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WO2022135591A1 - Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application - Google Patents

Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application Download PDF

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Publication number
WO2022135591A1
WO2022135591A1 PCT/CN2021/141360 CN2021141360W WO2022135591A1 WO 2022135591 A1 WO2022135591 A1 WO 2022135591A1 CN 2021141360 W CN2021141360 W CN 2021141360W WO 2022135591 A1 WO2022135591 A1 WO 2022135591A1
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group
alkyl
cycloalkyl
substituted
deuterium
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PCT/CN2021/141360
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English (en)
Chinese (zh)
Inventor
吕彬华
崔大为
刘连军
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Priority claimed from PCT/CN2021/071331 external-priority patent/WO2021143693A1/fr
Priority claimed from PCT/CN2021/099875 external-priority patent/WO2021249563A1/fr
Application filed by Suzhou Zelgen Biopharmaceutical Co Ltd, Shanghai Zelgen Pharmatech Co Ltd filed Critical Suzhou Zelgen Biopharmaceutical Co Ltd
Publication of WO2022135591A1 publication Critical patent/WO2022135591A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medicine, in particular to an aryl or heteroaryl pyridone or pyrimidone derivative and a preparation method and application thereof.
  • Lung cancer is one of the important causes of human cancer death.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market in 2016 was approximately US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
  • chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
  • molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment.
  • NSCLC molecularly targeted drugs include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, Rociletinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib, etc.), and VEGFR inhibitors ( Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.).
  • EGFR inhibitors such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, Rociletinib, osimertinib, etc
  • KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations.
  • the KRAS G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, there are still no drugs on the market that target the KRAS G12C mutation.
  • KRAS G12C target proteins are pathologically associated with various diseases, novel KRAS G12C inhibitors are still needed for clinical treatment.
  • Highly selective and highly active KRAS G12C inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS G12C mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
  • a and B are the same or different, and are each independently selected from the group consisting of CH, CR 5 or N;
  • X is selected from the group consisting of 4-14 membered saturated or unsaturated heterocyclic group, C 4 -C 14 cycloalkyl group, C 6 -C 14 aryl group or 5-14 membered heteroaryl group, wherein said heterocyclic group radical, cycloalkyl, aryl or heteroaryl can be optionally substituted with one or more (eg 2, 3 or 4) R8 ;
  • U, V, W and Q are the same or different and are each independently selected from the group consisting of CH, CR or N;
  • RA is absent, or independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C1 - C3 alkyl; each R B is independently selected from the group consisting of hydrogen, deuterium, cyano, or C1 -C 3 alkyl; wherein the alkyl may be substituted with one or more (eg 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes substituted or unsubstituted 4-8 membered heterocyclyl;
  • p is an integer of 1 or 2;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
  • L is selected from the group consisting of a bond, -C(O)-, C 1 -C 3 alkylene;
  • R 4 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 -aryl, 5-14-membered heteroaryl;
  • R 5 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, halogen, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group, urea group, 4-20-membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl group;
  • R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, 4-20 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
  • R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 1 is selected from the following group: Among them, p is 2;
  • R 1 is selected from the group consisting of: Among them, p is 2;
  • R is not selected from:
  • the compound of the present invention does not include the following compounds:
  • the compound does not include the following compounds:
  • each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, Sulfonamide group or urea group.
  • R 8 is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 - C 18 alkyl; wherein, the substitution refers to substitution by cyano.
  • R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl
  • each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl
  • the alkyl may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4- 7-membered heterocyclyl, NHR 9 or NR 9 R 10
  • R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , R 10 together with the N atom to which it is attached constitutes a substituted or unsubstituted 4 -8-membered heterocyclyl;
  • R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
  • substituted refers to being substituted by one or more groups selected from the following group unless otherwise specified: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy oxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamido or Urea group;
  • RA is independently selected from the following group: hydrogen, fluorine
  • each R B is the same or different, and independently selected from the group consisting of hydrogen or C 1 -C 3 alkyl groups, wherein the alkyl group may be substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10
  • R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 , to which R 10 is attached The N atoms together constitute a 4-8 membered heterocyclic group.
  • R 3 is halogen
  • a and B are the same or different, and are each independently CH or N.
  • Q is N.
  • U is N.
  • V and W are each independently CR 3 , and R 3 is H or halogen.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure represented by formula (II-A) or (II-B):
  • R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (III):
  • R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (IV):
  • R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (V):
  • R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown in formula (VI):
  • R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs is characterized by In that it has the structure shown in formula (VII):
  • R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown by formula (VIII):
  • R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • q is selected from: 1, 2, 3 or 4;
  • R 1 , R 4 , R 8 , R′, V, and Q are as described above.
  • R 8 may be 1, 2, 3 or 4, or two adjacent R 8 may together form a C 3 -C 6 cycloalkyl group with the C atom to which it is attached.
  • R 1 is selected from:
  • the compound has the structure shown in formula (VIII-A):
  • R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • q is selected from: 1, 2, 3 or 4;
  • R 1 , R 4 , R 8 , R′, V, and Q are as described above.
  • each R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, wherein the substitution refers to substitution by cyano.
  • each R 8 is independently a substituted or unsubstituted C 1 -C 3 alkyl group, wherein the substitution refers to being substituted by a cyano group.
  • each R 8 is methyl.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure shown by formula (IX):
  • R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
  • R4 , R', V, Q, R"' and q are as defined above.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4- 8-membered heterocyclyl, C 6 -C 10 aryl, 5-10-membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, Hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic group.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4- 6-membered heterocyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, wherein the substitution refers to being selected from the group consisting of Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl amino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl, Wherein, the substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
  • q is 1.
  • R 2 is selected from:
  • R 2 is selected from the following group:
  • K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
  • Parts are selected from the following group:
  • K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
  • the compound has the structure represented by formula (VIII-1) or (VIII-2):
  • Rx is selected from: F or Cl
  • Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
  • Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
  • R 1 is defined as above.
  • the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has The structure represented by formula (X) or (XI):
  • Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more (eg 2, 3, 4) groups from the following group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3 -C6 cycloalkyl, 4-6 membered heterocyclyl;
  • Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C3 alkyl , C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
  • Rx is selected from: F or Cl
  • R A is selected from: H, D, halogen, preferably R A is selected from: H or F.
  • R"' is as defined above;
  • q' is selected from 0, 1, 2, or 3.
  • the compound has the structure represented by formula (XII) or (XIII):
  • R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group;
  • R e can independently represent hydrogen, C1- C6 alkyl, C3 - C8 cycloalkyl, C
  • Rm, Rn, Rx, R A , q', R"' are as described above.
  • q' is 0.
  • the compound has the structure represented by formula (XIV) or (XV):
  • Rm, Rn, Rx, RA are as described above.
  • Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 3 alkyl.
  • Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Propylamino, azetidinyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxanyl , wherein the substitution refers to being substituted by one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide , C 1 -C 3 alkyl.
  • Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl;
  • Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
  • R 4b , R 4c and R 4d are H.
  • Rx is selected from: F or Cl.
  • RA is selected from: H, D, halogen, preferably RA is selected from: H or F.
  • the compound has the structure shown in formula (XVI):
  • R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • q is selected from: 1, 2, 3 or 4;
  • R 1 , R 4 , R 8 , R′, V, and Q are as described above.
  • the compound has the structure shown in formula (XVI-A):
  • R"' is each independently selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the following Substituted with one or more groups of the group: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C1 - C6 alkyl, C3 - C8 cycloalkyl, C4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • q is selected from: 1, 2, 3 or 4;
  • R 1 , R 4 , R 8 , R′, V, and Q are as described above.
  • the compound has the structure represented by formula (XVII):
  • R1 is selected from : Wherein, R A is selected from: H, D, halogen or cyano; R B and R B' are the same or different, each independently selected from: H, D, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of D, halogen, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4 -6-membered heterocyclyl or NR IV R V ; R IV and R V are the same or different, each independently selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered Heterocyclyl; or R IV , R V and adjacent N are cyclized together to form a 4-6 membered heterocyclyl;
  • R4 , R', V, Q, R"' and q are as defined above.
  • the compound has a structure represented by formula (XVIII-1) or (XVIII-2):
  • Rx is selected from: F or Cl
  • Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
  • Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
  • R 1 is defined as above.
  • the compound has the structure represented by formula (XIX) or (XX):
  • Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl;
  • Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group;
  • Rx is selected from: F or Cl
  • R A is selected from: H, D, halogen
  • q' is selected from 0, 1, 2 or 3;
  • R"' is selected from the group consisting of substituted or unsubstituted groups: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to one selected from the group or multiple groups substituted: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 Cycloalkenyl, 4-8 membered heterocyclyl, C6 - C14 aryl, 5-14 membered heteroaryl.
  • the compound has a structure represented by formula (XXI) or (XXII):
  • R b , R c can independently represent hydrogen, deuterium, C 1 - C6 alkyl, C3 - C8 cycloalkyl, 4-8 membered heterocyclyl, 5-14 membered heteroaryl or C6 - C14 aromatic ring, or Rb and Rc and N atom Together they can form a 4-8 membered heterocyclic group;
  • R e can independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl,
  • Rm, Rn, Rx, R A , q', R"' are as described above.
  • the compound has the structure represented by formula (XXIII) or (XXIV):
  • Rm, Rn, Rx, RA are as described above.
  • R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q, p, A, B, X, Rn, Rm, Rx, R A , R"', R 4a , R 4b , R 4c , R 4d , R 4e , q and q' are specific groups corresponding to the specific compounds in the examples.
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs the The compound is selected from the group consisting of:
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs do not contain
  • the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are selected from the examples compounds shown in.
  • the second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Include steps:
  • E is halogen, OH, OCOR 1 , OCO( i Bu), etc.
  • E 1 is -BH 2 , -B(OH) 2 , -Sn(Bu) 3 , -ZnBr, etc.;
  • PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
  • Y and Z are leaving groups selected from the group consisting of halogen or OTf;
  • the first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
  • the second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
  • R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined in the first aspect.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula (I), stereoisomers, tautomers and crystal forms thereof according to the first aspect , a pharmaceutically acceptable salt, hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab,
  • a preparation method of a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I), stereoisomer, tautomer described in the first aspect of the present invention
  • the form, pharmaceutically acceptable salt, hydrate, solvate or prodrug are mixed to form a pharmaceutical composition.
  • the fourth aspect of the present invention provides the compound of formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs , or the use of the pharmaceutical composition described in the third aspect, for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C .
  • the fifth aspect of the present invention provides a method for preventing and/or treating a disease related to the activity or expression level of KRAS G12C , comprising the step of: administering an effective amount of the compound of formula (I) described in the first aspect to a patient in need , a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or administer the pharmaceutical composition of the third aspect.
  • the disease is a tumor or a disordered disease.
  • the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the sixth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS G12C , which comprises the steps of: administering to a patient in need an effective amount of the compound of formula (I) described in the first aspect, its stereoisomeric isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer the pharmaceutical composition of the third aspect.
  • a seventh aspect of the present invention provides a method for inhibiting KRAS G12C in vitro, comprising the steps of: adding the compound described in the first aspect, its stereoisomer, tautomer, crystal form and pharmaceutically acceptable salt , hydrate, solvate or prodrug, or the composition of the third aspect, in contact with a somatic cell.
  • the somatic cells are derived from primates (eg, humans).
  • the present inventors unexpectedly prepared a new class of compounds with selective inhibition of KRAS G12C and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • substituents are described by conventional chemical formulae written from left to right, such substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.
  • substituents are described by conventional chemical formulae written from left to right, such substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left.
  • -CH2O- is equivalent to -OCH2- .
  • alkyl refers to a straight or branched chain alkane group, which may include any number of carbon atoms, wherein "C 1 -C 18 alkyl” refers to a group including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms, preferably for example C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 - C 5 , C 1 -C 6 , C 1 -C 7 , C 1 -C 8 , C 1 -C 9 , C 1 -C 10 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 , C 2 -C 6 , C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 4 -C 5 , C 4 -C 6 or C 5-6 .
  • alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • the alkyl group also includes a substituted alkyl group. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, wherein "C 3 -C 20 cycloalkyl” refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10, Fully saturated cyclic hydrocarbon groups of 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, including 1-4 rings, each containing 3-8 carbon atom.
  • C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 Preferably C 3 -C 4 , C 3 -C 5 , C 3 -C 6 , C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 .
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • cycloalkyl is intended to include “substituted cycloalkyl”.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group
  • heterocyclyl refers to a group containing 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms fully saturated or partially unsaturated cyclic groups (including but not limited to, such as 3-7 membered monocyclic, 6 -11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in the ring having at least one carbon atom.
  • Each heteroatom-containing heterocycle may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein nitrogen or sulfur may be oxidized or nitrogen may be quaternized.
  • a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroacridine Heptinyl, 4-piperidinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone sulfone, 1,3-dioxanyl And tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclolinked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups; heterocyclyl groups may be substituted or unsubstituted.
  • aryl refers to an aromatic cyclic hydrocarbon compound group, wherein "C6-C14 aryl” refers to a group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms.
  • Aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups, such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.).
  • “Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • heteroaryl refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur.
  • 5-14 membered heteroaryl refers to an aromatic cyclic hydrocarbon compound group containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein Contains 1-4 heteroatoms selected from N, O, S.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, heteroaryl includes but is not limited to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadi azolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • alkoxy refers to a straight chain or branched chain or cyclic alkoxy group
  • C1-C18 alkoxy refers to a straight chain or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms Oxy group, including C1-C18 alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, preferably C1-C8 alkoxy, more preferably C1-C6 alkoxy, alkoxy includes But not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy and the like.
  • Cycloalkenyl refers to a cyclic hydrocarbon group with one or more double bonds, wherein, “C 4 -C 10 cycloalkenyl” refers to one or more double bonds, including 4, 5, 6, 7, A cyclic hydrocarbon group of 8, 9 or 10 carbon atoms, preferably C 4 -C 6 cycloalkenyl, cycloalkenyl includes but is not limited to: cyclobutenyl, cyclopentenyl, cyclopentadienyl, cycloalkenyl Hexenyl, cyclohexadienyl, etc.
  • esters refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
  • amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
  • R and R' may be the same or different, and when both R and R' are H, the amine group is -NH 2 .
  • amine groups include, but are not limited to, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, butylamine, and the like.
  • R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
  • R and R' can be the same or different.
  • sulfonamido refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
  • R and R' can be the same or different.
  • aminonosulfonyl refers to a group with the structure -NRSO2R ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • R and R' can be the same or different.
  • ureido refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
  • the alkyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, the heteroaryl group, and the heterocyclic group have the above-mentioned definitions.
  • R, R' and R" can be the same or different.
  • an alkyl group is an alkylene group after one H atom is removed (such as : methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as ), etc.), cycloalkyl corresponds to cycloalkylene (such as: etc.), the heterocyclic group corresponds to the heterocyclic group (such as: ), cycloalkyl corresponds to heterocyclylene (such as: etc.), alkoxy corresponds to alkyleneoxy (-CH 2 O-, -CH 2 CH 2 -O-CH 2 -, -CH 2 OCH 2 CH 2 CH 2 -) and the like.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo means that the H in the group is replaced by a halogen.
  • deuterated refers to the replacement of an H in a group with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • substituted or unsubstituted means that the H atom of the selected group is substituted or unsubstituted, and the selected group does not contain an H atom and will not be substituted.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above-mentioned purposes.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position.
  • the groups include corresponding substituted groups and subgroups, for example, alkyl groups include substituted alkyl groups, cycloalkyl groups include substituted cycloalkyl groups, and aryl groups include substituted aryl groups , a heteroaryl group includes a substituted heteroaryl group, a heterocyclic group includes a substituted heterocyclic group, and the like. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, heteroaryl or aryl and their corresponding substituent groups and subunits may be optionally substituted, wherein , the alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl groups have the above definitions.
  • compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as deuterated compounds) or prodrugs.
  • the term also includes racemates, optical isomers.
  • the compound of formula (I) has the following structure:
  • R 1 , R 2 , R 4 , L, U, V, W, Q, A, B, and X are as described above.
  • the compound of formula (I) has the structure shown in formula (II-A) or (II-B):
  • R 1 , R 2 , R 4 , A, B, L, X, U, V, W, Q are defined as described above.
  • the compound of formula (I) has the structure shown in formula (III):
  • R 1 , R 2 , R 4 , X, L, U, V, W, and Q are as described above.
  • the compound of formula (I) has the structure shown in formula (IV):
  • R 1 , R 2 , R 4 , R 8 , L, U, V, W, Q are defined as above.
  • the compound of formula (I) has the structure shown in formula (V):
  • R 1 , R 2 , R 4 , R 8 , U, V, W, Q are defined as described above.
  • the compound of formula (I) has the structure shown in formula (VI):
  • R 1 , R 2 , R 4 , R 8 , U, V, and Q are as described above.
  • the compound of formula (I) has the structure shown in formula (VII):
  • R 1 , R 2 , R 4 , R 8 , V and Q are as described above.
  • R A is independently selected from the group consisting of hydrogen, deuterium, fluorine, cyano, or C 1 -C 3 alkyl
  • each R B is the same or different, and is independently selected from the group consisting of hydrogen, deuterium, cyano or C 1 -C 3 alkyl
  • the alkyl may be substituted with one or more (eg 2, 3, 4 or 5) substituents selected from the group consisting of deuterium, halogen, cyano, amine, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10
  • R 9 and R 10 are each independently C 1 -C 3 alkyl; or R 9 to which R 10 is attached The N atoms together form a substituted or unsubstituted 4-8 membered heterocyclic group;
  • R 6 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, 4-8 membered heterocyclic group, C 6 -C 14 aryl base, 5-14-membered heteroaryl;
  • Q is N.
  • V and W are each independently CR 3 , and R 3 is H or halogen; preferably, R 3 is halogen.
  • R 8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8 membered hetero Cyclic; said substitution means substitution with one or more (eg, 2, 3, 4, or 5) groups selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amido, sulfonamide or ureido; more preferably, R8 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C1 - C6 alkyl, deuterated C1- C 6 alky
  • each R8 is methyl.
  • the compound has the structure shown in formula (VIII):
  • R"' is each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C6 alkyl, C3 - C8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • q is selected from: 1, 2, 3, or 4;
  • R 1 , R 4 , R 8 , R′, V, and Q are as described above.
  • the compound has the structure shown in formula (IX):
  • R 1 , R 4 , R', V, R"', Q and q are as defined above.
  • Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
  • Rx is selected from: hydrogen, deuterium, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C C 3 alkoxy, halogen, nitro, hydroxyl, cyano, ester, 4-6 membered heterocyclic group, preferably, part of
  • R is selected from the group consisting of :
  • K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
  • the compound has the structure shown in formula (VIII):
  • R"' is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C 1 -C 6 alkyl, C 3 -C 8 -cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amido, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 - C 10 cycloalkenyl, 4-8 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 1 , R 4 , R 8 , R', V, Q, and q are as defined above.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 10 cycloalkenyl, 4-8 membered heterocycle base, C 6 -C 10 aryl, 5-10 membered heteroaryl, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano , ester group, amine group, amide group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, 4-8 membered heterocyclic group.
  • R"' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, 4-6 membered heterocycle group, more preferably, R"' is selected from the group consisting of substituted or unsubstituted groups: radical, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidinyl, azepanyl, azetidine, oxiranyl, oxetanyl, oxolane, oxanyl, wherein, The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alky
  • Parts are selected from the following group:
  • K is independently O, S, CH2 or NH; e and f are each independently 0, 1 or 2, preferably H in the above groups can be optionally deuterium, halogen, nitro, hydroxyl, cyano, Ester group, amine group, amide group, C 1 -C 3 alkyl substitution.
  • the compound has a structure represented by formula (X) or (XI):
  • Rm is selected from the group consisting of substituted or unsubstituted groups: amine group, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 4-6 membered heterocyclic group, wherein the substitution refers to the selected Substituted with one or more groups from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl, C3-C6 cycloalkyl, 4- 6-membered heterocyclic group;
  • Rn is selected from the group consisting of substituted or unsubstituted groups: amine, C1 - C6alkyl , C1 - C6alkoxy , C3 - C6cycloalkyl, -OC3 - C6cycloalkane base, C 1 -C 6 alkyl C 3 -C 6 cycloalkyl, -OC 1 -C 6 alkyl C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl, C1 - C3 haloalkyl , C3-C6 cycloalkyl, 4-6 membered heterocyclyl;
  • Rx is selected from: F or Cl
  • R A is selected from: H, D, halogen, or cyano, preferably R A is selected from: H or F.
  • R"' is as defined above;
  • q' is selected from 0, 1, 2, or 3.
  • the compound has a structure represented by formula (VIII-1):
  • R 1 , Rx, R 4 , Rm and Rn are defined as described above.
  • the compound has a structure represented by formula (X)
  • R A , Rx, R 4 , Rm, Rn, q"' and q' are defined as described above.
  • the compound has the structure represented by formula (XII)
  • R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx, R A , q' and R"' are as described above.
  • the compound has the structure shown in formula (XIV):
  • R 4a , R 4b , R 4c , R 4d , R 4e , Rm, Rn, Rx and RA are as described above.
  • Rn is selected from the group consisting of substituted or unsubstituted groups: ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, azetidine alkyl, azepanyl, azepanyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the substitution is means substituted with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxy, cyano, ester, amine, amide, C1 - C3 alkyl.
  • Rm is selected from the group consisting of substituted or unsubstituted groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, nitrogen cyclobutanyl, azepanyl, azetidinyl, oxiranyl, oxetanyl, oxolane, oxetanyl, wherein the The substitution refers to substitution with one or more groups selected from the group consisting of deuterium, halogen, nitro, hydroxyl, cyano, ester, amine, amide, C1 - C3 alkyl.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound of the present invention the compound obtained by successively preparing, isolating and purifying the compound has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text List.
  • very pure compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then the diastereomeric salt can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels or synthesized according to the reported literature unless otherwise specified.
  • E is halogen, OH, OCOR 1 , OCO( i Bu), etc.
  • E 1 is -BH 2 , -B(OH) 2 , -Sn(Bu) 3 , -ZnBr, etc.;
  • PG is an amino protecting group selected from the group consisting of Boc, Bn, Cbz or Fmoc;
  • Y and Z are leaving groups selected from the group consisting of halogen or OTf;
  • the first base is selected from the group consisting of KHMDS, NaHMDS, LiHMDS, NaH, NaOMe, NaOEt or tBuONa ;
  • the second base is selected from the group consisting of TEA, DIPEA, DMAP or N,N-dimethylaniline;
  • R 1 , R 2 , R 4 , L, A, B, X, U, V, W and Q are as defined above.
  • reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
  • reaction solvent the reaction solvent, reaction catalyst, base used in the reaction, reaction temperature, reaction time, etc.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula (I) may preferably be used.
  • Drug combinations also include administration of a compound of formula (I) with one or more other known drugs at overlapping time periods.
  • the doses of the compound of formula (I) or known drugs may be lower than their doses alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR -120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as Duval) Monoclonal antibody, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or any of the above Biosimilars, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofat
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention The compounds are mixed to form a pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of formula (I) described in the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof to a subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .
  • the present invention has the following main advantages:
  • the compound has a good selective inhibitory effect on KRAS G12C ;
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects; wherein, the experimental results show that the compound containing phenylsulfone structure has better pharmacokinetic properties than other structures, For example, compounds with pyridine sulfone structure, compounds containing dimethylpiperazine structure have better efficacy than monomethylpiperazine;
  • R 4 is a phenyl group
  • the biological activity is better than that of a heteroaryl group.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • 2,6-Dichloro-5-fluoronicotinamide (873 mg, 4.2 mmol) was dissolved in 15 mL of dry tetrahydrofuran, and oxalyl chloride (3.6 mL, 42.0 mmol) in dichloromethane (4.5 mL) was slowly added dropwise to this solution. mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 15 mL of dry tetrahydrofuran and cooled to zero.
  • Step 7 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4 Preparation of -methyl-2-(methylsulfo)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 5-1 Two isomers Example 5A and Example 5B were obtained by chiral separation:
  • Example 5A LC-MS: m/z 610 (M+H) + .
  • Example 5B LC-MS: m/z 610 (M+H) + .
  • Example 6-1 obtained two isomers Example 5A and Example 5B by chiral separation:
  • Example 6A LC-MS: m/z 622 (M+H) + .
  • Example 6B LC-MS: m/z 622 (M+H) + .
  • Example 10-1 Two isomers Example 10A and Example 10B were obtained by chiral separation:
  • Example 10A LC-MS: m/z 624 (M+H) + .
  • Example 10B LC-MS: m/z 624 (M+H) + .
  • Example 12 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(methylsulfonyl)phenyl )-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 16-1 Two isomers Example 16A and Example 16B were obtained by chiral separation:
  • Example 16A LC-MS: m/z 625 (M+H) + .
  • Example 16B LC-MS: m/z 625 (M+H) + .
  • Example 18-1 Two isomers Example 18A and Example 18B were obtained by chiral separation:
  • Example 18A LC-MS: m/z 625 (M+H) + .
  • Example 18B LC-MS: m/z 625 (M+H) + .
  • Example 20-1 Two isomers Example 20A and Example 20B were obtained by chiral separation:
  • Example 20A LC-MS: m/z 625 (M+H) + .
  • 1 H NMR 400MHz, DMSO
  • Example 20B LC-MS: m/z 625 (M+H) + .
  • Example 25-1 Two isomers Example 25A and Example 25B were obtained by chiral separation:
  • Example 25A LC-MS: m/z 636 (M+H) + .
  • Example 25B LC-MS: m/z 636 (M+H) + .
  • Example 29-1 Two isomers Example 29A and Example 29B were obtained by chiral separation:
  • Example 29A LC-MS: m/z 625 (M+H) + .
  • Example 29B LC-MS: m/z 625 (M+H) + .
  • Example 30-1 Two isomers Example 30A and Example 30B were obtained by chiral separation:
  • Example 30A LC-MS: m/z 624 (M+H) + .
  • Example 30B LC-MS: m/z 624 (M+H) + .
  • 1 H NMR 400MHz, DMSO
  • Example 31-1 Two isomers Example 31A and Example 31B were obtained by chiral separation:
  • Example 31A LC-MS: m/z 666 (M+H) + .
  • 1 H NMR 400MHz, DMSO
  • 7.66(t,J 7.8Hz,1H)
  • 7.56(td,J 8.4,6.6Hz,1H)
  • Example 32-1 Two isomers Example 32A and Example 32B were obtained by chiral separation:
  • Example 32A LC-MS: m/z 642 (M+H) + .
  • Example 32B LC-MS: m/z 642 (M+H) + .
  • Example 33-1 Two isomers Example 33A and Example 33B were obtained by chiral separation:
  • Example 33A LC-MS: m/z 625 (M+H) + .
  • Example 33B LC-MS: m/z 625 (M+H) + .
  • Example 34-1 Two isomers Example 34A and Example 34B were obtained by chiral separation:
  • Example 34A LC-MS: m/z 643 (M+H) + .
  • Example 34B LC-MS: m/z 643 (M+H) + .
  • Example 35-1 Two isomers Example 35A and Example 35B were obtained by chiral separation:
  • Example 35A LC-MS: m/z 636 (M+H) + .
  • Example 35B LC-MS: m/z 636 (M+H) + .
  • Example 36-1 Two isomers Example 36A and Example 36B were obtained by chiral separation:
  • Example 36A LC-MS: m/z 654 (M+H) + .
  • Example 36B LC-MS: m/z 654 (M+H) + .
  • Example 37-1 Two isomers Example 37A and Example 37B were obtained by chiral separation:
  • Example 37A LC-MS: m/z 625 (M+H) + .
  • Example 37B LC-MS: m/z 625 (M+H) + .
  • Example 38-1 Two isomers Example 38A and Example 38B were obtained by chiral separation:
  • Example 38A LC-MS: m/z 625 (M+H) + .
  • Example 38B LC-MS: m/z 625 (M+H) + .
  • Example 39-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
  • Example 39A LC-MS: m/z 625 (M+H) + .
  • Example 39B LC-MS: m/z 625 (M+H) + .
  • Example 40-1 Two isomers Example 39A and Example 39B were obtained by chiral separation:
  • Example 40A LC-MS: m/z 625 (M+H) + .
  • Example 40B LC-MS: m/z 625 (M+H) + .
  • Example 41-1 Two isomers Example 41A and Example 41B were obtained by chiral separation:
  • Example 41A LC-MS: m/z 606 (M+H) + .
  • Example 41B LC-MS: m/z 606 (M+H) + .
  • Example 42-1 Two isomers Example 42A and Example 42B were obtained by chiral separation:
  • Example 42A LC-MS: m/z 606 (M+H) + .
  • Example 42B LC-MS: m/z 606 (M+H) + .
  • Example 43-1 Two isomers Example 43A and Example 43B were obtained by chiral separation:
  • Example 43A LC-MS: m/z 606 (M+H) + .
  • Example 43B LC-MS: m/z 606 (M+H) + .
  • Example 44-1 Two isomers Example 44A and Example 44B were obtained by chiral separation:
  • Example 44A LC-MS: m/z 606 (M+H) + .
  • Example 44B LC-MS: m/z 606 (M+H) + .
  • Example 45-1 Two isomers Example 45A and Example 45B were obtained by chiral separation:
  • Example 45A LC-MS: m/z 680 (M+H) + .
  • Example 45B LC-MS: m/z 680 (M+H) + .
  • Example 46-1 Two isomers Example 46A and Example 46B were obtained by chiral separation:
  • Example 46A LC-MS: m/z 694 (M+H) + .
  • Example 46B LC-MS: m/z 694 (M+H) + .
  • Example 47-1 Two isomers Example 47A and Example 47B were obtained by chiral separation:
  • Example 47A LC-MS: m/z 681 (M+H) + .
  • Example 47B LC-MS: m/z 681 (M+H) + .
  • Example 48 (2-(4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-(methylsulfonyl) )phenyl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-7-yl)-3-fluorophenyl)carbamate
  • Example 48-1 Two isomers Example 48A and Example 48B were obtained by chiral separation:
  • Example 48A LC-MS: m/z 681 (M+H) + .
  • Example 48B LC-MS: m/z 681 (M+H) + .
  • Example 49-1 Two isomers Example 49A and Example 49B were obtained by chiral separation:
  • Example 49A LC-MS: m/z 680 (M+H) + .
  • Example 49B LC-MS: m/z 680 (M+H) + .
  • Example 50-1 Two isomers Example 50A and Example 50B were obtained by chiral separation:
  • Example 50A LC-MS: m/z 701 (M+H) + .
  • Example 50B LC-MS: m/z 701 (M+H) + .
  • 2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C.
  • the ethyl acetate layers were combined, dried, and concentrated.
  • Step 5 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
  • Example 53-1 Two isomers Example 53A and Example 53B were obtained by chiral separation:
  • Example 53A LC-MS: m/z 596 (M+H) + .
  • Example 53B LC-MS: m/z 596 (M+H) + .
  • Example 62-1 Two isomers Example 62A and Example 62B were obtained by chiral separation:
  • Example 62A LC-MS: m/z 692 (M+H) + .
  • Example 62B LC-MS: m/z 692 (M+H) + .
  • Example 63 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Zinc powder 52 g, 800 mmol, Acros
  • tetrahydrofuran 100 mL
  • trimethylsilyl chloride 8.7 g, 80 mmol
  • bromocyclobutane 54g, 400mmol
  • 2-bromo-6-(methylsulfonyl)aniline 10g, 40mmol
  • [1,1'-bis(diphenylphosphine) were added
  • ferrocene] palladium dichloride dichloromethane complex 3.3 g, 4 mmol
  • 2,6-Dichloro-5-fluoronicotinamide (7.7 g, 37 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and oxalyl chloride (47 g, 370 mmol) was slowly added dropwise to this solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 hours, and then concentrated to dryness under reduced pressure. The residue was diluted with 100 mL of anhydrous tetrahydrofuran and cooled to zero. 2-Cyclobutyl-6-(methylsulfonyl)aniline (8.8 g, 39 mmol) was dissolved in 50 mL of dry tetrahydrofuran and added dropwise to the above solution.
  • reaction solution was stirred at zero degrees for 2 hours, quenched with saturated ammonium chloride/saturated brine (1:1, 100 mL), and then extracted twice with ethyl acetate (50 mL).
  • the combined organic phases were dried, concentrated, and the residual solid was slurried with petroleum ether/ethyl acetate (5:1, 200 mL), suction filtered, and dried to obtain the target product (12.7 g, yield: 75%).
  • Step 6 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-7-chloro-1-(2-cyclobutyl-6-(methyl) Preparation of sulfonyl)phenyl)-6-fluoropyridin[2,3-d]pyrimidin-2(1H)-one
  • Step 7 4-((2S,5R)-4-Acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclobutyl-6-(methylsulfonyl) Preparation of phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 63-1 obtained two isomers Examples 63A and 63B by chiral separation:
  • Example 76 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(1,4-dimethyl-1H-imidazol-5-yl)-6-fluoro -1-(2-Isopropyl-6-(methylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 78 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 78-1 Two isomers Examples 78A and 78B were obtained by chiral separation:
  • Example 79-1 Two isomers Examples 79A and 79B were obtained by chiral separation:
  • Example 80 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-6-(isopropylsulfonyl)phenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 80-1 Two isomers Examples 80A and 80B were obtained by chiral separation:
  • Example 81 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-cyclopropyl-6-(methylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 81-1 Two isomers Examples 81A and 81B were obtained by chiral separation:
  • Example 82 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 82-1 Two isomers Examples 82A and 82B were obtained by chiral separation:
  • Example 83 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(2-ethyl-6-(isopropylsulfonyl)phenyl)-6- Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 83-1 Two isomer Examples 83A and 83B were obtained by chiral separation:
  • Example 84 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-ethyl-6-(methylsulfonyl) Acyl)phenyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Example 84-1 Two isomers Examples 84A and 84B were obtained by chiral separation:
  • 2,6-Dichloro-5-fluoronicotinamide (420 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (7 mL), and to this solution was slowly added dropwise oxalyl chloride (1.7 mL, 20.0 mmol) in dichloromethane ( 2mL) solution. After the dropwise addition, the mixture was stirred at 75°C under reflux for 2 h, and then concentrated to dryness under reduced pressure. The residue was diluted with anhydrous tetrahydrofuran (7 mL) and cooled to 0°C.
  • the ethyl acetate layers were combined, dried, and concentrated.
  • Step 5 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2 Preparation of -(methylsulfonyl)phenyl)pyridin[2,3-d]pyrimidin-2(1H)-one
  • Example 87-1 Two isomers Example 87A and Example 87B were obtained by chiral separation:
  • Example 87A LC-MS: m/z 596 (M+H) + .
  • Example 87B LC-MS: m/z 596 (M+H) + .

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Abstract

La présente invention concerne un dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application. Plus particulièrement, le composé a une structure telle que représentée dans la formule (I). L'invention concerne également un procédé de préparation du composé et une application du composé en tant qu'inhibiteur de KRASG12C. Le composé présente un bon effet d'inhibition sélective sur KRASG12C, et présente de meilleures performances pharmacodynamiques et pharmacocinétiques et une toxicité plus faible et moins d'effets secondaires.
PCT/CN2021/141360 2020-12-25 2021-12-24 Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application Ceased WO2022135591A1 (fr)

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CN202011563650.9A CN114671866A (zh) 2020-12-25 2020-12-25 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
CNPCT/CN2021/071331 2021-01-12
PCT/CN2021/071331 WO2021143693A1 (fr) 2020-01-13 2021-01-12 Dérivé de pyridone ou de pyrimidine aryle ou hétéroaryle, son procédé de préparation et son utilisation
CNPCT/CN2021/099875 2021-06-11
PCT/CN2021/099875 WO2021249563A1 (fr) 2020-06-12 2021-06-11 Dérivé de pyridone ou de pyrimidone aryle ou hétéroaryle, son procédé de préparation et son utilisation

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WO2021143693A1 (fr) * 2020-01-13 2021-07-22 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidine aryle ou hétéroaryle, son procédé de préparation et son utilisation

Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019051291A1 (fr) * 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
CN110366550A (zh) * 2016-12-22 2019-10-22 美国安进公司 作为用于治疗肺癌、胰腺癌或结直肠癌的KRAS G12C抑制剂的苯并异噻唑、异噻唑并[3,4-b]吡啶、喹唑啉、酞嗪、吡啶并[2,3-d]哒嗪和吡啶并[2,3-d]嘧啶衍生物
WO2019213516A1 (fr) * 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
US20190374542A1 (en) * 2018-06-12 2019-12-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019241157A1 (fr) * 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
WO2020106647A2 (fr) * 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
CN111205286A (zh) * 2020-01-13 2020-05-29 李丹 作为kras g12c突变蛋白抑制剂的腈甲基哌嗪类衍生物及其应用
CN111377918A (zh) * 2019-11-29 2020-07-07 苏州信诺维医药科技有限公司 一种kras抑制剂化合物
CN111484477A (zh) * 2019-01-29 2020-08-04 博瑞生物医药（苏州）股份有限公司 一种苯并吡啶酮杂环化合物及其用途
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application
CN112159405A (zh) * 2020-02-04 2021-01-01 广州必贝特医药技术有限公司 吡啶并嘧啶酮类化合物及其应用
CN112225734A (zh) * 2019-10-25 2021-01-15 南京瑞捷医药科技有限公司 Kras g12c抑制剂及其用途
WO2021011417A1 (fr) * 2019-07-12 2021-01-21 The Regents Of The University Of California Mise en contact avec la cible d'un anticorps monoclonal chimiquement régulé
CN112390818A (zh) * 2019-08-12 2021-02-23 劲方医药科技(上海)有限公司 取代的杂芳环并二氢嘧啶酮衍生物，其制法与医药上的用途
CN112390796A (zh) * 2019-08-19 2021-02-23 贝达药业股份有限公司 Kras g12c抑制剂及其在医药上的应用
CN112552294A (zh) * 2019-09-10 2021-03-26 上海翰森生物医药科技有限公司 含哌嗪杂环类衍生物抑制剂、其制备方法和应用
CN112585129A (zh) * 2019-05-21 2021-03-30 益方生物科技(上海)股份有限公司 杂环化合物，其制备方法和用途
CN112574199A (zh) * 2020-05-20 2021-03-30 首药控股(北京)股份有限公司 Kras-G12C抑制剂杂环化合物
WO2021076655A1 (fr) * 2019-10-15 2021-04-22 Amgen Inc. Multithérapie d'inhibiteur de kras et d'inhibiteur de shp2 pour le traitement de cancers
WO2021081212A1 (fr) * 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer
CN112920183A (zh) * 2019-12-06 2021-06-08 南京圣和药业股份有限公司 作为kras-g12c抑制剂的化合物及其应用
WO2021113595A1 (fr) * 2019-12-06 2021-06-10 Beta Pharma, Inc. Dérivés de phosphore utilisés comme inhibiteurs de kras
WO2021120045A1 (fr) * 2019-12-18 2021-06-24 InventisBio Co., Ltd. Composés hétérocycliques, leurs procédés de préparation et utilisations associées
WO2021126816A1 (fr) * 2019-12-16 2021-06-24 Amgen Inc. Schéma posologique d'un inhibiteur du kras g12c
WO2021121367A1 (fr) * 2019-12-19 2021-06-24 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de protéine mutante kras
CN113061132A (zh) * 2020-01-01 2021-07-02 上海凌达生物医药有限公司 一类稠环内酰胺类化合物、制备方法和用途
CN113105448A (zh) * 2020-01-13 2021-07-13 苏州泽璟生物制药股份有限公司 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
CN113286794A (zh) * 2019-11-04 2021-08-20 北京加科思新药研发有限公司 Kras突变蛋白抑制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134218A (zh) * 2009-06-15 2011-07-27 凯美隆(北京)药业技术有限公司 6-芳氨基吡啶酮磺酰胺和6-芳氨基吡嗪酮磺酰胺mek抑制剂
WO2021143693A1 (fr) * 2020-01-13 2021-07-22 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidine aryle ou hétéroaryle, son procédé de préparation et son utilisation
CN113801113A (zh) * 2020-06-12 2021-12-17 苏州泽璟生物制药股份有限公司 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110366550A (zh) * 2016-12-22 2019-10-22 美国安进公司 作为用于治疗肺癌、胰腺癌或结直肠癌的KRAS G12C抑制剂的苯并异噻唑、异噻唑并[3,4-b]吡啶、喹唑啉、酞嗪、吡啶并[2,3-d]哒嗪和吡啶并[2,3-d]嘧啶衍生物
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019051291A1 (fr) * 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213516A1 (fr) * 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019241157A1 (fr) * 2018-06-11 2019-12-19 Amgen Inc. Inhibiteurs de kras g12c pour le traitement du cancer
US20190374542A1 (en) * 2018-06-12 2019-12-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020106647A2 (fr) * 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
CN111484477A (zh) * 2019-01-29 2020-08-04 博瑞生物医药（苏州）股份有限公司 一种苯并吡啶酮杂环化合物及其用途
CN112585129A (zh) * 2019-05-21 2021-03-30 益方生物科技(上海)股份有限公司 杂环化合物，其制备方法和用途
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application
WO2021011417A1 (fr) * 2019-07-12 2021-01-21 The Regents Of The University Of California Mise en contact avec la cible d'un anticorps monoclonal chimiquement régulé
CN112390818A (zh) * 2019-08-12 2021-02-23 劲方医药科技(上海)有限公司 取代的杂芳环并二氢嘧啶酮衍生物，其制法与医药上的用途
CN112390796A (zh) * 2019-08-19 2021-02-23 贝达药业股份有限公司 Kras g12c抑制剂及其在医药上的应用
CN112552294A (zh) * 2019-09-10 2021-03-26 上海翰森生物医药科技有限公司 含哌嗪杂环类衍生物抑制剂、其制备方法和应用
WO2021076655A1 (fr) * 2019-10-15 2021-04-22 Amgen Inc. Multithérapie d'inhibiteur de kras et d'inhibiteur de shp2 pour le traitement de cancers
WO2021081212A1 (fr) * 2019-10-24 2021-04-29 Amgen Inc. Dérivés de pyridopyrimidine utiles en tant qu'inhibiteurs de kras g12c et de kras g12d dans le traitement du cancer
CN112225734A (zh) * 2019-10-25 2021-01-15 南京瑞捷医药科技有限公司 Kras g12c抑制剂及其用途
CN113286794A (zh) * 2019-11-04 2021-08-20 北京加科思新药研发有限公司 Kras突变蛋白抑制剂
CN111377918A (zh) * 2019-11-29 2020-07-07 苏州信诺维医药科技有限公司 一种kras抑制剂化合物
CN112920183A (zh) * 2019-12-06 2021-06-08 南京圣和药业股份有限公司 作为kras-g12c抑制剂的化合物及其应用
WO2021113595A1 (fr) * 2019-12-06 2021-06-10 Beta Pharma, Inc. Dérivés de phosphore utilisés comme inhibiteurs de kras
WO2021126816A1 (fr) * 2019-12-16 2021-06-24 Amgen Inc. Schéma posologique d'un inhibiteur du kras g12c
WO2021120045A1 (fr) * 2019-12-18 2021-06-24 InventisBio Co., Ltd. Composés hétérocycliques, leurs procédés de préparation et utilisations associées
WO2021121330A1 (fr) * 2019-12-18 2021-06-24 InventisBio Co., Ltd. Composés hétérocycliques, leurs procédés de préparation et leurs utilisations
WO2021121367A1 (fr) * 2019-12-19 2021-06-24 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de protéine mutante kras
CN113061132A (zh) * 2020-01-01 2021-07-02 上海凌达生物医药有限公司 一类稠环内酰胺类化合物、制备方法和用途
CN113105448A (zh) * 2020-01-13 2021-07-13 苏州泽璟生物制药股份有限公司 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
CN111205286A (zh) * 2020-01-13 2020-05-29 李丹 作为kras g12c突变蛋白抑制剂的腈甲基哌嗪类衍生物及其应用
CN112159405A (zh) * 2020-02-04 2021-01-01 广州必贝特医药技术有限公司 吡啶并嘧啶酮类化合物及其应用
CN112574199A (zh) * 2020-05-20 2021-03-30 首药控股(北京)股份有限公司 Kras-G12C抑制剂杂环化合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRIAN A. LANMAN, JENNIFER R. ALLEN, JOHN G. ALLEN, ALBERT K. AMEGADZIE, KATE S. ASHTON, SHON K. BOOKER, JIAN JEFFREY CHEN, NING CH: "Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, no. 1, 9 January 2020 (2020-01-09), US , pages 52 - 65, XP055666907, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01180 *
CHEN HAO, SMAILL JEFF B., LIU TONGZHENG, DING KE, LU XIAOYUN: "Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, no. 23, 23 November 2020 (2020-11-23), US , pages 14404 - 14424, XP055879585, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c01312 *
XIAO XUANZHENG; LAI MENGZHEN; SONG ZILAN; GENG MEIYU; DING JIAN; XIE HUA; ZHANG AO: "Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRASG12C inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 213, 4 December 2020 (2020-12-04), AMSTERDAM, NL , XP086503244, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2020.113082 *

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