WO2022111521A1 - Composé aromatique, son procédé de préparation et son utilisation - Google Patents

Composé aromatique, son procédé de préparation et son utilisation Download PDF

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WO2022111521A1
WO2022111521A1 PCT/CN2021/132771 CN2021132771W WO2022111521A1 WO 2022111521 A1 WO2022111521 A1 WO 2022111521A1 CN 2021132771 W CN2021132771 W CN 2021132771W WO 2022111521 A1 WO2022111521 A1 WO 2022111521A1
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alkyl
substituted
independently
unsubstituted
heteroatoms
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PCT/CN2021/132771
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Chinese (zh)
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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 CN202180066532.3A priority Critical patent/CN116390919A/zh
Publication of WO2022111521A1 publication Critical patent/WO2022111521A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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 compounds of the present invention can be used as protease degradation agents and/or inhibitors, and have good degradation and/or inhibitory effects on KRAS, especially KRAS G12C.
  • the present invention provides a kind of compound as shown in formula I or its pharmaceutically acceptable salt,
  • the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms;
  • Y is N or C(R 6 );
  • R 6 is H, C 1 -C 6 alkyl, F, OCH 3 , OH, CN, CONH 2 or COOH;
  • 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 base, C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , C 2 -C 6 alkynyl substituted or unsubstituted by R 5-3a , or C 1 substituted or unsubstituted by R 5-4a -C 6 alkoxy;
  • 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 , R 5-3a and R 5-4a are independently C 1 -C 6 alkyl, cyano, halogen or -N(R 7 R 8 );
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is OR 2-1 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 or substituted or unsubstituted by R 2-3 "heteroatom is selected from one of N, O and S One 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, -N(R 9 R 10 ), C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
  • R 7 , R 8 , R 9 and R 10 are independently H, C 1 -C 6 alkyl; or, R 7 and R 8 , R 9 and R 10 together with the attached N independently form a "heteroatom selected" From one or more of N, O and S, the number of heteroatoms is 1-3" 3-10-membered heterocycle;
  • 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, n7, n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 is independently 0, 1, 2, 3, 4, 5, or 6;
  • n1, m2 and m3 are independently 0, 1, 2, 3, 4 or 5; m4 is independently 1, 2, 3, 4 or 5; m5, m6 and m7 are independently 0 or 1;
  • R 6a is independently H or C 1 -C 6 alkyl
  • Ring D is C 3 -C 6 cycloalkane, 3-10-membered or 11-18-membered heteroatom "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" ring, C 6 -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, -OR 3-1a-3 or R 3-1a-4 ;
  • 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 F, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 3 is a 6-membered heteroaryl group substituted or unsubstituted by R 3-2 "the heteroatom is selected from N, and the number of hetero atoms is 1", then R 5-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • 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 number of the above-mentioned substitutions is one or more.
  • the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms;
  • Y is N or CH
  • 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 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 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 F, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 3 is a 6-membered heteroaryl group substituted or unsubstituted by R 3-2 "the heteroatom is selected from N, and the number of hetero atoms is 1", then R 5-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • 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 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 substituted or unsubstituted by R 5-3a
  • the C 2 -C 6 alkynyl group may 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 2 -C 6 alkynyl
  • the The C 2 -C 6 alkynyl group may 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 2 -C substituted by R 5-3a
  • the number of said R 5-3a can be 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 1 -C 6 alkoxy
  • all Said C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy , preferably methoxy.
  • 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 5-4a
  • the C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , sec-butoxy or tert-butoxy, preferably methoxy.
  • 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 5-4a
  • the number of said R 5-4a can be 1, 2 or 3.
  • 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" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (for example ), 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 independently 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 2-2 when R 2-2 is independently 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.
  • the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • R 2-3 when R 2-3 is independently 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 2-3 when R 2-3 is independently 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.
  • 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" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (for example ).
  • 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 cyclobutane base( for example ), cyclopentyl ( for example ) or 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" 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 ), or a 7-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", such as
  • ring D is an 11-18-membered heterocyclic 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 11-18-membered heterocycle may be
  • the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example for ).
  • 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.
  • R 5 can be methyl
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the 3-10-membered heterocycle can be a 5-6-membered heterocycloalkane with "the heteroatom is selected from N, and the number of heteroatoms is 1-2" base, preferably tetrahydropyrrolyl
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • R 3-1a-1 and R 3-1a-2 are independently C 3 -C 6 cycloalkyl
  • the C 3 -C 6 cycloalkyl can be cyclopropane, cyclo Butane, cyclopentane or cyclohexane, preferably cyclopropyl.
  • R 6b is independently halogen
  • the halogen can be F, Cl.
  • R 3-1 and R 3-2 are independently -LR 3-1a , R 3-1 and R 3-2 are located at Ortho, meta, or para of a bond; such as meta or para, also such as para.
  • R 3-1a-1 and R 3-1a-2 are independently
  • D is a phenyl group, a cycloalkyl group or a 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".
  • R1 can be hydrogen or methyl.
  • R 2-2 and R 2-1a can be independently -OH, -F, -Cl, -NH2 , -OMe,
  • R 2-1 can be
  • R 2 may be
  • R 3-1a may be
  • R 3-1a is -L- for Among them, m5, m6 and m7 are independently 0; n24, n25 and n26 are independently 0.
  • R 3-1 and R 3-2 can be independently OH, Me, Et, CN,
  • 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 can be F.
  • R 3 can be any organic compound
  • Y can be N.
  • Z can be NR5.
  • R 5 can be C 1 -C 6 alkyl
  • 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 be independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
  • R 1 can be C 1 -C 6 alkyl.
  • R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
  • R 2 can be phenyl substituted with R 2-2 .
  • R 2-2 can be hydroxyl, halogen, amino, C 1 -C 6 alkoxy,
  • R 2-2 can be hydroxyl, halogen, 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 C 6 -C 15 aryl substituted or unsubstituted by R 3-1 .
  • R 3 can be C 6 -C 15 aryl substituted with R 3-1 .
  • R3 can be phenyl substituted with R3-1 .
  • R 3-1 and R 3-2 can independently be hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a .
  • R 3-1 and R 3-2 can be independently E.g
  • R 3-1 and R 3-2 can independently be cyano or C 1 -C 6 alkyl.
  • R 3-1 can be C 1 -C 6 alkyl or -LR 3-1a .
  • R 3-1 can be C 1 -C 6 alkyl.
  • -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.
  • -L- can be The a-end is connected to R 3-1a , and the b-end is connected to a C 6 -C 15 aryl group.
  • -L- can be, The a-end is connected to R 3-1a , and the b-end is connected to a C 6 -C 15 aryl group.
  • n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 are independently 0, 1, 2, 3, 4, 5 or 6.
  • nl, n2 and n3 can be independently 0, 1, 2, 3, 4, 5 or 6.
  • n1 and m2 can be 0, 1, 2 or 3 independently.
  • m1 may be 0, 1, 2 or 3.
  • m3 can be independently 0, 1, 2 or 3.
  • m4 is independently 1, 2, 3, 4 or 5.
  • m5, m6 and m7 are independently 0 or 1, eg 0.
  • R 3-1a is a ligand of E3 ligase, and its structure can be, for example, -OR 3-1a-3 or R 3-1a-4 .
  • one of R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; R 3-1a- 1 and the other of R 3-1a-2 is
  • R 3-1a-1 and R 3-1a-2 can be independently hydrogen or
  • the number of R 3-1 and R 3-2 can be independently 1 or 2.
  • the number of R 2-2 can be 2 and different.
  • R 4 is F
  • Y is N or CH
  • Z is O or NR 5 ;
  • R 5 is C 1 -C 6 alkyl
  • 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 OR 2-1 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 is hydroxyl, halogen, amino
  • R 2-1a is halogen
  • 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, 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 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen, C 1 -C 6 alkyl,
  • Ring A is a 5-6 membered heterocycloalkyl with "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B is a C 6 -C 10 aromatic ring
  • Ring C 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";
  • R a , R b , R c , R d and Re are independently hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 are independently 0, 1, 2, 3 or 4.
  • R 4 is F
  • Y is N or CH
  • 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 5-3 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 OR 2-1 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 is hydroxyl, halogen, amino
  • R 2-1a is halogen
  • 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, 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 0, 1, 2 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen, C 1 -C 6 alkyl,
  • Ring A is a 5-6 membered heterocycloalkyl with "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B is a C 6 -C 10 aromatic ring
  • Ring C 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";
  • R a , R b , R c , R d and Re are independently hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 are independently 0, 1, 2, 3 or 4.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is phenyl 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 hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
  • a-terminus is connected with R 3-1a
  • the b-terminus is connected with C 6 -C 15 aryl or "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 are connected;
  • n1, n2 and n3 are independently 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
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is phenyl 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 cyano or C 1 -C 6 alkyl
  • R 3-1 and R 3-2 are independently one or two.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is C 1 -C 6 alkyl
  • R 2 is phenyl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is phenyl substituted by R 3-1 ;
  • R 3-1 is C 1 -C 6 alkyl
  • the number of R 2-2 is 2 and different.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is C 1 -C 6 alkyl
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is C 6 -C 15 aryl substituted by R 3-1 ;
  • R 3-1 is C 1 -C 6 alkyl or -LR 3-1a ;
  • a-end is connected with R 3-1a
  • the b-end is connected with C 6 -C 15 aryl
  • n1, n2 and n3 are independently 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
  • the present invention provides a kind of above-mentioned preparation method of compound shown in formula I, it 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 shown in formula II-1 and the compound shown in formula II-2 are subjected to the reaction shown below to obtain the 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-1 and the compound shown in formula III-2 or III-3 are subjected to the following reaction to obtain the Compounds 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-1 and the compound shown in IV-2 are subjected to the reaction shown below to obtain 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-1 and the compound represented by formula V-2 or V-3 are subjected to the following reaction to obtain the Compounds shown in formula I,
  • Z is O or NR 5 , and R 5 is C 1 -C 6 alkyl;
  • 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 adjuvant.
  • 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 the use of the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a kinase modulator.
  • the kinase modulator can be a kinase inhibitor or a kinase agonist.
  • the kinase can be KRAS, such as KRAS G12C.
  • the kinase modulators are used in vitro.
  • the present invention provides the use of the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a protease degrading agent.
  • the protease degrading agent is used in vitro.
  • the present invention provides an application of the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of medicine.
  • 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 provides a compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug , its crystalline form, or its solvate,
  • the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms;
  • Y is N or C(R 6 );
  • R 6 is H, C 1 -C 6 alkyl, F, OCH 3 , OH, CN, CONH 2 or COOH;
  • 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 base, C 2 -C 6 alkenyl substituted or unsubstituted by R 5-2a , C 2 -C 6 alkynyl substituted or unsubstituted by R 5-3a , or C 1 substituted or unsubstituted by R 5-4a -C 6 alkoxy;
  • 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 , R 5-3a and R 5-4a are independently C 1 -C 6 alkyl, cyano, halogen or -N(R 7 R 8 );
  • 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, -N(R 9 R 10 ), C 1 -C 6 alkyl, C 1 -C 6 alkoxy,
  • R 7 , R 8 , R 9 and R 10 are independently H, C 1 -C 6 alkyl; or, R 7 and R 8 , R 9 and R 10 together with the attached N independently form a "heteroatom selected" From one or more of N, O and S, the number of heteroatoms is 1-3" 3-10-membered heterocycle;
  • 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, n7, n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 is independently 0, 1, 2, 3, 4, 5, or 6;
  • n1, m2 and m3 are independently 0, 1, 2, 3, 4 or 5; m4 is independently 1, 2, 3, 4 or 5; m5, m6 and m7 are independently 0 or 1;
  • R 6a is independently H or C 1 -C 6 alkyl
  • Ring D is C 3 -C 6 cycloalkane, 3-10-membered or 11-18-membered heteroatom "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" ring, C 6 -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, -OR 3-1a-3 or R 3-1a-4 ;
  • 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 F, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 3 is a 6-membered heteroaryl group substituted or unsubstituted by R 3-2 "the heteroatom is selected from N, and the number of hetero atoms is 1", then R 5-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • 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 number of the above-mentioned substitutions is one or more.
  • the compound shown in formula I its pharmaceutically acceptable salts, its stereoisomers, its tautomers, its isotopic compounds, its nitrogen oxides, its metabolism product, its prodrug, its crystalline form, or its solvate,
  • the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or achiral carbon atoms;
  • Y is N or CH
  • 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 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 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 F, OCH 3 , OH, CN, CONH 2 or COOH;
  • R 3 is a 6-membered heteroaryl group substituted or unsubstituted by R 3-2 "the heteroatom is selected from N, and the number of hetero atoms is 1", then R 5-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy substituted or unsubstituted by R 5-1a ;
  • 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 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 substituted or unsubstituted by R 5-3a
  • the C 2 -C 6 alkynyl group may 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 2 -C 6 alkynyl
  • the The C 2 -C 6 alkynyl group may 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 2 -C substituted by R 5-3a
  • the number of said R 5-3a can be 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 1 -C 6 alkoxy
  • all Said C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy , preferably methoxy.
  • 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 5-4a
  • the C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , sec-butoxy or tert-butoxy, preferably methoxy.
  • 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 5-4a
  • the number of said R 5-4a can be 1, 2 or 3.
  • 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.
  • heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4".
  • the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (such as ), or an 8-10-membered bicyclic heteroaryl group with "heteroatoms selected from N, the number of heteroatoms is 1-2", preferably an indazolyl group, 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 2-3 when R 2-3 is independently 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 2-3 when R 2-3 is independently 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.
  • 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" 5-6 membered monocyclic heteroaryl, more preferably pyridyl (for example ).
  • 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 cyclobutyl ( for example ), cyclopentyl ( for example ) or 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" 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 ), or a 7-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", such as
  • ring D is an 11-18-membered heterocyclic 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 11-18-membered heterocycle may be
  • the C 6 -C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring ( for example for ).
  • 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.
  • R 5 can be methyl
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • the 3-10-membered heterocycle can be a 5-6-membered heterocycloalkane with "the heteroatom is selected from N, and the number of heteroatoms is 1-2" base, preferably tetrahydropyrrolyl
  • the C 1 -C 6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.
  • R 3-1a-1 and R 3-1a-2 are independently C 3 -C 6 cycloalkyl
  • the C 3 -C 6 cycloalkyl can be cyclopropane, cyclo Butane, cyclopentane or cyclohexane, preferably cyclopropyl.
  • R 6b is independently halogen
  • the halogen can be F, Cl.
  • R 3-1 and R 3-2 are independently -LR 3-1a , R 3-1 and R 3-2 are located at Ortho, meta, or para of a bond; such as meta or para, also such as para.
  • R 3-1a-1 and R 3-1a-2 are independently
  • D is a phenyl group, a cycloalkyl group or a 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".
  • R1 can be hydrogen or methyl.
  • R 2-2 and R 2-1a can be independently -OH, -F, -Cl, -NH2 , -OMe,
  • R 2-1 can be
  • R 2 may be
  • R 3-1a may be
  • R 3-1a is -L- for Among them, m5, m6 and m7 are independently 0; n24, n25 and n26 are independently 0.
  • R 3-1 and R 3-2 can be independently 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 promotion 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
  • Y can be N.
  • Z can be NR5.
  • R 5 can be C 1 -C 6 alkyl
  • 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 be independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
  • R 1 can be C 1 -C 6 alkyl.
  • R 2 can be C 6 -C 15 aryl substituted with R 2-2 .
  • R 2 can be phenyl substituted with R 2-2 .
  • R 2-2 can be hydroxyl, halogen, amino, C 1 -C 6 alkoxy,
  • R 2-2 can be hydroxyl, halogen, 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 C 6 -C 15 aryl substituted or unsubstituted by R 3-1 .
  • R 3 can be C 6 -C 15 aryl substituted with R 3-1 .
  • R3 can be phenyl substituted with R3-1 .
  • R 3-1 and R 3-2 can independently be hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a .
  • R 3-1 and R 3-2 can be independently E.g
  • R 3-1 and R 3-2 can independently be cyano or C 1 -C 6 alkyl.
  • R 3-1 can be C 1 -C 6 alkyl or -LR 3-1a .
  • R 3-1 can be C 1 -C 6 alkyl.
  • -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.
  • -L- can be The a-end is connected to R 3-1a , and the b-end is connected to a C 6 -C 15 aryl group.
  • -L- can be, The a-end is connected to R 3-1a , and the b-end is connected to a C 6 -C 15 aryl group.
  • n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 are independently 0, 1, 2, 3, 4, 5 or 6.
  • nl, n2 and n3 can be independently 0, 1, 2, 3, 4, 5 or 6.
  • n1 and m2 can be 0, 1, 2 or 3 independently.
  • m1 may be 0, 1, 2 or 3.
  • m3 can be independently 0, 1, 2 or 3.
  • m4 is independently 1, 2, 3, 4 or 5.
  • m5, m6 and m7 are independently 0 or 1, eg 0.
  • R 3-1a is a ligand of E3 ligase, and its structure can be, for example, -OR 3-1a-3 or R 3-1a-4 .
  • one of R 3-1a-1 and R 3-1a-2 can independently be hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; R 3-1a- 1 and the other of R 3-1a-2 is
  • R 3-1a-1 and R 3-1a-2 can be independently hydrogen or
  • the number of R 3-1 and R 3-2 can be independently 1 or 2.
  • the number of R 2-2 can be 2 and different.
  • R 4 is F
  • Y is N or CH
  • Z is O or NR 5 ;
  • R 5 is C 1 -C 6 alkyl
  • 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 OR 2-1 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 is hydroxyl, halogen, amino
  • R 2-1a is halogen
  • 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, 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 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen, C 1 -C 6 alkyl,
  • Ring A is a 5-6 membered heterocycloalkyl with "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B is a C 6 -C 10 aromatic ring
  • Ring C 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";
  • R a , R b , R c , R d and Re are independently hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 are independently 0, 1, 2, 3 or 4.
  • R 4 is F
  • Y is N or CH
  • 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 5-3 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 OR 2-1 , or C 6 -C 15 aryl substituted or unsubstituted by R 2-2 ;
  • R 2-1 is C 6 -C 15 aryl substituted or unsubstituted by R 2-1a ;
  • R 2-2 is hydroxyl, halogen, amino
  • R 2-1a is halogen
  • 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, 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 0, 1, 2 or 3;
  • R 3-1a is
  • R 3-1a-1 and R 3-1a-2 are independently hydrogen, C 1 -C 6 alkyl,
  • Ring A is a 5-6 membered heterocycloalkyl with "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2";
  • Ring B is a C 6 -C 10 aromatic ring
  • Ring C 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";
  • R a , R b , R c , R d and Re are independently hydrogen, hydroxy or C 1 -C 6 alkyl
  • o1, o2 and o3 are independently 0, 1, 2, 3 or 4.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is phenyl 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 hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a ;
  • a-terminus is connected with R 3-1a
  • the b-terminus is connected with C 6 -C 15 aryl or "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 are connected;
  • n1, n2 and n3 are independently 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
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is phenyl 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 cyano or C 1 -C 6 alkyl
  • R 3-1 and R 3-2 are independently one or two.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is C 1 -C 6 alkyl
  • R 2 is phenyl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is phenyl substituted by R 3-1 ;
  • R 3-1 is C 1 -C 6 alkyl
  • the number of R 2-2 is 2 and different.
  • R 4 is F
  • Y is N
  • Z is NR 5 ;
  • R 5-1 is C 2 -C 6 alkenyl
  • R 1 is C 1 -C 6 alkyl
  • R 2 is C 6 -C 15 aryl substituted by R 2-2 ;
  • R 2-2 is hydroxyl or halogen
  • R 3 is C 6 -C 15 aryl substituted by R 3-1 ;
  • R 3-1 is C 1 -C 6 alkyl or -LR 3-1a ;
  • a-end is connected with R 3-1a
  • the b-end is connected with C 6 -C 15 aryl
  • n1, n2 and n3 are independently 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
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, Its metabolites, its prodrugs, its crystal forms, or its solvates, and pharmaceutical excipients.
  • Said 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 a compound represented by formula I, 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 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 use of the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a protease degrading agent.
  • the protease degrading agent is used in vitro.
  • the present invention provides a compound represented by formula I, 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 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 I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a tautomer thereof body, 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. Described 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 in a strictly periodic manner in three-dimensional space in a certain 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 heteroatoms, preferably 3-10 membered or 11-membered, containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. 18-membered saturated monocyclic, bicyclic or fused ring, preferably 3-7-membered saturated monocyclic (more preferably 5-6-membered saturated monocyclic), 10- or 11-membered bicyclic.
  • 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 composition 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 or/and degradation effect on KRAS, especially KRAS G12C.
  • Example 1 Synthesis of N-(2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyrano[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzyl)-6-((((2-(2,6-dioxopiperidine) pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)hexanamide
  • Step A 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (200 mg, 0.72 mmol), 6 -aminocaproic acid (114mg, 0.87mmol) and N,N-diisopropylethylamine (185mg, 1.44mmol) were dissolved in N,N-dimethylformamide (3mL), the reaction solution was stirred at 100°C for 5 Hour.
  • Step B 2,6-dichloro-5-fluoronicotinic acid (21.2 g, 75 mmol) in dichloromethane solution (250 mL) was added dropwise oxalyl chloride (11.9 g, 93 mmol, dissolved in 50 mL of dichloromethane) methane), followed by the addition of 0.3 mL of N,N-dimethylformamide (DMF). After the reaction solution was stirred at room temperature overnight, the solvent was removed by swirl. The remainder was dissolved in dioxane (250 mL) and the temperature was controlled to 0 degrees Celsius with an ice bath.
  • oxalyl chloride 11.9 g, 93 mmol, dissolved in 50 mL of dichloromethane) methane
  • DMF N,N-dimethylformamide
  • aqueous ammonia solution (content 28-30% ammonia, 19 mL, 112 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at 0°C for 30 minutes. Then the solvent of the reaction solution was spun off, and the residue was added to a 1:1 ethyl acetate/petroleum ether mixed solution, stirred for 5 minutes, and then filtered. The filtered solid was washed with petroleum ether, then the solid was dried in vacuo to give the product 2,6-dichloro-5-fluoronicotinic acid amide (16.0 g, 74 mmol, white solid, 98% yield). MS (ESI) M/Z: 209.1 [M+H] + .
  • Step C under ice bath, slowly add oxalyl chloride (1.83 g, 14.4 mmol, dissolved in tetrahydrofuran (10 mL) solution of 2,6-dichloro-5-fluoronicotinic acid amide (2.5 g, 12 mmol). in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath.
  • Step D under ice bath, add 2,6-dichloro-N-((2-cyano-6-methylphenyl)carbamoyl)-5-fluoronicotinamide (1.4 g, 3.9 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise potassium bis(trimethylsilyl)amide (KHMDS, 1 M in tetrahydrofuran, 8.2 mL, 8.2 mmol). After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. Product formation was detected by liquid mass spectrometry. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate.
  • KHMDS potassium bis(trimethylsilyl)amide
  • Step E&F To 2-(7-Chloro-6-fluoro-2,4-dioxy-3,4-dihydropyridin[2,3-d]pyrimidin-1(2H)-yl) -3-Toluonitrile (0.1 g, 0.31 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (DIPEA, 80 mg, 0.62 mmol) and phosphorus oxychloride (95 mg, 0.62 mmol). Reaction The liquid was heated to 50 degrees Celsius and stirred for 50 minutes.
  • DIPEA N,N-diisopropylethylamine
  • Step G tert-butyl (S)-4-(7-chloro-1-(2,4-lutidine-3-yl)-6-fluoro-2-carbonyl-1,2 -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.14g, 0.28mmol), 2-fluoro-6-hydroxyphenylboronic acid (87mg , 0.56 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 25 mg, 0.03 mmol) and KOAc (potassium acetate, 0.14 g, 1.4 mmol) was mixed together and evacuated on an oil pump and displaced nitrogen several times.
  • Step H (3S)-tert-butyl 4-(1-(2-cyano-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl) )-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (160 mg, 0.27 mmol) in ammonia methanol (7M, 3 mL) solution, Raney nickel (20 mg) was added, evacuated and replaced with hydrogen several times, then the reaction was stirred under hydrogen atmosphere for 16 hours.
  • Step 1 (Step 1): 3S)-tert-butyl 4-(1-(2-(aminomethyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyl) Phenyl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.18 mmol) with HATU (N,N,N,N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, 69 mg, 0.18 mmol) and 6-((2-(2, 6-Dioxypiperidin-3-yl)-1,3-dioxadolin-4-yl)amino)hexanoic acid ((70 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (2 mL) at room temperature The reaction was stirred at low temperature for 6
  • Mass spectrometry detected the conversion of all starting materials to product, which was purified by reverse phase (nitrile: water (1/1000 formic acid)) to give the product (3S)-tert-butyl 4-(1-(2-(( 6-((2-(2,6-dioxopiperidin-3-yl1)-1,3-dioxoisoindol-4-yl)amino)hexaamino)methyl)-6-methyl Phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3- Methylpiperazine-1-carboxylate (100 mg, yellow solid, 57% yield).
  • Step J&K ((3S)-tert-butyl 4-(1-(2-((6-(((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-4-yl)amino)hexaamino)methyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2- Oxy-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.1 g, 0.10 mmol) was dissolved in dichloromethane (2 mL) ), then add 1mL trifluoroacetic acid. The reaction solution was stirred at 20 degrees Celsius for 1 hour.Liquid mass spectrometry showed that the raw material had been reacted.Stop the reaction, the solvent was spun under reduced pressure and removed, and the crude product was azeotroped twice with dichloromethane (2 m
  • Step A 2,6-dichloro-5-fluoronicotinonitrile (50 g, 263.0 mmol) was added to 250 mL of concentrated sulfuric acid. The reaction solution was stirred at room temperature at 50 degrees Celsius for 3 hours, poured into ice water, extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product 2,6-dichloro -5-Fluoronicotinamide (50.0 g, 74 mmol, white solid, 91.4% yield). MS (ESI) M/Z: 209.1; 211.1 [M+H] + .
  • Step B under ice bath, slowly add oxalyl chloride (36.63 g, 288.5 mmol) to a solution of 2,6-dichloro-5-fluoronicotinic acid amide (50 g, 240 mmol) in dichloroethane (500 mL) , dissolved in 150 mL of dichloromethane).
  • the reaction solution was heated at 80 degrees Celsius for one hour, and then the heating was stopped.
  • the reaction solution was spun off under reduced pressure to remove half of the solvent, and then placed under an ice bath and then added dropwise to the reaction solution 2-amino-3-methylbenzoic acid methyl ester (51.56g, 312.5mmol) in dichloroethane (100mL) solution.
  • Step C under -78 degrees Celsius dry ice bath, add 2-(3-(2,6-dichloro-5-fluoronicotinyl)ureido)-3-methylbenzoate ((50g) , 125.3 mmol) in tetrahydrofuran (500 mL) solution was slowly added dropwise with bis(trimethylsilyl) potassium amide (KHMDS, 1M solution in tetrahydrofuran, 250.6 mL, 250.6 mmol). After the addition was completed, the ice bath was removed, and the reaction The liquid was stirred at room temperature for 3 hours. Liquid phase mass spectrometry detected that the product was generated.
  • KHMDS bis(trimethylsilyl) potassium amide
  • Step D&E To 2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl )-methyl 3-methylbenzoate (4.5 g, 1.25 mmol) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (DIPEA, 9.52 g, 74.38 mmol) and phosphorus oxychloride (11.38 g g, 74.38 mmol). The reaction solution was heated to 80 degrees Celsius and stirred for 60 minutes.
  • DIPEA N,N-diisopropylethylamine
  • phosphorus oxychloride 11.38 g g, 74.38 mmol
  • Step F the obtained tert-butyl (S)-4-(7-chloro-6-fluoro-1-(2-(methoxycarbonyl)-6-methylphenyl)-2-oxygen -1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2g, 3.67mmol), 2-fluorophenylboronic acid (1.03g , 7.36 mmol), Pd(dppf)Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 268.5 mg, 0.37 mmol) and KOAc (potassium acetate, 0.72 g, 7.36 mmol) mmol) were mixed together and evacuated on an oil pump and replaced with nitrogen several times.
  • Step G the obtained tert-butyl (S)-4-(6-fluoro-7-(2-fluorophenyl)-1-(2-(methoxycarbonyl)-6-methylbenzene) yl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (1.5 g, 2.48 mmol, ) was dissolved in To a mixed solution of methanol (4 mL), tetrahydrofuran (4 mL) and water (4 mL), lithium hydroxide monohydrate (0.31 g, 7.44 mmol) was added. The reaction solution was stirred at 20°C for 1 hour.
  • Step H the obtained (S)-2-(4-(4-(4-(4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-fluoro-7 -(2-Fluorophenyl)-2-oxypyrido[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL) ), then 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (87.7mg, 0.26mmol); bis(dimethylamino)methylene-triazo[4,5-B]pyridine 3-oxide, hexafluorophosphate; 2-(7-azobenzotriazole)-N, N,N"",N""-tetramethylurea hexafluorophosphat
  • reaction solution was stirred at 20 degrees Celsius for 1 hour. Liquid mass spectrometry showed that the reaction substrate reacted completely, the reaction was stopped, quenched by adding water, extracted twice with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, Filtration and concentration.
  • Step I&J the obtained tert-butyl (3S)-4-(1-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin -4-yl)amino)butyl)carbamoyl)-6-methylphenyl)-6-fluoro-7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2, 3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (100mg, 0.11mmol) was dissolved in dichloromethane (5mL), then 1mL of trifluoroacetic acid was added, and the reaction solution was heated at 20°C Stir for 1 hour.
  • Liquid mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, the solvent was removed under reduced pressure, the crude product was azeotroped twice with dichloromethane, the crude product was redissolved in 3 mL of dichloromethane, and DIPEA was added to the reaction solution. (N,N-diisopropylethylamine, 43 mg, 0.33 mmol) and acryloyl chloride (10 mg, 0.11 mmol). The reaction solution was stirred at minus 20 degrees Celsius for 1 hour. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • step F was the same as in Example 2.
  • Step F tert-butyl (S)-4-(7-chloro-6-fluoro-1-(2-(methoxycarbonyl)-6-methylphenyl)-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2g, 3.67mmol),(2-fluoro-6-hydroxyphenyl ) boric acid (1.42g, 7.36mmol), Pd(dppf)Cl2([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 268.5mg, 0.37mmol) and KOAc (potassium acetate, 0.72 g, 7.36 mmol) were mixed together and evacuated on the oil pump and replaced with nitrogen several times.
  • Step G the obtained tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methoxycarbonyl)-6 -methylphenyl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (1.0 g, 1.61 mmol) Dissolve in dichloromethane (10 mL), add methoxymethyl hypobromite (338 mg, 2.42 mmol), DIPEA (N, N-diisopropylethylamine, 623 mg, 4.83 mmol), respectively, at room temperature under stirring for 4 hours.
  • methoxymethyl hypobromite 338 mg, 2.42 mmol
  • DIPEA N, N-diisopropylethylamine, 623 mg, 4.83 mmol
  • Step H tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-(methoxymethoxy)phenyl)-1-(2-(methoxy) ( 500 mg, 0.85 mmol) was dissolved in a mixed solution of methanol (4 mL), tetrahydrofuran (4 mL) and water (4 mL), and then lithium hydroxide monohydrate (107 mg, 2.55 mmol) was added. The reaction solution was stirred at 20°C for 1 hour. LC-MS mass spectrometry showed about 20% product, and the reaction was stopped.
  • Step 1 (Step 1): the obtained 2-(4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-fluoro-7-(2 -Fluoro-6-(methoxymethoxy)phenyl)-2-oxopyrrolo[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid (100 mg, 0.15 mmol ) was dissolved in dichloromethane (5 mL), then 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dione (61.9 mg, 0.18 mmol); bis(dimethylamino)methylidene-triazo[4,5-B]pyridine 3-oxide, hexafluorophosphate; 2-(7-azobenzene Triazole)-N,N,N"",N""-tetramethylurea he
  • reaction solution was stirred at 20 degrees Celsius for 1 hour. Liquid mass spectrometry showed that the reaction substrate was completely reacted. The reaction was stopped, quenched by adding water, and extracted twice with dichloromethane. The organic The phase was dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane) tert-butyl(3S)-4-(1- (2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin-4-yl)amino)butyl)carbamoyl)-6-methylphenyl)-6- Fluoro-7-(2-Fluoro-6-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)- 3-Meth
  • Step J&K tert-Butyl(3S)-4-(1-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin-4- yl)amino)butyl)carbamoyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-(methoxymethoxy)phenyl)-2-oxo-1,2 - Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL), then 1 mL was added Trifluoroacetic acid, the reaction solution was stirred at 20 degrees Celsius for 1 hour.
  • Liquid mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, the solvent was removed under reduced pressure, the crude product was azeotroped twice with dichloromethane, the crude product was redissolved in 3 mL of dichloromethane, and DIPEA was added to the reaction solution. (N,N-diisopropylethylamine, 22 mg, 0.18 mmol) and acryloyl chloride (5.5 mg, 0.06 mmol). The reaction solution was stirred at minus 20 degrees Celsius for 1 hour. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • Example 6 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-4-((2-(2,6-di Oxypiperidin-3-yl)-6-fluoro-1,3-dioxoisopropanediol-5-yl)amino)cyclohexane-1-carboxamide
  • Steps A-F are the same as those in Example 1, except that 2,2-lutidine-3-amino in StepB is replaced with 4-amino-3-isopropyl-5-toluonitrile.
  • Step G tert-Butyl(3S)-4-[1-(4-cyano-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6 -Hydroxyphenyl)-2-oxopyridine[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid (4.78 g, 7.59 mmol) was dissolved in methanol (48.92 mL) In a 100 mL round-bottomed flask, ammonia methanol solution (7M, 30 mL) and Raney nickel (129.99 mg, 1.52 mmol) were added, and the reaction was carried out under a hydrogen atmosphere (4.5 atm) at room temperature for 16 hours.
  • reaction solution was filtered with celite, eluted with methanol, and concentrated to obtain tert-butyl(3S)-4-[1-[4-(aminomethyl)-2-isopropyl-6-methylphenyl]-6 -Fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridine[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid (4.2g , 6.62 mmol, 87.22% yield).
  • Step H 2-(2,6-Dioxypiperidin-3-yl)-5,6-difluoroindoline-1,3-dione (148 mg, 0.50 mmol), 4-( Aminomethyl)cyclohexane-1-carboxylic acid (79mg, 0.50mmol), N,N-diisopropylethylamine (194mg, 1.50mmol), N-methylpyrrolidone (2ml) were added to the reaction flask, 110 The reaction was carried out at °C for 5 hours.
  • Step I 4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl ) cyclohexane-1-carboxylic acid (49 mg, 0.113 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl) -6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperidine oxazine-1-carboxylate (60 mg, 0.094 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (44 mg , 0.113 mmol
  • Step J&K tert-Butyl(3S)-4-(1-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1 ,3-Dioxisoindol-5-yl)amino)methyl)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro- 7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
  • the acid salt 50 mg, 0.047 mmol
  • dichloromethane (2 ml)
  • trifluoroacetic acid (1 ml) was added.
  • the reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 ml), and DIPEA (N,N-diisopropylethylamine, 31 mg, 0.235 mmol) and acryloyl chloride (4.3 mg, 0.047 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • DIPEA N,N-diisopropylethylamine, 31 mg, 0.235 mmol
  • acryloyl chloride 4.3 mg, 0.047 mmol
  • Example 18 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-4-(2-(2,6-dioxo Piperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclohexane-1-carboxamide
  • Step A 2-(2,6-Dioxypiperidin-3-yl)-5,6-difluoroindoline-1,3-dione (148 mg, 0.50 mmol), 4-( Aminomethyl)cyclohexane-1-carboxylic acid (79mg, 0.50mmol), N,N-diisopropylethylamine (194mg, 1.50mmol), N-methylpyrrolidone (2ml) were added to the reaction flask, 110 The reaction was carried out at °C for 5 hours.
  • Step B 4-((2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl ) cyclohexane-1-carboxylic acid (49 mg, 0.113 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl) -6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperidine oxazine-1-carboxylate (60 mg, 0.094 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (44 mg , 0.113 mmol), N, N-d
  • Step C&D tert-Butyl(3S)-4-(1-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1 ,3-Dioxisoindol-5-yl)amino)methyl)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro- 7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
  • the acid salt 50 mg, 0.047 mmol
  • dichloromethane (2 ml)
  • trifluoroacetic acid (1 ml) was added.
  • the reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 ml), and DIPEA (N,N-diisopropylethylamine, 31 mg, 0.235 mmol) and acryloyl chloride (4.3 mg, 0.047 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • DIPEA N,N-diisopropylethylamine, 31 mg, 0.235 mmol
  • acryloyl chloride 4.3 mg, 0.047 mmol
  • Example 22 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-2-(2-(2-(2,6 -Dioxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl)phenyl)acetamide
  • Step A 1,4-phenylenediacetic acid (144 mg, 0.716 mmol), thionyl chloride (94 mg, 0.788 mmol), and tetrahydrofuran (2 ml) were added to the reaction flask and reacted at room temperature for 3 hours.
  • 1 mol/L hydrochloric acid was added to quench, and ethyl acetate was extracted.
  • Step B 2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)amino) -2-Oxoethyl)phenyl)acetic acid (52 mg, 0.116 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylbenzene) yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methyl ylpiperazine-1-carboxylate (59 mg, 0.093 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (42 mg, 0.111 mmol), N,N-diisopropy
  • Step C&D tert-butyl(3S)-4-(1-(4-((2-(4-(2-)((2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxyisoindolin-4-yl)amino)-2-oxoethyl)phenyl)acetamido)methyl)-2-isopropyl-6-methylphenyl) -6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperidine
  • the oxazine-1-carboxylate 50 mg, 0.047 mmol
  • dichloromethane (4 mL)
  • trifluoroacetic acid 2 mL
  • the reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 mL), and DIPEA (N,N-diisopropylethylamine, 29 mg, 0.223 mmol) and acryloyl chloride (4.0 mg, 0.045 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • DIPEA N,N-diisopropylethylamine, 29 mg, 0.223 mmol
  • acryloyl chloride 4.0 mg, 0.045 mmol
  • Example 23 Synthesis of N1-(4-(4-(S)-4-acryloyl-2-methylpiperazin- 1 -yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene yl)-2-oxopyridine[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-N4-(2-(2,6-di Oxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)cyclohexane-1,4-dicarboxamide
  • Example 24 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-7-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisopropanol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide
  • Step A 2-(2,6-Dioxypiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (150 mg, 0.543 mmol), 2,7-dione Azaspiro[3.5]nonane-2-carboxylate tert-butyl ester (148 mg, 0.651 mmol), N,N-diisopropylethylamine (210 mg, 1.63 mmol), N-methylpyrrolidone (2 mL) were added to the reaction In a bottle, the reaction was carried out at 110°C for 5 hours.
  • Step B&C 7-(2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)-2,7-diazaspiro [3.5]
  • Nonane-2-carboxylate tert-butyl ester 250 mg, 0.518 mmol was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane.
  • the crude product was redissolved in dichloromethane (5 mL), and DIPEA (N,N-diisopropylethylamine, 321 mg, 2.480 mmol) was added to the reaction solution and stirred at 0 degrees Celsius for 30 minutes. Triphosgene in methyl chloride (48 mg, 0.298 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • DIPEA N,N-diisopropylethylamine, 321 mg, 2.480 mmol
  • Step D tert-Butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2 -Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50mg , 0.078mmol), 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)-2,7-diazaspiro[3.5 ]
  • Nonane-2-carbonyl chloride 45 mg, 0.094 mmol
  • N,N-diisopropylethylamine 51 mg, 0.394 mmol
  • dichloromethane (2 ml) were added to the reaction flask, and the reaction was carried out at 50° C.
  • Step E&F tert-Butyl(3S)-4-(1-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo isoindol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 -
  • the carboxylate salt (30 mg, 0.028 mmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (2 mL) was added.
  • the reaction solution was stirred at 25°C for 2 hours. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (3 mL), and DIPEA (N,N-diisopropylethylamine, 17 mg, 0.132 mmol) and acryloyl chloride (2.4 mg, 0.026 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off.
  • DIPEA N,N-diisopropylethylamine, 17 mg, 0.132 mmol
  • acryloyl chloride 2.4 mg, 0.026 mmol
  • Example 25 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridine[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisopropyl-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxamide
  • Example 26 Synthesis of 1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidine Iridinyl]-3-[[4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-4-[(2S)-2-methyl-4-prop-2-enyl -Piperazin-1-yl]-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-3-isopropyl-5-methyl-phenyl]methyl]urea
  • Example 27 Synthesis of 4-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]-N-[ [4-[6-Fluoro-7-(2-fluoro-6-hydroxy-phenyl)-4-[(2S)-2-methyl-4-prop-2-enyl-piperazin-1-yl ]-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-3-isopropyl-5-methyl-phenyl]methyl]piperidine-1-carboxamide
  • Example 28 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyrid[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-9-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisopropanol-4-yl)-3,9-diazaspiro-3-carboxamide
  • Example 29 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxapyrino[2,3-d]pyrimidin-1(2H)-yl)-3,5-dimethylbenzyl)-6-(((2-(2,6-dioxopipine) pyridin-3-yl)-1,3-dioxadolin-4-yl)amino)hexanamide
  • Step A (S)-4-(7-chloro-1-(4-cyano-2,6-dimethylphenyl)-6-fluoro-2-oxo-1,2 -dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester was dissolved in ammonia methanol (7M, 10 mL) solution, Raney nickel ( 20 mg), evacuated and replaced hydrogen several times, and then the reaction was stirred under hydrogen atmosphere for 5 hours.
  • Step B (3S)-4-(1-(4-(aminomethyl)-2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6- Hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (100 mg, 0.165 mmol ) with HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, 69mg, 0.18mmol) and 6-((2 -(2,6-Dioxypiperidin-3-yl)-1,3-dioxadolin-4-yl)amino)hexanoic acid ((63.8 mg, 0.165 mmol) was dissolved in DMF (1 mL), The reaction was stirred at room temperature
  • Step C (3S)-4-(1-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxa Cyclopenten-4-yl)amino)adipate)-2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo -1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (60 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL) , then add 1mL trifluoroacetic acid. The reaction solution was stirred at 20 degrees Celsius for 1 hour.
  • Liquid mass spectrometry showed that the raw material had been reacted. Stop the reaction, the solvent was spun under reduced pressure and removed, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 2 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 50 g, 0.4 mmol) and acryloyl chloride (15 mg, 0.1 mmol) were added to the reaction solution. The reaction solution was heated at 20 degrees Celsius. Stir for 2 hours. LCMS shows that the raw material has been completely converted into product. The reaction is stopped, and the solvent is removed.
  • DIPEA N,N-diisopropylethylamine, 50 g, 0.4 mmol
  • acryloyl chloride 15 mg, 0.1 mmol
  • Step B under ice bath, slowly add oxalyl chloride (1.46 g, 11.5 mmol, dissolved in tetrahydrofuran (10 mL) solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol). in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. The reaction solution was spun off under reduced pressure to remove the solvent, and then placed in an ice bath and added with 10 mL of tetrahydrofuran.
  • Step C under ice bath, add 2,6-dichloro-N-(((4-cyano-2,6-dimethylphenyl)carbamoyl)-5-fluoronicotinamide ( 3.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) solution was slowly added dropwise KHMDS (bis(trimethylsilyl) potassium amide, 1M solution in tetrahydrofuran, 16.8 mL, 16.8 mmol). After the dropwise addition, the ice bath was removed , the reaction solution was stirred overnight at room temperature. LCMS monitors that all raw materials have been converted into products.
  • KHMDS bis(trimethylsilyl) potassium amide
  • reaction solution is quenched with ammonium chloride solution, and extracted with ethyl acetate.
  • the organic phase is dried with anhydrous sodium sulfate, filtered and spin-dried.
  • Thick product Purification by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) afforded 4-(7-chloro-6-fluoro-2,4-dioxo-3,4- Dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3,5-dimethylbenzonitrile (1.4 g, 4.07 mmol, 48.5% yield).
  • MS (ESI) M/Z 345.1[M+H] + .
  • Step D&E To 4-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl )-3,5-dimethylbenzonitrile (0.572g, 1.663mmol) in toluene (10mL) was added DIPEA (N,N-diisopropylethylamine, 416mg, 3.22mmol) and phosphorus oxychloride ( 493.6 mg, 3.22 mmol). The reaction solution was heated to 50°C and stirred for 60 minutes.
  • Step F tert-butyl (3S)-4-[7-chloro-1-(4-cyano-2,6-dimethyl-phenyl)-6-fluoro-2-oxo -pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (0.16g, 0.304mmol), 2-fluoro-6-hydroxyphenylboronic acid (94.8mg , 0.608mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 22.24mg, 0.03mmol) Mixed with KOAc (potassium acetate, 0.15 g, 1.52 mmol) and evacuated on water pump and replaced nitrogen several times.
  • KOAc potassium acetate, 0.15 g, 1.52 mmol
  • Step G tert-butyl (3S)-4-[1-(4-cyano-2,6-dimethyl-phenyl)-6-fluoro-7-(2-fluoro-6 -Hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (140 mg, 0.232 mmol) in MeOH (5 ml), Raney nickel (10 mg) was added to the system, evacuated and hydrogen was replaced several times, and then the reaction was stirred for 5 hours under a hydrogen atmosphere.
  • Step H tert-butyl (3S)-4-[1-[4-(aminomethyl)-2,6-dimethyl-phenyl]-6-fluoro-7-(2- Fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (120mg 0.198mmol) in In DMF (2 ml), to the system was added 2-[2-(carboxymethoxy)ethoxy]acetic acid (42.22 mg, 0.237 mmol) and
  • Step 1 2-[2-[[[4-[4-[(2S)-4-tert-butoxycarbonyl-2-methyl-piperazin-1-yl]-6- Fluoro-7-(2-Fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-3,5-dimethyl-phenyl]methane Amino]-2-oxo-ethoxy]ethoxy]acetic acid (100mg, 0.13mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) was added during stirring and the system was stirred at room temperature for 1 hour TLC After monitoring the disappearance of the raw materials, the solvent was revolved to dryness, and then dissolved in dichloromethane (2 ml).
  • Example 41 Synthesis of 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]-N-[ [3-[6-Fluoro-7-(2-fluoro-6-hydroxy-phenyl)-4-[(2S)-2-methyl-4-prop-2-enyl-piperazin-1-yl ]-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-2,4-dimethyl-phenyl]methyl]pentanamide
  • Steps A-G are the same as in Example 1, except that 2-amino-3-methylbenzonitrile is replaced with 3-amino-2,4-dimethylbenzonitrile.
  • Step H 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]pentane
  • the acid (61.7 mg, 0.165 mmol) was dissolved in DMF (2 mL) and tert-butyl(3S)-4-[1-[3-(aminomethyl)-2,6-dimethyl-phenyl was added to the system ]-6-Fluoro-7-(2-fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine- 1-Carboxylic acid ester (100 mg, 0.165 mmol) N,N,N,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (68.4 mg, 0.18 mmol) ) was added and N
  • Step 1 (Step 1): tert-butyl (3S)-4-[1-[3-[[5-[[2-(2,6-dioxo-3-piperidinyl)-1,3- Dioxo-isoindolin-4-yl]amino]pentylamino]methyl]-2,6-dimethyl-phenyl]-6-fluoro-7-(2-fluoro-6-hydroxy-benzene yl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (96 mg, 0.1 mmol) was dissolved in dichloromethane (2 ml) ) During the stirring process, add trifluoroacetic acid (1ml) to the system, stir at room temperature for 1 hour, monitor the disappearance of the raw materials by TLC, spin dry the solvent, then dissolve in dichloromethane (2ml) and add N,N-diisopropylethyl
  • Example 42 Synthesis of 6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]-N-[ [3-[6-Fluoro-7-(2-fluoro-6-hydroxy-phenyl)-4-[(2S)-2-methyl-4-prop-2-enyl-piperazin-1-yl ]-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-2,4-dimethyl-phenyl]methyl]hexanamide
  • the synthetic route is the same as in Example 41, except 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]pentane
  • the acid was replaced with 6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexanoic acid.
  • the synthetic route is the same as in Example 41, except 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]pentane
  • the acid was replaced with 2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)amino)cyclobutyl)acetic acid.
  • Example 44 Synthesis of N-(4-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methylbenzyl)-4-((2-(2,6- Dioxypiperidin-3-yl)-1-oxopropanol-4-yl)cyclohexane-1-carboxamide
  • Step A 3-(4-hydroxy-1-oxoisoquinolin-2-yl) piperidine-2,6-dione (100 mg, 0.38 mmol), 4-(p-tolyloxy) ring Hexane-1-carboxylate tert-butyl ester (136mg, 0.38mmol), potassium carbonate ((104mg, 0.76mmol) potassium iodide (6.3mg, 0.04mmol) was dissolved in N,N-dimethylformamide (2ml), in The reaction was carried out at 80°C for 16 hours, and the mass spectrometry was monitored to complete the reaction.
  • Step B tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1 -Carboxylic acid ester (132mg, 0.3mmol) was dissolved in dichloromethane (2ml), then trifluoroacetic acid (1ml) was added, reacted at room temperature for 2 hours, the reaction solution was concentrated to obtain crude product 4-((2-(2 ,6-Dioxypiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylic acid (100 mg).
  • Step C tert-butyl (3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2 -Fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.16 mmol), 4 -((2-(2,6-Dioxypiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylic acid (61 mg, 0.16 mmol), 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (60mg, 0.16mmol), N,N-diisopropylethylamine (41mg , 0.32mmol) was dissolved in N
  • Step D&E tert-Butyl(3S)-4-(1-(4-((4-((2-(2,6-Dioxypiperidin-3-yl)-1-oxoisoquinoline -4-yl)oxy)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyl) Phenyl)-2-oxy-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.1 mmol) was dissolved in dichloromethane (2 ml) During the stirring process, trifluoroacetic acid (1ml) was added to the system, and the system was stirred at room temperature for 1 hour.

Abstract

L'invention concerne un composé représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation. Ce composé peut être utilisé en tant qu'agent de dégradation de protéase et/ou inhibiteur et a un bon effet de dégradation et/ou d'inhibition sur KRAS, en particulier KRAS/G12C.
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CN116239541A (zh) * 2023-05-11 2023-06-09 英矽智能科技(上海)有限公司 N-苯基-2-氧代喹唑啉类化合物及其应用
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WO2024034593A1 (fr) * 2022-08-09 2024-02-15 アステラス製薬株式会社 Composé hétérocyclique destiné à induire la dégradation de la protéine kras portant une mutation ｇ１２ｖ
WO2024050742A1 (fr) * 2022-09-08 2024-03-14 Nikang Therapeutics, Inc. Composés bifonctionnels pour dégrader kras g12d par l'intermédiaire de la voie ubiquitine-protéasome
CN116239541A (zh) * 2023-05-11 2023-06-09 英矽智能科技(上海)有限公司 N-苯基-2-氧代喹唑啉类化合物及其应用

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