL) was added, and it was replaced with nitrogen three times, and then heated at 100 degrees for 16 hours. After cooling and filtering, the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain N-(3-bromo-4-fluorophenyl)-2-ethyl-6- Methylaniline (4.2 g, brown-black oil, 82% yield). MS (ESI) M/Z: 308 [M+H + ].
步骤B(Step B):将N-(3-溴-4-氟苯基)-2-乙基-6-甲基苯胺(5.0g,16.22mmol)，3-氯-3-氧代丙酸甲酯(13.29g，97.34mmol)一起放进250mL的单口瓶中，加入无水二氯甲烷(150mL)，冷却到0度，缓慢加入三乙胺(16.77g，130mmol)。之后再室 温搅拌一小时。反应液再加入二氯甲烷(200mL)，用水，饱和氯化钠各洗涤一次，有机相用无水硫酸钠干燥和浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝4/1)得到3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)氨基)-3-羰基丙酸甲酯(4.2g，棕色油状物，收率63％)。MS(ESI)M/Z：409[M+H +]。 Step B (Step B): N-(3-bromo-4-fluorophenyl)-2-ethyl-6-methylaniline (5.0 g, 16.22 mmol), 3-chloro-3-oxopropionic acid Methyl ester (13.29 g, 97.34 mmol) was put into a 250 mL single-necked bottle together, anhydrous dichloromethane (150 mL) was added, cooled to 0 degrees, and triethylamine (16.77 g, 130 mmol) was slowly added. It was then stirred at room temperature for another hour. Dichloromethane (200 mL) was added to the reaction solution, washed once with water and saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ester=4/1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionate (4.2g, brown oil, 63% yield). MS (ESI) M/Z: 409 [M+H + ].
步骤C(Step C):将3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)氨基)-3-羰基丙酸甲酯(5.0g，12.25mmol)和氢氧化钠(2.45g，61.23mmol)一起放进250mL的单口瓶中，加入四氢呋喃(100mL)和水(20mL)。室温搅拌16小时。将大部分的四氢呋喃蒸出，加入100mL的水，用1摩尔的盐酸调pH值到3。用乙酸乙酯萃取(100mL×3),有机相用饱和氯化钠洗涤，无水硫酸钠干燥和浓缩得到3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)氨基)-3-羰基丙酸(4.2g，黄色固体，收率：87％)。MS(ESI)M/Z：394[M+H +]。 Step C (Step C): methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionate (5.0 g, 12.25 g mmol) and sodium hydroxide (2.45 g, 61.23 mmol) were put into a 250 mL single-neck flask, and tetrahydrofuran (100 mL) and water (20 mL) were added. Stir at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 3 with 1 molar hydrochloric acid. Extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 3-((3-bromo-4-fluorophenyl)(2-ethyl-6- Methylphenyl)amino)-3-carbonylpropionic acid (4.2 g, yellow solid, yield: 87%). MS (ESI) M/Z: 394 [M+H + ].
步骤D(Step D):将3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)氨基)-3-羰基丙酸(4.2g，10.65mmol)和伊顿试剂(15mL)一起放进100mL的单口瓶中，之后加热到90度反应16小时。降温，用饱和碳酸钾溶液调pH值到9，用乙酸乙酯萃取(100mL×3)，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩得到7-溴-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(3.5g，黄色固体，收率87％)。MS(ESI)M/Z：377[M+H +]。 Step D (Step D): 3-((3-Bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionic acid (4.2 g, 10.65 mmol) Put it into a 100mL single-neck bottle together with Eaton's reagent (15mL), and then heat it to 90 degrees to react for 16 hours. The temperature was lowered, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 7-bromo-1-(2- Ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (3.5 g, yellow solid, 87% yield). MS (ESI) M/Z: 377 [M+H + ].
步骤E(Step E):将7-溴-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮放进100mL的单口瓶中，加入20mL三氯氧磷，之后加热到80度反应3小时。降温蒸出大部分的三氯氧磷，用饱和碳酸钾溶液调pH值到9，用乙酸乙酯萃取(100mL×3)，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝4/1)得到7-溴-4-氯-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(1.0g，淡黄色固体，收率30％)。MS(ESI)M/Z：395[M+H +]。 Step E (Step E): Put 7-bromo-1-(2-ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione into a 100 mL single-port In the bottle, 20 mL of phosphorus oxychloride was added, and then heated to 80 degrees to react for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1) to give 7-bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6 -Fluoroquinolin-2(1H)-one (1.0 g, pale yellow solid, 30% yield). MS (ESI) M/Z: 395 [M+H + ].
步骤F(Step F):将7-溴-4-氯-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(1.0g,2.53mmol)，哌嗪-1-甲酸叔丁酯(2.36g，12.7mmol)和DIPEA(N,N-二异丙基乙胺，1.36g，12.7mmol)一起放进50mL的单口瓶中，加入5mL 1,4-二氧六环，之后加热到110度反应3天。液相质谱检测原料反应完，直接浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/5)得到4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.8g，淡黄色固体，收率58％)。MS(ESI)M/Z：544[M+H +]。 Step F (Step F): 7-Bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (1.0 g, 2.53 mmol ), piperazine-1-carboxylate tert-butyl ester (2.36g, 12.7mmol) and DIPEA (N,N-diisopropylethylamine, 1.36g, 12.7mmol) were put into the single-necked bottle of 50mL together, and 5mL 1 , 4-dioxane, and then heated to 110 degrees for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain 4-(7-bromo-1-(2-ethyl-6-methylphenyl)-6 - Fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.8 g, pale yellow solid, 58% yield). MS (ESI) M/Z: 544 [M+H + ].
步骤G(Step G):将4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.4g，0.73mmol)，2-氟-6-羟基苯硼酸(0.229g，1.47mmol)，1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(44mg，0.14mmol)，磷酸钾(312mg，1.47mmol)和Pd 2dba 3(三(二亚苄基丙酮)二钯，67mg，0.07mmol)一起放进50mL的单 口瓶中，加入溶剂四氢呋喃(10mL)和水(2.5mL)，用氮气置换三次，加热到60度反应16小时。降到室温，加入乙酸乙酯(100mL)用饱和氯化钠(20mL)洗涤，有机相用无水硫酸钠干燥，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/5)得到4-(1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.2g，淡黄色固体，收率38％)。MS(ESI)M/Z：576[M+H+]。 Step G (Step G): 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.4g, 0.73mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.229g, 1.47mmol), 1,3,5,7-tetramethyl-6 - Phenyl-2,4,8-trioxa-6-phosphoryladamantane (44 mg, 0.14 mmol), potassium phosphate (312 mg, 1.47 mmol) and Pd 2 dba 3 (tris(dibenzylideneacetone)di Palladium, 67 mg, 0.07 mmol) were put into a 50 mL single-necked bottle together, added solvent tetrahydrofuran (10 mL) and water (2.5 mL), replaced with nitrogen three times, heated to 60 degrees and reacted for 16 hours. After cooling to room temperature, ethyl acetate (100 mL) was added and the mixture was washed with saturated sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7 -(2-Fluoro-6-hydroxyphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.2 g, pale yellow solid, yield 38%). MS (ESI) M/Z: 576 [M+H+].
步骤H(Step H):将4-(1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.2g，0.28mmol)溶在5mL的二氯甲烷中，加入三氟乙酸(0.272g，2.8mmol)。室温反应2小时，液相质谱检测原料反应完，直接浓缩，用二氯甲烷共沸2次，得到产物1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐(0.2g，淡黄色固体，收率92％)。MS(ESI)M/Z：476[M+H] +。 Step H (Step H): 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (0.2 g, 0.28 mmol) was dissolved in 5 mL of dichloromethane and trifluoroacetic acid (0.272 g, 2.8 mmol) was added. The reaction was carried out at room temperature for 2 hours, and the reaction of the raw materials was detected by liquid phase mass spectrometry, and the reaction was directly concentrated, and azeotroped twice with dichloromethane to obtain the product 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-( 2-Fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.2 g, pale yellow solid, received rate 92%). MS (ESI) M/Z: 476 [M+H] + .
步骤I(Step I):将1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐(0.2g，纯度73％，0.255mmol)和三乙胺(77mg，0.75mmol)溶在5mL的二氯甲烷中，冷却到0度，加入烯丙基酰氯(23mg，0.255mmol)。室温反应2小时。直接浓缩，反应物通过高效液相制备纯化得到4-(4-丙烯酰哌嗪-1-基)-1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)喹啉-2(1H)-酮(23mg，白色固体，收率23％)。MS(ESI)M/Z：530[M+H +]。 Step 1 (Step 1): 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.2 g, 73% purity, 0.255 mmol) and triethylamine (77 mg, 0.75 mmol) were dissolved in 5 mL of dichloromethane , cooled to 0 degrees, and allyl chloride (23 mg, 0.255 mmol) was added. The reaction was carried out at room temperature for 2 hours. Directly concentrated, the reactant was purified by high performance liquid phase preparation to obtain 4-(4-acryloylpiperazin-1-yl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-7-( 2-Fluoro-6-hydroxyphenyl)quinolin-2(1H)-one (23 mg, white solid, 23% yield). MS (ESI) M/Z: 530 [M+H + ].
1H NMR(400MHz,DMSO)δ10.10(d,J＝12.8Hz,1H),7.70(d,J＝10.2Hz,1H),7.41-7.14(m,4H),6.93-6.81(m,1H),6.78-6.63(m,2H),6.37(d,J＝2.9Hz,1H),6.27-6.09(m,2H),5.82-5.69(m,1H),3.86(s,4H),3.19(s,4H),2.25-2.10(m,2H),1.86(d,J＝17.4Hz,3H),1.05-0.89(m,3H).1H NMR(400MHz, DMSO)δ10.10(d,J=12.8Hz,1H),7.70(d,J=10.2Hz,1H),7.41-7.14(m,4H),6.93-6.81(m,1H) ,6.78-6.63(m,2H),6.37(d,J＝2.9Hz,1H),6.27-6.09(m,2H),5.82-5.69(m,1H),3.86(s,4H),3.19(s ,4H),2.25-2.10(m,2H),1.86(d,J＝17.4Hz,3H),1.05-0.89(m,3H).
实施例3：合成4-(4-丙烯酰哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)喹啉-2(1H)-酮Example 3: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl) )quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000173
Figure PCTCN2021132725-appb-000173
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000174
Figure PCTCN2021132725-appb-000174
步骤A(Step A)：将2-溴-1-氟-4-碘苯(10g,33.23mmol)溶解在无水甲苯(100mL)中，然后加入2，6-二甲基苯胺(4.83g,39.88mmol)、Pd(OAC) 2(醋酸钯0.746g，3.323mmol)、BINAP(1,1'-联萘-2,2'-双二苯膦，2.069g,3.323mmol)和Cs 2CO 3(碳酸铯，16.24g,49.8mmol)。反应液在氮气保护下回流过夜。液相质谱显示原料消失后，用乙酸乙酯洗涤反应溶液，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1g，橙色油状物，收率93.4％)。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC) 2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs 2 CO 3 (Cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to give N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, orange oil, 93.4% yield).
MS(ESI)M/Z：296.0[M+H] +。 MS(ESI) M/Z: 296.0 [M+H] + .
步骤B(Step B)：将N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1g,31.06mmol)和3-氯-3-氧代丙酸甲酯(25.44g,186.35mmol)溶解在二氯甲烷(300mL)中,然后在室温下3小时内缓慢的滴加三乙胺(18.86g,186.35mmol)并搅拌10分钟。液相质谱显示原料消失后，加入二氯甲烷(200mL)稀释反应液并加入水(2×200mL),混合液用二氯甲烷(100mL×3次)萃取，合并有机相，有机相先用饱和食盐水(80mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸甲酯(8.8g,黄色油状物，收率72％)。MS(ESI)M/Z：396.1[M+H] +。 Step B (Step B): N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise at room temperature over 3 hours and stirred for 10 minutes. After the liquid phase mass spectrometry showed that the raw materials disappeared, dichloromethane (200 mL) was added to dilute the reaction solution and water (2×200 mL) was added. The mixture was extracted with dichloromethane (100 mL×3 times), and the organic phases were combined, and the organic phase was first saturated with Washed with brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl) )amino)-3-carbonylpropionic acid methyl ester (8.8 g, yellow oil, 72% yield). MS (ESI) M/Z: 396.1 [M+H] + .
步骤C(Step C)：将溶解在60mL水中的氢氧化钠(8.957g,223.9mmol)溶液加入到溶解在甲醇(240mL)中的3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸甲酯(8.8g,22.39mmol)溶液中，室温条件下搅拌1小时。液相质谱监测显示原料消失后，混合溶液用水(200mL)稀释，然后用稀盐酸调节水相pH为2。用乙酸乙酯(2×200mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸(7.7g，无色油状物，收率90.7％)。MS(ESI)M/Z：380.0[M+H +]。 Step C (Step C): A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2) dissolved in methanol (240 mL). , 6-dimethylphenyl)amino)-3-carbonylpropionic acid methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2 x 200 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (7.7 g, colorless oil, yield 90.7%) was obtained. MS (ESI) M/Z: 380.0 [M+H + ].
步骤D(Step D)：将3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸(6.7g， 17.67mmol)溶解在Eatons Reagent(伊顿试剂)(40mL)中并在55℃下搅拌过夜。液相质谱监测显示原料消失后，向饱和的碳酸氢钠溶液中逐滴缓慢加入反应液并用饱和碳酸氢钠溶液调节pH为7-8。用二氯甲烷(2×100mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到粗品7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮，(混合物，6.25g,白色固体，收率97％)。MS(ESI)M/Z：362.0[M+H +]。 Step D: Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) in Eatons Reagent (40 mL) and stirred overnight at 55°C. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. Obtained crude 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, yield 97 %). MS (ESI) M/Z: 362.0 [M+H + ].
步骤E(Step E)：将7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(6.25g,17.31mmol)溶解在三氯氧磷(40mL)中并在90℃下搅拌2小时。液相质谱监测显示原料消失后，减压蒸馏除去三氯氧磷，缓慢加入水(20mL)并用饱和碳酸氢钠溶液调节溶液pH为7-8。用乙酸乙酯(2×50mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氢喹啉-2(1H)-二酮(1.02g,白色固体，收率15.5％)。MS(ESI)M/Z：296.0[M+H] +。 Step E (Step E): 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25g, 17.31mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After LC-MS monitoring showed the disappearance of the raw materials, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 50 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro- 3,4-Dihydroquinoline-2(1H)-dione (1.02 g, white solid, 15.5% yield). MS(ESI) M/Z: 296.0 [M+H] + .
步骤F(Step F)：将7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氢喹啉-2(1H)-二酮(0.65g,1.71mmol)溶解在二氧六环(4.5mL)中，然后加入哌嗪-1-甲酸叔丁酯(1.59g,8.55mmol)和N,N-二异丙基乙胺(2.21g,17.1mmol)并在110℃下搅拌2天。LCMS监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/2)得到4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.711g，白色固体，收率78.6％)。Step F (Step F): 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (0.65 g, 1.71 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (1.59 g, 8.55 mmol) and N,N-diisopropylethylamine (2.21 g, 17.1 mmol) and stirred at 110 °C for 2 days. After LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-1-(2). ,6-Dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.711g, white solid, yield 78.6%).
MS(ESI)M/Z：530.2[M+H +]。 MS (ESI) M/Z: 530.2 [M+H + ].
步骤G(Step G)：将4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.711g,1.34mmol),2-氟-6-羟基苯硼酸(0.419g,2.688mmol)，正磷酸钾(570mg,2.688mmol)和Pd 2dba 3((三(二亚苄基丙酮)二钯，0.184g,0.21mmol)以及PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷，0.177g,0.4mmol)混合物溶解在用氩气置换空气15分钟的1,4-二氧六环和水混合溶液(15mL，4/1)中，再次用氩气置换空气，并在60℃下搅拌3天。液相质谱监测显示原料消失后，用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。粗品经制备纯化得到4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.251g,淡黄色固体，收率33.2％)。 Step G (Step G): 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) tert-Butyl piperazine-1-carboxylate (0.711 g, 1.34 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.419 g, 2.688 mmol), potassium orthophosphate (570 mg, 2.688 mmol) and Pd 2 dba 3 ( (tris(dibenzylideneacetone)dipalladium, 0.184 g, 0.21 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa- 6-Phosphoryladamantane, 0.177 g, 0.4 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (15 mL, 4/1) replaced with argon for 15 minutes, and replaced with argon again air, and stirred for 3 days at 60° C. After LC-MS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally reduced in pressure Concentrated. The crude product was preparatively purified to give 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1,2- Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.251 g, pale yellow solid, 33.2% yield).
MS(ESI)M/Z：562.2[M+H] +。 MS(ESI) M/Z: 562.2 [M+H] + .
步骤H(Step H)：将4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.251g,0.447mmol)溶解在二氯甲烷(9mL)中并加入三氟 乙酸(4.2mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.206g，棕色固体，收率96.8％)。Step H (Step H): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.251 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (4.2 mL) was added and stirred at room temperature After 1 hour, LC-MS monitoring showed the disappearance of the raw materials, concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and added dichloromethane (10 mL) and concentrated again under reduced pressure until dichloromethane and trifluoroacetic acid were completely removed to obtain 1. -(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one (0.206 g, brown solid, 96.8% yield).
MS(ESI)M/Z：462.3[M+H+]。MS (ESI) M/Z: 462.3 [M+H+].
步骤I(Step I)：将1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.206g,0.447mmol)溶解在二氯甲烷(9mL)中并加入DIEA(N,N-二异丙基乙胺)(0.289g，2.235mmol)和丙烯酰氯(0.041g，0.447mmol)并在室温下搅拌2小时，液相质谱监测显示原料消失后，减压浓缩除去溶剂并将所得固体溶解在N,N-二甲基甲酰胺(5mL)中制备纯化得到4-(4-丙烯酰哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)喹啉-2(1H)-酮(0.1276g,白色固体，收率55.4％)。Step I (Step I): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.206 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and DIEA (N,N-diisopropylethylamine) (0.289 g, 2.235 mmol) and acryloyl chloride were added (0.041 g, 0.447 mmol) and stirred at room temperature for 2 hours. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the obtained solid was dissolved in N,N-dimethylformamide (5 mL) for preparation and purification 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline- 2(1H)-one (0.1276 g, white solid, 55.4% yield).
MS(ESI)M/Z：516.2[M+H+]。MS (ESI) M/Z: 516.2 [M+H+].
1H NMR(400MHz,DMSO)δ10.12(s,1H),7.71(d,J＝10.3Hz,1H),7.36-7.15(m,4H),6.94-6.81(m,1H),6.76-6.65(m,2H),6.38(d,J＝6.2Hz,1H),6.26-6.09(m,2H),5.79-5.69(m,1H),3.86(s,4H),3.19(s,4H),1.88(d,J＝15.5Hz,6H).1H NMR(400MHz, DMSO)δ10.12(s,1H),7.71(d,J=10.3Hz,1H),7.36-7.15(m,4H),6.94-6.81(m,1H),6.76-6.65( m, 2H), 6.38(d, J＝6.2Hz, 1H), 6.26-6.09(m, 2H), 5.79-5.69(m, 1H), 3.86(s, 4H), 3.19(s, 4H), 1.88 (d, J=15.5Hz, 6H).
实施例4：合成4-(4-丙烯酰哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮Example 4: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methyl) pyridin-3-yl)quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000175
Figure PCTCN2021132725-appb-000175
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000176
Figure PCTCN2021132725-appb-000176
步骤A(Step A):将2-溴-1-氟-4-碘苯(10.0g,33.23mmol)，2-异丙基-4-甲基-3-胺基吡啶(4.99g，33.23mmol)，醋酸钯(0.746g，3.32mmol)，BIANP(1,1'-联萘-2,2'-双二苯膦，2.07g，3.32mmol)和碳酸铯(16.24g，49.85mmol)一起放进500mL的单口瓶中，加入无水甲苯(200mL)，再用氮气置换3次，之后加热100度反应16小时。冷却过滤，滤饼用乙酸乙酯洗涤。滤液浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到N-(3-溴-4-氟苯基)-2-异丙基-4-甲基-3-胺基吡啶(7.9g，棕色油状物，收率74％)。Step A (Step A): 2-bromo-1-fluoro-4-iodobenzene (10.0 g, 33.23 mmol), 2-isopropyl-4-methyl-3-aminopyridine (4.99 g, 33.23 mmol) ), palladium acetate (0.746g, 3.32mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07g, 3.32mmol) and cesium carbonate (16.24g, 49.85mmol) were put together Into a 500 mL single-necked bottle, anhydrous toluene (200 mL) was added, and the mixture was replaced with nitrogen for 3 times, and then heated at 100 degrees to react for 16 hours. After cooling and filtering, the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-4 -Methyl-3-aminopyridine (7.9 g, brown oil, 74% yield).
MS(ESI)M/Z：323[M+H +]。 MS (ESI) M/Z: 323 [M+H + ].
步骤B(Step B):将N-(3-溴-4-氟苯基)-2-异丙基-4-甲基-3-胺基吡啶(7.9g,24.44mmol)，3-氯-3-氧代丙酸甲酯(10.01g，73.33mmol)一起放进250mL的单口瓶中，加入无水二氯甲烷(150mL)，冷却到0度，缓慢加入三乙胺(12.3g，122mmol)。之后再室温搅拌一小时。反应液再加入二氯甲烷(200mL)，用水、饱和氯化钠各洗涤一次，有机相用无水硫酸钠干燥和浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-羰基丙酸甲酯(3.5g，棕色油状物，收率34％)。MS(ESI)M/Z：423[M+H+]。Step B (Step B): N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methyl-3-aminopyridine (7.9g, 24.44mmol), 3-chloro- Methyl 3-oxopropionate (10.01g, 73.33mmol) was put into a 250mL single-necked bottle together, anhydrous dichloromethane (150mL) was added, cooled to 0 degrees, and triethylamine (12.3g, 122mmol) was slowly added . It was then stirred at room temperature for another hour. Dichloromethane (200 mL) was added to the reaction solution, washed once with water and saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) ethyl ester=3/1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionate ( 3.5 g, brown oil, 34% yield). MS (ESI) M/Z: 423 [M+H+].
步骤C(Step C):将3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-羰基丙酸甲酯(3.5g，8.27mmol)和氢氧化钠(1.65g，41.34mmol)一起放进250mL的单口瓶中，加入四氢呋喃(100mL)和水(20mL)。室温搅拌16小时。将大部分的四氢呋喃蒸出，加入100mL的水，用1摩尔的盐酸调pH值到7。用二氯甲烷萃取(100mL×3),有机相用饱和氯化钠洗涤，无水硫酸钠干燥和浓缩得到3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-羰基丙酸(3.2g，黄色固体，收率：95％)。MS(ESI)M/Z：409[M+H] +。 Step C (Step C): methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionate ( 3.5 g, 8.27 mmol) and sodium hydroxide (1.65 g, 41.34 mmol) were put into a 250 mL single-neck flask, and tetrahydrofuran (100 mL) and water (20 mL) were added. Stir at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 7 with 1 molar hydrochloric acid. Extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4 -Methylpyridin-3-yl)amino)-3-carbonylpropionic acid (3.2 g, yellow solid, yield: 95%). MS (ESI) M/Z: 409 [M+H] + .
步骤D(Step D):将3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-羰基丙酸(3.2g，7.82mmol)和伊顿试剂(15mL)一起放进100mL的单口瓶中，之后加热到 90度反应16小时。降温，用饱和碳酸钾溶液调pH值到9，用二氯甲烷萃取(100mL×3)，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩得到7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2,4(1H,3H)-二酮(2.6g，黄色固体，收率85％)。MS(ESI)M/Z：391[M+H] +。 Step D (Step D): 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionic acid (3.2g , 7.82mmol) and Eaton's reagent (15mL) were put into a 100mL single-neck bottle, and then heated to 90 degrees for 16 hours of reaction. The temperature was lowered, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 7-bromo-6-fluoro-1 -(2-Isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)-dione (2.6 g, yellow solid, 85% yield). MS (ESI) M/Z: 391 [M+H] + .
步骤E(Step E):将7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2,4(1H,3H)-二酮(2.6g，6.65mmol)放进100mL的单口瓶中，加入20mL三氯氧磷，之后加热到80度反应3小时。降温蒸出大部分的三氯氧磷，用饱和碳酸钾溶液调pH值到9，用二氯甲烷萃取(100mL×3)，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩所得粗产品用高效液相制备纯化得到7-溴-4-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(0.4g，白色固体，收率15％)。MS(ESI)M/Z：409[M+H] +。 Step E (Step E): 7-Bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)-dione ( 2.6g, 6.65mmol) into a 100mL single-neck bottle, add 20mL phosphorus oxychloride, and then heat to 80 degrees to react for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result. The crude product was purified by HPLC to obtain 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one ( 0.4 g, white solid, 15% yield). MS (ESI) M/Z: 409 [M+H] + .
步骤F(Step F):将7-溴-4-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(0.4g,0.98mmol)，哌嗪-1-甲酸叔丁酯(909mg，4.88mmol)和DIPEA(N,N-二异丙基乙胺，631mg，4.88mmol)一起放进50mL的单口瓶中，加入3mL1,4-二氧六环，之后加热到110度反应3天。液相质谱检测原料反应完，直接浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/9)得到4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.35g，淡黄色固体，收率64％)。MS(ESI)M/Z：559[M+H] +。 Step F (Step F): 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one (0.4 g, 0.98 mmol), piperazine-1-carboxylate tert-butyl ester (909 mg, 4.88 mmol) and DIPEA (N, N-diisopropylethylamine, 631 mg, 4.88 mmol) were put into a 50 mL single-necked bottle together, added 3mL of 1,4-dioxane, then heated to 110 degrees and reacted for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/9) to obtain 4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methyl) Pyridin-3-yl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.35 g, pale yellow solid, 64% yield). MS (ESI) M/Z: 559 [M+H] + .
步骤G(Step G):将4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.35g，0.63mmol)，2-氟-6-羟基苯硼酸(0.195g，1.26mmol),正磷酸钾(267mg,1.26mmol)和Pd 2dba 3((三(二亚苄基丙酮)二钯，0.027g,0.03mmol)以及PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷，0.030g,0.06mmol)混合物溶解在用氩气置换空气15分钟的1,4-二氧六环和水混合溶液(10mL，4/1)中，再次用氩气置换空气，并在60℃下搅拌过夜。液相质谱监测显示原料消失后，用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。粗品经制备纯化得到4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.25g，淡黄色固体，收率68％)。MS(ESI)M/Z：591[M+H] +。 Step G (Step G): 4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinoline Lin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.35g, 0.63mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.195g, 1.26mmol), potassium orthophosphate (267mg, 1.26mmol) and Pd 2 dba 3 ((tris(dibenzylideneacetone)dipalladium, 0.027 g, 0.03 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4, 8-Trioxa-6-phosphoryladamantane, 0.030 g, 0.06 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (10 mL, 4/1) in which the air was replaced with argon for 15 minutes , replaced the air with argon again, and stirred overnight at 60 ° C. After the liquid phase mass spectrometry monitoring showed that the raw material disappeared, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, and dried over anhydrous sodium sulfate. Filtered and finally concentrated under reduced pressure. The crude product was purified by preparation to give 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3- (0.25 g, pale yellow solid, yield 68%). MS (ESI) M/ Z: 591[M+H] + .
步骤H(Step H):将4-(6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.25g，0.423mmol)溶在5mL的二氯甲烷中，加入三氟乙酸(0.482g，4.23mmol)。室温反应2小时，液相质谱检测原料反应完，直接浓缩，用二氯甲烷共沸2次，得到产物6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐，0.24g，淡黄色固体，收率97％。 MS(ESI)M/Z：491[M+H] +。 Step H (Step H): 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 -Carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.25g, 0.423mmol) was dissolved in 5mL of dichloromethane, trifluoroacetic acid (0.482g, 4.23 mmol). The reaction was carried out at room temperature for 2 hours, and the reaction of the raw materials was detected by liquid phase mass spectrometry. The reaction was directly concentrated, and azeotroped twice with dichloromethane to obtain the product 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)-4-(piperazin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate, 0.24g, light Yellow solid, 97% yield. MS (ESI) M/Z: 491 [M+H] + .
步骤I(Step I):将6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐(0.25g，0.4mmol)和三乙胺(80mg，0.8mmol)溶在5mL的二氯甲烷中，冷却到0度，加入丙烯酰氯(36mg，0.4mmol)。室温反应2小时。直接浓缩，反应物通过高效液相制备纯化得到4-(4-丙烯酰哌嗪-1-基)-6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(60mg，白色固体，收率68％)。MS(ESI)M/Z：545[M+H] +。 Step 1 (Step 1): 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(piperidine) Azin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.25 g, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) were dissolved in 5 mL of dichloromethane , cooled to 0 degrees, and acryloyl chloride (36 mg, 0.4 mmol) was added. The reaction was carried out at room temperature for 2 hours. Concentrated directly, the reactant was purified by HPLC to obtain 4-(4-acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one (60 mg, white solid, 68% yield). MS (ESI) M/Z: 545 [M+H] + .
1H NMR(400MHz,CDCl 3)δ10.27(s,1H),8.38(s,1H),7.64(d,J＝10.0Hz,1H),7.23-7.08(m,2H),6.80-6.58(m,4H),6.43-6.34(m,1H),6.31(s,1H),5.86-5.73(m,1H),3.95(d,J＝44.9Hz,4H),3.27(d,J＝17.0Hz,4H),2.71(d,J＝6.8Hz,1H),1.16(d,J＝6.7Hz,3H),0.99(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ 10.27(s, 1H), 8.38(s, 1H), 7.64(d, J=10.0Hz, 1H), 7.23-7.08(m, 2H), 6.80-6.58( m,4H),6.43-6.34(m,1H),6.31(s,1H),5.86-5.73(m,1H),3.95(d,J=44.9Hz,4H),3.27(d,J=17.0Hz ,4H),2.71(d,J＝6.8Hz,1H),1.16(d,J＝6.7Hz,3H),0.99(s,3H).
实施例5：合成4-(4-丙烯酰哌嗪-1-基)-7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮Example 5: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)- 6-Fluoroquinolin-2(1H)-one
Figure PCTCN2021132725-appb-000177
Figure PCTCN2021132725-appb-000177
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000178
Figure PCTCN2021132725-appb-000178
步骤A(Step A):将4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.3g，0.55mmol)，(2-氨基-6-氯苯基)硼酸(0.142g，0.83mmol)，1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(32mg，0.11mmol)，磷酸钾(233mg，1.1mmol)和Pd 2dba 3((三(二亚苄基丙酮)二钯，55mg，0.06mmol)一起放进50mL的单口瓶中，加入溶剂四氢呋喃(8mL)和水(2mL)，用氮气置换三次，加热到60度反应16小时。降到室温，加入乙酸乙酯(100mL)用饱和氯化钠(20mL)洗涤，有机相用无水硫酸钠干燥，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/5)得到4-(7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(30mg，淡黄色固体，收率9％)。 Step A (Step A): 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.3g, 0.55mmol), (2-amino-6-chlorophenyl)boronic acid (0.142g, 0.83mmol), 1,3,5,7-tetramethyl yl-6-phenyl-2,4,8-trioxa-6-phosphoramantane (32 mg, 0.11 mmol), potassium phosphate (233 mg, 1.1 mmol) and Pd 2 dba 3 ((tris(dibenzylidene) (base acetone) dipalladium, 55mg, 0.06mmol) put into the single-necked bottle of 50mL together, add solvent tetrahydrofuran (8mL) and water (2mL), replace three times with nitrogen, be heated to 60 degrees and react 16 hours.Reduce to room temperature, add Ethyl acetate (100 mL) was washed with saturated sodium chloride (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/ 5) Obtain 4-(7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydro Quinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (30 mg, pale yellow solid, 9% yield).
MS(ESI)M/Z：591[M+H] +。 MS (ESI) M/Z: 591 [M+H] + .
步骤B(Step B):将4-(7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(30mg，0.06mmol)溶在2mL的二氯甲烷中，加入三氟乙酸(63mg，0.6mmol)。室温反应2小时，LCMS检测原料反应完，直接浓缩，用二氯甲烷带2次，得到产物7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐(33mg，淡黄色固体，收率99％)。MS(ESI)M/Z：491[M+H] +。 Step B (Step B): 4-(7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (30 mg, 0.06 mmol) was dissolved in 2 mL of dichloromethane and trifluoroacetic acid (63 mg, 0.6 mmol) was added. The reaction was carried out at room temperature for 2 hours. LCMS detected the raw materials after the reaction was completed, and then concentrated directly, and banded twice with dichloromethane to obtain the product 7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methyl) Phenyl)-6-fluoro-4-(piperazin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (33 mg, pale yellow solid, 99% yield) . MS (ESI) M/Z: 491 [M+H] + .
步骤C(Step C):将7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-4-(哌嗪-1-基)喹啉-2(1H)-酮2,2,2-三氟乙酸盐(33mg,0.061mmol)和三乙胺(12mg，1.2mmol)溶在 2mL的二氯甲烷中，冷却到0度，加入烯丙基酰氯(5.5mg，0.061mmol)。室温反应2小时。直接浓缩，反应物通过高效液相制备得到两个产物4-(4-丙烯酰哌嗪-1-基)-7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮，3.5mg，白色固体，收率10.5％和4-(4-丙烯酰哌嗪-1-基)-7-(2-氨基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(2.5mg，白色固体，收率7.5％)。MS(ESI)M/Z：545[M+H] +。 Step C (Step C): 7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-4-(piperazine-1- yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (33 mg, 0.061 mmol) and triethylamine (12 mg, 1.2 mmol) were dissolved in 2 mL of dichloromethane and cooled to 0 degree, allyl chloride (5.5 mg, 0.061 mmol) was added. The reaction was carried out at room temperature for 2 hours. Concentrated directly, the reactants were prepared by high performance liquid phase to obtain two products 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-6-chlorophenyl)-1-(2-ethyl) -6-Methylphenyl)-6-fluoroquinolin-2(1H)-one, 3.5 mg, white solid, 10.5% yield and 4-(4-acryloylpiperazin-1-yl)-7- (2-Amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (2.5 mg, white solid, yield 7.5 %). MS (ESI) M/Z: 545 [M+H] + .
第一个产物1-a1核磁： 1H NMR(400MHz,CDCl 3)δ7.65(d,J＝9.7Hz,1H),7.33(d,J＝7.6Hz,1H),7.23(d,J＝8.0Hz,1H),7.08(s,1H),6.83(d,J＝7.9Hz,1H),6.70-6.59(m,2H),6.50(d,J＝6.1Hz,1H),6.41-6.32(m,2H),5.84-5.73(m,1H),3.96(d,J＝56.0Hz,4H),3.52(s,2H),3.25(s,4H),2.42-2.17(m,2H),1.97(s,3H),1.06(t,J＝7.6Hz,3H)。 The first product 1-a1 NMR: 1 H NMR (400MHz, CDCl 3 )δ7.65(d,J=9.7Hz,1H),7.33(d,J=7.6Hz,1H),7.23(d,J= 8.0Hz,1H),7.08(s,1H),6.83(d,J=7.9Hz,1H),6.70-6.59(m,2H),6.50(d,J=6.1Hz,1H),6.41-6.32( m,2H),5.84-5.73(m,1H),3.96(d,J=56.0Hz,4H),3.52(s,2H),3.25(s,4H),2.42-2.17(m,2H),1.97 (s, 3H), 1.06 (t, J=7.6 Hz, 3H).
第二个产物1-a2核磁： 1H NMR(400MHz,CDCl 3)δ7.65(d,J＝9.7Hz,1H),7.34(t,J＝7.5Hz,1H),7.28(s,1H),7.21(d,J＝7.4Hz,1H),7.08(t,J＝8.1Hz,1H),6.83(d,J＝8.0Hz,1H),6.70-6.59(m,2H),6.50(d,J＝6.1Hz,1H),6.43-6.34(m,2H),5.83-5.76(m,1H),3.96(d,J＝63.1Hz,4H),3.53(s,2H),3.25(s,4H),2.40-2.18(m,2H),1.98(s,3H),1.07(t,J＝7.6Hz,3H)。 The second product 1-a2 NMR: 1 H NMR (400MHz, CDCl 3 )δ7.65(d, J=9.7Hz, 1H), 7.34(t, J=7.5Hz, 1H), 7.28(s, 1H) ,7.21(d,J＝7.4Hz,1H),7.08(t,J＝8.1Hz,1H),6.83(d,J＝8.0Hz,1H),6.70-6.59(m,2H),6.50(d, J=6.1Hz, 1H), 6.43-6.34(m, 2H), 5.83-5.76(m, 1H), 3.96(d, J=63.1Hz, 4H), 3.53(s, 2H), 3.25(s, 4H) ), 2.40-2.18(m, 2H), 1.98(s, 3H), 1.07(t, J=7.6Hz, 3H).
实施例6：合成4-(4-丙烯酰基哌嗪-1-基)-1-(2,6-二乙基苯基)-6-氟-7-(2-氟苯基)喹啉-2(1H)-酮Example 6: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-diethylphenyl)-6-fluoro-7-(2-fluorophenyl)quinoline- 2(1H)-ketone
Figure PCTCN2021132725-appb-000179
Figure PCTCN2021132725-appb-000179
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000180
Figure PCTCN2021132725-appb-000180
其合成步骤与实施例4相同。The synthesis steps are the same as those in Example 4.
MS(ESI)M/Z：528.3[M+H] + MS(ESI)M/Z: 528.3[M+H] +
1H NMR(500MHz,CDCl3)δ7.59(d,J＝10.3Hz,1H),7.45–7.39(m,1H),7.36(d,J＝6.4Hz,1H),7.29(d,J＝7.6Hz,2H),7.18(dt,J＝14.6,7.4Hz,2H),7.11(t,J＝9.1Hz,1H),6.65(dd,J＝16.7,10.6Hz,1H),6.56(d,J＝6.1Hz,1H),6.39(t,J＝8.0Hz,2H),5.80(d,J＝10.5Hz,1H),3.94(d,J＝62.8Hz,4H),3.25(s,4H),2.34(dt,J＝14.9,7.4Hz,2H),2.23(dd,J＝15.0,7.5Hz,2H),1.09(t,J＝7.5Hz,6H).1H NMR(500MHz, CDCl3)δ7.59(d,J=10.3Hz,1H),7.45-7.39(m,1H),7.36(d,J=6.4Hz,1H),7.29(d,J=7.6Hz ,2H),7.18(dt,J＝14.6,7.4Hz,2H),7.11(t,J＝9.1Hz,1H),6.65(dd,J＝16.7,10.6Hz,1H),6.56(d,J＝ 6.1Hz, 1H), 6.39(t, J＝8.0Hz, 2H), 5.80(d, J＝10.5Hz, 1H), 3.94(d, J＝62.8Hz, 4H), 3.25(s, 4H), 2.34 (dt, J=14.9, 7.4Hz, 2H), 2.23 (dd, J=15.0, 7.5Hz, 2H), 1.09 (t, J=7.5Hz, 6H).
实施例7：4-(4-丙烯酰基哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)喹啉-2(1H)-酮Example 7: 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxybenzene yl)quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000181
Figure PCTCN2021132725-appb-000181
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000182
Figure PCTCN2021132725-appb-000182
步骤A(Step A)：将2-溴-1-氟-4-碘苯(10g,33.23mmol)溶解在无水甲苯(100mL)中，然后加入2，6-二甲基苯胺(4.83g,39.88mmol)、Pd(OAC) 2(醋酸钯0.746g，3.323mmol)、BINAP(1,1'-联萘-2,2'-双二苯膦,2.069g,3.323mmol)和Cs 2CO 3(碳酸铯，16.24g,49.8mmol)。反应液在氮气保护下回流过夜。液相质谱显示原料消失后，用乙酸乙酯洗涤反应溶液，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1g，橙色油状物，收率93.4％)。MS(ESI)M/Z：296.0[M+H] +。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC) 2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs 2 CO 3 (Cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to give N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, orange oil, 93.4% yield). MS(ESI) M/Z: 296.0 [M+H] + .
步骤B(Step B)：将N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1g,31.06mmol)和3-氯-3-氧代丙酸甲酯(25.44g,186.35mmol)溶解在二氯甲烷(300mL)中,然后在室温下3小时内缓慢的滴加三乙胺(18.86g,186.35mmol)并搅拌10分钟。液相质谱显示原料消失 后，加入二氯甲烷(200mL)稀释反应液并加入水(2×200mL),混合液用二氯甲烷(100mL×3次)萃取，合并有机相，有机相先用饱和食盐水(80mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸甲酯(8.8g,黄色油状物，收率72％)。MS(ESI)M/Z：396.1[M+H] +。 Step B (Step B): N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise at room temperature over 3 hours and stirred for 10 minutes. After the liquid phase mass spectrometry showed that the raw materials disappeared, dichloromethane (200 mL) was added to dilute the reaction solution and water (2×200 mL) was added. The mixture was extracted with dichloromethane (100 mL×3 times), and the organic phases were combined, and the organic phase was first saturated with Washed with brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl) )amino)-3-carbonylpropionic acid methyl ester (8.8 g, yellow oil, 72% yield). MS (ESI) M/Z: 396.1 [M+H] + .
步骤C(Step C)：将溶解在60mL水中的氢氧化钠(8.957g,223.9mmol)溶液加入到溶解在甲醇(240mL)中的3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸甲酯(8.8g,22.39mmol)溶液中，室温条件下搅拌1小时。液相质谱监测显示原料消失后，混合溶液用水(200mL)稀释，然后用稀盐酸调节水相pH为2。用乙酸乙酯(2×200mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸(7.7g，无色油状物，收率90.7％)。MS(ESI)M/Z：380.0[M+H] +。 Step C (Step C): A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water was added to 3-((3-bromo-4-fluorophenyl)(2) dissolved in methanol (240 mL). , 6-dimethylphenyl)amino)-3-carbonylpropionic acid methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2 x 200 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (7.7 g, colorless oil, yield 90.7%) was obtained. MS (ESI) M/Z: 380.0 [M+H] + .
步骤D(Step D)：将3-((3-溴-4-氟苯基)(2,6-二甲基苯基)氨基)-3-羰基丙酸(6.7g，17.67mmol)溶解在Eatons Reagent(伊顿试剂)(40mL)中并在55℃下搅拌过夜。液相质谱监测显示原料消失后，向饱和的碳酸氢钠溶液中逐滴缓慢加入反应液并用饱和碳酸氢钠溶液调节pH为7-8。用二氯甲烷(2×100mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到粗品7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮，(混合物，6.25g,白色固体，收率97％)。MS(ESI)M/Z：362.0[M+H] +。 Step D: Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) in Eatons Reagent (40 mL) and stirred overnight at 55°C. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. Obtained crude 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, yield 97 %). MS(ESI) M/Z: 362.0 [M+H] + .
步骤E(Step E)：将7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(6.25g,17.31mmol)溶解在三氯氧磷(40mL)中并在90℃下搅拌2小时。液相质谱监测显示原料消失后，减压蒸馏除去三氯氧磷，缓慢加入水(20mL)并用饱和碳酸氢钠溶液调节溶液pH为7-8。用乙酸乙酯(2×50mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)得到7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氢喹啉-2(1H)-二酮(1.02g,白色固体，收率15.5％)。MS(ESI)M/Z：296.0[M+H] +。 Step E (Step E): 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25g, 17.31mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After LC-MS monitoring showed the disappearance of the raw materials, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 50 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro- 3,4-Dihydroquinoline-2(1H)-dione (1.02 g, white solid, 15.5% yield). MS(ESI) M/Z: 296.0 [M+H] + .
步骤F(Step F)：将7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氢喹啉-2(1H)-二酮(300mg,0.78mmol)溶解在二氧六环(4.5mL)中，然后加入哌嗪-1-甲酸叔丁酯(725mg,3.9mmol)和N,N-二异丙基乙胺(603.0mg,4.68mmol)并在110℃下搅拌2天。LCMS监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/2)得到4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(205mg，白色固体，收率50％)。MS(ESI)M/Z：530.2[M+H] +。 Step F (Step F): 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (300 mg, 0.78 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (725 mg, 3.9 mmol) and N,N-diisopropylethylamine (603.0 mg, 4.68 mmol) and stirred at 110 °C for 2 days. After LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-1-(2). ,6-Dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (205mg, white solid, yield 50 %). MS (ESI) M/Z: 530.2 [M+H] + .
步骤G(Step G)：将4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(60mg,0.11mmol),2-氟-4-甲氧基苯硼酸(96mg,0.56mmol),醋酸钾(89mg,0.91mmol)和Pacl2(pddf)(8mg,0.01mmol)溶解在用氩气置换空气15分钟的1,4-二氧六环和水混合溶液(1mL，4/1)中，再次用氩气置换空气，并在60℃下搅拌3天。液相质谱监测显示原料消失后，用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。粗品经制备纯化得到4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(60mg,淡黄色固体，收率94.8％)。MS(ESI)M/Z：576.2[M+H] +。 Step G (Step G): 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) tert-Butyl piperazine-1-carboxylate (60 mg, 0.11 mmol), 2-fluoro-4-methoxyphenylboronic acid (96 mg, 0.56 mmol), potassium acetate (89 mg, 0.91 mmol) and Pacl2 (pddf) (8 mg , 0.01 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (1 mL, 4/1) in which the air was replaced with argon for 15 minutes, the air was replaced with argon again, and stirred at 60 °C for 3 days . After LC-MS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was preparatively purified to give 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-carbonyl-1,2- Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (60 mg, pale yellow solid, 94.8% yield). MS (ESI) M/Z: 576.2 [M+H] + .
步骤H(Step H)：将4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(60mg,0.11mmol)溶解在二氯甲烷(1mL)中并加入三氟乙酸(0.5mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg，棕色固体，收率76.5％)。MS(ESI)M/Z：476.2[M+H] +。 Step H: 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline-2(1H )-one (40 mg, brown solid, 76.5% yield). MS(ESI) M/Z: 476.2 [M+H] + .
步骤I(Step I)：将1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg,0.084mmol)溶解在二氯甲烷(1mL)中并加入DIPEA(N,N-二异丙基乙胺)(21.67g，0.168mmol)和丙烯酰氯(15mg，0.168mmol)并在室温下搅拌2小时，液相质谱监测显示原料消失后，减压浓缩除去溶剂并将所得固体溶解在N,N-二甲基甲酰胺(5mL)中制备纯化得到4-(4-丙烯酰哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羟基苯基)喹啉-2(1H)-酮(30.4mg,白色固体，收率68.4％)。MS(ESI)M/Z：530.2[M+H] + Step I (Step I): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.084 mmol) was dissolved in dichloromethane (1 mL) and DIPEA (N,N-diisopropylethylamine) (21.67 g, 0.168 mmol) and propylene were added Acyl chloride (15 mg, 0.168 mmol) was stirred at room temperature for 2 hours. After the disappearance of the starting material was detected by liquid phase mass spectrometry, the solvent was removed by concentration under reduced pressure and the obtained solid was dissolved in N,N-dimethylformamide (5 mL) for preparation and purification 4-(4-Acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline- 2(1H)-one (30.4 mg, white solid, 68.4% yield). MS(ESI)M/Z: 530.2[M+H] +
1H NMR(500MHz,DMSO)δ7.74(d,J＝10.5Hz,1H),7.33–7.30(m,1H),7.28(d,J＝7.0Hz,2H),7.21(t,J＝8.5Hz,1H),6.96–6.84(m,3H),6.34(d,J＝6.5Hz,1H),6.23(d,J＝8.5Hz,1H),6.18(dd,J＝16.5,2.4Hz,1H),5.75(dd,J＝10.5,2.5Hz,1H),3.86(d,J＝13.0Hz,4H),3.77(d,J＝10.0Hz,3H),3.19(s,4H),1.88(d,J＝9.5Hz,6H). 1 H NMR (500MHz, DMSO) δ 7.74 (d, J=10.5Hz, 1H), 7.33-7.30 (m, 1H), 7.28 (d, J=7.0Hz, 2H), 7.21 (t, J=8.5 Hz, 1H), 6.96–6.84 (m, 3H), 6.34 (d, J=6.5Hz, 1H), 6.23 (d, J=8.5Hz, 1H), 6.18 (dd, J=16.5, 2.4Hz, 1H) ),5.75(dd,J＝10.5,2.5Hz,1H),3.86(d,J＝13.0Hz,4H),3.77(d,J＝10.0Hz,3H),3.19(s,4H),1.88(d ,J=9.5Hz,6H).
实施例8：合成4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧酰胺Example 8: Synthesis of 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2- Dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide
Figure PCTCN2021132725-appb-000183
Figure PCTCN2021132725-appb-000183
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000184
Figure PCTCN2021132725-appb-000184
步骤A(Step A)：将2-甲氧基乙胺(100mg,1.33mmol)溶解DCM(1.5mL)中并加入DIPEA(344mg,2.67mmol)并在室温下搅拌0.5小时，加入对硝基苯基氯甲酸酯(320mg，1.60mml)，在室温反应1h,TLC监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得到4-硝基苯基(2-甲氧基乙基)氨基甲酸酯(200mg，白色固体，收率62.6％)。MS(ESI)M/Z：241.22[M+H] + Step A (Step A): 2-Methoxyethylamine (100 mg, 1.33 mmol) was dissolved in DCM (1.5 mL) and DIPEA (344 mg, 2.67 mmol) was added and stirred at room temperature for 0.5 h, p-nitrobenzene was added Ethyl chloroformate (320 mg, 1.60 mml) was reacted at room temperature for 1 h. After TLC monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) =5/1) to obtain 4-nitrophenyl(2-methoxyethyl)carbamate (200 mg, white solid, yield 62.6%). MS(ESI)M/Z: 241.22[M+H] +
步骤B(Step B)：将4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(60mg,0.11mmol)溶解在二氯甲烷(1mL)中并加入三氟乙酸(0.5mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg，浅黄色固体，收率76.5％)。MS(ESI)M/Z：476.2[M+H] + Step B (Step B): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline-2(1H )-one (40 mg, pale yellow solid, yield 76.5%). MS(ESI) M/Z: 476.2[M+H] +
步骤C(Step C)：将1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg,0.11mmol)溶解THF(1mL)中并加入KHMDS(0.52mL)并在室温下 搅拌0.5小时，加入4-硝基苯基(2-甲氧基乙基)氨基甲酸酯(62mg，0.261mml)，在50℃反应2h,LCMS监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到合成4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧酰胺(45mg，白色固体，收率92.9％)。MS(ESI)M/Z：577.2[M+H] + Step C (Step C): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in THF (1 mL) and KHMDS (0.52 mL) was added and stirred at room temperature for 0.5 h, 4-nitrophenyl (2-methoxy ethyl)carbamate (62 mg, 0.261 mml), reacted at 50 °C for 2 h, after LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane) Methane/methanol=20/1) to obtain the synthesis of 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo -1,2-Dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide (45 mg, white solid, 92.9% yield). MS(ESI) M/Z: 577.2[M+H] +
1H NMR(500MHz,CDCl 3)δ7.57(d,J＝10.5Hz,1H),7.28(s,1H),7.23(d,J＝7.5Hz,2H),7.13(t,J＝8.5Hz,1H),6.72(dd,J＝8.5,2.5Hz,1H),6.66(dd,J＝12.0,2.4Hz,1H),6.54(d,J＝6.5Hz,1H),6.37(s,1H),4.97(s,1H),3.81(s,3H),3.68(s,4H),3.55–3.47(m,4H),3.40(s,3H),3.23(s,4H),2.00(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ 7.57 (d, J=10.5Hz, 1H), 7.28 (s, 1H), 7.23 (d, J=7.5Hz, 2H), 7.13 (t, J=8.5Hz) ,1H),6.72(dd,J＝8.5,2.5Hz,1H),6.66(dd,J＝12.0,2.4Hz,1H),6.54(d,J＝6.5Hz,1H),6.37(s,1H) ,4.97(s,1H),3.81(s,3H),3.68(s,4H),3.55–3.47(m,4H),3.40(s,3H),3.23(s,4H),2.00(s,6H ).
实施例9：4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧酰胺Example 9: 4-(1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-di Hydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide
Figure PCTCN2021132725-appb-000185
Figure PCTCN2021132725-appb-000185
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000186
Figure PCTCN2021132725-appb-000186
步骤A(Step A)：将1-(2-氨基乙氧基)-2-甲氧基乙烷(130mg,1.1mmol)溶解DCM(1.5mL)中并加入DIPEA(284mg,2.2mml)并在室温下搅拌0.5小时，加入对硝基苯基氯甲酸酯(331mg，1.65mml)，在室温反应1h,LCMS监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得到4-硝基苯基(2-(2-甲氧基乙氧基)乙基)氨基甲酸酯(250mg，白色固体，收率80.0％)。Step A: 1-(2-Aminoethoxy)-2-methoxyethane (130 mg, 1.1 mmol) was dissolved in DCM (1.5 mL) and DIPEA (284 mg, 2.2 mml) was added and added to Stir at room temperature for 0.5 hours, add p-nitrophenyl chloroformate (331 mg, 1.65 mml), react at room temperature for 1 hour, after LCMS monitoring shows that the raw materials disappear, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)carbamate (250 mg, white solid, obtained rate 80.0%).
MS(ESI)M/Z：285.1[M+H] + MS(ESI)M/Z: 285.1[M+H] +
步骤B(Step B)：将4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(60mg,0.11mmol)溶解在二氯甲烷(1mL)中并加入三氟乙酸(0.5mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg，浅黄色固体，收率76.5％)。MS(ESI)M/Z：476.2[M+H] + Step B (Step B): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , tert-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the mixture was heated at room temperature After stirring for 1 hour, after the monitoring of liquid phase mass spectrometry showed that the raw materials disappeared, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline-2(1H )-one (40 mg, pale yellow solid, yield 76.5%). MS(ESI) M/Z: 476.2[M+H] +
步骤C(Step C)：将1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40mg,0.11mmol)溶解THF(1mL)中并加入KHMDS(0.52mL)并在室温下搅拌0.5小时，加入4-硝基苯基(2-(2-甲氧基乙氧基)乙基)氨基甲酸酯(93.72mg，0.33mml)，在50℃反应2h,LCMS监测显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到合成4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧酰胺(42mg，白色固体，收率61.5％)。MS(ESI)M/Z：621.2[M+H] + Step C (Step C): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in THF (1 mL) and KHMDS (0.52 mL) was added and stirred at room temperature for 0.5 h, 4-nitrophenyl (2-(2 -Methoxyethoxy)ethyl)carbamate (93.72mg, 0.33mml), reacted at 50°C for 2h, after LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography Purification (eluent: dichloromethane/methanol = 20/1) gave the synthesis of 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxy) phenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide (42mg , white solid, yield 61.5%). MS(ESI)M/Z: 621.2[M+H] +
1H NMR(500MHz,CDCl 3)δ7.57(d,J＝10.5Hz,1H),7.28(d,J＝2.0Hz,1H),7.22(d,J＝7.6Hz,2H),7.13(t,J＝8.3Hz,1H),6.72(dd,J＝8.6,2.4Hz,1H),6.66(dd,J＝11.9,2.4Hz,1H),6.53(d,J＝6.2Hz,1H),6.34(s,1H),5.21(t,J＝5.3Hz,1H),3.81(s,3H),3.70–3.65(m,6H),3.64–3.62(m,2H),3.59–3.56(m,2H),3.52–3.49(m,2H),3.41(s,3H),3.22(d,J＝4.5Hz,4H),2.00(s,6H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.57 (d, J=10.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 2H), 7.13 (t , J=8.3Hz, 1H), 6.72 (dd, J=8.6, 2.4Hz, 1H), 6.66 (dd, J=11.9, 2.4Hz, 1H), 6.53 (d, J=6.2Hz, 1H), 6.34 (s, 1H), 5.21 (t, J=5.3Hz, 1H), 3.81 (s, 3H), 3.70–3.65 (m, 6H), 3.64–3.62 (m, 2H), 3.59–3.56 (m, 2H) ), 3.52–3.49(m, 2H), 3.41(s, 3H), 3.22(d, J=4.5Hz, 4H), 2.00(s, 6H).
实施例10：合成4-(4-丙烯酰基哌嗪-1-基)-6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)喹啉-2(1H)-酮Example 10: Synthesis of 4-(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl) )quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000187
Figure PCTCN2021132725-appb-000187
步骤A(Step A)：将2-溴-1-氟-4-碘苯(10g,33.23mmol)溶解在无水甲苯(110mL)中，然后加入2-异丙基苯胺(5.39g,39.86mmol)、Pd(OAC) 2(醋酸钯，0.75g，3.34mmol)、BINAP(1,1'-联萘-2,2'-双二苯膦，2.07g,3.34mmol)和碳酸铯(16.24g,49.72mmol)。反应液在氮气保护下回流过夜。液相质谱显示原料消失后，用乙酸乙酯洗涤反应溶液，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到N-(3-溴-4-氟苯基)-2-异丙基苯胺(9.6g，黄色油状物，收率93.75％)。MS(ESI)M/Z：308.2[M+H] +。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (110 mL), then add 2-isopropylaniline (5.39 g, 39.86 mmol) ), Pd(OAC) 2 (palladium acetate, 0.75g, 3.34mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07g, 3.34mmol) and cesium carbonate (16.24g) , 49.72 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to give N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, Yellow oil, yield 93.75%). MS(ESI) M/Z: 308.2 [M+H] + .
步骤B(Step B)：将N-(3-溴-4-氟苯基)-2-异丙基苯胺(9.6g,31.15mmol)和3-氯-3-氧代丙酸甲酯(8.5g,62.26mmol)溶解在二氯甲烷(100mL)中,然后在室温下1小时内缓慢的滴加三乙胺(6.3g,62.26mmol)并搅拌30分钟。液相质谱监测显示原料消失后，加入二氯甲烷(100mL)稀释反应液并加入水(100mL),混合液用二氯甲烷(80mL×3次)萃取，合并有机相，有机相先用饱和食盐水(80mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1) 得到3-((3-溴-4-氟苯基)(2-异丙基苯基)氨基)-3-羰基丙酸甲酯(11.2g,白色固体，收率88.2％)。MS(ESI)M/Z：408.3[M+H] +。 Step B (Step B): N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, 31.15 mmol) and methyl 3-chloro-3-oxopropionate (8.5 g, 62.26 mmol) was dissolved in dichloromethane (100 mL), then triethylamine (6.3 g, 62.26 mmol) was slowly added dropwise over 1 hour at room temperature and stirred for 30 minutes. After the liquid phase mass spectrometry monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added. The mixture was extracted with dichloromethane (80 mL × 3 times), and the organic phases were combined, and the organic phase was first used with saturated salt Washed with water (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1) to give 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino )-methyl 3-carbonylpropionate (11.2 g, white solid, 88.2% yield). MS(ESI) M/Z: 408.3 [M+H] + .
步骤C(Step C)：将56mL 2N氢氧化钠加入到溶解在甲醇(110mL)中的3-((3-溴-4-氟苯基)(2-异丙基苯基)氨基)-3-羰基丙酸甲酯(11.2g,27.47mmol)溶液中，室温条件下搅拌1小时。LCMS监测显示原料消失后，混合溶液用水(100mL)稀释，然后用稀盐酸调节水相pH为2。用乙酸乙酯(2×100mL)萃取两次，有机层用盐水清洗，Na 2SO 4干燥，过滤，最后减压浓缩。得到3-((3-溴-4-氟苯基)(2-异丙基苯基)氨基)-3-氧丙酸(g，9.8淡黄色固体，收率90.74％)。MS(ESI)M/Z：394.2[M+H] +。 Step C (Step C): 56 mL of 2N sodium hydroxide was added to 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3 dissolved in methanol (110 mL) - methyl carbonylpropionate (11.2 g, 27.47 mmol) solution, stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2 x 100 mL), the organic layer was washed with brine, dried over Na2SO4 , filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionic acid (g, 9.8 pale yellow solid, yield 90.74%) was obtained. MS(ESI) M/Z: 394.2 [M+H] + .
步骤D(Step D)：将3-((3-溴-4-氟苯基)(2-异丙基苯基)氨基)-3-氧丙酸(9.8g，24.86mmol)溶解在Eatons Reagent(伊顿试剂)(70mL)中并在70℃下搅拌过夜。液相质谱监测显示原料消失后，向饱和的碳酸氢钠溶液中逐滴缓慢加入反应液并用饱和碳酸氢钠溶液调节pH为7-8。用二氯甲烷(2×100mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到7-溴-6-氟-1-(2-异丙基苯基)喹啉-2,4(1H,3H)-二酮(7.3g,白色固体，收率78.07％)。MS(ESI)M/Z：376.2[M+H] +。 Step D: Dissolve 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionic acid (9.8 g, 24.86 mmol) in Eatons Reagent (Eaton's reagent) (70 mL) and stirred at 70 °C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 7-Bromo-6-fluoro-1-(2-isopropylphenyl)quinoline-2,4(1H,3H)-dione (7.3 g, white solid, 78.07% yield) was obtained. MS(ESI) M/Z: 376.2 [M+H] + .
步骤E(Step E)：将7-溴-6-氟-1-(2-异丙基苯基)喹啉-2,4(1H,3H)-二酮(7.3g,19.40mmol)溶解在三氯氧磷(45mL)中并在80℃下搅拌6小时。液相质谱显示原料消失后，减压蒸馏除去三氯氧磷，缓慢加入水(40mL)并用饱和碳酸氢钠溶液调节溶液pH为7-8。用乙酸乙酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。得到固体用N,N-二甲基甲酰胺溶解并制备得到7-溴-4-氯-6-氟-1-(2-异丙基苯基)喹啉-2(1H)-酮(2.4g,淡黄色固体，收率36.32％)。MS(ESI)M/Z：394.7[M+H] +。 Step E (Step E): 7-Bromo-6-fluoro-1-(2-isopropylphenyl)quinoline-2,4(1H,3H)-dione (7.3 g, 19.40 mmol) was dissolved in Phosphorus oxychloride (45 mL) and stirred at 80°C for 6 hours. After LC mass spectrometry showed the disappearance of the starting material, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained solid was dissolved with N,N-dimethylformamide and prepared to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (2.4 g, pale yellow solid, yield 36.32%). MS (ESI) M/Z: 394.7 [M+H] + .
步骤F(Step F)：将7-溴-4-氯-6-氟-1-(2-异丙基苯基)喹啉-2(1H)-酮(2.4g,6.08mmol)溶解在二氧六环(20mL)中，然后加入哌嗪-1-甲酸叔丁酯(5.65g,30.38mmol)和N,N-二异丙基乙胺(4.72g,36.52mmol)并在110℃下搅拌2天。液相质谱显示原料消失后，减压蒸馏除去溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/2)得到4-(7-溴-6-氟-1-(2-异丙基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(2.9g，白色固体，收率87.88％)。MS(ESI)M/Z：544.5[M+H] +。 Step F (Step F): Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (2.4 g, 6.08 mmol) in two oxane (20 mL), then add piperazine-1-carboxylate tert-butyl ester (5.65 g, 30.38 mmol) and N,N-diisopropylethylamine (4.72 g, 36.52 mmol) and stir at 110 °C 2 days. After the disappearance of the starting material was shown by liquid phase mass spectrometry, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-6-fluoro). -1-(2-Isopropylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (2.9 g, white solid, yield 87.88 %). MS (ESI) M/Z: 544.5 [M+H] + .
步骤G(Step G)：将4-(7-溴-6-氟-1-(2-异丙基苯基)-2-羰基-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.500g,0.918mmol),(2-氟-4-甲氧基苯基)硼酸(0.624g,3.6717mmol),醋酸钾(0.54g,3.923mmol)和PdCl 2(dppf)1,1'-双二苯基膦二茂铁二氯化钯，0.134g,0.183mmol)混合物溶解在用氩气置换空气15分钟的1,4-二氧六环和水混合溶液(8mL/2mL)中，再次用氩气置换空气，并在90℃下搅拌48h，液相质谱显示原料消失后，用乙酸乙 酯(2×40mL)萃取两次，有机层用盐水清洗，无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.340g,淡黄色固体，收率80.3％)。MS(ESI)M/Z：589.7[M+H] +。 Step G (Step G): 4-(7-Bromo-6-fluoro-1-(2-isopropylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine - 1-Carboxylic acid tert-butyl ester (0.500g, 0.918mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.624g, 3.6717mmol), potassium acetate (0.54g, 3.923mmol ) and PdCl (dppf) 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, 0.134 g, 0.183 mmol) was dissolved in a mixed solution of 1,4-dioxane and water in which the air was replaced with argon for 15 minutes (8mL/2mL), the air was replaced with argon again, and stirred at 90°C for 48h. After the liquid chromatography mass spectrometry showed the disappearance of the raw material, it was extracted twice with ethyl acetate (2×40mL), and the organic layer was washed with brine. Dry over sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1) -(2-Isopropylphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, pale yellow solid, yield 80.3% ). MS (ESI) M/Z: 589.7 [M+H] + .
步骤H(Step H)：将4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.340g,0.577mmol)溶解在二氯甲烷(6mL)中并加入三氟乙酸(3mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.281g，棕色固体，收率99.6％)。MS(ESI)M/Z：489.6[M+H] +。 Step H (Step H): 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, 0.577 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one ( 0.281 g, brown solid, 99.6% yield). MS (ESI) M/Z: 489.6 [M+H] + .
步骤I(Step I)：将6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.281g,0.574mmol)溶解在二氯甲烷(10mL)中并加入DIPEA(N,N-二异丙基乙胺)(0.371g,2.87mmol)和丙烯酰氯(0.104g，1.15mmol)并在室温下搅拌2小时，LCMS监测显示原料消失后，减压浓缩除去溶剂并将所得固体溶解在N,N-二甲基甲酰胺(5mL)中送制备得到4-(4-丙烯酰哌嗪-1-基)-6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)喹啉-2(1H)-酮(0.0562g,白色固体，收率17.95％)。MS(ESI)M/Z：543.6[M+H] + Step I (Step I): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.281 g, 0.574 mmol) was dissolved in dichloromethane (10 mL) and DIPEA (N,N-diisopropylethylamine) (0.371 g, 2.87 mmol) and acryloyl chloride were added (0.104 g, 1.15 mmol) and stirred at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to prepare 4. -(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)quinoline-2( 1H)-ketone (0.0562 g, white solid, 17.95% yield). MS(ESI)M/Z: 543.6[M+H] +
1H NMR(500MHz,DMSO)δ7.74(dd,J＝7.9,1.3Hz,1H),7.51(dd,J＝7.7,1.2Hz,1H),7.43–7.37(m,2H),7.30(dd,J＝16.7,8.4Hz,2H),7.19(dd,J＝6.5,2.3Hz,1H),6.96(dd,J＝12.2,2.4Hz,1H),6.87(ddd,J＝20.9,10.8,6.5Hz,2H),6.16(dd,J＝16.7,2.3Hz,1H),6.03(s,1H),5.76–5.71(m,1H),3.82(s,2H),3.81(s,3H),3.11(s,5H),2.62–2.53(m,1H),1.25(d,J＝11.9Hz,1H),0.84(d,J＝6.6Hz,6H). 1 H NMR (500MHz, DMSO) δ 7.74 (dd, J=7.9, 1.3Hz, 1H), 7.51 (dd, J=7.7, 1.2Hz, 1H), 7.43-7.37 (m, 2H), 7.30 (dd , J＝16.7, 8.4Hz, 2H), 7.19 (dd, J＝6.5, 2.3Hz, 1H), 6.96 (dd, J＝12.2, 2.4Hz, 1H), 6.87 (ddd, J＝20.9, 10.8, 6.5 Hz, 2H), 6.16(dd, J=16.7, 2.3Hz, 1H), 6.03(s, 1H), 5.76–5.71(m, 1H), 3.82(s, 2H), 3.81(s, 3H), 3.11 (s, 5H), 2.62–2.53 (m, 1H), 1.25 (d, J=11.9Hz, 1H), 0.84 (d, J=6.6Hz, 6H).
实施例11：合成4-(6-氟-7-(2-氟-4-甲氧基苯基)-7-(2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧酰胺Example 11: Synthesis of 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-7-(2-isopropylphenyl)-2-oxo-1,2-dihydro Quinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide
Figure PCTCN2021132725-appb-000188
Figure PCTCN2021132725-appb-000188
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000189
Figure PCTCN2021132725-appb-000189
步骤A(Step A):将2-甲氧基乙胺(0.2g，2.66mmol)溶解在THF(3mL)中并加入DIPEA(N,N-二异丙基乙胺)(0.688g,5.32mmol)在冰浴下搅拌10分钟，缓慢加入4-硝基苯基碳酰氯(0.805g,3.99mmol)自然升至室温搅拌2h，液相质谱监测显示原料消失后，减压浓缩除去溶剂，制备得到4-硝基苯基(2-甲氧基乙基)氨基甲酸酯(0.487g，黄色油状物，收率93.8％)MS(ESI)M/Z：240.2[M+H] +。 Step A (Step A): 2-Methoxyethylamine (0.2 g, 2.66 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) (0.688 g, 5.32 mmol) was added ) under an ice bath and stirred for 10 minutes, slowly added 4-nitrophenylcarbonyl chloride (0.805g, 3.99mmol) and naturally raised to room temperature and stirred for 2h. After the liquid phase mass spectrometry monitoring showed that the raw materials disappeared, the solvent was concentrated under reduced pressure to remove the solvent to prepare 4-Nitrophenyl(2-methoxyethyl)carbamate (0.487 g, yellow oil, 93.8% yield) MS (ESI) M/Z: 240.2 [M+H] + .
步骤B(Step B):将4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-)2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.3g,0.509mmol)溶解在二氯甲烷(6mL)中并加入三氟乙酸(3mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248g，棕色固体，收率99.6％)。MS(ESI)M/Z：489.6[M+H] +。 Step B (Step B): 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one ( 0.248 g, brown solid, 99.6% yield). MS (ESI) M/Z: 489.6 [M+H] + .
步骤C(Step C):将6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248g，0.506mmol)溶解在二氯甲烷(4mL)中并加入4-硝基苯基(2-甲氧基乙基)氨基甲酸酯(0.243g，1.01mmol)，在冰浴下缓慢加入1M的KHMDS(2ml)，撤去冰浴在65℃下搅拌12h，液相质谱监测显示原料消失后，减压浓缩除去溶剂，制备得到4-(6-氟-7-(2-氟-4-甲氧基苯基)-7-(2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)-N-(-甲氧基乙基)哌嗪-1-羧酰胺(0.0367g，淡黄色固体，收率12.3％)。MS(ESI)M/Z：590.7[M+H] +。 Step C (Step C): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl(2-methoxyethyl)carbamate (0.243 g, 1.01 mmol), slowly add 1M KHMDS (2 ml) under ice bath, remove the ice bath and stir at 65°C for 12 h. After monitoring by liquid phase mass spectrometry shows the disappearance of the raw materials, concentrate under reduced pressure to remove the solvent to prepare 4-(6-fluoro). -7-(2-Fluoro-4-methoxyphenyl)-7-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-( -Methoxyethyl)piperazine-1-carboxamide (0.0367 g, pale yellow solid, 12.3% yield). MS (ESI) M/Z: 590.7 [M+H] + .
1H NMR(500MHz,CDCl 3)δ7.60(d,J＝7.9Hz,1H),7.36(d,J＝7.6Hz,1H),7.28(s,1H),7.22(s,1H),7.18–7.15(m,2H),7.09(d,J＝6.0Hz,1H),6.67(d,J＝8.6Hz,1H),6.61(d,J＝11.7Hz,1H),6.08(s,1H),4.88(s,1H),3.75(d,J＝1.8Hz,3H),3.56(s,3H),3.42(d,J ＝9.8Hz,5H),3.31(d,J＝1.7Hz,3H),3.09(s,4H),2.55(d,J＝6.5Hz,1H),0.82(d,J＝6.4Hz,6H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.60 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.18 –7.15(m, 2H), 7.09(d, J=6.0Hz, 1H), 6.67(d, J=8.6Hz, 1H), 6.61(d, J=11.7Hz, 1H), 6.08(s, 1H) ,4.88(s,1H),3.75(d,J=1.8Hz,3H),3.56(s,3H),3.42(d,J=9.8Hz,5H),3.31(d,J=1.7Hz,3H) ,3.09(s,4H),2.55(d,J＝6.5Hz,1H),0.82(d,J＝6.4Hz,6H).
实施例12：合成4-(6-氟-7-)2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧酰胺Example 12: Synthesis of 4-(6-fluoro-7-)2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-di Hydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide
Figure PCTCN2021132725-appb-000190
Figure PCTCN2021132725-appb-000190
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000191
Figure PCTCN2021132725-appb-000191
步骤A(Step A):将2-(2-甲氧基乙氧基)乙胺(0.2g，1.68mmol)溶解在THF(3mL)中并加入DIPEA(N,N-二异丙基乙胺)(434g,3.36mmol)在冰浴下搅拌10分钟，缓慢加入4-硝基苯基碳酰氯(0.507g,2.51mmol)自然升至室温搅拌2h，液相质谱监测显示原料消失后，减压浓缩除去溶剂，制备得到4-硝基苯基(2-(2-甲氧基乙氧基)乙基)氨基甲酸酯(0.419g，黄色油状物，收率88.2％)MS(ESI)M/Z：284.3[M+H] +。 Step A (Step A): 2-(2-Methoxyethoxy)ethylamine (0.2 g, 1.68 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) was added ) (434g, 3.36mmol) was stirred under ice bath for 10 minutes, 4-nitrophenylcarbonyl chloride (0.507g, 2.51mmol) was slowly added to room temperature and stirred for 2h. Concentrated to remove the solvent to prepare 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)carbamate (0.419 g, yellow oil, yield 88.2%) MS (ESI) M /Z: 284.3[M+H] + .
步骤B(Step B):将4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-)2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.3g,0.509mmol)溶解在二氯甲烷(6mL)中并加入三氟乙酸(3mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248 g，棕色固体，收率99.6％)。MS(ESI)M/Z：489.6[M+H] +。 Step B (Step B): 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one ( 0.248 g, brown solid, 99.6% yield). MS (ESI) M/Z: 489.6 [M+H] + .
步骤C(Step C):将6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248g，0.506mmol)溶解在二氯甲烷(4mL)中并加入4-硝基苯基(2-(2-甲氧基乙氧基)乙基)氨基甲酸酯(0.216g，0.76mmol)，在冰浴下缓慢加入1M的KHMDS(2ml)，撤去冰浴在65℃下搅拌12h，液相质谱监测显示原料消失后，减压浓缩除去溶剂，制备得到4-(6-氟-7-)2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧酰胺(0.0416g，淡黄色固体，收率13.1％)。MS(ESI)M/Z：634.7[M+H] +。 Step C (Step C): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)amino was added Formate (0.216g, 0.76mmol), slowly add 1M KHMDS (2ml) under an ice bath, remove the ice bath and stir at 65°C for 12h. After the liquid mass spectrometry monitoring shows that the raw materials disappear, concentrate under reduced pressure to remove the solvent to prepare to give 4-(6-fluoro-7-)2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinoline- 4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide (0.0416 g, pale yellow solid, 13.1% yield). MS (ESI) M/Z: 634.7 [M+H] + .
1H NMR(500MHz,CDCl 3)δ7.61(d,J＝7.7Hz,1H),7.36(d,J＝7.5Hz,1H),7.33–7.26(m,1H),7.21(d,J＝8.9Hz,1H),7.18(s,1H),7.17–7.14(m,1H),7.10(d,J＝4.1Hz,1H),6.67(dd,J＝8.5,2.1Hz,1H),6.65–6.59(m,1H),6.08(s,1H),5.10(s,1H),3.75(s,3H),3.56(dt,J＝9.9,4.6Hz,8H),3.52–3.48(m,2H),3.42(s,2H),3.33(s,3H),3.09(s,4H),2.56(dt,J＝13.0,6.5Hz,1H),0.82(d,J＝6.5Hz,6H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.61 (d, J=7.7 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.33-7.26 (m, 1H), 7.21 (d, J= 8.9Hz, 1H), 7.18 (s, 1H), 7.17–7.14 (m, 1H), 7.10 (d, J=4.1Hz, 1H), 6.67 (dd, J=8.5, 2.1Hz, 1H), 6.65– 6.59(m, 1H), 6.08(s, 1H), 5.10(s, 1H), 3.75(s, 3H), 3.56(dt, J=9.9, 4.6Hz, 8H), 3.52–3.48(m, 2H) ,3.42(s,2H),3.33(s,3H),3.09(s,4H),2.56(dt,J=13.0,6.5Hz,1H),0.82(d,J=6.5Hz,6H).
实施例13：合成6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(4-(3-(2-甲氧基乙氧基)丙酰基)哌嗪-1-基)喹啉-2(1H)-酮Example 13: Synthesis of 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(4-(3-(2-methoxyphenyl) ethoxy)propionyl)piperazin-1-yl)quinolin-2(1H)-one
Figure PCTCN2021132725-appb-000192
Figure PCTCN2021132725-appb-000192
合成路线：synthetic route:
Figure PCTCN2021132725-appb-000193
Figure PCTCN2021132725-appb-000193
步骤B(Step B):将4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-)2-异丙基苯基)-2-氧-1,2-二氢喹啉-4-基)哌嗪-1-羧酸叔丁酯(0.3g,0.509mmol)溶解在二氯甲烷(6mL)中并加入三氟乙酸(3mL)并在室温下搅拌1小时，液相质谱监测显示原料消失后，减压浓缩除去二氯甲 烷和三氟乙酸，并加入二氯甲烷(10mL)再次减压浓缩直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.228g，棕色固体，收率91.6％)。MS(ESI)M/Z：489.6[M+H] +。 Step B (Step B): 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 -Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 After the disappearance of the raw materials by liquid phase mass spectrometry monitoring, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6- Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one ( 0.228 g, brown solid, 91.6% yield). MS (ESI) M/Z: 489.6 [M+H] + .
步骤C(Step C):将6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.228g，0.466mmol)溶解在二氯甲烷(4mL)中并加入3-(2-甲氧基乙氧基)丙酸(0.103g，0.695mmol)和三乙胺(0.118g，1.15mmol)，再加入BOP试剂(0.226g，0.512mmol)在室温下搅拌12h，液相质谱监测显示原料消失后，减压浓缩除去溶剂，制备得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-异丙基苯基)-4-(4-(3-(2-甲氧基乙氧基)丙酰基)哌嗪-1-基)喹啉-2(1H)-酮(0.0386g，淡黄色固体，收率12.2％)。MS(ESI)M/Z：619.7[M+H] +。 Step C (Step C): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.228 g, 0.466 mmol) was dissolved in dichloromethane (4 mL) and 3-(2-methoxyethoxy)propionic acid (0.103 g, 0.695 mmol) and trichloromethane were added Ethylamine (0.118 g, 1.15 mmol), then BOP reagent (0.226 g, 0.512 mmol) was added and stirred at room temperature for 12 h. After the disappearance of the raw material was detected by liquid phase mass spectrometry, the solvent was removed by concentration under reduced pressure to prepare 6-fluoro-7- (2-Fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(4-(3-(2-methoxyethoxy)propionyl)piperazine- 1-yl)quinolin-2(1H)-one (0.0386 g, pale yellow solid, 12.2% yield). MS(ESI) M/Z: 619.7 [M+H] + .
1H NMR(500MHz,CDCl 3)δ7.60(dd,J＝7.9,1.4Hz,1H),7.37(dd,J＝7.7,1.3Hz,1H),7.31–7.27(m,1H),7.20(s,1H),7.18(s,1H),7.16(d,J＝8.8Hz,1H),7.10(dd,J＝6.4,2.3Hz,1H),6.67(dd,J＝8.5,2.5Hz,1H),6.62(dd,J＝11.7,2.4Hz,1H),6.09(s,1H),3.78(d,J＝6.6Hz,2H),3.76–3.74(m,3H),3.73–3.66(m,3H),3.61–3.55(m,3H),3.48(dt,J＝4.3,3.1Hz,3H),3.32(d,J＝3.3Hz,3H),3.09(s,4H),2.66(t,J＝6.6Hz,2H),2.62–2.51(m,2H),0.82(d,J＝6.7Hz,6H). 1 H NMR (500 MHz, CDCl 3 ) δ 7.60 (dd, J=7.9, 1.4 Hz, 1H), 7.37 (dd, J=7.7, 1.3 Hz, 1H), 7.31-7.27 (m, 1H), 7.20 ( s,1H),7.18(s,1H),7.16(d,J=8.8Hz,1H),7.10(dd,J=6.4,2.3Hz,1H),6.67(dd,J=8.5,2.5Hz,1H) ), 6.62(dd, J=11.7, 2.4Hz, 1H), 6.09(s, 1H), 3.78(d, J=6.6Hz, 2H), 3.76–3.74(m, 3H), 3.73–3.66(m, 3H), 3.61–3.55(m, 3H), 3.48(dt, J=4.3, 3.1Hz, 3H), 3.32(d, J=3.3Hz, 3H), 3.09(s, 4H), 2.66(t, J =6.6Hz,2H),2.62–2.51(m,2H),0.82(d,J=6.7Hz,6H).
实施例14：合成6-氟-7-(2-氟-6-羟基-苯基)-1-(2-异丙基-4-甲基-3-吡啶基)-4-[(3S)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮Example 14: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)-4-[(3S) -3-Methyl-4-prop-2-enyl-piperazin-1-yl]quinolin-2-one
Figure PCTCN2021132725-appb-000194
Figure PCTCN2021132725-appb-000194
Figure PCTCN2021132725-appb-000195
Figure PCTCN2021132725-appb-000195
步骤A(Step A):将2-异丙基-4-甲基-吡啶-3-胺(2g，13.3mmol)，醋酸钯(147.8mg，0.66mmol),BINAP(808mg，1.3mmol)和碳酸铯(8.6g，26.6mmol)加入到甲苯中(30ml)置换氮气三次在110℃下搅拌过夜，质谱监测反应完全后旋干溶剂，柱层析纯化得到N-(3-溴-4-氟苯基)-2-异丙基-4-甲基吡啶-3-胺(2.8g，8.7mmol收率：65％)。MS(ESI)M/Z：323.3[M+H]+。Step A (Step A): 2-isopropyl-4-methyl-pyridin-3-amine (2g, 13.3mmol), palladium acetate (147.8mg, 0.66mmol), BINAP (808mg, 1.3mmol) and carbonic acid Cesium (8.6g, 26.6mmol) was added to toluene (30ml) to replace nitrogen three times and stirred overnight at 110°C. After the reaction was completed by mass spectrometry, the solvent was spin-dried and purified by column chromatography to obtain N-(3-bromo-4-fluorobenzene yl)-2-isopropyl-4-methylpyridin-3-amine (2.8 g, 8.7 mmol yield: 65%). MS (ESI) M/Z: 323.3 [M+H]+.
步骤B(Step B)将N-(3-溴-4-氟苯基)-2-异丙基-4-甲基吡啶-3-胺(2.8g，8.7mmol)用二氯乙烷(30ml)溶解，向溶液中滴入3-氯-3-氧代丙酸甲酯(2.4g。17.4)在70摄氏度下搅拌过夜，冷却至室温，用碳酸钠饱和溶液洗涤，乙酸乙酯萃取，干燥旋干有机相得到3-(3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-氧代丙酸甲酯(4g粗品)。MS(ESI)M/Z：423.4[M+H]+Step B (Step B) N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8g, 8.7mmol) was dissolved in dichloroethane (30ml) ) was dissolved, and methyl 3-chloro-3-oxopropionate (2.4 g. 17.4) was added dropwise to the solution, stirred at 70 degrees Celsius overnight, cooled to room temperature, washed with saturated sodium carbonate solution, extracted with ethyl acetate, and dried. The organic phase was spin-dried to obtain methyl 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionate (4g crude product) . MS(ESI)M/Z: 423.4[M+H]+
步骤C(Step C)：将3-(3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-氧代丙酸甲酯(3g，7mmol)用甲醇(5ml)溶解向溶液中滴加2M氢氧化钠溶液(10ml)搅拌1小时TLC监测，反应完全后用2M盐酸溶液将PH调至中性，旋干溶剂，用flash(乙腈/水)纯化得到3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-氧代丙酸(2g，5mmol)。MS(ESI)M/Z：409.5[M+H]+Step C (Step C): 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid methyl ester ( 3g, 7mmol) dissolve with methanol (5ml), add dropwise 2M sodium hydroxide solution (10ml) to the solution and stir for 1 hour TLC monitoring, after the reaction is complete, adjust the pH to neutrality with 2M hydrochloric acid solution, spin dry the solvent, use flash ( acetonitrile/water) to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2 g, 5 mmol ). MS(ESI) M/Z: 409.5[M+H]+
步骤D(Step D)：将3-((3-溴-4-氟苯基)(2-异丙基-4-甲基吡啶-3-基)氨基)-3-氧代丙酸(2g，5mmol)溶于5ml伊顿试剂在80℃下搅拌1小时，冷却至室温，加入冰水中用2M氢氧化钠溶液将体系调至中性，用乙酸乙酯萃取，旋干溶剂得到7-溴-6-氟-1-(2-异丙基-6-甲基-吡啶基)喹啉-2，4-二酮(2g粗品).Step D (Step D): 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2g , 5mmol) was dissolved in 5ml of Eaton's reagent, stirred at 80°C for 1 hour, cooled to room temperature, added to ice water and adjusted to neutrality with 2M sodium hydroxide solution, extracted with ethyl acetate, and the solvent was spin-dried to obtain 7-bromo- 6-Fluoro-1-(2-isopropyl-6-methyl-pyridyl)quinoline-2,4-dione (2 g crude).
MS(ESI)M/Z：391.2[M+H]MS(ESI) M/Z: 391.2[M+H]
步骤E(Step E)：7-溴-6-氟-1-(2-异丙基-4-甲基-3-吡啶基)喹啉-2，4-二酮(1g粗品) 用三氯氧磷(8ml)溶解，在80℃下搅拌2小时，旋干溶剂，用2M氢氧化钠溶液将PH调至中性用二氯甲烷萃取，旋干有机相，柱层析纯化(PE/EA0～100％)得到7-溴-4-氯-6-氟-1-(2-异丙基-4-甲基-3-吡啶基)喹啉-2-酮(360mg，0.88mmol)Step E (Step E): 7-Bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinoline-2,4-dione (1 g crude) was treated with trichloro Phosphorus oxide (8ml) was dissolved, stirred at 80°C for 2 hours, the solvent was spin-dried, the pH was adjusted to neutral with 2M sodium hydroxide solution, extracted with dichloromethane, the organic phase was spin-dried, and purified by column chromatography (PE/EA0 ~100%) to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol)
MS(ESI)M/Z：408.1[M+H]MS(ESI) M/Z: 408.1[M+H]
步骤F(Step F)：将7-溴-4-氯-6-氟-1-(2-异丙基-4-甲基-3-吡啶基)喹啉-2-酮(360mg，0.88mmol)用DMF溶解，加入N,N-二异丙基乙胺(260mg，2mmol)和(S)-1-N-Boc-2-甲基哌嗪(200mg，1mmol)在60℃下搅拌两小时，质谱确认反应完全后用flash(乙腈/水0～100％)纯化,得到叔丁基(2S)-4-[7-溴-6-氟-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯(404mg，0.7mmol收率80％)。MS(ESI)M/Z：573.1[M+H]Step F (Step F): 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol ) was dissolved in DMF, added N,N-diisopropylethylamine (260mg, 2mmol) and (S)-1-N-Boc-2-methylpiperazine (200mg, 1mmol) and stirred at 60°C for two hours , after confirming that the reaction was complete by mass spectrometry, it was purified by flash (acetonitrile/water 0-100%) to obtain tert-butyl (2S)-4-[7-bromo-6-fluoro-1-(2-isopropyl-4-methyl] (404 mg, 0.7 mmol, 80% yield). MS(ESI) M/Z: 573.1[M+H]
步骤G(Step G)：叔丁基(2S)-4-[7-溴-6-氟-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯(200mg0.348mmol)溶于1,4二氧六环中，向体系中加入1，3，5，7-四甲基-6-苯基-2，4，8-三氧杂-6-磷金刚烷(10.16mg，0.0348)，磷酸钾(148mg，0.7mmol)2-氟-6-羟基苯硼酸(108mg，0.7)和三(二亚芐基丙酮)二钯(31mg，0.0348mmol)置换氮气三次之后在60℃下搅拌过夜，旋干溶剂，用flash(乙腈/水0～100％)纯化，得到叔丁基(2S)-4-[6-氟-7-(2-氟-6-羟基-苯基)-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯(110mg)0.18mmol收率52％)。MS(ESI)M/Z：605.3[M+H]Step G: tert-Butyl(2S)-4-[7-bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo- 4-Quinolinyl]-2-methyl-piperazine-1-carboxylate (200 mg, 0.348 mmol) was dissolved in 1,4 dioxane, and 1,3,5,7-tetramethyl was added to the system yl-6-phenyl-2,4,8-trioxa-6-phosphoadamantane (10.16 mg, 0.0348), potassium phosphate (148 mg, 0.7 mmol) 2-fluoro-6-hydroxyphenylboronic acid (108 mg, 0.7 ) and tris(dibenzylideneacetone)dipalladium (31 mg, 0.0348 mmol) replaced nitrogen three times, then stirred at 60°C overnight, spin-dried the solvent, and purified with flash (acetonitrile/water 0-100%) to obtain tert-butyl (2S)-4-[6-Fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo -4-Quinolinyl]-2-methyl-piperazine-1-carboxylate (110 mg) 0.18 mmol, 52% yield). MS(ESI)M/Z: 605.3[M+H]
步骤H(StepH)：叔丁基(2S)-4-[6-氟-7-(2-氟-6-羟基-苯基)-1-(2-异丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯(55mg)0.09mmol)用二氯甲烷溶解(1ml)加入三氟乙酸(0.5ml)室温搅拌1小时，旋干，再加入二氯甲烷(2ml)和N,N-二异丙基乙胺(64mg，0.5mmol)搅拌过程中加入烯丙酰氯(8Fmg，0.09mmol)反应半小时后质谱确认反应完全，旋干溶剂，用flash(乙腈/水)纯化得到6-氟-7-(2-氟-6-羟基-苯基)-1-(2-异丙基-4-甲基-3-吡啶基)-4-[(3S)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮(22.3mg，0.04mmo l收率44％)。MS(ESI)M/Z：559.3[M+H]Step H (StepH): tert-Butyl(2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3 -pyridyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-1-carboxylate (55mg) 0.09mmol) was dissolved in dichloromethane (1ml) trifluoroacetic acid (0.5ml) was added ml) stirred at room temperature for 1 hour, spin-dried, then added dichloromethane (2ml) and N,N-diisopropylethylamine (64mg, 0.5mmol) and added acryloyl chloride (8Fmg, 0.09mmol) during stirring to react half After one hour, mass spectrometry confirmed that the reaction was complete, the solvent was spun dry, and purified by flash (acetonitrile/water) to obtain 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4- Methyl-3-pyridyl)-4-[(3S)-3-methyl-4-prop-2-enyl-piperazin-1-yl]quinolin-2-one (22.3 mg, 0.04 mmol yield 44%). MS(ESI) M/Z: 559.3[M+H]
1H NMR(500MHz,DMSO)δ10.21(s,1H),8.54(d,J＝4.7Hz,1H),7.77(dd,J＝10.3,4.4Hz,1H),7.32(s,1H),7.26–7.18(m,1H),6.86(dd,J＝15.9,10.6Hz,1H),6.74(d,J＝8.3Hz,1H),6.69(t,J＝8.9Hz,1H),6.41–6.30(m,1H),6.25(s,1H),6.18(d,J＝16.6Hz,1H),5.75(d,J＝12.0Hz,1H),4.67(d,J＝156.6Hz,1H),4.24(d,J＝161.2Hz,1H),3.77–3.54(m,2H),3.03(s,2H),2.79(s,1H),2.59(dd,J＝12.8,6.5Hz,1H),1.92(t,J＝19.3Hz,3H),1.46(s,3H),1.01(dd,J＝51.7,6.3Hz,6H). 1 H NMR (500MHz, DMSO) δ 10.21(s, 1H), 8.54(d, J=4.7Hz, 1H), 7.77(dd, J=10.3, 4.4Hz, 1H), 7.32(s, 1H), 7.26–7.18 (m, 1H), 6.86 (dd, J=15.9, 10.6Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.69 (t, J=8.9Hz, 1H), 6.41–6.30 (m,1H),6.25(s,1H),6.18(d,J=16.6Hz,1H),5.75(d,J=12.0Hz,1H),4.67(d,J=156.6Hz,1H),4.24 (d, J=161.2Hz, 1H), 3.77–3.54(m, 2H), 3.03(s, 2H), 2.79(s, 1H), 2.59(dd, J=12.8, 6.5Hz, 1H), 1.92( t,J=19.3Hz,3H),1.46(s,3H),1.01(dd,J=51.7,6.3Hz,6H).
实施例15：合成6-氟-7-(2-氟-6-羟基-苯基)-1-(2-异丙基-4-甲基-3-吡啶基)-4-[(3R)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮Example 15: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)-4-[(3R) -3-Methyl-4-prop-2-enyl-piperazin-1-yl]quinolin-2-one
Figure PCTCN2021132725-appb-000196
Figure PCTCN2021132725-appb-000196
合成路线同实施例14Synthetic route is the same as Example 14
MS(ESI)M/Z：559.3[M+H]MS(ESI) M/Z: 559.3[M+H]
1H NMR(500MHz,DMSO)δ10.15(s,1H),8.54(d,J＝4.7Hz,1H),7.77(dd,J＝10.3,4.4Hz,1H),7.32(s,1H),7.22(dd,J＝15.4,8.1Hz,1H),6.86(dd,J＝16.0,10.6Hz,1H),6.73(t,J＝7.8Hz,1H),6.69(t,J＝8.9Hz,1H),6.40–6.30(m,1H),6.25(s,1H),6.19(t,J＝13.6Hz,1H),5.79–5.72(m,1H),4.67(d,J＝155.9Hz,1H),4.24(d,J＝160.8Hz,1H),3.69(d,J＝66.1Hz,2H),3.50–3.41(m,1H),3.05(s,1H),2.79(s,1H),2.66–2.54(m,1H),1.90(d,J＝19.8Hz,3H),1.46(s,3H),1.09–0.94(m,6H). 1 H NMR (500MHz, DMSO) δ 10.15(s, 1H), 8.54(d, J=4.7Hz, 1H), 7.77(dd, J=10.3, 4.4Hz, 1H), 7.32(s, 1H), 7.22(dd,J＝15.4,8.1Hz,1H),6.86(dd,J＝16.0,10.6Hz,1H),6.73(t,J＝7.8Hz,1H),6.69(t,J＝8.9Hz,1H) ), 6.40–6.30 (m, 1H), 6.25 (s, 1H), 6.19 (t, J=13.6Hz, 1H), 5.79–5.72 (m, 1H), 4.67 (d, J=155.9Hz, 1H) ,4.24(d,J＝160.8Hz,1H),3.69(d,J＝66.1Hz,2H),3.50–3.41(m,1H),3.05(s,1H),2.79(s,1H),2.66– 2.54(m, 1H), 1.90(d, J=19.8Hz, 3H), 1.46(s, 3H), 1.09–0.94(m, 6H).
生物活性biological activity
测试方法(1)Test method(1)
实验材料：Experimental Materials:
KRAS G12C(SignalChem,Cat.No.R06-32DH-BULK)KRAS G12C (SignalChem, Cat. No. R06-32DH-BULK)
SOS1 exchange domain(564-1049)protein(Cytoskeleton,Inc.,Cat.No.GE02-XL)SOS1 exchange domain (564-1049) protein (Cytoskeleton, Inc., Cat. No. GE02-XL)
Transcreener GDP FI Assay(BellBrook,Cat.No.3014-1K)Transcreener GDP FI Assay(BellBrook,Cat.No.3014-1K)
384-well plate(Perkin Elmer,Cat.No.6007279)384-well plate (Perkin Elmer, Cat. No. 6007279)
BAY-293(MCE,Cat.No.HY-114398)BAY-293(MCE,Cat.No.HY-114398)
AMG-510(MCE,Cat.HY-114277)AMG-510(MCE,Cat.HY-114277)
实验步骤：Experimental steps:
1.化合物的处理1. Handling of Compounds
配制400倍终浓度的化合物，如检测终浓度为25μM，配制成400倍浓度，即10mM。用自动微孔移液器将化合物梯度稀释成设置的浓度点个数。Compounds with a 400-fold final concentration, such as the final detection concentration of 25 μM, are prepared to a 400-fold concentration, that is, 10 mM. The compound was serially diluted to the set number of concentration points using an automatic micropipette.
2.转移化合物到384孔板反应板2. Transfer Compounds to a 384-well Plate Reaction Plate
用超声波纳升液体处理***将上述稀释好的化合物从Echo 384孔板中转移75nL到384孔反应板中，阴性对照和阳性对照均转移75nL的100％DMSO。Transfer 75nL of the above diluted compounds from the Echo 384-well plate to the 384-well reaction plate using the ultrasonic nanoliter liquid processing system, and transfer 75nL of 100% DMSO for both the negative and positive controls.
3.配制1倍反应缓冲液3. Prepare 1x Reaction Buffer
1倍反应缓冲液中含50mM Tris(pH7.5)，50mM NaCl，1mM EDTA，0.1％BSA，14mM MgCl 2，0.01％Tween-20，1mM DTT。 1x reaction buffer containing 50 mM Tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.1% BSA, 14 mM MgCl2 , 0.01% Tween-20, 1 mM DTT.
4.配制3倍KRAS G12C酶溶液，6倍SOS1酶溶液，6倍GTP(BellBrook,Cat.No.3014-1K)溶液，3倍检测溶液4. Prepare 3 times KRAS G12C enzyme solution, 6 times SOS1 enzyme solution, 6 times GTP (BellBrook, Cat.No.3014-1K) solution, 3 times detection solution
用1倍反应缓冲液分别配制3倍KRAS G12C酶溶液，6倍SOS1酶溶液，6倍GTP溶液，3倍检测溶液(Antibody-IRDye和GDP-Tracer)。3 times KRAS G12C enzyme solution, 6 times SOS1 enzyme solution, 6 times GTP solution and 3 times detection solution (Antibody-IRDye and GDP-Tracer) were prepared with 1 times reaction buffer.
5.转移3倍KRAS G12C酶溶液5. Transfer 3x KRAS G12C Enzyme Solution
转移10μL 3倍KRAS G12C酶溶液到反应板中，对于阴性对照孔，用10μL的1倍反应缓冲液替代酶溶液。1000rpm离心1分钟，室温下孵育15分钟。Transfer 10 μL of 3x KRAS G12C enzyme solution to the reaction plate, and for negative control wells, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min.
6.转移6倍SOS1酶溶液6. Transfer 6x SOS1 Enzyme Solution
转移5μL 6倍SOS1酶溶液到反应板中。Transfer 5 μL of 6x SOS1 enzyme solution to the reaction plate.
7.转移6倍GTP溶液7. Transfer 6x GTP Solution
转移5μL 6倍GTP溶液到反应板中。Transfer 5 μL of 6x GTP solution to the reaction plate.
8.转移3倍检测溶液8. Transfer 3x Assay Solution
转移10μL 3倍检测溶液到反应板中。1000rpm离心1分钟。Transfer 10 μL of 3x detection solution to the reaction plate. Centrifuge at 1000 rpm for 1 minute.
9.读数9. Reading
用酶标仪SpectraMax Paradigm连续读取2小时内(每5分钟读取一次)荧光信号数值(Ex580/Em620)。The fluorescence signal value (Ex580/Em620) was continuously read within 2 hours (read every 5 minutes) with a microplate reader SpectraMax Paradigm.
10.抑制率计算与IC 50拟合 10. Inhibition rate calculation and IC50 fitting
从读板仪器上复制数值并计算斜率值，其中最大值是指阳性对照的读值，最小值是指阴性对照的读值。抑制率(％)＝(最大值-样本值)/(最大值-最小值)×100％。Values were replicated from the plate reader and slope values were calculated, where the maximum value refers to the positive control reading and the minimum value refers to the negative control reading. Inhibition rate (%)=(maximum value-sample value)/(maximum value-minimum value)×100%.
将数据导入MS Excel并用XLFit excel add-in version5.4.0.8拟合IC 50值； Import data into MS Excel and fit IC50 values with XLFit excel add-in version 5.4.0.8;
拟合公式：Y＝Bottom+(Top-Bottom)/(1+(IC 50/X)^HillSlope)。 Fitting formula: Y=Bottom+(Top-Bottom)/(1+( IC50 /X)^HillSlope).
本发明化合物在1μM和10μM时对KRAS G12C的抑制率、抑制KRAS G12C的IC 50如表1所示。 Table 1 shows the inhibition rate and IC50 of the compounds of the present invention on KRAS G12C at 1 μM and 10 μM.
测试方法(2)Test method(2)
检测方法：CTG方法Detection method: CTG method
实验方法：experimental method:
1.将处于对数生长期的细胞重新悬浮于生长培养基并稀释至目标密度。将上述细胞悬浮液按照每孔100μL接种至96孔板中，在37℃，5％CO 2培养箱中孵育过夜。 1. Resuspend cells in log phase growth medium in growth medium and dilute to target density. The above cell suspension was seeded into a 96-well plate at 100 μL per well, and incubated overnight at 37°C in a 5% CO2 incubator.
2.将待测化合物溶解在DMSO中，配制成浓度为10mM的储备液。首先用DMSO将储备液稀释至2mM，10个浓度，3倍梯度稀释。然后用生长培养基稀释至30μM。按50μL/孔加入接种细胞的96孔板中。2. Dissolve the test compound in DMSO to prepare a stock solution with a concentration of 10 mM. The stock solution was first diluted with DMSO to 2 mM, 10 concentrations, 3-fold serial dilution. Then dilute to 30 μM with growth medium. Add 50 μL/well to the 96-well plate seeded with cells.
3.将加入待测化合物的细胞置于37℃，5％CO 2培养箱中孵育72小时。室温下平衡96孔板，每孔中加入40μL
Figure PCTCN2021132725-appb-000197
试剂(Promega G7573)，混合2分钟，室温孵育60分钟，EnVision RMultilabel Reader读取发光值，用GraphPad Prism 5.0 software软件计算化合物的IC 50。 3. Incubate the cells with the compounds to be tested in a 37°C, 5% CO 2 incubator for 72 hours. Equilibrate 96-well plate at room temperature and add 40 μL to each well
Figure PCTCN2021132725-appb-000197
Reagent (Promega G7573), mixed for 2 minutes, incubated at room temperature for 60 minutes, the luminescence value was read by EnVision RMultilabel Reader, and the IC 50 of the compound was calculated by GraphPad Prism 5.0 software.
测试方法(3)Test method(3)
Western Blot protocolWestern Blot protocol
细胞铺板：Cell plating:
1.将处于对数生长期的细胞重新悬浮于生长培养基并稀释至目标密度。将上述细胞悬浮液按照每孔2ml接种至6孔板中，在37℃，5％CO 2培养箱中孵育过夜。 1. Resuspend cells in log phase growth medium in growth medium and dilute to target density. The above cell suspension was seeded into a 6-well plate at 2 ml per well, and incubated overnight at 37°C in a 5% CO2 incubator.
2.将待测化合物溶解在DMSO中，配制成浓度为10mM的储备液。首先用DMSO将储备液分别稀释至3mM，2mM，1mM，然后用生长培养基分别稀释至150μM，100μM，50μM。弃去6孔板培养基，加入200μl稀释化合物使6孔板体积为2ml。37℃，5％CO 2培养箱中分别孵育8小时，24小时，48小时。 2. Dissolve the test compound in DMSO to prepare a stock solution with a concentration of 10 mM. The stock solutions were first diluted with DMSO to 3 mM, 2 mM, 1 mM, and then diluted with growth medium to 150 μM, 100 μM, and 50 μM, respectively. The 6-well plate medium was discarded and 200 μl of diluted compound was added to bring the 6-well plate volume to 2 ml. Incubate in a 37°C, 5% CO 2 incubator for 8 hours, 24 hours, and 48 hours, respectively.
样品制备(8小时、24小时、48小时)Sample preparation (8 hours, 24 hours, 48 hours)
1.将6孔板平衡到室温。1. Equilibrate the 6-well plate to room temperature.
2.用150μL含蛋白酶/磷酸酶抑制剂的RIPA裂解缓冲液重悬细胞，将样品置于冰中孵育30分钟以完成细胞裂解。2. Resuspend cells in 150 μL of RIPA lysis buffer containing protease/phosphatase inhibitors and incubate samples on ice for 30 minutes to complete cell lysis.
3.样品13000rpm,4℃，离心10分钟,去沉淀。BCA定量，用4X上样缓冲液制备蛋白样品，95℃水浴煮沸15分钟。3. The sample was centrifuged at 13000rpm, 4°C for 10 minutes to remove the sediment. For BCA quantification, protein samples were prepared with 4X loading buffer and boiled in a 95°C water bath for 15 minutes.
WB实验步骤WB experimental procedure
1.将15μL细胞裂解液加入SDS-PAGE凝胶中，200v电泳40分钟，直到蓝色条带脱离凝胶。1. Add 15 μL of cell lysate to the SDS-PAGE gel and electrophoresis at 200v for 40 minutes until the blue band breaks off the gel.
2.使用电转移将凝胶转至PVDF膜(2.5A,3分钟)。2. Transfer the gel to a PVDF membrane using electrotransfer (2.5A, 3 minutes).
3.用5％BSA缓冲液将PVDF膜室温下孵育1小时。3. Incubate the PVDF membrane with 5% BSA buffer for 1 hour at room temperature.
4.一抗孵育:稀释抗体KRAS(1:1000)和a-tubulin(1:1000)，4℃过夜。4. Primary antibody incubation: Dilute antibodies KRAS (1:1000) and a-tubulin (1:1000) at 4°C overnight.
5.二抗孵育:以1:3000的比例稀释抗体，室温孵育1小时。5. Secondary antibody incubation: Dilute the antibody at a ratio of 1:3000 and incubate at room temperature for 1 hour.
6.使用Westem ECL显影液显影。6. Use Western ECL developer to develop.
蛋白降解的结果如表1所示。The results of protein degradation are shown in Table 1.
表1Table 1
Figure PCTCN2021132725-appb-000198
Figure PCTCN2021132725-appb-000198
Figure PCTCN2021132725-appb-000199
Figure PCTCN2021132725-appb-000199
Figure PCTCN2021132725-appb-000200
Figure PCTCN2021132725-appb-000200
Figure PCTCN2021132725-appb-000201
Figure PCTCN2021132725-appb-000201

Claims (13)

  1. 一种如式A所示化合物或其药学上可接受的盐，A compound of formula A or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021132725-appb-100001
    Figure PCTCN2021132725-appb-100001
    其中，in,
    Z为O或NR 5； Z is O or NR 5 ;
    R 5为C 1-C 6烷基、
    Figure PCTCN2021132725-appb-100002
    被R 5-5取代或未取代的C 2-C 6烯基、
    Figure PCTCN2021132725-appb-100003
    R 5 is C 1 -C 6 alkyl,
    Figure PCTCN2021132725-appb-100002
    C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 ,
    Figure PCTCN2021132725-appb-100003
    R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为氢、被R 5-1a取代或未取代的C 1-C 6烷基、被R 5-2a取代或未取代的C 2-C 6烯基、C 2-C 6炔基或C 1-C 6烷氧基； R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently hydrogen, R 5-1a substituted or unsubstituted C 1 -C 6 alkanes group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-2a ;
    R 5-5为氰基或卤素； R 5-5 is cyano or halogen;
    R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
    R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
    R 5-2a为C 1-C 6烷基、氰基或卤素； R 5-2a is C 1 -C 6 alkyl, cyano or halogen;
    R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
    R 2为OR 2-1、被R 2-2取代或未取代的C 6-C 15芳基或被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 2 is OR 2-1 , a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , or a "heteroatom substituted or unsubstituted by R 2-3 selected from one of N, O and S" or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
    R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基； R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
    R 2-2、R 2-3和R 2-1a独立地为羟基、卤素、氨基、C 1-C 6烷基、C 1-C 6烷氧基、
    Figure PCTCN2021132725-appb-100004
    Figure PCTCN2021132725-appb-100005
    R 2-2 , R 2-3 and R 2-1a are independently hydroxy, halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
    Figure PCTCN2021132725-appb-100004
    Figure PCTCN2021132725-appb-100005
    R 2-2a和R 2-2b独立地为被R 2-2a-1取代或未取代的C 1-C 6烷基； R 2-2a and R 2-2b are independently C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 ;
    R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基； R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a ;
    R 2-2a-1a为C 1-C 6烷氧基； R 2-2a-1a is C 1 -C 6 alkoxy;
    R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
    R 3-1和R 3-2独立地为羟基、氰基、氨基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-L-R 3-1a； R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
    -L-为
    Figure PCTCN2021132725-appb-100006
    Figure PCTCN2021132725-appb-100007
    a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接；     -L- for
    Figure PCTCN2021132725-appb-100006
    Figure PCTCN2021132725-appb-100007
    The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
    n1、n2、n3、n4、n5、n6和n7独立地为0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;
    m1和m2独立地为0、1、2、3、4或5；m1 and m2 are independently 0, 1, 2, 3, 4 or 5;
    环D为C 3-C 6环烷烃、“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环、C 6-C 10芳环或“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环； Ring D is a C 3 -C 6 cycloalkane, a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3", C 6 - A C 10 aromatic ring or a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
    R 3-1a为E3连接酶的配体，其结构例如可为
    Figure PCTCN2021132725-appb-100008
    R 3-1a is the ligand of E3 ligase, and its structure can be, for example,
    Figure PCTCN2021132725-appb-100008
    R 3-1a-1和R 3-1a-2独立地可为氢、C 1-C 6烷基、
    Figure PCTCN2021132725-appb-100009
    Figure PCTCN2021132725-appb-100010
    R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl,
    Figure PCTCN2021132725-appb-100009
    Figure PCTCN2021132725-appb-100010
    环A可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环；Ring A can be a 5-6 membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
    环B可为C 6-C 10芳环； Ring B can be a C 6 -C 10 aromatic ring;
    环C可为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环；Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";
    R a、R b、R c、R d和R e独立地为氢、羟基或C 1-C 6烷基； R a , R b , R c , R d and Re are independently hydrogen, hydroxy or C 1 -C 6 alkyl;
    o1、o2和o3独立地为0、1、2、3或4；o1, o2 and o3 are independently 0, 1, 2, 3 or 4;
    R 4为卤素、OCH 3、OH、CN、CONH 2或COOH； R 4 is halogen, OCH 3 , OH, CN, CONH 2 or COOH;
    R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2的个数独立地为1、2、3、4或5个，当为2、3、4或5个时，R 5-1a、R 5-1a-1、R 2-2、R 2-1a、R 2-2a-1、R 2-2a-1a、R 3-1和R 3-2独立地相同或不同。 The numbers of R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 are independently 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a -1 , R 2-2a-1a , R 3-1 and R 3-2 are independently the same or different.
  2. 如权利要求1所述的如式A所示化合物或其药学上可接受的盐，其特征在于，The compound of formula A or its pharmaceutically acceptable salt according to claim 1, wherein,
    所述的如式A所示化合物为如式I或式I’所示的化合物，The compound shown in the formula A is the compound shown in the formula I or the formula I',
    Figure PCTCN2021132725-appb-100011
    Figure PCTCN2021132725-appb-100011
    其中，标“*”的碳原子为S构型碳原子、R构型碳原子或非手性碳原子；R 1、R 2、R 3、R 4和Z的定义如权利要求1所示。 Wherein, the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms; the definitions of R 1 , R 2 , R 3 , R 4 and Z are as shown in claim 1 .
  3. 如权利要求1所述的如式A所示化合物或其药学上可接受的盐，其特征在于，The compound of formula A or its pharmaceutically acceptable salt according to claim 1, wherein,
    Figure PCTCN2021132725-appb-100012
    为
    Figure PCTCN2021132725-appb-100013
    R 1为C 1-C 6烷基；
    Figure PCTCN2021132725-appb-100012
    for
    Figure PCTCN2021132725-appb-100013
    R 1 is C 1 -C 6 alkyl;
    和/或，当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 5 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tert-butyl;
    和/或，当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的R 5-5的个数为1、2或3个； And/or, when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the number of said R 5-5 is 1, 2 or 3;
    和/或，当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的C 2-C 6烯基为C 2-C 4烯基； And/or, when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl is a C 2 -C 4 alkenyl;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，R 5-1a的个数独立地为1、2或3个； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 - substituted or unsubstituted by R 5-1a When C 6 alkyl, the number of R 5-1a is independently 1, 2 or 3;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 - substituted or unsubstituted by R 5-1a When C 6 alkyl, the C 1 -C 6 alkyl is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的R 5-2a的个数为1、2或3个； And/or, when R 5-1 is C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the number of said R 5-2a is 1, 2 or 3;
    和/或，当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的烯基为C 2-C 4烯基； And/or, when R 5-1 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the alkenyl is a C 2 -C 4 alkenyl;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 2-C 6炔基时，所述的C 2-C 6炔基为C 2-C 4炔基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl, the Described C 2 -C 6 alkynyl is C 2 -C 4 alkynyl;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基独立地为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy, The C 1 -C 6 alkoxy groups are independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy ;
    和/或，当R 5-5为卤素时，所述的卤素为氟、氯、溴或碘； And/or, when R 5-5 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，R 4-1a-1的个数为1、2或3个； And/or, when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1, the number of R 4-1a-1 is 1, 2 or 3;
    和/或，当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 , the C 1 -C 6 alkoxy is methoxy, ethoxy group, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 5-1a-1为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 5-1a-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 5-2a为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 5-2a is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 5-2a为卤素时，所述的卤素为氟、氯、溴或碘； And/or, when R 5-2a is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 1为C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，R 2-2的个数为1、2、3或4个； And/or, when R 2 is a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , the number of R 2-2 is 1, 2, 3 or 4;
    和/或，当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为C 6-C 10芳基； And/or, when R 2 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-2 , the C 6 -C 15 aryl group is a C 6 -C 10 aryl group;
    和/或，当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 2-3的个数为1、2、3或4个； And/or, when R 2 is substituted or unsubstituted by R 2-3 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the number of R 2-3 is 1, 2, 3 or 4;
    和/或，当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基为“杂原子选自N、O和S中 的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基； And/or, when R 2 is substituted or unsubstituted by R 2-3 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered Heteroaryl is a 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"base;
    和/或，当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，R 2-1a的个数为1、2、3或4个； And/or, when R 2-1 is a C 6 -C 15 aryl substituted or unsubstituted by R 2-1a , the number of R 2-1a is 1, 2, 3 or 4;
    和/或，当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为C 6-C 10芳基； And/or, when R 2-1 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-1a , the C 6 -C 15 aryl group is a C 6 -C 10 aryl group;
    和/或，当R 2-2为卤素时，所述的卤素为氟、氯、溴或碘； And/or, when R 2-2 is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2-2为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 2-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-propoxy butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 2-1a为卤素时，所述的卤素为氟、氯、溴或碘； And/or, when R 2-1a is halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R 2-1a为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 2-1a is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 2-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 2-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-propoxy butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数为1、2或3个； And/or, when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 is 1, 2 or 3;
    和/或，当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 2-2a is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl group is methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，R 2-2a-1的个数为1、2或3个； And/or, when R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a -1 , the number of R 2-2a-1 is 1, 2 or 3;
    和/或，当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 2-2b is C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl group is methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，R 2-2a-1a的个数为1、2或3个； And/or, when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a -1a , the number of R 2-2a-1a is 1, 2 or 3 ;
    和/或，当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 2-2a-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 2-2a-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，R 3-1的个数为1、2、3或4个； And/or, when R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , the number of R 3-1 is 1, 2, 3 or 4;
    和/或，当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为C 6-C 10 芳基； And/or, when R 3 is a C 6 -C 15 aryl group substituted or unsubstituted by R 3-1 , the C 6 -C 15 aryl group is a C 6 -C 10 aryl group;
    和/或，当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，R 3-2的个数为1、2、3或4个； And/or, when R 3 is substituted or unsubstituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the number of R 3-2 is 1, 2, 3 or 4;
    和/或，当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基或双环杂芳基； And/or, when R 3 is substituted or unsubstituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered Heteroaryl is a 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"base;
    和/或，当R 3-1为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 3-1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 3-1为C 1-C 6烷氧基时，所述的C 1-C 6烷基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 3-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkyl group is methoxy, ethoxy, propoxy, isopropoxy, n-butyl oxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当R 3-2为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 3-2 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl;
    和/或，当R 3-2为C 1-C 6烷氧基时，所述的C 1-C 6烷基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； And/or, when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkyl group is methoxy, ethoxy, propoxy, isopropoxy, n-butyl oxy, isobutoxy, sec-butoxy or tert-butoxy;
    和/或，当环D为C 3-C 6环烷烃时，所述的C 3-C 6环烷烃为环丙烷、环丁烷、环戊烷或环己烷； And/or, when Ring D is C 3 -C 6 cycloalkane, the C 3 -C 6 cycloalkane is cyclopropane, cyclobutane, cyclopentane or cyclohexane;
    和/或，当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-6元杂环；And/or, when Ring D is a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "hetero-atom is 1-3". Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3. The 3-10-membered heterocyclic ring is "the heteroatoms are selected from one or more of N, O and S. Species, the number of heteroatoms is 1-3" 3-6 membered heterocycle;
    和/或，当环D为C 6-C 10芳环时，所述的C 6-C 10芳环为苯环或萘环； And/or, when Ring D is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring;
    和/或，当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-6元杂芳环；And/or, when Ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the " The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3. The 5-10-membered heteroaromatic ring is "the heteroatom is selected from one of N, O and S". or more, the number of heteroatoms is 1-3" 5-6 membered heteroaromatic ring;
    和/或，当R 3-1a-1为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 3-1a-1 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl or tert-butyl;
    和/或，当R 3-1a-2为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 3-1a-2 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl or tert-butyl;
    和/或，环A中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2 个”的5-6元杂环烷基为“杂原子选自N，杂原子个数为1-2个”的5-6元杂环烷基；And/or, in Ring A, the 5-6 membered heterocycloalkyl of "heteroatoms selected from N, O and S, and the number of heteroatoms is 1-2" is " The heteroatom is selected from N, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl;
    和/或，环B中，所述的C 6-C 10芳环为苯环或萘环； And/or, in ring B, the C 6 -C 10 aromatic ring is a benzene ring or a naphthalene ring;
    和/或，环C中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环或双环杂芳环；And/or, in ring C, the 5-10-membered heteroaromatic ring of "heteroatoms is selected from N, O and S, and the number of heteroatoms is 1-3" is "heteroaromatic". The atom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring;
    和/或，当R a、R b、R c、R d和R e独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当R 4为卤素时，所述的卤素为氟、氯、溴或碘。 And/or, when R4 is halogen, said halogen is fluorine, chlorine, bromine or iodine.
  4. 如权利要求3所述的如式A所示化合物或其药学上可接受的盐，其特征在于，The compound of formula A or its pharmaceutically acceptable salt as claimed in claim 3, characterized in that,
    当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基； When R 5 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a methyl group;
    和/或，当R 5为被R 5-5取代或未取代的C 2-C 6烯基时，所述的C 2-C 6烯基为
    Figure PCTCN2021132725-appb-100014
    Figure PCTCN2021132725-appb-100015
    And/or, when R 5 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-5 , the C 2 -C 6 alkenyl is
    Figure PCTCN2021132725-appb-100014
    Figure PCTCN2021132725-appb-100015
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为被R 5-1a取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基或叔丁基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 - substituted or unsubstituted by R 5-1a When C 6 alkyl, the C 1 -C 6 alkyl is independently methyl, ethyl or tert-butyl;
    和/或，当R 5-1为被R 5-2a取代或未取代的C 2-C 6烯基时，所述的烯基为乙烯基； And/or, when R 5-1 is a C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , the alkenyl is vinyl;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 2-C 6炔基时，所述的C 2-C 6炔基为乙炔基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 2 -C 6 alkynyl, the Described C 2 -C 6 alkynyl is ethynyl;
    和/或，当R 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7独立地为独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基独立地为甲氧基； and/or, when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 and R 5-7 are independently C 1 -C 6 alkoxy, The C 1 -C 6 alkoxy groups are independently methoxy groups;
    和/或，当R 5-5为卤素时，所述的卤素为氟； And/or, when R 5-5 is halogen, the halogen is fluorine;
    和/或，当R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基或乙氧基； And/or, when R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 , the C 1 -C 6 alkoxy is methoxy or ethoxy base;
    和/或，当R 5-1a-1为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基； And/or, when R 5-1a-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy;
    和/或，当R 5-2a为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基； And/or, when R 5-2a is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a methyl group;
    和/或，当R 5-2a为卤素时，所述的卤素为氟； And/or, when R 5-2a is halogen, the halogen is fluorine;
    和/或，当R 1为C 1-C 6烷基时，所述的C 1-C 6烷基可独立地为甲基； And/or, when R 1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group may independently be a methyl group;
    和/或，当R 2为被R 2-2取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为苯基或萘基； And/or, when R 2 is a C 6 -C 15 aryl group substituted or unsubstituted by R 2-2 , the C 6 -C 15 aryl group is phenyl or naphthyl;
    和/或，当R 2为被R 2-3取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基，所述的“杂原子选自N、O和S中的一种 或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基为“杂原子选自N，杂原子个数为1-2个”的5-6元单环杂芳基，优选吡啶基，例如
    Figure PCTCN2021132725-appb-100016
    或“杂原子选自N，杂原子个数为1-2个”的8-10元双环杂芳基，优选吲唑基，例如
    Figure PCTCN2021132725-appb-100017
    And/or, when R 2 is substituted or unsubstituted by R 2-3 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" The 5-15-membered heteroaryl group, the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups When the aryl group is a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4", the said "The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4". The 5-15-membered monocyclic heteroaryl group is "the heteroatom is selected from N, A 5-6 membered monocyclic heteroaryl group with 1-2" heteroatoms, preferably a pyridyl group, such as
    Figure PCTCN2021132725-appb-100016
    Or "heteroatoms are selected from N, the number of heteroatoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as
    Figure PCTCN2021132725-appb-100017
    和/或，当R 2-1为被R 2-1a取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为苯基或萘基； And/or, when R 2-1 is a substituted or unsubstituted C 6 -C 15 aryl group by R 2-1a , the C 6 -C 15 aryl group is phenyl or naphthyl;
    和/或，当R 2-2为卤素时，所述的卤素为氟或氯； And/or, when R 2-2 is halogen, the halogen is fluorine or chlorine;
    和/或，当R 2-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基； And/or, when R 2-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy;
    和/或，当R 2-1a为卤素时，所述的卤素为氟或氯； And/or, when R 2-1a is halogen, the halogen is fluorine or chlorine;
    和/或，当R 2-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基； And/or, when R 2-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy may be methoxy;
    和/或，当R 2-2a为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基为甲基或乙基； And/or, when R 2-2a is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl group is methyl or ethyl;
    和/或，当R 2-2b为被R 2-2a-1取代或未取代的C 1-C 6烷基时，所述的C 1-C 6烷基为甲基或乙基； And/or, when R 2-2b is a C 1 -C 6 alkyl substituted or unsubstituted by R 2-2a-1 , the C 1 -C 6 alkyl group is methyl or ethyl;
    和/或，当R 2-2a-1为被R 2-2a-1a取代或未取代的C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基或乙氧基； And/or, when R 2-2a-1 is C 1 -C 6 alkoxy substituted or unsubstituted by R 2-2a-1a , the C 1 -C 6 alkoxy is methoxy or ethoxy;
    和/或，当R 2-2a-1a为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为甲氧基； And/or, when R 2-2a-1a is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is methoxy;
    和/或，当R 3为被R 3-1取代或未取代的C 6-C 15芳基时，所述的C 6-C 15芳基为苯基或萘基； And/or, when R 3 is a C 6 -C 15 aryl group substituted or unsubstituted by R 3-1 , the C 6 -C 15 aryl group is phenyl or naphthyl;
    和/或，当R 3为被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基为“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元单环杂芳基为“杂原子选自N，杂原子个数为1-2个”的5-6元单环杂芳基，优选吡啶基，例如
    Figure PCTCN2021132725-appb-100018
    And/or, when R 3 is substituted or unsubstituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" The 5-15-membered heteroaryl group, the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups When the aryl group is a 5-15-membered monocyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4", the said "The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4". The 5-15-membered monocyclic heteroaryl group is "the heteroatom is selected from N, A 5-6 membered monocyclic heteroaryl group with 1-2" heteroatoms, preferably a pyridyl group, such as
    Figure PCTCN2021132725-appb-100018
    和/或，当R 3-1为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基或异丙基； And/or, when R 3-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl or isopropyl;
    和/或，当R 3-1为C 1-C 6烷氧基时，所述的C 1-C 6烷基为甲氧基； And/or, when R 3-1 is a C 1 -C 6 alkoxy group, the C 1 -C 6 alkyl group is a methoxy group;
    和/或，当R 3-2为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基或异丙基； And/or, when R 3-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl or isopropyl;
    和/或，当R 3-2为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基可为甲氧基； And/or, when R 3-2 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy may be methoxy;
    和/或，当环D为C 3-C 6环烷基时，所述的C 3-C 6环烷基为环己烷，
    Figure PCTCN2021132725-appb-100019
    例如为
    Figure PCTCN2021132725-appb-100020
    And/or, when Ring D is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclohexane,
    Figure PCTCN2021132725-appb-100019
    for example
    Figure PCTCN2021132725-appb-100020
    和/或，当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的3-10元杂环为四氢呋喃、哌啶或哌嗪，
    Figure PCTCN2021132725-appb-100021
    例如为
    Figure PCTCN2021132725-appb-100022
    Figure PCTCN2021132725-appb-100023
    And/or, when Ring D is a 3-10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "hetero-atom is 1-3". The atom is selected from one or more of N, O and S, and the 3-10-membered heterocyclic ring with 1-3" heteroatoms is tetrahydrofuran, piperidine or piperazine,
    Figure PCTCN2021132725-appb-100021
    for example
    Figure PCTCN2021132725-appb-100022
    Figure PCTCN2021132725-appb-100023
    和/或，当环D为C 6-C 10芳环时，所述的C 6-C 10芳环为苯环，
    Figure PCTCN2021132725-appb-100024
    例如为
    Figure PCTCN2021132725-appb-100025
    And/or, when ring D is a C 6 -C 10 aromatic ring, the C 6 -C 10 aromatic ring is a benzene ring,
    Figure PCTCN2021132725-appb-100024
    for example
    Figure PCTCN2021132725-appb-100025
    和/或，当环D为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环为吡啶环或吡嗪环，
    Figure PCTCN2021132725-appb-100026
    例如为
    Figure PCTCN2021132725-appb-100027
    Figure PCTCN2021132725-appb-100028
    And/or, when Ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the " The heteroatom is selected from one or more of N, O and S, and the 5-10-membered heteroaromatic ring with 1-3" heteroatoms is a pyridine ring or a pyrazine ring,
    Figure PCTCN2021132725-appb-100026
    for example
    Figure PCTCN2021132725-appb-100027
    Figure PCTCN2021132725-appb-100028
    和/或，环A中，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-2个”的5-6元杂环为四氢吡咯，
    Figure PCTCN2021132725-appb-100029
    例如为
    Figure PCTCN2021132725-appb-100030
    And/or, in Ring A, the 5-6 membered heterocycle of the "heteroatoms selected from N, O and S, and the number of heteroatoms is 1-2" is tetrahydropyrrole ,
    Figure PCTCN2021132725-appb-100029
    for example
    Figure PCTCN2021132725-appb-100030
    和/或，环B中，所述的C 6-C 10芳环可为苯环，
    Figure PCTCN2021132725-appb-100031
    例如为
    Figure PCTCN2021132725-appb-100032
    And/or, in ring B, the C 6 -C 10 aromatic ring can be a benzene ring,
    Figure PCTCN2021132725-appb-100031
    for example
    Figure PCTCN2021132725-appb-100032
    和/或，环C中，当所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元杂芳环为“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个” 的5-10元单环杂芳环时，所述的“杂原子选自N、O和S中的一种或多种，杂原子个数为1-3个”的5-10元单环杂芳环为“杂原子选自N和S中的一种或多种，杂原子个数为1-2个”的5-6元单环杂芳环，优选噻唑环，
    Figure PCTCN2021132725-appb-100033
    例如为
    Figure PCTCN2021132725-appb-100034
    And/or, in Ring C, when the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the 5-10-membered heteroaromatic ring is " The heteroatom is selected from one or more of N, O and S, and when the number of heteroatoms is 1-3" of a 5-10 membered monocyclic heteroaromatic ring, the "heteroatom is selected from N, O" And one or more of S, the number of heteroatoms is 1-3" and the 5-10-membered monocyclic heteroaromatic ring is "the heteroatom is selected from one or more of N and S, and the heteroatoms are A 5-6 membered monocyclic heteroaromatic ring with a number of 1-2", preferably a thiazole ring,
    Figure PCTCN2021132725-appb-100033
    for example
    Figure PCTCN2021132725-appb-100034
    和/或，当R a、R b、R c、R d和R e独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基或叔丁基； and/or, when R a , R b , R c , R d and R e are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl or tert-butyl;
    和/或，当R 4为卤素时，所述的卤素为氟。 And/or, when R4 is halogen, said halogen is fluorine.
  5. 如权利要求4所述的如式A所示化合物或其药学上可接受的盐，其特征在于，The compound of formula A or its pharmaceutically acceptable salt as claimed in claim 4, characterized in that,
    R 5为甲基、
    Figure PCTCN2021132725-appb-100035
    Figure PCTCN2021132725-appb-100036
    R 5 is methyl,
    Figure PCTCN2021132725-appb-100035
    Figure PCTCN2021132725-appb-100036
    和/或，R 1为氢或甲基； and/or, R 1 is hydrogen or methyl;
    和/或，R 2-2和R 2-1a独立地可为-OH、-F、-Cl、-NH 2或-OMe； and/or, R 2-2 and R 2-1a independently can be -OH, -F, -Cl, -NH 2 or -OMe;
    和/或，R 2-1为
    Figure PCTCN2021132725-appb-100037
    and/or, R 2-1 is
    Figure PCTCN2021132725-appb-100037
    和/或，-L-为
    Figure PCTCN2021132725-appb-100038
    Figure PCTCN2021132725-appb-100039
    Figure PCTCN2021132725-appb-100040
    a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接；     and/or, -L- for
    Figure PCTCN2021132725-appb-100038
    Figure PCTCN2021132725-appb-100039
    Figure PCTCN2021132725-appb-100040
    The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
    和/或，R 3-1a为
    Figure PCTCN2021132725-appb-100041
    and/or, R 3-1a is
    Figure PCTCN2021132725-appb-100041
  6. 如权利要求5所述的如式A所示化合物或其药学上可接受的盐，其特征在于，The compound of formula A or its pharmaceutically acceptable salt as claimed in claim 5, characterized in that,
    Figure PCTCN2021132725-appb-100042
    为
    Figure PCTCN2021132725-appb-100043
    Figure PCTCN2021132725-appb-100044
    Figure PCTCN2021132725-appb-100042
    for
    Figure PCTCN2021132725-appb-100043
    Figure PCTCN2021132725-appb-100044
    和/或，R 2为
    Figure PCTCN2021132725-appb-100045
    Figure PCTCN2021132725-appb-100046
    and/or, R2 is
    Figure PCTCN2021132725-appb-100045
    Figure PCTCN2021132725-appb-100046
    和/或，R 3为
    Figure PCTCN2021132725-appb-100047
    Figure PCTCN2021132725-appb-100048
    and/or, R3 is
    Figure PCTCN2021132725-appb-100047
    Figure PCTCN2021132725-appb-100048
    和/或，所述的E3连接酶为VHL、CRBN、MDM2、cIAP、Cereblon、XIAP、E3A、APC、UBR5(EDD1)、SOCS/BC-box/eloBC/CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、 UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box蛋白15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、Mind Bomb 1/MIB1、Mind Bomb 2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5或ZNRF3，优选VHL、CRBN、MDM2或cIAP。And/or, described E3 ligase is VHL, CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, APC, UBR5(EDD1), SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54, β-TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-box protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP-2/HIAP-1, cIAP(pan), ITCH/AIP4 , KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF -2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, preferably VHL, CRBN, MDM2 or cIAP.
  7. 如权利要求1所述的如式A所示化合物或其药学上可接受的盐，其特征在于，当R 1为C 1-C 6烷基时，与R 1相连的C原子的构型为S构型； The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R 1 is a C 1 -C 6 alkyl group, the configuration of the C atom connected to R 1 is S configuration;
    和/或，R 4为F； and/or, R4 is F ;
    和/或，R 3为
    Figure PCTCN2021132725-appb-100049
    Figure PCTCN2021132725-appb-100050
    and/or, R3 is
    Figure PCTCN2021132725-appb-100049
    Figure PCTCN2021132725-appb-100050
    和/或，Z为NR 5 and/or, Z is NR 5
    和/或，R 5为
    Figure PCTCN2021132725-appb-100051
    优选R 5为
    Figure PCTCN2021132725-appb-100052
    更优选R 5为
    Figure PCTCN2021132725-appb-100053
    and/or, R5 is
    Figure PCTCN2021132725-appb-100051
    Preferably R 5 is
    Figure PCTCN2021132725-appb-100052
    More preferably R5 is
    Figure PCTCN2021132725-appb-100053
    和/或，R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基，优选R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基，更优选R 5-1为C 2-C 6烯基； And/or, R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a , preferably R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a , more preferably R 5-1 is C 2 -C 6 alkenyl;
    和/或，R 5-2为C 1-C 6烷基； And/or, R 5-2 is C 1 -C 6 alkyl;
    和/或，R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； And/or, R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
    和/或，R 1为氢； and/or, R 1 is hydrogen;
    和/或，R 2为被R 2-2取代或未取代的C 6-C 15芳基，优选R 2为被R 2-2取代的C 6-C 15芳基； And/or, R 2 is a C 6 -C 15 aryl substituted or unsubstituted by R 2-2 , preferably R 2 is a C 6 -C 15 aryl substituted by R 2-2 ;
    和/或，R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基，优选R 2-2为羟基、卤素或氨基，更优选R 2-2为羟基或卤素； And/or, R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy, preferably R 2-2 is hydroxyl, halogen or amino, more preferably R 2-2 is hydroxyl or halogen;
    和/或，R 2-1a为卤素； and/or, R 2-1a is halogen;
    和/或，R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基，优选R 3可为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； And/or, R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S, and a hetero atom substituted by R 3-2 . The number is 1, 2, 3 or 4" 5-15-membered heteroaryl group, preferably R 3 can be substituted by R 3-2 "heteroatom is selected from one or more of N, O and S , the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl;
    和/或，R 3-1和R 3-2独立地为C 1-C 6烷基或-L-R 3-1a，优选R 3-1和R 3-2独立地为C 1-C 6烷基，更优选R 3-1和R 3-2独立地为甲基或异丙基； And/or, R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a , preferably R 3-1 and R 3-2 are independently C 1 -C 6 alkyl , more preferably R 3-1 and R 3-2 are independently methyl or isopropyl;
    和/或，-L-为
    Figure PCTCN2021132725-appb-100054
    a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接；     and/or, -L- for
    Figure PCTCN2021132725-appb-100054
    The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
    和/或，n1为0、1、2、3、4、5或6；and/or, n1 is 0, 1, 2, 3, 4, 5 or 6;
    和/或，m1为0、1、2或3；and/or, m1 is 0, 1, 2 or 3;
    和/或，R 3-1a为
    Figure PCTCN2021132725-appb-100055
    and/or, R 3-1a is
    Figure PCTCN2021132725-appb-100055
    和/或，R 3-1a-1和R 3-1a-2独立地为氢或
    Figure PCTCN2021132725-appb-100056
    and/or, R 3-1a-1 and R 3-1a-2 are independently hydrogen or
    Figure PCTCN2021132725-appb-100056
    和/或，R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同。 And/or, the number of R 3-1 and R 3-2 is two, and R 3-1 and R 3-2 are different.
  8. 如权利要求1所述的如式A所示化合物或其药学上可接受的盐，其特征在于，所述的如式A所示化合物为如下任一方案，The compound represented by formula A or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound represented by formula A is any of the following schemes,
    方案1：plan 1:
    R 4为F； R 4 is F;
    Z为NR 5； Z is NR 5 ;
    R 5为
    Figure PCTCN2021132725-appb-100057
     R5 is
    Figure PCTCN2021132725-appb-100057
    R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基、C 2-C 6烯基或C 1-C 6烷氧基； R 5-1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
    R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
    R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
    R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
    R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
    R 1为氢或C 1-C 6烷基； R 1 is hydrogen or C 1 -C 6 alkyl;
    R 2为被R 2-2取代或未取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
    R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
    R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
    R 3-1和R 3-2独立地为C 1-C 6烷基或-L-R 3-1a； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl or -LR 3-1a ;
    -L-为
    Figure PCTCN2021132725-appb-100058
    a端与R 3-1a相连接，b端与C 6-C 15芳基或“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基相连接；     -L- for
    Figure PCTCN2021132725-appb-100058
    The a terminal is connected to R 3-1a , the b terminal is connected to a C 6 -C 15 aryl group or a "heteroatom selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl groups are connected;
    n1为0、1、2、3、4、5或6；n1 is 0, 1, 2, 3, 4, 5 or 6;
    m1为0、1、2或3；m1 is 0, 1, 2 or 3;
    R 3-1a为
    Figure PCTCN2021132725-appb-100059
    R 3-1a is
    Figure PCTCN2021132725-appb-100059
    R 3-1a-1和R 3-1a-2独立地为氢或
    Figure PCTCN2021132725-appb-100060
    R 3-1a-1 and R 3-1a-2 are independently hydrogen or
    Figure PCTCN2021132725-appb-100060
    方案2：Scenario 2:
    R 4为F； R 4 is F;
    Z为NR 5； Z is NR 5 ;
    R 5为
    Figure PCTCN2021132725-appb-100061
     R5 is
    Figure PCTCN2021132725-appb-100061
    R 5-1为被R 5-1a取代或未取代的C 1-C 6烷基或C 2-C 6烯基； R 5-1 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl substituted or unsubstituted by R 5-1a ;
    R 5-2为C 1-C 6烷基； R 5-2 is C 1 -C 6 alkyl;
    R 5-3和R 5-4独立地为氢、或被R 5-1a取代或未取代的C 1-C 6烷基； R 5-3 and R 5-4 are independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a ;
    R 5-1a为被R 5-1a-1取代或未取代的C 1-C 6烷氧基； R 5-1a is C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a-1 ;
    R 5-1a-1为C 1-C 6烷氧基； R 5-1a-1 is C 1 -C 6 alkoxy;
    R 1为氢； R 1 is hydrogen;
    R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
    R 2-2为羟基、卤素、氨基或C 1-C 6烷氧基； R 2-2 is hydroxyl, halogen, amino or C 1 -C 6 alkoxy;
    R 3为被R 3-1取代或未取代的C 6-C 15芳基、或被R 3-2取代或未取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl substituted or unsubstituted by R 3-1 , or a "hetero atom substituted or unsubstituted by R 3-2 is selected from one or more of N, O and S, 5-15-membered heteroaryl with 1, 2, 3 or 4"heteroatoms;
    R 3-1和R 3-2独立地为C 1-C 6烷基； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl;
    方案3：Scenario 3:
    R 4为F； R 4 is F;
    Z为NR 5； Z is NR 5 ;
    R 5为
    Figure PCTCN2021132725-appb-100062
     R5 is
    Figure PCTCN2021132725-appb-100062
    R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
    R 1为氢； R 1 is hydrogen;
    R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
    R 2-2为羟基、卤素或氨基； R 2-2 is hydroxyl, halogen or amino;
    R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
    R 3-1和R 3-2独立地为C 1-C 6烷基； R 3-1 and R 3-2 are independently C 1 -C 6 alkyl;
    R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同； The number of R 3-1 and R 3-2 is 2, and R 3-1 and R 3-2 are different;
    方案4：Scenario 4:
    R 4为F； R 4 is F;
    Z为NR 5； Z is NR 5 ;
    R 5为
    Figure PCTCN2021132725-appb-100063
     R5 is
    Figure PCTCN2021132725-appb-100063
    R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
    R 1为氢； R 1 is hydrogen;
    R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
    R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
    R 3为被R 3-1取代的C 6-C 15芳基、或被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a C 6 -C 15 aryl group substituted by R 3-1 , or a "heteroatom selected from one or more of N, O and S" substituted by R 3-2 , and the number of hetero atoms is 1 , 2, 3 or 4" 5-15-membered heteroaryl;
    R 3-1和R 3-2独立地为甲基或异丙基； R 3-1 and R 3-2 are independently methyl or isopropyl;
    R 3-1和R 3-2的个数为2个，且R 3-1和R 3-2不同； The number of R 3-1 and R 3-2 is 2, and R 3-1 and R 3-2 are different;
    方案5：Scenario 5:
    R 4为F； R 4 is F;
    Z为NR 5； Z is NR 5 ;
    R 5为
    Figure PCTCN2021132725-appb-100064
     R5 is
    Figure PCTCN2021132725-appb-100064
    R 5-1为C 2-C 6烯基； R 5-1 is C 2 -C 6 alkenyl;
    R 1为氢； R 1 is hydrogen;
    R 2为被R 2-2取代的C 6-C 15芳基； R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
    R 2-2为羟基或卤素； R 2-2 is hydroxyl or halogen;
    R 3为被R 3-2取代的“杂原子选自N、O和S中的一种或多种，杂原子个数为1、2、3或4个”的5-15元杂芳基； R 3 is a 5-15-membered heteroaryl group substituted by R 3-2 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";
    R 3-2为C 1-C 6烷基。 R 3-2 is C 1 -C 6 alkyl.
  9. 如权利要求1-8中任一项所述的如式A所示化合物或其药学上可接受的盐，其特征在于，所述的如式A所示化合物为如下任一结构，The compound represented by formula A or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein the compound represented by formula A is any of the following structures,
    Figure PCTCN2021132725-appb-100065
    Figure PCTCN2021132725-appb-100065
    Figure PCTCN2021132725-appb-100066
    Figure PCTCN2021132725-appb-100066
  10. 一种如权利要求1-9中任一项所述的如式A所示化合物的制备方法，其特征在于，其为方法一、方法二、方法三或方法四，A preparation method of the compound shown in formula A as described in any one of claims 1-9, is characterized in that, it is method one, method two, method three or method four,
    方法一包括以下步骤：溶剂中，在碱的存在下，将如式II-1A所示化合物和如式II-2所示化合物进行如下所示的反应，得所述的如式A所示化合物，The first method includes the following steps: in a solvent, in the presence of a base, the compound represented by the formula II-1A and the compound represented by the formula II-2 are subjected to the following reaction to obtain the compound represented by the formula A. ,
    Figure PCTCN2021132725-appb-100067
    Figure PCTCN2021132725-appb-100067
    方法二包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式III-1A所示化合物和如式III-2或III-3所示化合物进行如下所示的反应，得所述的如式A所示化合物，The second method includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1A and the compound shown in formula III-2 or III-3 are subjected to the following reaction to obtain the described Compounds of formula A,
    Figure PCTCN2021132725-appb-100068
    Figure PCTCN2021132725-appb-100068
    方法一或方法二中，Z为NR 5，R 5为
    Figure PCTCN2021132725-appb-100069
    In the first method or the second method, Z is NR 5 , and R 5 is
    Figure PCTCN2021132725-appb-100069
    方法三包括以下步骤：溶剂中，在碱的存在下，将如式IV-1A所示化合物和IV-2所示化合物进行如下所示的反应，得所述的如式A所示化合物，The third method includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1A and the compound shown in IV-2 are subjected to the reaction shown below to obtain the compound shown in formula A,
    Figure PCTCN2021132725-appb-100070
    Figure PCTCN2021132725-appb-100070
    方法三中，Z为NR 5，R 5为
    Figure PCTCN2021132725-appb-100071
    In the third method, Z is NR 5 , and R 5 is
    Figure PCTCN2021132725-appb-100071
    方法四包括以下步骤：溶剂中，在碱和催化剂的存在下，将如式V-1A所示化合物和如式V-2或V-3所示化合物进行如下所示的反应，得所述的如式A所示化合物，Method 4 includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound represented by formula V-1A and the compound represented by formula V-2 or V-3 are subjected to the following reaction to obtain the described Compounds of formula A,
    Figure PCTCN2021132725-appb-100072
    Figure PCTCN2021132725-appb-100072
    方法四中，Z为O或NR 5，R 5为C 1-C 6烷基； In method four, Z is O or NR 5 , and R 5 is C 1 -C 6 alkyl;
    其中，R 1、R 2、R 3、R 4、R 5-1、R 5-3和R 5-4的定义如权利要求1-9中任一项所述。 Wherein, the definitions of R 1 , R 2 , R 3 , R 4 , R 5-1 , R 5-3 and R 5-4 are as described in any one of claims 1-9.
  11. 一种药物组合物，其包括如权利要求1-9中任一项所述的如式A所示化合物或其药学上可接受的盐，和药用辅料；所述的如式A所示化合物或其药学上可接受的盐可为治疗有效量的。A pharmaceutical composition comprising the compound shown in formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, and a pharmaceutical adjuvant; the compound shown in formula A or a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.
  12. 一种如权利要求1-9中任一项所述的如式A所示化合物或其药学上可接受的盐、或如权利要求11所述的药物组合物在制备激酶调节剂的应用，所述的激酶调节剂可为激酶抑制剂或激酶激动剂，所述的激酶可为KRAS，例如KRAS G12C。A compound shown in formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9 or the application of the pharmaceutical composition as claimed in claim 11 in the preparation of a kinase regulator, the The kinase modulator can be a kinase inhibitor or a kinase agonist, and the kinase can be KRAS, such as KRAS G12C.
  13. 一种如权利要求1-9中任一项所述的如式A所示化合物或其药学上可接受的盐、或如权利要求11所述的药物组合物在制备药物中的应用；A compound shown in formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9 or the application of the pharmaceutical composition as claimed in claim 11 in the preparation of medicine;
    所述的药物可为预防和/或治疗KRAS相关疾病的药物或用于预防和/或治疗癌症的药物；The drug may be a drug for preventing and/or treating KRAS-related diseases or a drug for preventing and/or treating cancer;
    所述的KRAS优选KRAS G12C；Described KRAS is preferably KRAS G12C;
    所述的KRAS相关疾病可为癌症；The KRAS-related disease can be cancer;
    所述的癌症可为肺癌、胰腺癌、胰腺导管癌、大肠癌、结肠癌、直肠癌、阑尾癌、食管鳞癌、头颈鳞癌或乳腺癌；所述的癌症可为以KRAS突变为特征的癌症。The cancer can be lung cancer, pancreatic cancer, pancreatic ductal carcinoma, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma or breast cancer; the cancer can be characterized by KRAS mutation. cancer.
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