WO2024017392A1 - Composé cyclique de pyrimidine, intermédiaire de celui-ci, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Composé cyclique de pyrimidine, intermédiaire de celui-ci, composition pharmaceutique de celui-ci et utilisation associée Download PDF

Info

Publication number
WO2024017392A1
WO2024017392A1 PCT/CN2023/108961 CN2023108961W WO2024017392A1 WO 2024017392 A1 WO2024017392 A1 WO 2024017392A1 CN 2023108961 W CN2023108961 W CN 2023108961W WO 2024017392 A1 WO2024017392 A1 WO 2024017392A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
atropisomer
atrop
configuration
Prior art date
Application number
PCT/CN2023/108961
Other languages
English (en)
Chinese (zh)
Inventor
张朝欣
夏广新
马星
楼江松
李志龙
赵永新
王雪松
柯樱
Original Assignee
上海医药集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海医药集团股份有限公司 filed Critical 上海医药集团股份有限公司
Publication of WO2024017392A1 publication Critical patent/WO2024017392A1/fr

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to pyrimidine ring compounds, their intermediates, their pharmaceutical compositions and their applications.
  • RAS represents a group of closely related monomeric globular proteins of 189 amino acids (21 kDa molecular weight) that are associated with the plasma membrane and bind GDP or GTP.
  • RAS acts as a molecular switch. When RAS contains bound GDP, it is in a resting or closed position and "inactive.” In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. Upon binding GTP, RAS is "turned on” and able to interact with and activate other proteins (its "downstream targets”).
  • the RAS protein itself has a very low inherent ability to hydrolyze GTP back to GDP, thereby turning itself into a closed state.
  • GAP GTPase-activating protein
  • the RAS protein contains a G domain responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to membranes.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop).
  • the P-loop represents the nucleotide-binding pocket in the protein and is a rigid part of the domain with conserved amino acid residues required for nucleotide binding and hydrolysis (glycine 12, threon amino acid 26 and lysine 16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), which are dynamic parts of the protein that switch between resting and loaded states
  • switch I region switches 30-40
  • switch II region switches 60-76
  • the capability is often expressed as a "spring-loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 and the ⁇ -phosphate of GTP, which allows the switch 1 and switch 2 regions to maintain their active conformations respectively. After hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.
  • RAS The most noteworthy members of the RAS subfamily are HRAS, KRAS, and NRAS, which are mainly involved in many types of cancer.
  • many other members exist including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS and RRAS2.
  • KRAS Mutations in any of the three major isoforms of the RAS gene (HRAS, NRAS, or KRAS) are one of the most common events in human tumorigenesis. Approximately 30% of all human tumors are found to carry some mutation in the RAS gene. Notably, KRAS mutations are detected in 25%-30% of tumors. In contrast, the rates of oncogenic mutations in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found in the P-loop at residues G12 and G13 and at residue Q61. Among tumor-related KRAS G12 mutations, KRAS G12D mutations account for the highest probability, about 40%.
  • KRAS has been a target of interest for drug developers. Although progress has been made in this field, there is still a need in the art for improved KRAS G12D mutein inhibitors.
  • PROTAC proteolysis-targeting chimeras
  • CN110684015A discloses an ALK-targeting PROTAC molecule.
  • the ALK-targeting PROTAC molecule was successfully prepared. It can effectively target the target protein and reduce the content of ALK in cells. It also has good anti-tumor activity in vivo and in vitro. It has low toxicity to normal cells and is consistent with the characteristics of high efficiency and low toxicity.
  • PROTAC molecules targeting KRAS G12D have not been reported in this field.
  • the technology to be solved by the present invention is to overcome the shortcoming in the prior art that there are few types of compounds that can target degradation or inhibit KRAS mutants.
  • a pyrimidine ring compound, its intermediates, and its pharmaceutical composition are provided. and its applications.
  • the compound of the present invention has good inhibitory effect or protein degradation effect on KRAS mutant.
  • the present invention solves the above technical problems through the following methods.
  • the present invention provides a compound represented by Formula I or Formula II, their pharmaceutically acceptable salts, their solvates or solvates of their pharmaceutically acceptable salts;
  • R 1 is a C 6 to C 14 aryl group, a C 6 to C 14 aryl group substituted by one or more R 1-1 , a 6 to 14-membered heteroaryl group, or a C 6 to C 14 aryl group substituted by one or more R 1-2 Substituted 6-14 membered heteroaryl;
  • R 1-a , R 1-b and R 1-c are each independently H or a C 1 to C 6 alkyl group
  • R 1-d is independently a C 6 to C 14 aryl group substituted by one or more R 1-d-1 ;
  • R 1-d-1 is independently NO 2 ;
  • R 1-e is independently a C 1 to C 6 alkyl group
  • X is N or CR 2 ;
  • R 2 is halogen
  • M is a 3- to 10-membered heterocycloalkylene group or a 3- to 10-membered heterocycloalkylene group substituted by one or more halogens;
  • L is any of the following situations (the left end of L is connected to M, and the right end is connected to G):
  • L is -L 5 -L 6 -L 7 -L 8 -
  • L 5 is a C 1 to C 6 alkylene group or a heteroalkylene group with 2 to 9 chain atoms
  • L 6 is 5 to 6 Yuan heterocycloalkylene group or oxo 5- to 6-membered heterocycloalkylene group
  • L 7 is a connecting bond or a C 1 to C 6 alkylene group
  • L 8 is a connecting bond or a 5 to 6-membered heterocycloalkylene group.
  • Heterocycloalkyl
  • the above-mentioned connecting bond means that the two groups connected by the bond are directly connected (for example, L is -L 5 -L 6 -L 7 -L 8 -, if L 7 is a connecting bond, L is -L 5 -L 6 -L 8 -);
  • G is case 1, case 2 or case 3:
  • R 1 is an aryl group of C 6 to C 14 , C 6 to C substituted by one or more R 1-1 Aryl group of 14 ;
  • heteroatoms in the heterocycloalkylene group, the heteroalkylene group or the heteroaryl group are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is respectively independently 1, 2, 3 or 4;
  • X' is N, O or S
  • n 1 ' is 1, 2, 3 or 4;
  • L' is -O-(CR L-1 R L-2 ) n2' - * , -(CR L-3 R L-4 ) n3' - * or * represents the end connected to R 1' ;
  • n 2 ' and n 3 ' are each independently 1, 2, 3 or 4;
  • R L-1 , R L-2 , R L-3 and R L-4 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, surrounded by one or more R L- 1-1 substituted C 1 -C 6 alkyl or halogen;
  • Each R L-1-1 is independently halogen or C 1 -C 6 alkoxy
  • Each R 1' is a 4-10-membered heterocycloalkyl group substituted by one or more R 1-1' ; 4 of the 4-10-membered heterocycloalkyl group substituted by one or more R 1-1' -The heteroatoms in the 10-membered heterocycloalkyl group are independently 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 1-1' is independently halogen, hydroxyl, -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, or C 1 -C 6 substituted by one or more R 1-1-1' alkyl;
  • Each R 1-1-1' is independently a hydroxyl group, a 4-10-membered heterocycloalkyl group, or a 4-10-membered heterocycloalkyl group substituted by one or more R 1-1-1-1' ; said The heteroatoms in the 4-10-membered heterocycloalkyl and the 4-10-membered heterocycloalkyl substituted by one or more R 1-1-1-1' are independently N, O or S 1, 2 or 3 types, the number of heteroatoms is 1, 2 or 3;
  • Each R 1-1-1-1' is independently a C 1 -C 6 alkyl group
  • R 2' is H or halogen
  • R 3' is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3-1' or one or more R 3-2' Substituted 5-10-membered heteroaryl, the heteroatoms in the 5-10-membered heteroaryl and the "5-10-membered heteroaryl substituted by one or more R 3-2' " are independently It is 1, 2 or 3 types of N, O or S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 3-1' and R 3-2' are independently OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-1-1' , C 2 -C 6 alkynyl, 3-8 membered cycloalkyl, -SC(R 3-1-2' ) 3 , -S(R 3-1-3' ) 5 , amino, C 1 -C 6 alkyl base, 5-10 membered heteroaryl or -OC 1 -C 6 alkyl;
  • R 3-1-2' and R 3-1-3' are independently halogen
  • Each R 3-1-4' is independently a C 1 -C 6 alkyl group
  • R 4' is H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, "C 1 -C 6 alkyl substituted by one or more R 4-1' ", cyano or halogen;
  • Each R 4-1' is independently halogen
  • R 9' and R 10' are each independently H, C 1 -C 6 alkyl or halogen
  • Lb is the linker connecting R 1' and E;
  • E is the ligand of E3 ubiquitin ligase.
  • R 1 is a C 6 to C 14 aryl group or a C 6 to C 14 aryl group substituted by one or more R 1-1 ;
  • Each R 1-1 is independently OH, C 1 to C 6 alkyl group, C 3 to C 8 cycloalkyl group, halogen or C 2 to C 6 alkynyl group;
  • X is N or CR 2 ;
  • R 2 is halogen
  • M is a 3- to 10-membered heterocycloalkylene group or a 3- to 10-membered heterocycloalkylene group substituted by one or more halogens;
  • L is any of the following situations (the left end of L is connected to M, and the right end is connected to G):
  • L is -L 5 -L 6 -L 7 -L 8 -
  • L 5 is a C 1 to C 6 alkylene group or a heteroalkylene group with 2 to 9 chain atoms
  • L 6 is 5 to 6 Yuan heterocycloalkylene group or oxo 5- to 6-membered heterocycloalkylene group
  • L 7 is a connecting bond or a C 1 to C 6 alkylene group
  • L 8 is a connecting bond or a 5 to 6-membered heterocycloalkylene group.
  • Heterocycloalkyl
  • the above-mentioned connecting bond means that the two groups connected by the bond are directly connected (for example, L is -L 5 -L 6 -L 7 -L 8 -, if L 7 is a connecting bond, L is -L 5 -L 6 -L 8 -);
  • heteroatoms in the heterocycloalkylene group and the heteroalkylene group are each independently one or more of nitrogen, oxygen or sulfur, and the heteroatoms
  • the number of children is independently 1, 2, 3 or 4;
  • R 1 is a C 6 to C 14 aryl group or a C 6 to C 14 aryl group substituted by one or more R 1-1 ;
  • Each R 1-1 is independently OH, C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl or halogen;
  • X is N or CR 2 ;
  • R 2 is halogen
  • M is a 3- to 10-membered heterocycloalkylene group or a 3- to 10-membered heterocycloalkylene group substituted by one or more halogens;
  • L is any of the following situations (the left end of L is connected to M, and the right end is connected to G):
  • L is -L 5 -L 6 -L 7 -L 8 -
  • L 5 is a C 1 to C 6 alkylene group or a heteroalkylene group with 2 to 9 chain atoms
  • L 6 is 5 to 6 Yuan heterocycloalkylene group or oxo 5- to 6-membered heterocycloalkylene group
  • L 7 is a connecting bond or a C 1 to C 6 alkylene group
  • L 8 is a connecting bond or a 5 to 6-membered heterocycloalkylene group.
  • Heterocycloalkyl
  • the above-mentioned connecting bond means that the two groups connected by the bond are directly connected (for example, L is -L 5 -L 6 -L 7 -L 8 -, if L 7 is a connecting bond, L is -L 5 -L 6 -L 8 -);
  • heteroatoms in the heterocycloalkylene group and the heteroalkylene group are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is independently 1, 2 or 3. or 4;
  • the definition of Lb is the same as the definition of L in the compound represented by Formula I.
  • the definition of E is the same as the definition of G in the compound represented by Formula I.
  • the C 6 to C 14 aryl group or the C 6 to C 14 aryl group substituted by one or more R 1-1 may independently be a C 6 -C 10 aryl group, such as phenyl or naphthyl, preferably naphthyl, such as
  • the C 6 to C 14 heteroaryl group in the 6 to 14 membered heteroaryl group or the 6 to 14 membered heteroaryl group substituted by one or more R 1-2 can be independently a C 6 to C 10 heteroaryl group, such as pyridyl, pyrimidinyl, indolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, quinolyl, isoquinoline base, benzothiazolyl, pyridopyrazolyl, benzothienyl, for example
  • the C 1 to C 6 alkyl groups can be independently methyl, ethyl, n-propyl, iso- Propyl, n-butyl, isobutyl or tert-butyl, for example ethyl.
  • the C 3 to C 8 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl.
  • the halogen can be independently fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 2 to C 6 alkynyl group is an ethynyl group.
  • the halogen in R 2 and R 2' , can be independently fluorine, chlorine, bromine or iodine, such as fluorine.
  • the 4-10 membered heterocycloalkyl group in the 4-10 membered heterocycloalkyl group substituted by one or more R 1-1' is independently 5 to 8.
  • membered monocyclic heterocycloalkyl or in , ring A and ring B are each independently a 3-5 membered saturated heterocyclic ring, the type of heteroatom in the saturated heterocyclic ring is nitrogen, oxygen or sulfur, and the number of heteroatoms is 1 or 2; Y is C or a heteroatom; preferably, ring A and ring B are each independently a 5-membered saturated heterocyclic ring.
  • the heteroatom in the 5-membered saturated heterocyclic ring is, for example, nitrogen, and the number of heteroatoms is, for example, 1. More preferably, ring A and ring B are each independently a tetrahydropyrrole ring.
  • R 3' the 5-10 membered heteroaryl group or the 5-10 membered heteroaryl group in the 5-10 membered heteroaryl group substituted by one or more R 3-2' Independently pyridyl, pyrimidinyl, indolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, quinolyl, iso Quinolyl, benzothiazolyl, pyridopyrazolyl, benzothienyl, e.g.
  • the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens is
  • the cycloalkyl group can be independently a 5- to 8-membered monocyclic heterocycloalkylene group or in , Ring A and Ring B are each independently a 3-5 membered saturated heterocyclic ring.
  • the type of heteroatom in the saturated heterocyclic ring can be nitrogen, oxygen or sulfur, and the number of heteroatoms can be 1 or 2.
  • Y is C or heteroatom; Indicates that any connectable site in Ring A or Ring B is connected to other parts of the molecule.
  • the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens when the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens, the 3-10-membered heterocycloalkylene group is Heterocycloalkyl is independently
  • Ring A is a 5-membered saturated heterocyclic ring.
  • the heteroatom in the 5-membered saturated heterocyclic ring may be N, and the number of heteroatoms may be 1.
  • Ring A is a tetrahydropyrrole ring.
  • the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens when the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens, the 3-10-membered heterocycloalkylene group is Heterocycloalkyl is independently
  • Ring B is a 5-membered saturated heterocyclic ring.
  • the heteroatom in the 5-membered saturated heterocyclic ring may be N, and the number of heteroatoms may be 1.
  • Ring B is a tetrahydropyrrole ring.
  • the heterocycloalkylene group in the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens is
  • the atom can be independently N, and the number of heteroatoms can be independently 1.
  • the 3-10-membered heterocycloalkylene group or the 3-10-membered heterocycloalkylene group substituted by one or more halogens is
  • the cycloalkyl group may independently be tetrahydropyrrolylene or hexahydropyrrolidene-1H-pyrrolizinyl, e.g. The a end in the structural formula is connected to L.
  • the halogen in the 3-10 membered heterocycloalkylene group substituted by one or more halogens can be Fluorine, chlorine, bromine or iodine, such as fluorine.
  • the one or more halogen-substituted 3-10-membered heterocycloalkylene groups can be The a end is connected to L.
  • the heteroalkylene group in the heteroalkylene group having 2 to 9 chain atoms may be a straight-chain heteroalkylene group.
  • the heteroalkylene group with 2 to 9 chain atoms can be a heteroalkylene group with 2 to 6 chain atoms, such as a heteroalkylene group with 2 chain atoms. , a heteroalkylene group of 3 chain atoms, a heteroalkylene group of 4 chain atoms, a heteroalkylene group of 5 chain atoms or a heteroalkylene group of 6 chain atoms.
  • the type of heteroatom in the heteroalkylene group having 2 to 9 chain atoms may be oxygen, and the number of heteroatoms may be 1.
  • the heteroalkylene group with 2 to 9 chain atoms can be -(CH 2 ) n1 O(CH 2 ) n2 -, n1 and n2 are each independently 0, 1, 2 or 3, the left end of the group is connected to M, for example -(CH 2 ) 3 O(CH 2 ) 2 -, -(CH 2 ) 2 O(CH 2 ) 2 -, -(CH 2 )O( CH 2 )-, -O(CH 2 )- or -(CH 2 ) 1 O(CH 2 ) 2 -.
  • the C 1 to C 6 alkylene group in L 2 and L 4 , can be independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-, for example -CH 2 - or -CH 2 CH 2 -, when the above group is a group in L 2 , its left end is the same as M When the above group is a group in L 4 , its left end is connected to L 3 .
  • the C 1 to C 6 alkylene group in L 2 and L 4 , can be independently -CH 2 CH 2 CH 2 -.
  • this group is the group in L 2 , Its left end is connected to M.
  • this group is a group in L 4 , its left end is connected to L 3 .
  • the 5- to 6-membered heterocycloalkylene group may be a 6-membered heterocycloalkylene group.
  • the type of heteroatom in the 5- to 6-membered heterocycloalkylene group may be nitrogen, and the number of heteroatoms may be one.
  • the 5- to 6-membered heterocycloalkylene group in L 3 , can be connected to L 2 or L 4 through a heteroatom.
  • the 5- to 6-membered heterocycloalkylene group may be a piperidylene group, for example
  • the d end in the structural formula is connected to L 2 .
  • L 2 is a connecting bond
  • L 3 is a 5- to 6-membered heterocycloalkylene group
  • L 4 is a C 1 to C 6 alkylene group
  • L 2 is a C 1 to C 6 alkylene group
  • L 3 is a 5 to 6-membered heterocycloalkylene group
  • L 4 is a connecting bond.
  • the C 1 to C 6 alkylene group in L 5 and L 7 , can be independently -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-, such as -CH 2 -, where, when the above group is a group in L 5 , its left end is connected to M, when the above group When the group is a group in L 7 , its left end is connected to L 6 .
  • the C 1 to C 6 alkylene group in L 5 and L 7 , can be independently -CH 2 CH 2 -.
  • the heteroalkylene group in the heteroalkylene group having 2 to 9 chain atoms may be a straight-chain heteroalkylene group.
  • the heteroalkylene group with 2 to 9 chain atoms can be a heteroalkylene group with 2 to 4 chain atoms, such as a heteroalkylene group with 2 chain atoms. group or a heteroalkylene group of 3 chain atoms.
  • the type of heteroatom in the heteroalkylene group having 2 to 9 chain atoms may be oxygen, and the number of heteroatoms may be 1.
  • the heteroalkylene group with 2 to 9 chain atoms can be -(CH 2 ) n3 O(CH 2 ) n4 -, the left end of this group is connected to M, n3 and n4 are each independently 0, 1 or 2, and further may be -(CH 2 ) 2 O or -CH 2 O-.
  • the 5- to 6-membered heterocycloalkylene group or the 5- to 6-membered heterocycloalkylene group in the oxo-substituted 5 to 6-membered heterocycloalkylene group can be independently a 6-membered heterocycloalkylene group.
  • the 5- to 6-membered heterocycloalkylene group in the 5- to 6-membered heterocycloalkylene group or the oxo-substituted 5 to 6-membered heterocycloalkylene group is
  • the type of heteroatom can be independently nitrogen, and the number of heteroatoms can be independently 1 or 2.
  • the 5- to 6-membered heterocycloalkylene group in the 5- to 6-membered heterocycloalkylene group or the oxo-substituted 5 to 6-membered heterocycloalkylene group is Atoms can be connected to L 5 or L 7 .
  • the 5- to 6-membered heterocycloalkylene group or the 5- to 6-membered heterocycloalkylene group in the oxo-substituted 5 to 6-membered heterocycloalkylene group can be independently piperidylene or piperazinylene, for example
  • the f end is connected to L 5 .
  • the oxo 5-6 membered heterocycloalkylene group in L 6 , can be The f end is connected to L 5 .
  • the 5- to 6-membered heterocycloalkylene group may be a 6-membered heterocycloalkylene group.
  • the type of heteroatom of the 5- to 6-membered heterocycloalkylene group may be nitrogen, and the number of heteroatoms may be 2.
  • the heteroatom of the 5- to 6-membered heterocycloalkylene group can be connected to L7 or the G.
  • the 5- to 6-membered heterocycloalkylene group can be a piperazinylene group, for example
  • -L 5 -L 6 -L 7 -L 8 - can be any of the following situations:
  • L 5 is a C 1 to C 6 alkylene group
  • L 6 is a 5 to 6-membered heterocycloalkylene group
  • L 7 and L 8 are connecting bonds
  • L 5 is a C 1 to C 6 alkylene group
  • L 6 is a 5 to 6-membered heterocycloalkylene group
  • L 7 is a C 1 to C 6 alkylene group
  • L 8 is 5 to 6 Yuan heterocycloalkylene
  • L 5 is a heteroalkylene group with 2 to 9 chain atoms
  • L 6 is an oxo-substituted 5 to 6-membered heterocycloalkylene group
  • L 7 and L 8 are connecting bonds.
  • the -L 5 -L 6 -L 7 -L 8 - is Or the -L 5 -L 6 -L 7 -L 8 - is The g end is connected to G.
  • the R 1 is
  • the R 1 is
  • X is N or CF.
  • M is The a end in the structural formula is connected to L.
  • L is The c terminal in the above structural formula is connected to G, the e terminal is connected to G, and the g terminal is connected to G.
  • L is The c terminal in the above structural formula is connected to G, the e terminal is connected to G, and the g terminal is connected to G.
  • n 1 ' is 1 or 2.
  • X' is O.
  • R 2' is F.
  • R 4' is F.
  • R 9' and R 10' are each independently H.
  • L' is -OCH 2 -.
  • R 1' is The a end in the structural formula is connected to Lb.
  • Lb is The c terminal in the above structural formula is connected to E, the e terminal is connected to E, and the g terminal is connected to E.
  • E is preferred
  • R 3' is
  • the compound represented by formula I is any one of the following compounds:
  • the compound represented by Formula II is any one of the following compounds;
  • the compound represented by formula I is any one of the following compounds:
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound B1, which is The compound that peaks first under the following conditions: Chiral column CHIRAL ART Cellulose-SC, 2 ⁇ 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (0.5%, 2 mol/L ammonia methanol), phase B is Ethanol; flow rate: 20 ml/min; 20% of phase B for elution; preferably, under the conditions described, the retention time of the compound that peaks first is 6 minutes;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound B2, which is The compounds that elute the peak under the following conditions: chiral column CHIRAL ART Cellulose-SC, 2 ⁇ 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (0.5%, 2 mol/L ammonia methanol), phase B is Ethanol; flow rate: 20 ml/min; 20% of phase B for elution; preferably, under the conditions described, the retention time of the compound that peaks later is 8.7 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1, which is The compound that peaks first under the following conditions: chiral column NB_CHIRALPAK AD, 3 x 25 cm, 5 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is propanol (0.1% 2 mol/L ammonia methanol); Flow rate: 100 ml/min; 50% mobile phase B elution; preferably, under the described conditions, the retention time of the compound that peaks first is 1.68 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C2, which is The compounds that elute the peak under the following conditions: chiral column NB_CHIRALPAK AD, 3 x 25 cm, 5 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is propanol (0.1% 2 mol/L ammonia methanol); Flow rate: 100 ml/min; 50% mobile phase B elution; preferably, under the described conditions, the retention time of the compound that peaks later is 3.63 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1 as described above;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C2 as described above;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound D1, which is The compound that peaks first under the following conditions: Chiral column CHIRAL ART Cellulose-SC, 2 ⁇ 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (0.5% 2 mol/L ammonia-methanol), phase B is Ethanol; flow rate: 20 ml/min; 50% phase B elution; preferably, under the conditions described, the retention time of the compound that peaks first is 4.5 minutes;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound D2, which is The compounds that elute the peak under the following conditions: chiral column CHIRAL ART Cellulose-SC, 2 ⁇ 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (0.5% 2 mol/L ammonia-methanol), phase B is Ethanol; flow rate: 20 ml/min; 50% phase B elution; preferably, under the conditions described, the retention time of the compound that peaks later is 9.5 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound E1, which is The compound that peaks first under the following conditions: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 microns; mobile phase: phase A is n-hexane (0.1% 2 mol/L ammonia methanol), phase B is ethanol; flow rate: 20 ml/min; elution with 10% mobile phase B; preferably, under the described conditions, the retention time of the compound that peaks first is 8.1 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound E2, which is Compounds that elute later under the following conditions: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (0.1% 2 mol/L ammonia methanol), phase B is ethanol; flow rate: 20 ml/min; 10% mobile phase B wash Remove; Preferably, under the described conditions, the retention time of the compound that peaks later is 10.4min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1.
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C2.
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of the compound C2;
  • the atrop configuration is the same as the atrop configuration of compound C1;
  • the atrop configuration is the same as the atrop configuration of the compound C2;
  • the atrop configuration is the same as the atrop configuration of compound C1;
  • the atrop configuration is the same as the atrop configuration of the compound C2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of the compound C2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound B2;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound C1.
  • the compound represented by formula II is any one of the following compounds:
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound F1, which is The compound that peaks first under the following conditions: Chiral column CHIRALPAK ID, 2 x 25 cm, 5 ⁇ m; mobile phase: Phase A is n-hexane/methyl tert-butyl ether (1/1) (0.5% 2 mol/ ammonia methanol), phase B is methanol; 10% mobile phase B elutes; preferably, under the conditions described, the retention time of the compound that peaks first is 5.05 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound F2, which is The compound that elutes the peak under the following conditions: Chiral column CHIRALPAK ID, 2 x 25 cm, 5 ⁇ m; mobile phase: Phase A is n-hexane/methyl tert-butyl ether (1/1) (0.5% 2 mol/ ammonia methanol), phase B is methanol; 10% mobile phase B elutes; preferably, under the conditions described, the retention time of the compound that peaks later is 6.47 min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound G1, which is The compound that peaks first under the following conditions: Chiral column CHIRALPAK ID, 2 x 25 cm, 5 ⁇ m; mobile phase: Phase A is n-hexane/methyl tert-butyl ether (0.5% 2 mol/L ammonia methanol), where The volume ratio of n-hexane and methyl tert-butyl ether (0.5% 2 mol/L ammonia methanol) is 1:1, phase B is methanol; flow rate: 20 ml/min; 10% mobile phase B elution; preferably , under the described conditions, the retention time of the compound with the first peak is 7.73min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound G2, which is The compound that elutes the peak under the following conditions: Chiral column CHIRALPAK ID, 2 x 25 cm, 5 ⁇ m; Mobile phase: Phase A is n-hexane/methyl tert-butyl ether (0.5% 2 mol/L ammonia methanol) where The volume ratio of n-hexane and methyl tert-butyl ether (0.5% 2 mol/L ammonia methanol) is 1:1, phase B is methanol; flow rate: 20 ml/min; 10% mobile phase B elution; preferably , under the described conditions, the retention time of the compound that peaks later is 13.395min;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as that of compound H1, which is The compound that peaks first under the following conditions: Chiral column CHIRALPAK IE, 3 x 25 cm, 5 micron; mobile phase: phase A is n-hexane (10 mmol/L ammonia methanol solution), phase B is ethanol; flow rate: 35 ml/min; 30% phase B Carry out elution; preferably, under the described conditions, the retention time of the compound that peaks first is 32.5 minutes;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of compound H2, which is Compounds that peak after the following conditions: Chiral column CHIRALPAK IE, 3 x 25 cm, 5 ⁇ m; mobile phase: phase A is n-hexane (10 mmol/L ammonia methanol solution), phase B is ethanol; flow rate: 35 ml/min; 30% of phase B is used for elution; preferably, under the conditions described, the retention time of the compound that peaks first is 42 minutes;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of the compound H1;
  • An atropisomer of, in said atropisomer, The atrop configuration is the same as the atrop configuration of the compound H2.
  • the above test conditions for retention time do not limit the compound. As long as the above test conditions are used for measurement, the obtained retention time is the same as the above described or within the error range, and the compound is a stereotype among the compounds defined by the above retention time. Isomers fall within the protection scope of the present invention.
  • the pharmaceutically acceptable salt of the compound represented by Formula I is preferably the formate salt of the compound represented by Formula I or the trifluoroacetate salt of the compound represented by Formula I.
  • the pharmaceutically acceptable salt of the compound represented by Formula I is preferably the formate salt of the compound represented by Formula I or the hydrochloride salt of the compound represented by Formula I.
  • the pharmaceutically acceptable salt of the compound represented by Formula II is preferably the formate, hydrochloride or trifluoroacetate salt of the compound represented by Formula II, preferably formic acid. salt or trifluoroacetate.
  • the number of pharmaceutically acceptable salts of the compound represented by Formula I is preferably 1, 2, 3 or 4.
  • the number of pharmaceutically acceptable salts of the compound represented by Formula II is preferably 1, 2, 3 or 4.
  • the pharmaceutically acceptable salt of the compound represented by Formula I is any one of the following compounds: of trifluoroacetate, of trifluoroacetate, of trifluoroacetate, of formate, of formate, of formate or of formate;
  • the pharmaceutically acceptable salt of the compound represented by Formula II is any one of the following compounds
  • the compound of the present invention has a stereoconfiguration, and its stereoconfiguration is the same as that of the corresponding numbered compound in the examples.
  • compound 55a' has the same configuration as compound 55a
  • compound 55b' has the same configuration as compound 55b
  • compound 56a' has the same configuration as compound 56a
  • compound 56b' has the same configuration as compound 56b
  • compound 63a ' has the same configuration as compound 63
  • compound 60a' has the same configuration as compound 60
  • compound 61a' has the same configuration as compound 61
  • compound 62' has the same configuration as compound 62a
  • compound 62" has the same configuration as compound 62b
  • the configurations of compound 65a and compound 65 are the same.
  • the present invention also provides a pharmaceutical composition, which includes substance X-1' and one or more pharmaceutical excipients, where the substance X-1' is the above-mentioned formula I, formula II
  • the pharmaceutical composition includes substance X' and one or more pharmaceutical excipients, and the substance X' is the above-mentioned compound represented by formula I or its pharmaceutical acceptable salts, compounds of formula II or pharmaceutically acceptable salts thereof of salt.
  • the pharmaceutical composition includes substance X and one or more pharmaceutical excipients, and the substance X is the above-mentioned compound represented by formula I or its pharmaceutically acceptable of salt.
  • the pharmaceutical composition includes substance X" and one or more pharmaceutical excipients, and the substance with an acceptable salt.
  • the present invention also provides the application of a substance Y-1' in the preparation of drugs for the treatment and/or prevention of cancer mediated by KRAS mutations;
  • the substance Y-1' is the above-mentioned formula I
  • the substance Y-1' is substance Y'
  • the substance Y' is the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, such as formula II
  • formula II the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, such as formula II
  • the KRAS mutant protein is preferably KRAS_G12D mutant protein.
  • the cancer mediated by KRAS mutation is preferably hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer or lung cancer, etc.
  • the substance Y-1' is substance Y
  • the substance Y is the above-mentioned compound represented by Formula I, its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
  • the present invention also provides an application of the above-mentioned substance Y-1' in the preparation of drugs for the treatment and/or prevention of cancer, such as blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer or lung cancer.
  • cancer such as blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer or lung cancer.
  • the substance Y-1' is the above-mentioned substance Y'.
  • the substance Y-1' is the above-mentioned substance Y.
  • the present invention also provides a method for preventing and/or treating cancer mediated by KRAS mutations, which includes administering a therapeutically effective amount of the above-mentioned substance Y-1' to a patient.
  • the substance Y-1' is substance Y'.
  • the substance Y-1' is substance Y.
  • Cancers mediated by KRAS mutations include blood cancers, pancreatic cancer, MYH-related polyposis, colorectal cancer, lung cancer, etc.
  • the KRAS mutation may be KRAS_G12D mutation.
  • the present invention also provides a method for treating, preventing and/or treating cancer, which includes administering a therapeutically effective amount of the above-mentioned substance Y-1' to a patient.
  • the substance Y-1' is substance Y'.
  • the substance Y-1' is substance Y.
  • the present disclosure also relates to a method of treating a hyperproliferative disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof Solvates of salts.
  • the method includes administering to the mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the present disclosure.
  • Ras mutations including, but not limited to, K-Ras, H-Ras, or N-Ras mutations that have been identified in hematologic cancers or malignancies (e.g., cancers affecting the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments involve administering the disclosed compounds (eg, in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological cancer or malignancy.
  • the disclosed compounds eg, in the form of a pharmaceutical composition
  • the present disclosure relates to methods for treating lung cancer, comprising administering an effective amount of any of the above compounds (or pharmaceutical compositions comprising the compounds) to a subject in need thereof.
  • the cancer or malignant tumor includes but is not limited to leukemia and lymphoma.
  • the blood disease is, for example, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia Myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and/or other leukemias.
  • the lymphoma is, for example, all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma.
  • the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer or large cell lung cancer.
  • NSCLC non-small cell lung cancer
  • the lung cancer is small cell lung cancer.
  • Other lung cancers include, but are not limited to, adenomas, carcinoids, and anaplastic carcinomas.
  • the cancer such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical cancer, AIDS-related cancer (such as lymphoma and Kaposi's sarcoma), anal cancer, appendix Carcinoma, astrocytoma, atypical anomaly, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid, Atypical malformations, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic Myeloproliferative diseases, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in
  • the present invention also provides a compound represented by formula IA, formula IB or formula II-A:
  • Xa is independently or halogen
  • h1 is independently 0, 1 or 2;
  • PG 1 is independently a hydroxyl protecting group, PG 2 is an amino protecting group independently;
  • T 1 is independently -L 1 -T2, C 1 ⁇ substituted by one or more OH C 4 alkylene or -(CH2) h2 -CHO, h2 is 0, 1, 2, 3 or 4,
  • the compound represented by formula IA is a compound represented by formula IA-1
  • the compound represented by formula IB is a compound represented by formula IB-1
  • the compound represented by formula II-A The compound shown is a compound represented by formula II-A-1:
  • the present invention also provides any compound shown below:
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound.
  • Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent of an organic base and processing according to conventional methods.
  • salt formation examples include: for base addition salts, it is possible by using alkali metal or alkaline earth metal hydroxides or alkoxides (e.g. ethoxide or methoxide) or appropriately basic organic amines (e.g. diethanolamine, cholesterin) in an aqueous medium.
  • alkali metal or alkaline earth metal hydroxides or alkoxides e.g. ethoxide or methoxide
  • appropriately basic organic amines e.g. diethanolamine, cholesterin
  • alkali metal such as sodium, potassium or lithium
  • alkaline earth metal such as aluminum, magnesium, calcium, zinc or bismuth
  • salts form salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts with organic acids, such as formic acid, acetic acid, benzenesulfonic acid, benzoic acid, and camphorsulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, benzenesulfonic acid, benzoic acid, and camphorsulfonic acid.
  • citric acid citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, Malonic acid, mandelic acid, methanesulfonic acid, mufuric acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.
  • pharmaceutical excipients may refer to those excipients widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide a method to enable the active ingredients to dissolve at a desired rate after administration, or promote the activity of the composition after administration. Ingredients are absorbed effectively.
  • the pharmaceutical excipients may be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, and anti-adhesion agents. Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.
  • excipients binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, and anti-adhesion agents.
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
  • compositions of the present invention may be administered in any form, including injectable (intravenous), mucosal, oral (solid and liquid formulations), inhaled, ocular, rectal, topical or parenteral (infusion, injection, implant). Intravenous, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical composition of the present invention may also be in a controlled-release or delayed-release dosage form (eg, liposomes or microspheres).
  • solid oral dosage forms include, but are not limited to, powders, capsules, caplets, softgels, and tablets.
  • liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • formulations for parenteral administration include, but are not limited to, injectable solutions, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.
  • Treatment means any treatment of a disease in a mammal, including: (1) preventing the disease, that is, causing the symptoms of clinical disease not to develop; (2) inhibiting the disease, that is, preventing the development of clinical symptoms; (3) alleviating the disease, That is to say, the clinical symptoms subside.
  • Effective amount means an amount of a compound sufficient to (i) treat the disease in question, (ii) attenuate, ameliorate or eliminate the disease when administered to a patient in need of treatment. eliminate one or more symptoms of a particular disease or condition, or (iii) delay the onset of one or more symptoms of a particular disease or condition described herein.
  • the amount corresponding to the amount of the carbonyl heterocyclic compound represented by Formula II or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above will depend on, for example, the specific compound, the disease condition and its severity, This will vary depending on factors such as the characteristics (eg, weight) of the patient requiring treatment, but can nevertheless be routinely determined by one skilled in the art.
  • Prevention means reducing the risk of acquiring or developing a disease or disorder.
  • solvate refers to a substance formed by combining a compound of the invention with a stoichiometric or non-stoichiometric amount of solvent.
  • the solvent molecules in a solvate may exist in an ordered or unordered arrangement.
  • pharmaceutically acceptable salt and “solvate” in the term “pharmaceutically acceptable salt solvate” are as described above and refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid. Or a substance prepared from a base; and combined with a stoichiometric or non-stoichiometric solvent.
  • aryl refers to a cyclic, unsaturated monovalent hydrocarbon group with a specified number of carbon atoms (for example, C 6 to C 14 ), which is a monocyclic or polycyclic ring (for example, 2), which is polycyclic.
  • the single rings share two atoms and one bond, and (at least one ring/each ring) is aromatic, such as phenyl and naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 6-14 or 5-10 membered monocyclic rings independently selected from nitrogen, oxygen and sulfur (e.g. 6-membered monocyclic ring), 6-14-membered or 5-10-membered bicyclic ring (such as 9-10-membered bicyclic ring), such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, Oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl , benzothiazolyl, benzisothiazolyl, benzoxazolyl, benziso
  • alkyl refers to a straight or branched chain alkyl group having the specified 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 is similar to an alkyl group. Unless a substituent is specifically stated, an alkyl group is unsubstituted.
  • cycloalkyl refers to a non-aromatic, saturated, monovalent cyclic hydrocarbon group with a specified number of ring carbon atoms (for example, C 3 to C 8 ), which is a monocyclic ring.
  • cycloalkyl include but are not limited to cyclic Propyl, cyclobutyl, cyclopentyl.
  • halogen refers to F, Cl, Br, I.
  • heterocycloalkylene refers to a non-aromatic saturated dicyclic group having a specified number of ring atoms (e.g., 3 to 10 members) and at least one ring carbon atom replaced by a heteroatom selected from N, O, and S. Valent cyclic hydrocarbon group. Heterocycloalkylene groups can be linked to other moieties in the molecule through heteroatoms or carbon atoms within them. Examples of monocyclic heterocycloalkylene groups include, but are not limited to Examples of cyclic heterocycloalkylene groups include, but are not limited to
  • heteroalkylene refers to a saturated straight-chain divalent hydrocarbon group with a specified number of chain atoms (for example, 2 to 9), in which at least one chain atom is selected from N, O, and heteroatoms of S, and the remaining chain atoms are carbon. Heteroalkylene groups can be connected to other parts of the molecule through heteroatoms or carbon atoms within them. Heteroalkylene groups with 2 chain atoms, such as -O-CH 2 -, -CH 2 -O-, etc., have Heteroalkylene groups with 3 chain atoms such as -CH 2 -CH 2 -O-, -CH 2 -O-CH 2 -, etc.
  • Heteroalkylene groups with 4 chain atoms such as -CH 2 -O-CH 2 -CH 2 -, etc., heteroalkylene groups with 5 chain atoms, such as -CH 2 -CH 2 -O-CH 2 -CH 2 -, etc., heteroalkylene groups with 6 chain atoms, such as -CH 2 - CH 2 -CH 2 -O-CH 2 -CH 2 -etc.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon radical having a specified number of carbon atoms.
  • alkylene groups include, but are not limited to -CH 2 -, -CH 2 CH 2 -.
  • saturated heterocycle refers to a specified number of heteroatoms (for example, 1 or 2), a specified number of heteroatoms (N, One or more of O and S) saturated rings, examples of alicyclic rings include but are not limited to:
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the carbon marked with "*" refers to S configuration chiral carbon, R configuration chiral carbon or achiral carbon.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of the present invention has a degrading effect on KRAS protein or a good inhibitory effect on KRAS G12D mutant protein.
  • the compounds and their salts (or free bases) finally prepared in the following examples, if there are three-dimensional configurations produced by axial chirality in these compounds, these compounds and their salts (or free bases) are formed by axial chirality.
  • the resulting stereoconfiguration is consistent with that of the chiral axis-containing intermediates used to prepare these compounds.
  • compound 50 in Example 1 Compound 50 is prepared through intermediate 50-2a containing a chiral axis, then the configuration of compound 50 resulting from axial chirality is consistent with the configuration of intermediate 50-2a.
  • the configurations generated by axial chirality in other embodiments of the present invention are the same as those in Embodiment 1.
  • the compounds with the same number in the following examples have the same configuration.
  • the compound 55-4a obtained in step 5 of Example 6 has the same configuration as the raw material compound 55-4a used in Example 21.
  • step 1
  • the mixture was cooled to 25 degrees Celsius, diluted with 30 ml of water, extracted with ethyl acetate (50 ml x 3), and the organic phases were combined.
  • the organic phase was washed with 50 ml of saturated sodium carbonate solution, 50 ml of saturated sodium sulfite solution and 50 ml of saturated brine in sequence.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product obtained was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 45% ethyl acetate/petroleum ether.
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 30% ethyl acetate/dichloromethane.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 38-6 (yellow solid, 700 mg, yield 97%).
  • compound 25-1 (10.0 g, 132.6 mmol, 2.0 equivalents) and potassium hydroxide (7.44 g, 132.6 mmol, 2.0 equivalents) were sequentially added to a 100 ml single-mouth bottle.
  • the mixture was heated to 75 degrees Celsius and reacted for 30 minutes.
  • compound 1,3-propanediol (15.0 g, 62.9 mmol, 1.0 equivalent) was slowly added dropwise to the above system at 75 degrees Celsius. The dropping time was not less than 30 minutes.
  • the reaction system was heated to 80 degrees Celsius. React for 30 minutes. The reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction system was cooled to 25 degrees Celsius.
  • reaction system was quenched with 200 ml of water, extracted with ethyl acetate (200 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the solvent was removed from the filtrate obtained by distillation under reduced pressure.
  • the mobile phase was eluted with a gradient of 0% ⁇ 25% ethyl acetate/petroleum ether, and the solvent was removed from the obtained fraction by rotary evaporation under reduced pressure to obtain compound 25-2 (colorless oil, 2.15 g, yield 25%).
  • reaction solution is cooled to room temperature, poured into an aqueous solution to quench, adjust the pH to 1 to 3 with 2 moles of hydrochloric acid, extract with ethyl acetate, combine the organic phases and dry, filter to remove the desiccant, and concentrate the filtrate to obtain the crude product compound.
  • 48-1 yellow oil, 30 g, yield 56%), the crude product was directly used in the next step of synthesis.
  • reaction solution was poured into saturated sodium bicarbonate solution to quench, extracted with dichloromethane (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure.
  • a crude product is obtained.
  • the crude product was purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 5% methanol/dichloromethane mobile phase. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 48-5 (white solid, 3 g, Yield 84%).
  • reaction solution was poured into saturated ammonium chloride solution to quench, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 30% ethyl acetate/petroleum ether mobile phase. The solvent was removed from the obtained fraction by rotary evaporation under reduced pressure to obtain compound 48-7 (white solid, 1.9 g , yield 55%).
  • the mixture was reacted at 80 degrees Celsius for 4 hours, and the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature, and the mixture was concentrated to obtain a crude product.
  • the crude product was purified by silica gel column chromatography, eluted with a gradient of 0% ⁇ 20% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 46-1 (white solid, 550 mg, Yield 64%).
  • step 1
  • Compound 50-1 was synthesized with reference to patent WO 2022031678A1.
  • compound 40-2 500 mg, 0.713 mmol, 1.00 equivalent
  • 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl were added to the reaction bottle in sequence.
  • compound 50-1 (308.04 mg, 0.856 mmol, 1.2 equivalent)
  • potassium phosphate (318.43 mg, 1.426 mmol, 2.0 equivalent)
  • tris(dibenzylideneacetone) Dipalladium(0) (68.69 mg, 0.071 mmol, 0.1 equiv)
  • water 1 mL
  • toluene 5 mL).
  • the resulting mixture was reacted at 80 degrees Celsius under nitrogen-protected stirring conditions for 3 hours.
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • the reaction solution is filtered, and the filtrate is evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product is purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 10% methanol/dichloromethane mobile phase to obtain The solvent was evaporated under reduced pressure from the fraction to obtain compound 50-2 (yellow solid, 483 mg, yield 80%).
  • reaction solution is poured into ice water (10 ml) to quench the resulting mixture with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3).
  • chloroform/isopropyl alcohol 3/1, 20 ml ⁇ 3
  • the organic phases are combined, and then anhydrous sodium sulfate is used. dry.
  • the desiccant was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to obtain a crude product.
  • compound 50-3a (50 mg, 0.058 mmol, 1.00 equivalent) was added sequentially to the reaction flask, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (30.14 mg, 0.075 mmol, 1.3 equiv) and N,N- Dimethylformamide (1 ml). The mixture was reacted with stirring at 25 degrees Celsius for 10 minutes. Add N,N-diisopropylethylamine (31.53 mg, 0.232 mmol, 4.01 equivalent) and (2S,4R)-1-[(2S)-2-amino to the reaction system under stirring conditions at 25 degrees Celsius.
  • reaction solution was directly purified through a reversed-phase chromatography column (C18 column), and eluted with 0% ⁇ 30% methanol/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes; the detector UV254/ 220 nm; compound 50-4a was obtained (white solid, 54.0 mg, yield 71%).
  • the resulting mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product obtained was purified through a reversed-phase chromatography column (C18 column), and eluted with 0% ⁇ 30% methanol/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes; detector UV254/220 nm; obtained Compound 50 (white solid, 16.5 mg, 35% yield).
  • step 1
  • the mixture was stirred at 60 degrees Celsius under nitrogen protection for 6 hours, and the reaction process was monitored by thin layer chromatography. After the reaction is completed, cool to room temperature, and add 20 ml of saturated aqueous ammonium chloride solution to the mixture to dilute the reaction solution. The mixture was extracted with ethyl acetate (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography. The mobile phase was eluted with a gradient of 0% ⁇ 10% ethyl acetate/petroleum ether.
  • the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product obtained was purified by silica gel column chromatography, and the mobile phase was 0% ⁇ 20% methyl.
  • Tert-butyl ether/petroleum ether gradient elution was performed, and the solvent was removed from the obtained fraction by rotary evaporation under reduced pressure to obtain compound 51-2 (yellow oily liquid, 700 mg, yield 44%).
  • N,N-diisopropylethylamine (860.56 ⁇ m) was slowly added to a solution of compound 51-2 (650 mg, 2.347 mmol, 1 equivalent) in dichloromethane (10 ml). liter, 4.694 mmol, 2 equiv) and chloromethyl methyl ether (298.32 mg, 3.521 mmol, 1.5 equiv).
  • the mixture was stirred at 25°C for 2 hours, and the reaction progress was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography.
  • the mixture was stirred at -78 degrees Celsius for 1 hour and then returned to room temperature and stirred at room temperature for 30 minutes.
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, 50 ml of saturated aqueous ammonium chloride solution was added to quench the reaction at 0 degrees Celsius.
  • the mixture was extracted with ethyl acetate (60 ml x 3) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 12% ethyl acetate/petroleum ether.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 51-4 (colorless oily liquid, 290 mg, yield 79%).
  • step 1
  • reaction solution was cooled to room temperature, and the reaction was quenched with water (500 ml) to obtain a mixture Extract with dichloromethane (500 ml ⁇ 3), combine the organic phases, dry with anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent from the filtrate by rotary evaporation under reduced pressure to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography. The mobile phase was eluted with a gradient of 0% ⁇ 60% petroleum ether/methyl tert-butyl ether. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 48-6 (white solid, 19 g, yield 47%).
  • Paraformaldehyde (3.5 g, 73.860 mmol, 2.0 equivalent) was added to the reaction system under nitrogen protection and stirring at -78°C, and then the mixture was slowly raised to 25°C. The mixture was reacted under nitrogen-protected stirring conditions at 25 degrees Celsius for 2.5 hours. The reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction is completed, slowly add saturated aqueous ammonium chloride solution (500 ml) to the reaction solution at zero degrees Celsius to quench the reaction. The mixture is extracted with ethyl acetate (500 ml ⁇ 3), the organic phases are combined, and then anhydrous sodium sulfate is used. Dry and filter to remove the desiccant.
  • the filtrate is rotary evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 100% petroleum ether/methyl tert-butyl ether.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 52-2 (yellow oil, 5.5 g, yield 32%).
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction is completed, the reaction solution is lowered to zero degrees Celsius. Saturated ammonium chloride aqueous solution (500 ml) was added to the reaction solution under stirring conditions to quench the reaction. The mixture was extracted with ethyl acetate (500 ml ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was rotary evaporated under reduced pressure to remove the solvent to obtain a crude product. The obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 40% petroleum ether/methyl tert-butyl ether.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 52-3 (yellow oil, 1.57 g, yield 51%).
  • the resulting mixture was reacted under stirring conditions at 25 degrees Celsius for 1 hour, and the reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • the reaction solution was cooled to zero degrees Celsius, ice water (20 ml) was added to quench the reaction, the mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3), the organic phases were combined, and then Dry with anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent from the filtrate by rotary evaporation under reduced pressure to obtain a crude product.
  • reaction solution was purified through a reversed-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; the detector UV254/ 220 nm; compound 52-7a was obtained (white solid, 50 mg, yield 66%).
  • the resulting mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. .
  • the crude product was purified through a reversed-phase chromatography column (C18 column) and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% hydrochloric acid) within 20 minutes; detector, UV254/220 nm; compound 52 was obtained (White solid, 24.8 mg, 95% yield).
  • step 1
  • N-tert-butoxycarbonyl-(R)-3-carboxylic acid piperidine (371.31 mg, 1.538 mmol, 1.200 equivalents), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (769.72 mg, 1.923 mmol, 1.50 equiv) and N,N-dimethylformamide (1 mL).
  • the resulting mixture was reacted with stirring at 25 degrees Celsius for 15 minutes.
  • reaction solution was purified through a reversed-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; the detector UV254/ 220 nm; compound 53-1 was obtained (white solid, 720 mg, yield 81%).
  • allyl bromide (1.06 g, 8.309 mmol, 1.2 equivalents) was added dropwise to the reaction solution under nitrogen protection and stirring at minus 78 degrees Celsius.
  • the mixture was slowly raised to 25 degrees Celsius, and reacted for 2 hours under nitrogen-protected stirring conditions at 25 degrees Celsius.
  • the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography.
  • the reaction solution was slowly poured into saturated ammonium chloride solution (100 ml) to quench the reaction, and the resulting mixture was extracted with ethyl acetate (100 ml ⁇ 3). Combine the organic phases and dry over anhydrous sodium sulfate. Filter to remove the desiccant.
  • the filtrate is rotary evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product is purified by silica gel column chromatography, using 0% ⁇ 50% methyl tert-butyl. Base ether/petroleum ether mobile phase gradient elution, the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 53-3 (colorless oil, 1.09 g, yield 33%).
  • N-tert-butoxycarbonyl-(S)-3-carboxylic acid piperidine was used to replace N-tert-butoxycarbonyl-(R)-3-carboxylic acid piperidine to synthesize compound 54 (white solid, 19.30 mg, yield 39%).
  • reaction solution is cooled to room temperature, poured into ice water (100 ml), extracted with ethyl acetate (100 ml x 3), the organic phases are combined and dried, filtered to remove the desiccant, and the filtrate is concentrated to obtain a crude product, which is passed Purify by silica gel column chromatography, use 0% ⁇ 50% ethyl acetate/petroleum ether mobile phase gradient elution, and the solvent is removed by rotary evaporation under reduced pressure to obtain compound 55-1 (green solid, 900 mg, yield 35%).
  • the product with a shorter retention time (3.60 minutes) is compound 55-1a (green solid, 440 mg, recovery rate 42%), compound 55-1a: MS (ESI, m/z): 407.2 [M+H] + ;
  • the product with a longer retention time (4.58 minutes) is compound 55-1b (green solid, 480 mg, recovery rate 45%), compound 55-1b: MS (ESI, m/z): 407.2 [M+H] + .
  • the reaction process Monitor by liquid quality. After the reaction, the reaction solution was poured into water (10 ml) to quench, and extracted with a mixed solvent of chloroform and isopropyl alcohol (20 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove. Drying agent, the filtrate was concentrated under reduced pressure to obtain crude product compound 55-4a (yellow oil, 40 mg, yield 50%). MS(ESI,m/z):794.3[M+H] + .
  • Mobile phase A water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 100 ml/min; use 40%-65 % mobile phase B elution for 30 minutes; detector UV254/220 nm; compound 55-5a (white solid, 20 mg, yield 73%) was obtained.
  • Mobile phase A water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 100 ml/min; use 40%-65 % mobile phase B elution for 30 minutes; detector UV254/220 nm; compound 56-5a (white solid, 60 mg, yield 79%) was obtained.
  • step 1
  • reaction solution is purified through a reverse-phase chromatography column (C18 column), and gradient elution is performed with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate) within 25 minutes; the detector UV254/ 220 nm; compound 57-1 was obtained (white solid, 100 mg, yield 49%).
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, the reaction solution was slowly poured into saturated ammonium chloride solution (20 ml) to quench, and the resulting mixture was extracted with a chloroform/isopropyl alcohol mixed solvent (3/1, 30 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was rotary evaporated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 10% methanol/dichloromethane mobile phase. The obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 57-2 (white solid, 70 mg, product rate 70%). MS(ESI,m/z):852.3[M+H] + .
  • reaction solution was purified through a reverse-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate) within 25 minutes; detector UV254/220 Nano; obtained compound 57-3 (white solid, 50 mg, yield 76%).
  • reaction process was monitored by liquid mass spectrometry and thin-layer chromatography. After the reaction is completed, purify through a reverse-phase chromatography column (C18 column), and perform gradient elution with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes; detector UV254/220 nm; Compound 57-4 was obtained (white solid, 35.0 mg, yield 47%). MS(ESI,m/z):1294.6[M+H] + .
  • 1,4-dioxane hydrochloride solution (4 mol/L, 1 ml).
  • the mixture was reacted with stirring at 25 degrees Celsius for 1 hour.
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • the solvent is concentrated under reduced pressure to obtain a crude product.
  • the crude product is purified through a reversed-phase chromatography column (C18 column), using 0% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes. ) for elution; detector, UV254/220 nm; compound 57 (white solid, 25.0 mg, yield 83%) was obtained.
  • step 1
  • the mixture was extracted with ethyl acetate (50 ml ⁇ 2), the organic phases were combined, and then washed with anhydrous sodium sulfate. Dry and filter to remove the desiccant. The filtrate is rotary evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product was purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 20% ethyl acetate/petroleum ether mobile phase. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 58-21 (1.5 g, yield 56%), MS (ESI, m/z): 438.0[M+H] + .
  • bottle B Under nitrogen-protected stirring conditions at 25 degrees Celsius, 58-24 (1.5 g, 3.39 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide ( 10 ml). The mixture was then lowered to 0 degrees Celsius. Under nitrogen-protected stirring conditions at 0 degrees Celsius, sodium hydrogen (60%, 679 mg, 16.98 mmol, 5 equivalents) was added in portions to the mixture. The mixture was reacted for 1 hour under nitrogen protection and stirring at 0°C. Under nitrogen-protected stirring conditions at 0 degrees Celsius, add liquid A dropwise into bottle B. The resulting mixture was reacted under nitrogen-protected stirring conditions at 25 degrees Celsius for 16 hours.
  • the reaction was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, water (20 ml) was added to the reaction solution at 0 degrees Celsius to quench the reaction. The mixture was extracted with ethyl acetate (50 mL product. The crude product was purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 20% ethyl acetate/petroleum ether mobile phase. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain the crude product.
  • compound 40-1 (2.4 g, 4.655 mmol, 1.0 equivalent), compound 50-1 (1.51 g, 4.190 mmol, 0.9 equivalent), and potassium phosphate (2.08 g, 9.310 mmol, 2.0 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxy , phosphine pentylene (0.24 g, 0.698 mmol, 0.15 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.31 g, 0.326 mmol, 0.07 equiv), toluene (20 ml) and water (4 ml).
  • the mixture was reacted under nitrogen-protected stirring conditions at 80 degrees Celsius for 3 hours, and the reaction process was monitored by liquid mass spectrometry and thin-layer chromatography.
  • the reaction solution was cooled to room temperature. 50 ml of water was added to the reaction solution to dilute, and the resulting mixture was extracted with ethyl acetate (50 ml x 2) and dichloromethane (50 ml), and the organic phases were combined.
  • the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography.
  • reaction solution was cooled to zero degrees Celsius, ice water (20 ml) was added to quench the reaction, the mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3), the organic phases were combined, and then Dry with anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent from the filtrate by rotary evaporation under reduced pressure to obtain a crude product.
  • reaction solution was purified through a reversed-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; the detector UV254/ 220 nm; compound 58-5 was obtained (white solid, 50 mg, yield 90%).
  • the resulting mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. .
  • the crude product was purified through a reversed-phase chromatography column (C18 column) and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate) in 20 minutes; detector, UV254/220 nm; obtained Compound 58 (white solid, 16.2 mg, 41% yield).
  • the crude product was purified through a reversed-phase chromatography column (C18 column) and eluted with 5% ⁇ 95% acetonitrile/water mobile phase (0.1% ammonia solution) within 25 minutes; detector UV254/220 nm; compound 59 was obtained -1 (yellow oil, 4.5 g, yield 86%).
  • compound 59-2a 950 mg, 1.93 mmol, 1.0 equivalent
  • carbonylbis(triphenylphosphine)iridium chloride 158.5 mg, 0.193 mmol, 0.1 equiv
  • dichloromethane 10 mL
  • the mixture is extracted with chloroform/isopropyl alcohol (3/1, 10 ml x 3).
  • the organic phases are combined.
  • the organic phases are dried over anhydrous sodium sulfate and filtered to remove the dryness. agent, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product obtained was purified by reverse phase chromatography (C18 column).
  • Mobile phase A water (0.1% ammonium bicarbonate); mobile phase B: methanol, eluting with 5% ⁇ 95% phase B within 25 minutes; Detector UV254/220 nm; compound 59-6a (white solid, 50 mg, yield 65%) was obtained.
  • step 1
  • Compound 60-1 was synthesized according to the patent (WO2019179515A1).
  • the mixture was extracted with dichloromethane (1500 ml x 3), and the organic phases were combined; the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography, and eluted with a gradient of 0% ⁇ 10% ammonia methanol (7 mol/L)/dichloromethane mobile phase. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 60-2. (Colorless oil, 10.8 g, 87% yield).
  • the obtained crude product was purified by silica gel column chromatography, and eluted with a gradient of 0% ⁇ 5% methanol/dichloromethane mobile phase.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 60-3 (white solid, 13.7 mg, Yield 88%).
  • Triethylamine (12 ml) was slowly added dropwise to compound 60-8 (11.4 g, 36.7 mmol, 1 equivalent) in phosphorus oxychloride (120 ml) under nitrogen protection and stirring at 0°C. After the dropwise addition, react at 100 degrees Celsius for 16 hours. The reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction is completed, concentrate under reduced pressure to remove excess solvent to obtain a crude product. The obtained crude product was purified by silica gel column chromatography. The mobile phase was eluted with a 0% ⁇ 10% ethyl acetate/petroleum ether gradient.
  • the obtained crude product was purified by silica gel column chromatography, and eluted with a gradient of 0% ⁇ 20% ethyl acetate/petroleum ether mobile phase.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 60-10 (white solid, 10 g , yield 96%).
  • compound 60-11 (2 g, 3.790 mmol, 1.00 equivalent), compound 50-1 (1.64 g, 4.548 mmol, 1.2 equivalent), 3-( tert-Butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxy, phosphine pentyl (263.6 mg, 0.758 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (365.34 mg, 0.379 mmol, 0.1 equiv), potassium phosphate (1.69 g, 7.580 mmol, 2.0 equiv), water (4 ml) and toluene ( 20 ml).
  • the resulting mixture was reacted at 80 degrees Celsius under nitrogen-protected stirring conditions for 2 hours.
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • the reaction solution is filtered, and the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product is purified by silica gel column chromatography and eluted with a gradient of 0% ⁇ 50% ethyl acetate/petroleum ether mobile phase to obtain The solvent was removed from the fractions by concentration under reduced pressure to obtain compound 60-12 (white solid, 2 g, yield 78%).
  • reaction solution is directly purified through a reverse-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; detector UV254 /220 nm; compound 60-13 (white solid, 800 mg, yield 40%) was obtained.
  • step 1
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 30% methyl tert-butyl ether/petroleum ether.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 61-1 (light yellow). Solid, 33 g, 77% yield).
  • the mixture was extracted with ethyl acetate (500 ml x 3), and the combined organic phases were added with saturated brine (1 liter x 3 ), and after drying with anhydrous sodium sulfate, filter to remove the desiccant, and the filtrate is rotary evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • the crude product was purified with methyl tert-butyl ether/n-hexane (1/5, 200 ml) to obtain compound 61-2 (white solid, 29 g, yield 84%).
  • Chiral separation of compound 61-2 (28 g) obtained in step 2 of this example was carried out by supercritical liquid chromatography: chiral column CHIRALPAK IC, 5 x 25 cm, 5 ⁇ m; mobile phase A: supercritical carbon dioxide, mobile phase B: Isopropyl alcohol (0.5%, 2 mol/L ammonia methanol); flow rate: 200 ml/min; column temperature: 35 degrees Celsius; elute with 40% mobile phase B; detector UV220 nm, two products were obtained.
  • the mobile phase was eluted with a 0% ⁇ 10% methanol/dichloromethane gradient.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 61-8 (colorless oil, 370 mg , yield 97%).
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a gradient of 0% ⁇ 20% ethyl acetate/petroleum ether.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 61-9 (yellow solid, 580 mg). , yield 87%).
  • N,N-dimethylmethane was added to compound 61-9 (400 mg, 0.571 mmol, 1 equivalent) and compound 52-4 (151.47 mg, 0.628 mmol, 1.1 equivalent).
  • Cesium carbonate (391.34 mg, 1.142 mmol, 2 equiv) and triethylenediamine (13.47 mg, 0.114 mmol, 0.2 equiv) were added to the amide (5 mL) solution.
  • the resulting mixture was reacted at 50 degrees Celsius under nitrogen-protected stirring conditions for 2 hours. The reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • reaction solution was slowly added to 50 ml of ice water to quench the reaction.
  • the mixture was extracted with ethyl acetate (50 ml x 3).
  • the combined organic phases were washed with saturated brine (50 ml x 3), and then Dry over anhydrous sodium sulfate, filter to remove the desiccant, and remove the solvent by rotary evaporation under reduced pressure from the filtrate to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography. The mobile phase was eluted with a 0% ⁇ 10% methanol/dichloromethane gradient.
  • compound 61-11 (290 mg, 0.380 mmol, 1 equivalent) and compound 50-1 (205.45 mg, 0.570 mmol, 1.5 equivalent) were added to toluene (5 ml) and water ( 1 ml) to the mixed solution, add tris(dibenzylideneacetone)dipalladium (36.65 mg, 0.038 mmol, 0.1 equivalent), 3-(tert-butyl)-4-(2,6-dimethoxybenzene) in sequence base)-2,3-dihydrobenzo[D][1,3]oxy, phosphine pentylene (26.44 mg, 0.076 mmol, 0.2 equiv) and potassium phosphate (254.85 mg, 0.570 mmol, 3 equiv).
  • the resulting mixture was reacted at 80 degrees Celsius under nitrogen-protected stirring conditions for 4 hours.
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography.
  • the solvent is removed by rotary evaporation under reduced pressure from the reaction solution to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography.
  • the mobile phase was eluted with a 0% ⁇ 10% methanol/dichloromethane gradient.
  • the solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 61-12 (white solid, 210 mg, product rate 61%).
  • reaction solution was purified through a reversed-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; the detector UV254/ 220 nm; compound 62-3 was obtained (off-white solid, 760 mg, yield 51%).
  • triethylamine (40 mg, 0.40 mmol, 8.0 equivalent) was added to the above reaction system under nitrogen-protected stirring conditions at minus 78 degrees Celsius, and the mixture reacted for 20 minutes under nitrogen-protected stirring conditions at minus 78 degrees Celsius, and then slowly heated up. to 25 degrees Celsius, and reacted for 1 hour under nitrogen-protected stirring conditions at 25 degrees Celsius.
  • the reaction process was monitored by liquid mass chromatography and thin layer chromatography.
  • reaction solution was poured into ice water (20 ml) to quench, the mixture was extracted with chloroform/isopropyl alcohol (3/1, 20 ml x 3), the organic phases were combined, and then washed with anhydrous sodium sulfate. Dry, filter to remove the drying agent, and concentrate the filtrate under reduced pressure to obtain compound 62-6a (yellow oil, 50 mg).
  • step 1
  • reaction solution is rotary evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • step 1
  • reaction solution was purified through a reversed-phase chromatography column (C18 column), and eluted with 5% ⁇ 95% methanol/water (0.1% hydrochloric acid) mobile phase within 20 minutes; detector, UV254/220 nm. ; Obtain compound 64-6 (yellow solid, 50 mg, yield 75%). MS(ESI,m/z):1303.6.
  • the crude product obtained was purified by high performance liquid chromatography: chromatographic column: XBridge Shield RP18 OBD Column 30*150 mm, 5 microns; mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile; flow rate: 60 ml/ minutes; eluting with a gradient of 10% ⁇ 28% mobile phase B in 8 minutes, detector: 254/220 nm, gave compound 64 (yellow solid, 18 mg, yield 30%). MS(ESI,m/z):1159.5.
  • step 1
  • Compound 66-1 was synthesized with reference to the document WO2020207395.
  • step 1
  • step 1
  • step 1
  • the reaction process was monitored by liquid mass spectrometry and thin layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography. The mobile phase was eluted with a gradient of 0% ⁇ 10% methanol/dichloromethane. The solvent was removed from the obtained fractions by rotary evaporation under reduced pressure to obtain compound 72-3 (light yellow solid, 3.01 g, 81%). MS(ESI,m/z):436.4[M+H]+.
  • step 1
  • Compound 74-1 was prepared by referring to the procedure on page 861 of document WO2022147465.
  • the drug screening system based on the binding of KRAS_G12D and SOS1 was used to detect the inhibitory ability of small molecule compounds on the binding activity of KRAS-G12D and SOS1.
  • BI-2852 is used as a positive control, and its storage solution is the first point of dilution, diluted 3 times, and diluted 10+0 points. Similarly, the first dilution point of the compound to be tested is also its stock solution, diluted 3 times, diluted 11+0 points.
  • the final concentrations of the compounds to be tested were 200, 66.67, 22.22, 7.41, 2.47, 0.27, 0.091, 0.03, 0.0152, 0.01, and 0 ⁇ M.
  • BI-2852 is used as a positive control, and its storage solution is the first point of dilution, diluted 3 times, and diluted 10+0 points. Similarly, the first dilution point of the compound to be tested is also its stock solution, diluted 3 times, diluted 11+0 points.
  • the final concentrations of positive controls were 100, 33.33, 11.11, 3.70, 1.23, 0.412, 0.137, 0.046, 0.015, 0.005, 0 ⁇ M.
  • the final concentrations of the compounds to be tested were 200, 66.67, 22.22, 7.41, 2.47, 0.27, 0.091, 0.03, 0.0152, 0.01, and 0 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé cyclique de pyrimidine, un intermédiaire de celui-ci, une composition pharmaceutique de celui-ci et une utilisation associée. Le composé cyclique de pyrimidine est un composé tel que représenté par la formule (I) ou la formule (II), un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci. Le composé selon la présente invention a un bon effet inhibiteur ou un bon effet de dégradation de protéine sur un mutant de KRAS.
PCT/CN2023/108961 2022-07-22 2023-07-24 Composé cyclique de pyrimidine, intermédiaire de celui-ci, composition pharmaceutique de celui-ci et utilisation associée WO2024017392A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202210873453 2022-07-22
CN202210873453.X 2022-07-22
CN202211099004.0 2022-09-06
CN202211099004 2022-09-06
CN202211339276 2022-10-28
CN202211339276.3 2022-10-28
CN202211436744.9 2022-11-16
CN202211436744 2022-11-16
CN202310719570.5 2023-06-16
CN202310719570 2023-06-16

Publications (1)

Publication Number Publication Date
WO2024017392A1 true WO2024017392A1 (fr) 2024-01-25

Family

ID=89557240

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/108961 WO2024017392A1 (fr) 2022-07-22 2023-07-24 Composé cyclique de pyrimidine, intermédiaire de celui-ci, composition pharmaceutique de celui-ci et utilisation associée

Country Status (2)

Country Link
CN (1) CN117430620A (fr)
WO (1) WO2024017392A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112442030A (zh) * 2018-01-19 2021-03-05 南京明德新药研发有限公司 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物
WO2022148422A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022173678A1 (fr) * 2021-02-09 2022-08-18 Genentech, Inc. Composés d'oxazépine tétracycliques et leurs utilisations
WO2022228568A1 (fr) * 2021-04-30 2022-11-03 劲方医药科技(上海)有限公司 Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023081476A1 (fr) * 2021-11-05 2023-05-11 Ranok Therapeutics (Hangzhou) Co. Ltd. Procédés et compositions pour la dégradation ciblée de protéines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112442030A (zh) * 2018-01-19 2021-03-05 南京明德新药研发有限公司 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物
WO2022148422A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022173678A1 (fr) * 2021-02-09 2022-08-18 Genentech, Inc. Composés d'oxazépine tétracycliques et leurs utilisations
WO2022228568A1 (fr) * 2021-04-30 2022-11-03 劲方医药科技(上海)有限公司 Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023081476A1 (fr) * 2021-11-05 2023-05-11 Ranok Therapeutics (Hangzhou) Co. Ltd. Procédés et compositions pour la dégradation ciblée de protéines

Also Published As

Publication number Publication date
CN117430620A (zh) 2024-01-23

Similar Documents

Publication Publication Date Title
CN113563323B (zh) 一类苯并噻唑基联芳基类化合物、制备方法和用途
CN111484477B (zh) 一种苯并吡啶酮杂环化合物及其用途
CN113121530B (zh) 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物
CN110963994B (zh) 异吲哚啉类化合物、其制备方法、药物组合物及用途
TWI585088B (zh) 作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
CN116964036A (zh) Kras g12d抑制剂
EP4293027A1 (fr) Composés cycliques aromatiques de pyrimidine
JP2021073246A (ja) Ｂ−ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
KR20060054300A (ko) 선택적인 사이클린 의존성 키나제 4 억제제로서의이세싸이오네이트 염
CN113527335A (zh) 作为egfr抑制剂的大环类化合物及其应用
CN114846005A (zh) Shp2抑制剂及其应用
CN115746000A (zh) 用于调节布鲁顿酪氨酸激酶的化合物及方法
WO2022228576A1 (fr) Composé ciblant un régulateur de protéine et son application
JP2024505732A (ja) ピリドピリミジノン系誘導体及びその製造方法と使用
EP4324828A1 (fr) Composés d'acide carboxylique aromatique substitués bicycliques
WO2023125989A1 (fr) Composé de quinazoline et son application
CN114163457A (zh) 嘧啶并五元氮杂环化合物及其用途
CN114685531A (zh) 四并环化合物及其药物组合物和应用
WO2022194192A1 (fr) Composé hétéroaromatique, son procédé de préparation et son utilisation
CN116082360A (zh) 作为sos1抑制剂的多环化合物
WO2024017392A1 (fr) Composé cyclique de pyrimidine, intermédiaire de celui-ci, composition pharmaceutique de celui-ci et utilisation associée
CN115433207A (zh) 作为egfr抑制剂的大环杂环类化合物及其应用
CN112125908B (zh) Cdk激酶抑制剂、其制备方法、药物组合物和应用
CN117209501A (zh) 磺酰胺衍生物及其用途
WO2022198904A1 (fr) Intermédiaire clé d'un inhibiteur de kras et son procédé de préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23842454

Country of ref document: EP

Kind code of ref document: A1