WO2024041606A1 - Compound with anti-kras mutant tumor activity - Google Patents

Compound with anti-kras mutant tumor activity Download PDF

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WO2024041606A1
WO2024041606A1 PCT/CN2023/114683 CN2023114683W WO2024041606A1 WO 2024041606 A1 WO2024041606 A1 WO 2024041606A1 CN 2023114683 W CN2023114683 W CN 2023114683W WO 2024041606 A1 WO2024041606 A1 WO 2024041606A1
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alkyl
halogen
cancer
compound
pharmaceutically acceptable
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PCT/CN2023/114683
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French (fr)
Chinese (zh)
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尚尔昌
仲伯禹
张彦涛
宋光琳
郑爱军
陈国猛
侯福良
汪瑞祥
董春兰
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泰励生物科技（上海）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with novel structures useful as KRAS inhibitors, pharmaceutical compositions containing such compounds, methods for preparing such compounds and the use of these compounds in the treatment of cancer or tumors.
  • Ras the rat sarcoma oncogene homolog
  • Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, differentiation and other functions.
  • These regulatory functions of Ras are performed through the conversion between the GDP-bound state and the GTP-bound state, a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401).
  • Ras bound to GDP is an inactive form and is in a dormant or off state. At this time, the signaling system is turned off. It will be activated when it is exposed to some growth-promoting stimuli.
  • Ras guanine nucleotide exchange factor
  • GDP is released and combined with GTP.
  • Ras is "turned on” and converted into the active form of Ras, which recruits and activates various downstream effectors for signal transmission and can transmit signals on the cell surface to the cytoplasm.
  • Controls numerous key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).
  • Ras has GTPase activity, which can cleave the terminal phosphate of GTP and convert it into GDP, that is, convert itself into an inactive state.
  • the endogenous GTPase activity of Ras is very low, and the exogenous protein GAP (GTPase activating protein) is required to convert GTP-Ras into GDP-Ras.
  • GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation that affects the interaction between Ras and GAP or the conversion of GTP to GDP will cause Ras to remain active for a long time, thus continuously transmitting growth and division signals to cells, stimulating continuous cell proliferation, and ultimately leading to tumor formation. And development.
  • Ras ubiquitously expressed Ras genes
  • H-RAS H-RAS
  • K-RAS K-RAS
  • N-RAS N-RAS
  • HRas HRas
  • NRas NRas
  • KRas proteins of approximately 21KDa.
  • researchers first discovered that Ras was mutated and activated in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852).
  • Subsequent large genome sequencing studies in different cancer types revealed that the Ras protein is mutated in more than 30% of cancer types, especially in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%) has the highest mutation rate.
  • Ras tumor protein is a very attractive anti-cancer drug target that is widely accepted in the pharmaceutical field.
  • Ras mutations are most common in KRas, and KRas mutations can be observed in about 85% of cancers driven by Ras mutations; the vast majority of Ras mutations occur in codons G12, G13, and Q61, of which about 80% of KRas mutations are hair Born at glycine in codon 12, such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation, etc.
  • KRas mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma, and are also found in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21(8 ),1797-1801,2015). Therefore, KRas mutant protein has become the most important branch of Ras drug target research, and the development of its inhibitors is also regarded as a very promising research direction in the development of anti-cancer/tumor drugs.
  • Ras due to the smooth surface of Ras protein, it lacks obvious grooves or pocket structures for binding small molecule inhibitors, and its affinity for guanine substrates is very high (Pi). molar level), causing the development of its small molecule inhibitors to fall into an insurmountable dilemma.
  • Ras has long been considered an "undruggable" target in the industry.
  • KRas inhibitors there is still a great need for compounds with more structural types or patterns as KRas inhibitors to provide more treatment options, or to provide further improved inhibitory activity relative to existing Kras inhibitors, thereby providing stronger clinical benefits. effective therapeutic drugs.
  • the present invention addresses these and other needs.
  • the present invention provides novel structural inhibitor compounds with KRas mutein inhibitory activity. Because these compounds of the present invention have improved structural patterns, compared with existing KRas mutant protein inhibitors in the prior art, they have enhanced activity in inhibiting KRas mutant proteins and related tumor inhibitory activities, and have good pharmacokinetic properties. Therefore, it has good drug-forming properties, such as being more easily absorbed in the body after administration in a convenient manner, with reduced toxic and side effects, improved drug resistance and safety, and reduced risk of drug interactions.
  • the invention provides compounds of structural formula (I), their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof as defined herein below:
  • the invention also provides a compound comprising a compound of the invention or its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate and optional pharmaceutically acceptable excipients or Carrier for pharmaceutical compositions.
  • the invention also provides a compound of the invention or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof for use as a medicament.
  • the invention also provides the compounds of the invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates for use as Ras mutein, especially KRas mutein (for example, G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and inhibitor of KRAS amplified cells.
  • Ras mutein especially KRas mutein (for example, G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and inhibitor of KRAS amplified cells.
  • the invention also provides a method for treating and/or preventing mutations caused by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and Compounds of the invention, or stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing the same, for diseases mediated by KRAS amplification.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • Compounds of the invention or stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing the same, for diseases mediated by KRAS amplification.
  • the invention also provides compounds of the invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing the same for the treatment and/or Or the use of preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • the present invention also provides the compounds of the present invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing them for use in the treatment of and/or prevent diseases mediated by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification Uses in medicines.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • the present invention also provides treatment and/or prevention of mutations caused by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • KRAS amplification KRAS amplification.
  • a method of increasing mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof substances, or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating tumors or cancer, which includes administering a compound of the present invention or a stereoisomer, tautomer, stable isotope variant, or pharmaceutically acceptable salt thereof to a patient in need thereof or solvates, or pharmaceutical compositions containing the same.
  • the present invention also provides the compounds of the present invention or their pharmaceutically acceptable salts or solvates in research as KRas inhibitors, especially as inhibitors of KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, Use of tool compounds for research on G12R mutations, G12S mutations, G13D mutations and Q61H mutant proteins) and KRAS amplification.
  • KRas inhibitors especially as inhibitors of KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, Use of tool compounds for research on G12R mutations, G12S mutations, G13D mutations and Q61H mutant proteins) and KRAS amplification.
  • the invention also provides pharmaceutical combinations comprising a compound of the invention as a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof and one or more other pharmaceutically active agent.
  • the invention also provides methods for preparing the compounds of the invention.
  • Ras mutation refers to the protein encoded and expressed by the Ras gene in which one or more codons are mutated, typically including but not limited to glycine at position 12 of the codon of Ras, Ras proteins with mutations in glycine at codon 13 or glutamine at codon 61, such as mutated HRas, NRas or KRas. These residues are located in the active site of Ras, and their mutations can impair the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the persistence of GTP-bound Ras.
  • Ras mutant or “Ras mutein” and “Ras” with respect to which inhibitory activity is described are used interchangeably and generally refer to mutated HRas, NRas or KRas, such as, but not limited to KRas-G12C (mutation of glycine to cysteine at codon G12), KRas-G12D (mutation of glycine to aspartate at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12 from glycine to aspartate) Mutation of glycine to valine at G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); specifically refers to the KRas mutant protein, and more particularly refers to the KRas-G12C mutant protein, KRas- G12D mutant protein, KRas-G12V
  • treatment refers to the administration of one or more compounds of the present invention or pharmaceuticals thereof as described herein to a subject, such as a mammal, such as a human, suffering from the disease, or having symptoms of the disease.
  • a subject such as a mammal, such as a human
  • Acceptable salts or solvates of the above are used to cure, alleviate, reduce or affect the disease or the symptoms of the disease.
  • the treatment is curative or ameliorative.
  • prevention refers to a subject, such as a mammal, suspected of suffering from or susceptible to a Ras mutation-mediated disease, in particular a cancer or tumor, as defined herein.
  • a subject such as a mammal, suspected of suffering from or susceptible to a Ras mutation-mediated disease, in particular a cancer or tumor, as defined herein.
  • administration of one or more compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, to a human results in a reduced risk of developing a defined disease, or prevents the onset of a disease.
  • prophylaxis encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological symptoms.
  • the terms “inhibit” and “reduce” or any variations of these terms refer to the ability of a biologically active agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target, and refers to Any measurable reduction or complete inhibition of the activity of a target of interest.
  • the activity e.g., KRas activity
  • the activity may be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% compared to normal conditions. %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.
  • Ras mutation-mediated disease refers to a disease in which a Ras mutation promotes the occurrence and development of the disease, or in which inhibition of the Ras mutation will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease.
  • Ras mutation-mediated disease preferably refers to a disease mediated by a KRas mutation, and more preferably a cancer or tumor mediated by a KRas mutation.
  • cancer refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.
  • the cancer or tumor mass Including but not limited to lung adenocarcinoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer , fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer , Penile cancer, Prostate cancer, Chronic or acute leukemia, Lymphocytic lymphoma, Bladder cancer, Kidney or ureter cancer, Renal cell carcinoma, Renal
  • the cancer or tumor is associated with Ras mutations, especially KRas mutations and amplifications, including but not limited to the above-mentioned tumor types and preferred ranges thereof.
  • Ras mutations especially KRas mutations and amplifications, including but not limited to the above-mentioned tumor types and preferred ranges thereof.
  • Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, cholangiocarcinoma, leukemia and ovarian cancer.
  • the terms "subject,” “individual,” or “patient” refer to a vertebrate animal.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, farm animals (such as cattle), sporting animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.
  • the mammal is a human.
  • terapéuticaally effective amount refers to an amount or dosage generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment of said "Ras mutation-mediated disease” such as cancer or tumors.
  • Those skilled in the art can determine the effective amount or dosage of the active ingredients in the present invention through conventional methods and combined with conventional influencing factors.
  • pharmaceutical combination means that the compounds of the invention may be combined with other active agents for carrying out the purposes of the invention.
  • the other active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., a third) compound that is compatible with the compound of the invention, that is, does not adversely affect each other, or has complementary activity.
  • compounds, for example, these active agents are known to modulate other biologically active pathways, or modulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention.
  • Such active agents are suitably present in combination in an amount effective to achieve the intended purpose.
  • the other active agents may be co-administered with the compound of the invention in a single pharmaceutical composition, or may be administered separately from the compound of the invention in separate discrete units, and when administered separately may be administered simultaneously or sequentially.
  • the sequential administrations may be close or distant in time.
  • pharmaceutically acceptable means molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered in appropriate amounts to animals, such as humans.
  • pharmaceutically acceptable salts refers to those salts, including acid addition salts and base addition salts, which retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable acid addition salts” can be formed from compounds with basic groups and inorganic acids or organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc.
  • organic acids can be selected from Aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, apple Acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, naphthalene Acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, as well as those derived from pharmaceutically acceptable base addition salts.
  • organic nontoxic bases including but not Limited to primary, secondary and tertiary amines, substituted ammoniums, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, Ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, seaweed Pamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.
  • substituted ammoniums including naturally occurring substituted amines, cyclic amines and basic ion exchange resins
  • isomer refers to any stereoisomer or enantiomeric mixture that may exist in the structure of a compound, including racemates, diastereomeric mixtures, geometric isomers, and antirotation Isomers and/or tautomers. Methods for determining the stereochemistry and separation of such isomers are well known to those skilled in the art (S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994).
  • Certain compounds of the present invention contain at least one asymmetric center and thus produce stereoisomers. Therefore, the present invention encompasses all possible isomeric forms of the compounds defined herein, as well as pharmaceutically acceptable salts or solvates thereof. , unless otherwise instructed.
  • R or S represents the absolute configuration of the chiral center; in some definitions of the compounds of the present invention, it is also Axial chirality can be used to represent the configuration of a compound. The determination of these configurations uses the Cahn-Ingold-Prelog rule, which is well known to those skilled in the art.
  • the absolute configuration of the axial chirality in the two example structures shown below is described as follows:
  • the bond indicating its intersection is the bond connecting the structural fragment to the rest of the molecule.
  • substituents in the cyclic structural fragments referred to herein are shown as spanning the chemical bond, for example -(R 3 ) m means that one or more R 3 substituents can substitute for one or more substitution sites in the ring that are chemically feasible, including Z.
  • Compounds of the invention include unlabeled forms of compounds of the invention and isotopically labeled forms thereof.
  • Isotopically labeled forms of compounds are compounds that differ only in the replacement of one or more atoms by the corresponding isotopically enriched atom.
  • isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O , 17 O, 35 S, 18 F, 37 Cl and 125 I.
  • Such isotopically labeled compounds may be used, for example, as probes in biological assays, analytical tools, or as therapeutic agents.
  • the compounds of the invention are provided in unlabeled form.
  • solvate refers to solvent addition forms of compounds containing stoichiometric or non-stoichiometric solvents, including any solvated form of the compounds of the present invention, including, for example, solvates with water, such as hydrates or as a solvate with an organic solvent such as methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrile respectively; or in the form of any polymorphic form. It is to be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.
  • metabolite means the product of a compound metabolized in the body. Such products may, for example, result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Identification and analysis of metabolite products is performed in a manner well known to those skilled in the art.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein refers to one or more compatible solid or liquid filler or gel materials suitable for human use and having sufficient purity and sufficiently low toxicity, examples of which include but are not limited to cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), Calcium sulfate, vegetable oil, polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers agents, antioxidants, preservatives, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, cellulose acetate, etc.
  • gelatin talc
  • solid lubricants such as magnesium stearate
  • Calcium sulfate such
  • halogen or "halo” as used herein means F, Cl, Br or I.
  • halogen-substituted group as used herein in defining a group is intended to include mono- or polyhalogenated groups in which one or more of the same or different halogens replaces one or more of the corresponding groups.
  • a hydrogen
  • alkyl as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1 to 10, for example 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include methyl, ethyl, propyl (including n- Propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2 -Methylpentyl etc.
  • alkoxy as used herein means an alkyl group as defined herein attached to the remainder of the molecule through an oxygen atom. Specifically, the alkoxy group has 1 to 10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 alkoxy refers to a straight or branched saturated hydrocarbon group of 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom, examples of which are, for example, - O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O- Isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O -n-hexyl, 2-methylpentyl-O-, etc.
  • C 1-6 alkyl optionally substituted by halogen refers to the C 1-6 alkyl groups described above, in which one or more (e.g. 1, 2, 3, 4 or 5 ) hydrogen atoms are optionally replaced by halogens.
  • the halogens may be the same or different and may be located on the same or different C atoms.
  • halogen-substituted C 1-6 alkyl examples include -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3 or -CF (CF 3 ) 2 , etc.
  • alkenyl refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond. Specifically, the alkenyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms.
  • C 2-6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, Pentenyl, etc., the carbon atom in the alkenyl group connected to the rest of the molecule can be saturated or it can be an olefinic carbon atom.
  • alkynyl refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Specifically, the alkynyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms.
  • C 2-6 alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, propargyl, butynyl Etc., the carbon atom in the alkynyl group attached to the rest of the molecule can be saturated or it can be an alkyne bonded carbon atom.
  • cycloalkyl as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring carbon atoms.
  • Cycloalkyl groups can have 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms.
  • Suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or polycyclic (eg bicyclic) structures including spiro Ring, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1]heptyl or bicyclo[3.2.1]octyl, etc.
  • C 3-6 cycloalkyl refers to monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyl is meant to include one or more (eg, 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of O, N, P, Se, and S and the specified number of ring atoms.
  • heterocycloalkyl In the case of polycyclic heterocycloalkyl, it is sufficient that the ring structure connected to the rest of the molecule is a non-aromatic ring, even if the ring further fused, spiro or bridged with the non-aromatic ring is an aromatic ring. Heterocyclic systems are still defined herein as heterocycloalkyl.
  • Heterocycloalkyl groups may have 3 to 12 ring members (can be referred to as 3-12 membered heterocycloalkyl groups), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 7 ring members, 5 to 6 ring members, 6 to 10 ring members, 6 to 12 ring members, such as 5 to 7 membered monocyclic heterocycloalkanes Such as 5-7 membered monocyclic saturated heterocycloalkyl group, or 6 to 12 membered polycyclic heterocycloalkyl group.
  • Heterocycloalkyl groups generally contain at least 1 and up to 4 (eg 1, 2, 3 or 4) heteroatoms, such as 5- containing 1 to 3 heteroatoms independently selected from N, O, S 7-membered monocyclic heterocycloalkyl such as 5-7-membered monocyclic saturated heterocycloalkyl, or 6-12-membered polycyclic ring containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S Heterocycloalkyl.
  • heteroatoms such as 5- containing 1 to 3 heteroatoms independently selected from N, O, S 7-membered monocyclic heterocycloalkyl such as 5-7-membered monocyclic saturated heterocycloalkyl, or 6-12-membered polycyclic ring containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S Heterocycloalkyl.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl).
  • -pyrrolidinyl tetrahydrofuranyl (such as 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl) base
  • tetrahydrothienyl such as 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl
  • piperidinyl such as 1-piperidinyl, 2-piperidinyl, 3- Piperidinyl and 4-piperidinyl
  • tetrahydropyranyl such as 4-tetrahydropyranyl
  • tetrahydrothiopyranyl such as 4-tetrahydrothiopyranyl
  • morpholinyl such as morpholine generation
  • thiomorpholinyl such as dioxanyl, piperazinyl or azepanyl, diazepanyl such as 1,4-diazepanyl, 3,6-diaza - Bicycl
  • exemplary heterocycloalkyl groups include, but are not limited to, the following: It is to be understood that structures having asymmetric centers encompass their racemic and/or single enantiomeric forms, e.g. representative and / or
  • Preferred heterocycloalkyl groups are for example
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • the term "optionally substituted”, unless otherwise indicated, means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5 or more, or any derivative thereof range) is substituted with the substituents listed for this group, wherein the substituents may be the same or different.
  • the optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents that may be the same or different.
  • the optionally substituted group has 3 substituents that may be the same or different.
  • an optionally substituted group has 4 substituents that may be the same or different.
  • an optionally substituted group has 5 substituents that may be the same or different.
  • C n-n+m or C n -C m in the definition of the compound of the present invention includes various situations of n to n+m carbons, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , also includes any range from n to n+m, for example, C 0-6 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 0- 1.
  • n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is n to n+m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring.
  • 12-membered rings also include any range from n to n+m members, for example, 3-12-membered rings include 3-6-membered rings, 3-8-membered rings, 3-9-membered rings, 4-10-membered rings, 4-7-membered ring, 4-5-membered ring, 5-6-membered ring, 5-7-membered ring, 5-8-membered ring, 5-9-membered ring, 6-7-membered ring, 6-8-membered ring, 6- 10-membered rings and 6 to 12-membered rings, etc.
  • 3-12-membered rings include 3-6-membered rings, 3-8-membered rings, 3-9-membered rings, 4-10-membered rings, 4-7-membered ring, 4-5-membered ring, 5-6-membered ring, 5-7-membered ring, 5-8-membered ring, 5-9-membered ring, 6-7-membered
  • the word “comprises” and variations of this word such as “includes” and “contains” mean “including but not limited to” and are not intended to exclude, for example, other additives , ingredient, integer or step.
  • the element may also be described as including any combination of such multiple ingredients, steps or conditions, or as “consisting of a plurality or combination of ingredients, “consisting essentially of a plurality or combination of ingredients, steps or conditions”.
  • the dosages referred to are based on the weight of the free form, excluding any salts, hydrates or salts thereof. Solvates, unless the instructions state that the dosage is based on the weight of the salt, hydrate, or solvate.
  • Ras mutant proteins especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS mutant protein.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • Compounds that generate expanded cells can be used to treat or prevent diseases (eg, cancer or tumors) mediated by the mutant protein. Therefore, in this field, various structural types of Ras inhibitors have been developed.
  • existing KRas inhibitors still have problems that need to be solved, including, for example, the anti-tumor activity of many inhibitors is unsatisfactory, or they have toxic side effects leading to poor drug resistance, or their pharmacokinetic properties are not sufficient to allow convenient delivery.
  • the way of administration means that the "drugability" is poor, or the inhibition of the cytochrome P450 enzyme system may lead to undesirable drug interactions, etc. Furthermore, even for inhibitors with good anti-tumor activity, people still expect to further improve their selective inhibitory activity against target proteins in vivo and further improve their drug resistance (less toxicity) through structural optimization. side effects or better safety) and further improve its pharmacokinetic properties to provide more and better treatment options for clinical use.
  • KRas mutant proteins such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein.
  • KRAS amplified cells have significant inhibitory activity.
  • structural modification and activity verification the inventor found that specific types of substituent modifications were carried out at several specific sites of the benzopyrimidine ring and quinazoline of the KRas inhibitor structure.
  • the implemented several substitution sites and substitutions The specific combination of base types has further improved the inhibitory activity against KRas mutant protein compared with the existing technology inhibitors, and the compound obtained by such modification has good safety, reduced risk of drug interaction, and good performance.
  • the even further improved pharmacokinetic properties enable administration in a convenient manner.
  • the present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification inhibitor) compounds; Pharmaceutical compositions containing such compounds as active ingredients; as medicaments, for the treatment or prevention of mutations caused by Ras, in particular KRas (e.g.
  • G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations and KRAS amplifications
  • KRas e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplifications.
  • KRas e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation, and KRAS amplification
  • Methods e.g., the preparation of said compounds for use in the treatment or prevention of mutations caused by Ras, specifically KRas (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplifications)
  • KRas e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplification
  • KRas e.g., G12C mutations, G12D mutations, G12V mutations, G12A
  • the present invention therefore provides the following technical solutions.
  • the invention also encompasses N-oxides of the compounds of the invention, provided these compounds contain basic nitrogen atoms such as those present in nitrogen-containing heterocycles and are chemically and biologically feasible. Certain compounds of the invention may exist in polymorphic or amorphous forms and thus fall within the scope of the invention.
  • Embodiment 1 Compounds of formula (I), their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,
  • M is selected from N or CR 7 ;
  • X is selected from C and S, p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C;
  • Y is selected from O, S and Se;
  • W is selected from OH and NH 2 ;
  • B is selected from 5-7 membered monocyclic heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from N, O, P, Se, and S, and containing 1 to 4 heteroatoms independently selected from N, O, 6-12 membered polycyclic heterocycloalkyl groups of heteroatoms of P, Se and S, provided that each is connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom;
  • Z is selected from N, C, O, S and Se;
  • k is selected from 0 or 1;
  • n are each independently selected from an integer from 0 to 2;
  • R 1 is selected from -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen or C 1-6 alkoxy;
  • R 2 is selected from H, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl or C 3-6 cycloalkyl is independently optional Substituted by halogen or C 1-6 alkoxy,
  • R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 -6 alkynyl and - (CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3
  • Each -6 cycloalkyl group is independently optionally substituted by halogen, CN or C 1-6 alkoxy group,
  • R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
  • R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally optionally replaced by halogen, CN, -C 1-6 alkoxy or -O-CON (C 1-6 alkyl) 2 substitution;
  • R 5 is selected from H and halogen
  • R 6 is selected from H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl and -C 2-6 alkynyl, Each independently optionally substituted by halogen;
  • R 7 is selected from H, halogen, CN and -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by halogen or CN;
  • R 8 is selected from -OH, halogen, -CN, -B(OH) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl), -CON(C 1-6 alkyl)(C 2- 6 alkynyl), -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl), -PO(C 1-6 alkyl)(C 2-6 alkynyl), -SO-N (C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N(C 1-6 alkyl)(C 2-6 alkynyl ), -SO 2 -N(C 1-6 alkyl) 2 , -SO 2 -N(
  • R 9 and R 10 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted by halogen;
  • R 11 is selected from H, halogen, -C 1-6 alkyl optionally substituted by halogen, -OC 1-6 alkyl optionally substituted by halogen, and optionally -C 2-6 alkynyl substituted by halogen; and
  • t is selected as an integer from 1 to 4.
  • Embodiment 1.1 The compound of formula (I) of Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein
  • R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 -6 alkynyl and - (CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3
  • Each -6 cycloalkyl group is independently optionally substituted by halogen, CN or C 1-6 alkoxy group,
  • R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
  • R 11 is selected from H, halogen, -C 1-6 alkyl optionally substituted by halogen, and -OC 1-6 alkyl optionally substituted by halogen.
  • Embodiment 1.2 The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, which is the following formula (I- 1),
  • X is selected from C and S, p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C;
  • Y is selected from O, S and Se;
  • W is selected from OH and NH 2 ;
  • B is selected from 5-7 membered monocyclic heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from N, O, P, Se, and S, and containing 1 to 4 heteroatoms independently selected from N, O, 6-12 membered polycyclic heterocycloalkyl groups of heteroatoms of P, Se and S, provided that each is connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom;
  • Z is selected from N, C, O, S and Se;
  • k is selected from 0 or 1;
  • n are each independently selected from an integer from 0 to 2;
  • R 1 is selected from -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen or C 1-6 alkoxy;
  • R 2 is selected from H, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl or C 3-6 cycloalkyl is independently optional Substituted by halogen or C 1-6 alkoxy,
  • R 3 is selected from H, halogen, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl , wherein each occurrence of C 1-6 alkyl or C 3-6 cycloalkyl is independently optionally substituted by halogen or C 1-6 alkoxy,
  • R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
  • R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally optionally replaced by halogen, CN, -C 1-6 alkoxy or -O-CON (C 1-6 alkyl) 2 substitution;
  • R 5 is selected from H and halogen
  • R 6 is selected from H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl and -C 2-6 alkynyl, Each independently optionally substituted by halogen;
  • R 7 is selected from H, halogen, CN and -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by halogen or CN;
  • R 8 is selected from -OH, halogen, -CN, -B(OH) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl), -CON(C 1-6 alkyl)(C 2- 6 alkynyl), -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl), -PO(C 1-6 alkyl)(C 2-6 alkynyl), -SO-N (C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N(C 1-6 alkyl)(C 2-6 alkynyl ), -SO 2 -N(C 1-6 alkyl) 2 , -SO 2 -N(
  • R 9 and R 10 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted by halogen;
  • t is selected as an integer from 1 to 4.
  • Embodiment 2.1 The compound of formula (I) of Embodiment 1 or 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein p is 1 and X is C, that is, the fused bicyclic part where X is located is
  • Embodiment 2.1.1 The compound of formula (I) of Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 5 is H ; Or R 5 is halogen, selected from F, Cl, Br, I; preferably R 5 is halogen, most preferably F.
  • Embodiment 2.1.2 The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is H; or R 6 is halogen, selected from F, Cl, Br, and I.
  • Embodiment 2.1.3 The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl, optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C( CH 3 ) 3 , -CH 2 Cl , -CH 2 F , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH
  • Embodiment 2.1.4 The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 2-6 alkynyl, optionally substituted by halogen, such as but not limited to preferred
  • Embodiment 2.1.5 The compound of formula (I) according to any one of embodiments 2.1 to 2.1.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 9 and R 10 are each H; or R 9 and R 10 are each halogen, preferably F.
  • Embodiment 2.1.6 The compound of formula (I) according to any one of embodiments 2.1 to 2.1.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Object, wherein one of R 9 and R 10 is H and the other is selected from halogen, preferably F; preferably R 10 is H and R 9 is selected from halogen, preferably F, as exemplified above.
  • Embodiment 2.1.7 The compound of formula (I) according to any one of embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -OH.
  • Embodiment 2.1.8 The compound of formula (I) according to any one of embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -NH 2 .
  • Embodiment 2.1.9 The compound of formula (I) of Embodiment 2.1, its stereoisomers, tautomers, and stable isotopes peptide variants, pharmaceutically acceptable salts or solvates, in which the fused bicyclic part where X is located is
  • R is halogen at position 5 , preferably F
  • R 6 is selected from -C 1-6 alkyl, -C 2-6 alkynyl and halogen, preferably selected from -C 1-6 alkyl and -C 2-6 alkynyl,
  • R is halogen at position 5 , preferably F
  • R 6 is selected from -C 1-6 alkyl, -C 2-6 alkynyl and halogen, preferably selected from -C 1-6 alkyl and -C 2-6 alkynyl,
  • R is halogen at position 5 , preferably F
  • R 6 is selected from -C 1-6 alkyl, -C 2-6 alkynyl and hal
  • Embodiment 2.2 Compounds of formula (I) of Embodiment 1, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein p is 0 and X is S, that is, the fused bicyclic part where X is located is
  • Embodiment 2.2.1 The compound of formula (I) of Embodiment 2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 5 is H ; Or R 5 is halogen, selected from F, Cl, Br, I; preferably R 5 is halogen, most preferably F.
  • Embodiment 2.2.2 The compound of formula (I) of Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is H; or R 6 is halogen, selected from F, Cl, Br, and I.
  • Embodiment 2.2.3 The compound of formula (I) of Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl, optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C( CH 3 ) 3 , -CH 2 Cl , -CH 2 F , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH
  • Embodiment 2.2.4 The compound of formula (I) of embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 2-6 alkynyl, optionally substituted by halogen, such as but not limited to preferred
  • Embodiment 2.2.5 The compound of formula (I) according to any one of embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 9 and R 10 are each H; or R 9 and R 10 are each halogen, preferably F.
  • Embodiment 2.2.6 The compound of formula (I) according to any one of embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein one of R 9 and R 10 is H and the other is selected from halogen; preferably R 10 is H and R 9 is selected from halogen, as exemplified above.
  • Embodiment 2.2.7 The compound of formula (I) according to any one of embodiments 2.2 to 2.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -OH.
  • Embodiment 2.2.8 The compound of formula (I) according to any one of embodiments 2.2 to 2.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -NH 2 .
  • Embodiment 2.2.9 The compound of formula (I) of Embodiment 2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein The combined double ring part is for example
  • Embodiment 3.1 The compound of formula (I) according to any one of embodiments 1 to 2.2.9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is a 5-7 membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, P, Se and S, linked to the pyrimidine ring portion of the molecule through a nitrogen heteroatom, such as but not limited to Each Z in each ring can be C, or at most two of them are heteroatoms selected from N, O, P, Se and S, such as a 5-7-membered heterocycloalkyl group containing 1-3 nitrogen atoms.
  • Embodiment 3.1.1 The compound of formula (I) of Embodiment 3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Substituted by 1-2 R 8 , preferably substituted by R 8 at the meta position of N, such as but not limited to
  • Embodiment 3.1.1.1 The compound of formula (I) of Embodiment 3.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B
  • the substituent R 8 is in stereoisomeric form, such as R or S configuration, only if it is chemically feasible.
  • Embodiment 3.1.2 The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein
  • the substituents R 8 carried on B are each independently selected from -OH, halogen, CN, -C 1-6 alkyl and -OC 1-6 alkyl, in which -C 1-6 alkyl is optionally replaced by halogen or CN substitution; preferably one of the two R 8 attached to the same ring carbon atom is -OH and the other is -C 1-6 alkyl optionally substituted by halogen or CN, preferably methyl; more preferably in the same molecule
  • the meta-ring carbon yard of the N atom connected to the remaining part (such as the pyrimidine ring) is connected to two R 8 , one of which is -OH and the other is -C 1-6 alkyl, preferably methyl, for example, B is preferred
  • Embodiment 3.1.3 Compounds of formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof according to embodiments 3.1 to 3.1.1.1, wherein
  • the substituent R 8 carried on B is selected from -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl ) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl) ), -CON(C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally replaced by halogen or CN Substitution; preferably -CON(C 1-6 alkyl) 2 , for example -CON(CH 3 ) 2 , for example B is
  • Embodiment 3.1.4 The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein
  • the substituent R 8 carried on B is selected from -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl) and -PO(C 1-6 alkyl) ) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN.
  • Embodiment 3.1.5 The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein
  • the substituent R 8 carried on B is selected from -SO-N(C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N( C 1-6 alkyl) (C 2-6 alkynyl), -SO 2 -N (C 1-6 alkyl) 2 , -SO 2 -N (C 1-6 alkyl) (C 2-6 alkene base) and -SO 2 -N(C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optional Substituted by halogen or CN; preferably -SO-N(C 1-6 alkyl
  • Embodiment 3.1.6 The compound of formula (I) of Embodiment 3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Substituted by 1-2 R 8 , preferably substituted by R 8 at the meta position of N, each R 8 is independently selected from -OH, halogen, CN, -C 1-6 alkyl and -OC 1-6 alkyl, The -C 1-6 alkyl group is optionally substituted by halogen or CN; preferably one of the two R 8 attached to the same ring carbon atom is -OH and the other is -C 1 optionally substituted by halogen or CN -6 alkyl, preferably methyl; more preferably two R 8 , one of which is -OH and the other is -C, is attached to the meta-ring carbon yard of the N atom attached to the rest of the molecule (e.g., pyrimidine ring) 1-6 alkyl,
  • Embodiment 3.1.6.1 The compound of formula (I) of Embodiment 3.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B
  • the substituent R 8 is in stereoisomeric form, such as R or S configuration, only if it is chemically feasible.
  • Embodiment 3.2 The compound of formula (I) according to any one of embodiments 1 to 2.2.9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,
  • B is a 6-12 membered polycyclic heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S (such as 6-10 member, 6-9 member, 6-8 member membered, 6-7 membered polycyclic heterocycloalkyl), connected to the pyrimidine ring part of the molecule through a nitrogen heteroatom, for example, containing 1-4 nitrogen atoms, containing 1 nitrogen atom and 1-3 selected from O, S , heteroatoms of P and Se, containing 2 nitrogen atoms and 1-2 heteroatoms selected from O, S, P and Se, containing 3 nitrogen atoms and 1 heteroatom selected from O, S, P and Se atoms, such as but not limited to Each is substituted by 1-4 R8 , preferably by 1-2
  • Embodiment 3.2.1 The compound of formula (I) of Embodiment 3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Replaced by 1 R 8 such as but not limited to
  • Embodiment 3.2.2 The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein
  • the substituents R 8 carried on B are each independently selected from -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2- 6 alkenyl), -CON (C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally Halogen or CN substitution; preferably -CON(C 1-6 alkyl) 2 , for example -CON(CH 3 ) 2 , for example B is
  • Embodiment 3.2.3 The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein
  • the substituent R 8 carried on B is selected from -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl) and -PO(C 1-6 alkyl) ) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN.
  • Embodiment 3.2.4 The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, and stable Isotopic variants, pharmaceutically acceptable salts or solvates, wherein the substituent R 8 carried on B is selected from -SO-N(C 1-6 alkyl) 2 , -SO-N(C 1-6 Alkyl) (C 2-6 alkenyl), -SO-N (C 1-6 alkyl) (C 2-6 alkynyl), -SO 2 -N (C 1-6 alkyl) 2 , -SO 2 -N(C 1-6 alkyl)(C 2-6 alkenyl) and -SO 2 -N(C 1-6 alkyl)(C 2-6 alkynyl ) , where -C 1-6 alkyl Base, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN; preferably -SO-N (C 1-6 alkyl)
  • Embodiment 4.1 The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
  • Embodiment 4.2 The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is for example
  • Embodiment 4.2.1 The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )( CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2
  • Embodiment 4.2.2 The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - (CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.2.3 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 2 is H.
  • Embodiment 4.2.4 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Materials, wherein at least one R 2 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3.
  • Embodiment 4.2.5 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Materials, wherein at least one R 2 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.2.6 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which the two R 2s , together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl.
  • Embodiment 4.2.7 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
  • Embodiment 4.2.8 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers and tautomers isotopes, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 3 is halogen, selected from F, Cl, Br, I; F is preferred.
  • Embodiment 4.2.9 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
  • Embodiment 4.2.10 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl
  • Embodiment 4.2.11 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2
  • Embodiment 4.2.12 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.2.13 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.2.14 The compound of formula (I) according to any one of embodiments 4.2.8 to 4.2.13, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or Solvate, in which there is at least one R 3 ; preferably there is one R 3 , more preferably the one R 3 is adjacent to R 1 , for example, the one R 3 is selected from halogen such as F, -C 1-6 alkyl such as Methyl, -C 1-6 alkoxy such as methoxy.
  • Embodiment 4.2.15 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates A substance in which R 1 and R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
  • Embodiment 4.2.16 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
  • Embodiment 4.2.17 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof thing, where R 4 is H.
  • Embodiment 4.2.18 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate substance, wherein R 4 is -C 1-6 alkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 , such as but not limited to - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , - C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , - CH(CH 3 )CH 2
  • Embodiment 4.2.19 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not limited to vinyl, propenyl, ethynyl, each optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 substituted.
  • Embodiment 4.2.20 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 replace, such as but not limited to
  • Embodiment 4.2.21 The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is methyl.
  • Embodiment 4.2.22 The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - C 1-6 alkyl, R 2 is H, R 3 is selected from halogen, C 1-6 alkyl and C 1-6 alkoxy, and R 4 is C 1-6 alkyl, for example, Q is For example
  • Embodiment 4.3 The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
  • Embodiment 4.3.1 The compound of formula (I) of Embodiment 4.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein k is 0, Then Q is for example preferred
  • Embodiment 4.3.2 The compound of formula (I) of Embodiment 4.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein k is 1, Then Q is for example
  • Embodiment 4.3.3 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3
  • Embodiment 4.3.4 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.3.5 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 and R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group, and the corresponding structural fragments are such as but not limited to
  • Embodiment 4.3.6 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
  • Embodiment 4.3.7 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is halogen, selected from F, Cl, Br, I, preferably F.
  • Embodiment 4.3.7.1 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is CN.
  • Embodiment 4.3.8 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
  • Embodiment 4.3.9 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3
  • Embodiment 4.3.9.1 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -C 2-6 alkenyl or -C 2-6 alkynyl, optionally substituted by halogen, CN or -C 1-6 alkoxy; for example, but not limited to, each is optionally substituted by halogen, CN Or -C 1-6 alkoxy substituted vinyl, propenyl, ethynyl.
  • Embodiment 4.3.10 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2
  • Embodiment 4.3.11 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.3.12 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.3.13 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group, preferably cyclopropyl; the corresponding ring is such as but not limited to
  • Embodiment 4.3.13.2 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, in which two R 3 connected to the same carbon atom form a spiro C 3-6 cycloalkyl group or a spiro 4-7 membered heterocycloalkyl group, such as but not limited to spiro cyclopropyl, spiro cyclobutyl, spiro cycloalkyl Cyclopentyl, spiroazetidine, spiroazetidine.
  • Embodiment 4.3.14 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 's attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group.
  • Embodiment 4.3.14.1 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is selected from halogen, CN, OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkynyl, -(CH 2 ) n -C 3-6 cycloalkyl, wherein each occurrence of C 1-6 alkyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is independently optionally replaced by halogen or -OC 1- 6Alkyl substitution;
  • R 3 attached to the same carbon atom form C(R c ) 2
  • Embodiment 4.3.14.2 The compound of formula (I) of Embodiment 4.3.14.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 3 The attached ring carbon atom is adjacent to the ring carbon atom to which R 1 is attached and not adjacent to ring NR 4 , e.g.
  • Embodiment 4.3.15 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof thing, where R 4 is H.
  • Embodiment 4.3.16 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -C 1-6 alkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 , such as but not limited to - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , - C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , - CH(CH 3 )
  • R 4 is -C 1-3 alkyl, such as methyl
  • R 4 is -C 1-3 alkyl substituted by one or more deuteriums, such as -CD 3 .
  • Embodiment 4.3.17 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers and tautomers Conformations, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 4 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not limited to vinyl, propenyl, Ethynyl, each optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 .
  • Embodiment 4.3.18 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 replace, such as but not limited to
  • Embodiment 4.3.19 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is methyl.
  • Embodiment 4.3.20 The compound of formula (I) of Embodiment 4.3, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein Z is selected from C , Se and O, R 1 is -C 1-6 alkyl, R 3 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy, and R 4 is C 1-6 alkyl; Preferably Z is selected from C.
  • Embodiment 4.3.21 The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is selected From C, R 1 is -C 1-6 alkyl, R 3 is selected from halogen, CN, OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, - C 2-6 alkynyl, -(CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is each independently optionally substituted by halogen or -OC 1-6 alkyl,
  • R 4 is C 1-6 alkyl
  • Embodiment 4.3.21.1 The compound of formula (I) according to any one of embodiments 4.3 to 4.3.21, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which the two hydrogen atoms in the Q moiety connected to the methylene group of Y are optionally replaced by deuterium.
  • Embodiment 4.3.22 The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q Examples include but are not limited to
  • the two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
  • the two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
  • Embodiment 4.4 The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
  • Embodiment 4.4.1 The compound of formula (I) of Embodiment 4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q is selected from
  • Embodiment 4.4.2 The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R2 is H.
  • Embodiment 4.4.3 The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein At least one R 2 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 - O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , - CCl 3
  • Embodiment 4.4.4 The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein At least one R 2 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.4.5 The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Two R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, for example Q is
  • Two R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, for example Q is
  • Embodiment 4.4.6 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
  • Embodiment 4.4.7 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is halogen, selected from F, Cl, Br, I; F is preferred.
  • Embodiment 4.4.8 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
  • Embodiment 4.4.9 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3
  • Embodiment 4.4.10 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2
  • Embodiment 4.4.11 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.4.12 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
  • Embodiment 4.4.13 The compound of formula (I) according to any one of embodiments 4.4.7 to 4.4.12, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or Solvates in which at least one R 3 is present; preferably one R 3 is present.
  • Embodiment 4.4.14 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
  • Embodiment 4.4.15 The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3's attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group, for example Q is
  • Embodiment 4.4.16 The compound of formula (I) of Embodiment 4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is selected from C , Se and O, two R 2 together with the carbon atoms to which they are attached form cyclopropyl or cyclobutyl, and R 3 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy.
  • Embodiment 5.1 The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is O.
  • Embodiment 5.2 The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is S.
  • Embodiment 5.3 The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is Se.
  • Embodiment 6a The compound of formula (I) of any one of embodiments 1 to 5.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M It's N.
  • Embodiment 6b The compound of formula (I) according to any one of embodiments 1 to 5.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M It's CR 7 .
  • Embodiment 6.1 The compound of formula (I) of Embodiment 6b, wherein R 7 is H, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.
  • Embodiment 6.2 The compound of formula (I) of Embodiment 6b, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 7 is halogen, preferably From F, Cl, Br and I; preferably F or Cl.
  • Embodiment 6.3 The compound of formula (I) of Embodiment 6b, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 7 is CN.
  • Embodiment 6.4 Compounds of formula (I) according to Embodiment 6b, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 7 is -C 1 -6 alkyl, optionally substituted by halogen or CN; for example but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3 , -CCl 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 CN.
  • Embodiment 7a The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is H.
  • Embodiment 7b The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is halogen, preferably F.
  • Embodiment 7c The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 1-6 alkyl optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, - CH
  • Embodiment 7d A compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 11 is -OC 1-6 alkyl optionally substituted by halogen, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F, -O-CH 2 Cl, -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F, -O-CH 2 CHF 2 , -O- CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -
  • Embodiment 7e The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 2-6 alkynyl optionally substituted by halogen, preferably ethynyl.
  • Embodiment 7 The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, which has the following subgeneral formula:
  • Embodiment 7.1 The compound of formula (I) of Embodiment 7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein:
  • Y is O
  • Z is selected from C, Se and O, preferably O or C;
  • W is -OH
  • R 1 is C 1-6 alkyl, preferably methyl
  • R 2 is H, or two R 2 connected to the same carbon atom together form a cyclopropyl group
  • R 3 is selected from H, C 1-6 alkyl, -OC 1-6 alkyl and halogen, preferably C 1-6 alkyl, -OC 1-6 alkyl and halogen, such as methyl, ethyl, methoxy radical, ethoxy and F; or
  • R 4 is selected from H and C 1-6 alkyl, preferably C 1-6 alkyl, such as methyl or ethyl; more preferably, R 4 is -C 1-3 alkyl or substituted by one or more deuterium -C 1-3 alkyl, such as methyl, -CD 3 ;
  • R 5 is selected from H and halogen, preferably halogen, such as F;
  • R 6 is selected from halogen, C 1-6 alkyl and C 2-6 alkynyl, preferably F, ethyl or ethynyl;
  • R 7 is selected from H, halogen, CN and halogen-substituted C 1-6 alkyl, preferably H, F, Cl, CN, CF 3 ;
  • R 8 is selected from -OH, halogen, -CN, -C 1-6 alkyl, -OC 1-6 alkyl and -CON(C 1-6 alkyl) 2 ;
  • R 9 and R 10 are each independently H or halogen, such as each independently H or F, or both are H, or both are halogen, such as F;
  • R 11 is selected from H, halogen, C 1-6 alkyl optionally substituted by halogen, C 1-6 alkoxy optionally substituted by halogen, and -C 2-6 alkynyl optionally substituted by halogen; preferably H, halogen, C 1-6 alkyl, C 1-6 alkoxy and -C 2-6 alkynyl;
  • n is selected from 0, 1 and 2
  • k is selected from 0 and 1
  • m and t are each independently selected from 1 or 2, preferably 2;
  • the two hydrogen atoms of the methylene group of Q connected to Y are optionally replaced by deuterium.
  • Embodiment 8 The compound of formula (I) of Embodiment 7 or 7.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, which have the following substructure Mode:
  • R 8 is selected from -OH and -C 1-6 alkyl, preferably one of them is -OH and the other is C 1-6 alkyl, such as -CH 3 ;
  • Y is O
  • R 9 is H
  • R5 is selected from halogen, preferably F.
  • R 6 is selected from C 1-6 alkyl and C 2-6 alkynyl, preferably ethyl or ethynyl;
  • R 11 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy;
  • k is selected from 0, m is selected from 1 or 2;
  • the two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
  • Embodiment 8.1 The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein in each subgeneral formula The B structure fragment is
  • Embodiment 8.2 The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein in each subgeneral formula The B structure fragment can be replaced by preferred From this, the sub-general formulas (IA”), (IA”'-1), (IA”’-2), (IA”’-3), (IA”’-4), (IB”’), (IB"'-1), (IB”'-2), (IB"'-3), (IB”'-4), (IC"'), (IC"'-1), (IC”' -2), (IC”'-3), (IC”’-4), (ID”’), (ID”’-1), (ID”’-2), (ID”’-3), (ID”'-4) compounds, such as
  • Embodiment 9 The compound of formula (I) of Embodiment 7 or 7.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, which have the following substructure Mode:
  • R 8 is -CON(C 1-6 alkyl) 2 , preferably -CON(CH 3 ) 2 .
  • Embodiment 10 A compound selected from the compounds of Examples 1-185 below or a pharmaceutically acceptable salt or solvate thereof.
  • Ras mutant proteins are known to play a role in tumorigenesis and various other diseases.
  • the compounds of the present invention with the above structural characteristics carry the KRas mutant protein (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS wild-amplified cell lines can potently inhibit cell proliferation, thus having potential value as anti-proliferation, pro-apoptosis and/or anti-invasive drugs in the prevention, containment and/or treatment of related tumor diseases.
  • KRas mutant protein such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • the compounds of the present invention are expected to be useful in the prevention or treatment of those Ras mutant proteins (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H mutant proteins) or KRAS wild-type amplification mediated Diseases or conditions that are caused by or benefit from suppression of Ras mutations (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H mutations) or KRAS wild amplification, such as cancers as defined herein or tumors.
  • Ras mutant proteins e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H mutant proteins
  • High mutant protein inhibitory activity The compounds of the invention, especially the compounds specifically exemplified in this context, have a high inhibitory activity in KRAS mutant cells (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification cell proliferation inhibition experiments show proliferation inhibitory activity, the IC50 value is in the range of 0.0001-10 ⁇ M, preferably in the range of 0.0001-1 ⁇ M; for example, 0.0001 ⁇ 1 ⁇ M, 0.001 ⁇ 1 ⁇ M, 0.0001 ⁇ 0.5 ⁇ M, 0.001 ⁇ 0.5 ⁇ M, 0.0001 ⁇ 0.1 ⁇ M, 0.001 ⁇ 0.5 ⁇ M, 0.001 ⁇ 0.1 ⁇ M;
  • ⁇ It has an obviously satisfactory safety profile, reduced risk of drug interactions, and no significant inhibitory effect on key CYP subtypes of drug metabolism, as verified by Active Example 4.
  • the present invention also provides technical solutions in the following aspects.
  • the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a KRas mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations and Q61H mutant protein) and KRAS wild-amplified cellular inhibitors.
  • a KRas mutant protein e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations and Q61H mutant protein
  • KRAS wild-amplified cellular inhibitors e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations and Q61H mutant protein
  • the invention provides compounds of the invention, preferably pharmaceutically acceptable salts or solvates thereof, for the treatment and/or prevention of Ras muteins, in particular KRas muteins (e.g. G12C mutations, G12D mutations, G12V mutations , G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification mediated or benefiting from Ras mutation, specifically KRas mutant protein (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and diseases or conditions that inhibit KRAS amplification.
  • KRas muteins e.g. G12C mutations, G12D mutations, G12V mutations , G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein
  • KRas mutant protein such as G12C mutation, G12D mutation,
  • the present invention provides for the treatment and/or prevention of Ras mutant proteins, in particular KRas mutant proteins (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H Mutated proteins) and KRAS amplification play a role in promoting the occurrence and development of the disease or inhibiting Ras mutant proteins, specifically KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification will reduce the incidence of disease, reduce or eliminate disease symptoms, such as tumors or cancers, including but not limited to: lung cancer, lung adenocarcinoma, bone Cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, anal
  • the present invention provides a method for treating patients with pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, Compounds of formula (I) or isomers thereof, their pharmaceutically acceptable salts or solvates for patients with lung adenocarcinoma and cholangiocarcinoma.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined above, preferably a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S, KRas G13D mutations or KRas Q61H mutations, and diseases mediated by KRAS amplification, such as tumors or cancers.
  • KRas mutations such as KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S, KRas G13D mutations or KRas Q61H mutations
  • composition of the present invention described above can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th Edition. For example, it can be formulated into tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • composition may contain conventional components found in pharmaceutical preparations, such as diluents (such as glucose, lactose or mannitol), carriers, pH adjusters, buffers, Sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents , flavoring agents, other known additives and other active agents.
  • diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, Sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents , flavoring agents, other known additives and other active agents.
  • diluents such as glucose, lactose or manni
  • the administration and administration of the pharmaceutical compositions of the invention are in accordance with good medical practice.
  • Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of agent delivery, the method of administration, the schedule of administration, and other factors well known to the medical practitioner.
  • the optimal dosage level and frequency of administration of the compounds or pharmaceutical compositions of the present invention can be determined by those skilled in the art through standard experiments in the field of pharmaceutical research.
  • compositions of the present invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation and epidural and intranasal, and if local treatment is required, intralesional administration may also be used.
  • Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • pharmaceutical compositions of the invention are administered orally.
  • a suitable dosage range for the compounds of the invention can be routinely determined by those skilled in the art and may, for example, be 1-1000 mg/day.
  • the compounds of the invention and the compounds of its various embodiments show resistance to Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V , KRas G12A, KRas G12R, KRas G12S or KRas G13D mutations, or KRas Q61H, and the inhibitory effect of KRAS amplified cells.
  • KRas mutations such as KRas G12C, KRas G12D, KRas G12V , KRas G12A, KRas G12R, KRas G12S or KRas G13D mutations, or KRas Q61H
  • the invention provides a method for inhibiting Ras mutation, especially KRas mutation, preferably KRas G12D mutation in a cell, comprising combining the cell with a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof.
  • a compound of the invention preferably a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also correspondingly provides a method for inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof. or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for treating and/or preventing mutations caused by Ras mutations, especially KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations) and Methods for KRAS amplification-mediated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, A pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, is preferred.
  • KRas mutations such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations
  • Methods for KRAS amplification-mediated diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of
  • the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof.
  • KRas mutations preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations, and diseases mediated by KRAS amplification .
  • the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, in Preparation for the treatment and/or prevention of diseases mediated by Ras mutations, especially KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations) and KRAS amplifications uses in medicines.
  • KRas mutations such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations
  • KRAS amplifications uses in medicines.
  • the abnormal cell growth may be caused by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D , or KRas Q61H mutation, and diseases mediated by KRAS amplification particularly refer to cancer or tumors.
  • KRas mutation especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D , or KRas Q61H mutation
  • diseases mediated by KRAS amplification particularly refer to cancer or tumors.
  • Exemplary such cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer , stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal gland cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors (CNS), primary idiopathic CNS lymphoma, spinal tumors, brainstem glioma, or pituitary a
  • the abnormal cell growth may be caused by Ras mutation, especially KRas mutation (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification-mediated diseases are preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, Colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.
  • KRas mutation such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation
  • the present invention provides each of the above methods and uses for treating or preventing cancer or tumors by inhibiting KRas mutation or amplification.
  • the present invention provides the above methods and application technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and cholangiocarcinoma by inhibiting KRas mutation or amplification.
  • the invention also provides compounds of the invention, preferably pharmaceutically acceptable salts or solvates thereof, in studies as KRas inhibitors (e.g. G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations, Q61H mutations and KRAS amplification inhibitors). Therefore, the present invention relates to the in vitro use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a KRas inhibitor, and in particular to the use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a KRas inhibitor. Studies on the effectiveness of inhibitors In vitro uses of tool compounds.
  • KRas inhibitors e.g. G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations, Q61H mutations and KRAS amplification inhibitors. Therefore, the present invention relates
  • the present invention also relates to methods for inhibiting KRas (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification), especially in vitro methods, the method comprising
  • the compound preferably a pharmaceutically acceptable salt or solvate thereof, is administered to a sample (eg, a biological sample).
  • in vitro is used in this particular context in the sense of "in vitro in living humans or animals", which specifically includes experiments with cells, cellular or subcellular extracts and/or biomolecules in artificial environments,
  • an aqueous solution or culture medium may be provided in a flask, test tube, petri dish, microtiter plate, etc.
  • the compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies.
  • the invention provides pharmaceutical combinations comprising or consisting of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, and other active agents.
  • the pharmaceutical combination is used to inhibit abnormal cell growth in mammals, or to treat and/or prevent mutations caused by Ras mutations, preferably KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations). and Q61H mutations) and KRAS amplification-mediated diseases.
  • KRas mutations such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations.
  • Q61H mutations KRAS amplification-mediated diseases.
  • the other active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., a third) compound that is compatible with the compound of the invention, that is, does not adversely affect each other, or has complementary activity.
  • these active agents can be compounds known to modulate other biologically active pathways, or can be compounds that modulate different components in the biologically active pathways involved in the compounds of the present invention, or even biological targets related to the compounds of the present invention. Overlapping compounds.
  • active agents used in combination with the invention may be administered simultaneously, separately or sequentially with the compounds of the invention by the same or different routes of administration.
  • the other active agents may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered separately from the compound of the present invention in different discrete units, such as a combination product, preferably in the form of a kit, and when administered separately may be simultaneously or Performed sequentially, the successive administrations may be close or distant in time. They may be prepared and/or formulated by the same or different manufacturers.
  • the compounds of the present invention and other active agents may be administered (i) before the combination product is sent to the physician (for example, in the case of a kit containing a compound of the present invention and an additional drug); (ii) immediately before administration.
  • the physician himself (or under the direction of the physician); (iii) the patient himself, for example, during the sequential administration of a compound of the invention and other active agents together in the combination therapy.
  • the compounds of the present invention can also be combined with anti-tumor therapies, including but not limited to surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • anti-tumor therapies including but not limited to surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • the invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and Devices for separately containing the compositions, such as containers, portion bottles or discrete foil packages, such as blister packs for packaging tablets, capsules, etc., also including Use instructions.
  • the kit of the invention is particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, or for administering different compositions at different dosage intervals.
  • the abnormal cell growth involved may be caused by Ras mutations, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations, and KRAS amplification-mediated diseases are as defined above for the methods and uses of the invention.
  • KRas mutations preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations
  • the present invention also provides methods for preparing the compounds defined in the present invention.
  • the compounds of the present invention can be prepared by a variety of methods, including the general methods given below, the methods disclosed in the examples, or methods similar thereto.
  • suitable solvents are those conventional solvents known to those skilled in the art to be suitable for the specific reaction type involved, for example water, esters, ethers, liquid aromatic hydrocarbons, alcohols , nitriles, halogenated hydrocarbons, amides, bases, carboxylic anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents.
  • solvent mixtures can also be used for work-up, for example by chromatography or partitioning.
  • the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging.
  • the materials can be characterized using conventional methods including physical constants and spectral data.
  • the reaction mixture is worked up in a customary manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography.
  • the mixture of isomers formed can be separated into the individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, e.g. Racemates or mixtures of diastereomers, see for example "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).
  • the individual stereoisomers of the compound of the invention can be obtained by resolution, for example, by starting from a compound of the invention obtained as a mixture of stereoisomers.
  • Well-known methods are used, such as formation of diastereomeric pairs by salt formation with optically active acids followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography; alternatively, starting materials or intermediates with established stereochemistry can be used , or any known chiral resolution method can be used to obtain optically pure or enantiomerically enriched synthetic intermediates, which can then be used as such in subsequent steps at various stages of the above synthetic process.
  • Suitable protecting groups and methods for protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples may be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • step A compound 1 is commercially available or can be obtained according to the method used in the examples herein or a method similar thereto.
  • Compound 1 is introduced into fragment B-(R 8 ) t through an aromatic nucleophilic substitution reaction to obtain compound 2.
  • Typical aromatic nucleophilic substitution conditions are well known in the art, such as DIEA/THF, etc.
  • step B compound 2 is reacted with the corresponding amine compound under conditions such as DIEA/dioxane to obtain compound 3 or 4.
  • the corresponding amine compounds are commercially available, or can be obtained according to the methods used in the examples herein or methods similar to them, or can be obtained according to the methods of relevant literature in the field of organic chemistry.
  • the latter introduces naphthalene or benzothiophene compounds through Suzuki-Miyaura coupling reaction in step C to obtain compounds 5 or 6 or 7 or 8.
  • step D the protective groups of compounds 5 to 8 are removed to obtain compounds of general formulas I-A-1, I-B-1, I-A-4 and I-B-4.
  • Typical Suzuki-Miyaura coupling conditions are well known in the art, and those skilled in the art are aware of a variety of conditions for promoting such cross-coupling reactions, typical conditions such as Pd(dtbpf)Cl 2 /K 3 PO 4 /di Oxygen/water, or Pd(OAc) 2 /rac-BIDIME/K 2 CO 3 /toluene;
  • suitable palladium catalysts also include XantPhos Pd G2, A Pd G3, bis(triphenylphosphine)palladium(II) chloride, Pd(dppf)Cl 2 , Pd 2 dba 3 , tetraphenylphosphine palladium and palladium acetate (II), etc.; if necessary, suitable ligands may include Tricyclohexylphosphine, triphenylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium ter
  • step D can be adjusted according to the protecting group carried by the molecule, and can be a one-step reaction or a multi-step reaction.
  • the protective group PG carried is TIPS, it can be removed by reagents such as CsF.
  • step A compound 2 can be obtained according to the method steps described in synthetic scheme A.
  • Compound 2 is fluorinated through a halogen exchange reaction under conditions such as KF/DMSO or KF/MsOH/DABCO/DMSO to obtain compound 9.
  • Compound 9 then undergoes the Suzuki-Miyaura coupling reaction in step B, the aromatic nucleophilic substitution reaction in step C, and the protecting group removal reaction in step D to obtain the final compounds I-A-1, I-B-1, I-A-4 and I-B- 4.
  • the typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protecting group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.
  • step A compound 9 introduces fragment B-(R 8 ) t through a condensation reaction under conditions such as condensation agent BOP to obtain compound 10.
  • step B compound 10 is introduced into naphthalene or benzothiophene compounds through Suzuki-Miyaura coupling reaction to obtain compound 11 or 12.
  • step C the thioether in compound 11 or 12 is oxidized to obtain sulfoxide or sulfone, or a mixture of sulfoxide and sulfone, to obtain compound 13 or 14.
  • step D the YQ group is introduced through aromatic nucleophilic substitution reaction to obtain compound 15 or 16.
  • step E compound 15 or 16 removes possible protective groups to obtain a compound of general formula IC or ID.
  • the typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protecting group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.
  • ACN acetonitrile
  • Boc tert-butoxycarbonyl
  • BOP benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate
  • CDCl 3 deuterated chloroform
  • cataCXium A Pd G 3 Metalhanesulfonate[n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)); DABCO(1,4-diaza Bicyclo[2.2.2]octane); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethylformamide) Methyl sulfoxide); DMSO-d 6 (hexadeuterated dimethyl sulfoxide); EA or EtOAc (eth
  • experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.
  • Step B 7-bromo-2,4-dichloro-8-fluoroquinazoline
  • Step A Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate
  • Step B 7-bromo-6,8-difluoroquinazoline-2,4-diol
  • Step B (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester
  • Step C 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester
  • Step D 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride
  • Step F 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
  • Step G 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
  • Step B 4-Amino-6-chloro-5-fluoronicotinic acid ethyl ester
  • Step C 4-(Bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid ethyl ester
  • Boc 2 O (65.9g, 302mmol) was added dropwise to the anhydrous solution of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (30.0g, 137mmol) and DMAP (3.4g, 27.5mmol).
  • Dichloromethane (600mL) solution After the dropwise addition is completed, the mixture is heated to 45°C for overnight reaction.
  • imidazole (9.33g, 137mmol) to the system, stir for half an hour, add saturated ammonium chloride solution for washing (300mL ⁇ 3), separate the liquids, and wash the organic phase with saturated brine (300mL ⁇ 2).
  • Step D 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester
  • Step E 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester ⁇ HCl
  • Step F 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid
  • Step A 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol
  • Step A 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • intermediate A-II is as described in the synthesis of intermediate A-I.
  • step A N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a is used ][1,4]diaza-2-carboxamide (prepared with reference to document WO2022132200) instead of 3-methylpiperidin-3-ol ⁇ hydrochloride.
  • Step A (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step B (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step A (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine- 6-alcohol
  • Step B (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine-6- alcohol
  • Step A (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol
  • Step B (R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol
  • Step B (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxane-6- alcohol
  • Step C (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxane-6- alcohol
  • Step A (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3- Methylpiperidin-3-ol
  • Step A 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxaazepine Cycloheptan-6-ol
  • intermediate G-II-A The synthesis of intermediate G-II-A is carried out according to the protocol described in intermediate G-II.
  • step A (S)-6-methyl-1,4-oxepan-6-ol ⁇ hydrochloric acid is used The salt replaces 6-methyl-1,4-oxazepan-6-ol ⁇ hydrochloride.
  • Step A (S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl 1,4-Oxaazepan-6-ol
  • intermediate I-II-A The synthesis of intermediate I-II-A is carried out according to the protocol described in intermediate I-I-A.
  • step A (R)-6-methylpiperidin-3-ol ⁇ hydrochloride is used instead of (S)-6-methyl. -1,4-oxepane-6-ol hydrochloride.
  • Step A (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine -4-yl)-3-methylpiperidin-3-ol
  • step A (S)-6-methyl-1,4- Oxeptan-6-ol ⁇ hydrochloride was used instead of (R)-3-methyl-3-hydroxypiperidine ⁇ hydrochloride.
  • Step A 1-(tert-butyl)2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate
  • Step B 1-(tert-butyl)2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate
  • Step C 1-(tert-butyl)2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate
  • Step A (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate-1-(tert-butyl)ester-3-methyl ester
  • LCMS (m/z): 214.1 (M-56+H), 292.1 (M+Na).
  • Step B (3S)-3,4-dimethylpiperidine-1,3-dicarboxylate-1-(tert-butyl)ester-3-methyl ester
  • Step A (S)-4-Fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid-1-(tert-butyl)ester-3-methyl ester
  • Step B (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol
  • Step A (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester and (S,Z )-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester
  • Step B (S,E)-4-(Fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride
  • Step C (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
  • Step D (S,E)–(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol
  • reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with anhydrous tetrahydrofuran. Collect the filtrate and concentrate to dryness to obtain colorless oily product (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (300 mg, yield 92% ).
  • Step A (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester and (S,Z )-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester
  • step A The synthesis of step A is carried out as described in the synthesis of step A of intermediate e.
  • Step B (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl)-3-methyl ester
  • Step D (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
  • Step E ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol
  • reaction solution was filtered through diatomaceous earth to remove the solid, and the filtrate was concentrated to obtain a colorless oily liquid ( S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol (120 mg, yield 80%), was directly used in subsequent reactions.
  • Step A (S)-4-(Difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester
  • Step B (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester
  • (S)-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (6.20g , 20.31 mmol) was dissolved in methanol (150 mL), and replaced with nitrogen three times. Palladium on carbon (2.16g, 10% w/w) was added and replaced with hydrogen three times. Stir at 30°C for 4 hours under a hydrogen atmosphere of 15 Psi. After the reaction was monitored by LCMS, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with methanol.
  • Step D (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
  • Step B (3R)-4-Methoxy-3-methylpiperidine-1,3-dicarboxylate 1-(tert-butyl)ester 3-methyl ester
  • Step B (S)-(4,6-dimethyl-6-azaspiro[2.5]oct-4-yl)methanol
  • Step A (S,E)-4-(Fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidine-3-carboxylic acid methyl ester
  • Step B (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methanol
  • Step A (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methylene-d 2 -ol
  • Step A 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazoline -4-yl)-3-methylpiperidin-3-ol
  • LCMS monitored the completion of the reaction, added saturated aqueous ammonium chloride solution (20 mL) to the system, and extracted with ethyl acetate (15 mL ⁇ 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure.
  • Step B 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene- 1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl piperidin-3-ol
  • Step C 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step A 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • reaction solution was filtered through diatomaceous earth, and the filtrate was filtered through a filter head, concentrated, and lyophilized to obtain a white solid 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- Fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiper Din-3-ol (7.0 mg, yield 41%).
  • Step A 1-(7-bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3 -Methylpiperidin-3-ol
  • Step B 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triiso Propylsilyl)ethynyl)-3-(triisopropylsiloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step C 1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -(yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ formate
  • Step A 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperidin-3-ol
  • Step B 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1- (yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step C 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidine) -2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate
  • Step A (R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-( (Triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol
  • Step B (R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-(triisopropylsilyl)ethynyl) -3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)piperidin-3-ol and (R)-3-methyl-1-(2, 6,8-Trifluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)quinazolin-4-yl)piperidin-3-ol
  • Chiral analysis method SFC-32A, Rt 2.539.
  • the subsequently eluted isomer 2 is intermediate 32-A-P2, (R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro- 8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidine-3- Alcohol (7.0g, relatively large retention time).
  • Chiral analysis method SFC-32A, Rt 3.978.
  • Step C (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6, 8-Difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -(yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step D (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- ((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step E (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6, 8-Difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -(yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step F (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- ((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step A (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step B (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • reaction solution was poured into saturated NH 4 Cl solution (50 mL), and extracted with EA (50 mL ⁇ 3). Combine the organic phases, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate.
  • Step C (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step D (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step A (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol
  • Step A (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol
  • Step B (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • the mixed solution was heated to 110°C and stirred for 2 hours. After the reaction was monitored by LCMS, the reaction solution was poured into water (50 mL), extracted with EA (60 mL ⁇ 3), and the combined organic phases were washed with saturated NaCl (20 mL).
  • Step C (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step D (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxy pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step E (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine -3-ol
  • the reaction solution was prepared by Pre-HPLC to obtain a light yellow solid (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(( (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol (30 mg, yield 44%).
  • Step A (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol
  • Step A (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio) Pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step B (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(methylsulfenic acid) Acyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • reaction solution was diluted with DCM (100 mL), washed with half-saturated NaHCO 3 aqueous solution (20 mL), the aqueous phase was extracted with DCM (60 mL ⁇ 3), and the combined organic phases were washed with saturated NaCl aqueous solution (30 mL).
  • Step C (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methyl piperidin-3-ol
  • Step D (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step A (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-( (Triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-1,4-oxaazepan-6-ol
  • Step B (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6 ,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl) Quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Step C (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol
  • Step A (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine alkan-6-ol
  • Step A (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,6,8-trifluoroquinazoline -4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Step B (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-6,8-difluoro-2-(( (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4 -Oxaazepan-6-ol
  • Step C (6S)-4-(7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S, E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxa Azepan-6-ol trifluoroacetate and (6S)-4-(7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6 ,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl )-6-Methyl-1,4-oxaazepan-6-ol trifluoroacetate
  • Step A (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio) -5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • LCMS monitored the end of the reaction, cooled to room temperature, added 30 mL of saturated aqueous ammonium chloride solution to quench, and then extracted with EtOAc (30 mL ⁇ 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness.
  • Step B (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylsulfenic acid) Acyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step C (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-((triisopropylsilane (yl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step D (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido [4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
  • Step E (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol
  • Step A (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) yl)oxy)naphth-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazole Phin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Step B (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4 -(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepine alkan-6-ol
  • Example 110-1 and Example 110-2 are Example 110-1 and Example 110-2.
  • Step A (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-methoxy-2 -(Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
  • Step B (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-methoxy-2 -(Methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
  • Step C (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((S, E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl )-6-methyl-1,4-oxazepan-6-ol
  • LCMS monitored the end of the reaction. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (10 mL). EA (20 mL) ⁇ 2) Extraction. Collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate the organic phase to obtain yellow solid (S)-4-(7-(8-ethyl-7-fluoro-3-methoxy Methoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methane Oxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, yield 64 %).
  • Step D (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoro (Methylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl- 1,4-Oxaazepan-6-ol
  • Step A (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol
  • LCMS monitors the end of the reaction, returns the reaction solution to room temperature, filters through diatomaceous earth to remove the palladium catalyst and alkali, and concentrates the organic liquid.
  • Step B (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol
  • Step C (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy) Naphthyl-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxy Pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
  • Step D (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol
  • Step D (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris( Isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol
  • Step E (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)- 6-Chloro-8-fluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris(isopropyl)silyl)ethynyl)-1 -naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol
  • Step F (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)- 6-Chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxaheterocycle Propan-6-ol
  • Step A (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene- 1-yl)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
  • Step B (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidine-4 -yl)-6-methyl-1,4-oxazepan-6-ol
  • Step A (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidine-4 -yl)-6-methyl-1,4-oxazepan-6-ol
  • Step A (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl) Silyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step B (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazole lin-4-yl)-3-methylpiperidin-3-ol
  • LCMS monitored the reaction to completion. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (50 mL), extract with EA (50 mL ⁇ 3), and collect the organic phase. , washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na 2 SO 4 .
  • Step C (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ trifluoroacetic acid
  • Step A (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ trifluoroacetic acid and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8 -Ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ trifluoroacetic acid
  • Step A (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) )oxy)naphth-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazole lin-4-yl)-3-methylpiperidin-3-ol
  • LCMS monitored the reaction to completion. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (20 mL), and extracted with EA (20 mL ⁇ 3). After collecting the organic phase, wash with saturated NaCl aqueous solution (20 mL) and dry over anhydrous Na 2 SO 4 .
  • Step B (3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ trifluoroethyl acid salt
  • Step A (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoroquine Zozolin-4-yl)-3-methylpiperidin-3-ol
  • Step B (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-( ((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine- 3-alcohol
  • Step C (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol ⁇ trifluoroethyl acid salt
  • the present invention also prepared the following compounds.
  • Example 1 The inhibitory effect of the compound of the present invention on the proliferation of NCI-H727 cells with KRAS G12V mutation
  • This experiment evaluates and verifies the proliferation inhibitory activity of the representative compounds of the present invention on KRAS G12V mutant cell NCI-H727 cells.
  • Method A This experiment uses the following cell lines:
  • fetal bovine serum FBS Gibco, Cat#10091-148
  • CellTiter- Luminescent Cell Viability Assay Promega, Cat#G7573
  • 96-well transparent flat bottom black wall plate Cat#3603
  • Envision multifunctional microplate reader PE, 2105; CO 2 incubator, Thermo Scientific, Model 371; Biological safety cabinet, Thermo Scientific, Model 1300 Series A2; Inverted microscope, Olympus, CKX53.
  • NCI-H727 cell line was purchased from ATCC with the catalog number CRL-5815.
  • Cell culture and seeding Harvest cells in logarithmic growth phase and count using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 ⁇ L of cell suspension to the 96-well plate; culture the cells in the 96-well plate at 37°C and 5% CO2 .
  • Single-point inhibition rate determination Drug preparation: Prepare 10 times the drug solution, add 10 ⁇ L drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is 1 ⁇ M, and set three times for each drug concentration. A compound hole.
  • IC50 determination drug preparation Prepare 10 times drug solution, add 10 ⁇ L drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 ⁇ M, 3 ⁇ dilution, 9 concentrations, and set three replicates for each drug concentration. hole.
  • the cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 3 days, and then CTG detection was performed.
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • Method B Place NCI-H727 cells (Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60182, adherent, culture medium RPMI-1640+10% FBS (GIBCO, Cat#10091-148)) at 37°C, 5% Culture under CO 2 and 95% humidity conditions.
  • 3D cell viability assay Harvest cells in logarithmic growth phase and count cells using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Prepare RPMI-1640 culture medium containing 1% MC (methylcellulose, Sigma, Cat#M0512) and add 10% FBS to prepare a 3D cell culture medium. Use the 3D culture medium to adjust the details. The cell concentration was approximately 14815 cells/mL and the content of methylcellulose (MC) was 0.65%; 135 ⁇ L of cell suspension was added to a 96-well transparent flat-bottomed black wall plate (Greiner, Cat#655096); The cells in the plate were cultured overnight at 37°C and 5% CO2 .
  • MC methylcellulose
  • IC 50 determination drug preparation Use culture medium to prepare 10-fold drug solution, add 10 ⁇ L drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 ⁇ M, 3 ⁇ dilution, 9 concentrations, each drug concentration Set up 2 multiple holes.
  • the cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 7 days, and then CTG detection was performed ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • Representative compounds of the present invention show satisfactory anti-proliferative activity against KRAS G12V mutated NCI-H727 human lung cancer cells. Part of the activity data is shown in the table below:
  • Example 2 The inhibitory effect of the compound of the present invention on the proliferation of AGS cells with KRAS G12D mutation
  • This experiment evaluates and verifies the proliferation inhibitory activity of the representative compounds of the present invention on KRAS G12D mutant AGS cells.
  • Method A This experiment uses the following cell lines:

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Abstract

The present invention provides a compound represented by formula (I) for use as a KRAS inhibitor, a pharmaceutical composition comprising the compound, a method for preparing the compound, and use of the compound in treating a cancer.

Description

具有抗KRAS突变肿瘤活性的化合物Compounds with activity against KRAS mutated tumors 技术领域Technical field
本发明涉及药物化学领域。更具体地，本发明涉及一类可用作KRAS抑制剂的具有新结构的化合物、包含这类化合物的药物组合物、制备这类化合物的方法以及这些化合物在治疗癌症或肿瘤中的用途。The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with novel structures useful as KRAS inhibitors, pharmaceutical compositions containing such compounds, methods for preparing such compounds and the use of these compounds in the treatment of cancer or tumors.
背景技术Background technique
Ras，即大鼠肉瘤致癌基因同系物，代表一组密切相关的单体球形蛋白，属于GTP酶蛋白家族。具体而言，在正常生理条件下，Ras接受生长因子和各种其他细胞外信号而被激活，负责调节细胞生长、存活、迁移和分化等功能。Ras的这些调节功能是通过GDP结合状态和GTP结合状态之间的转换即“分子开关”来进行(Alamgeer等人，Current Opin Pharmacol.2013,13:394-401)。与GDP结合的Ras是非活性形式，处于休眠或关闭状态，此时信号系统关闭，当其暴露于一些促生刺激时会被活化，例如其可以被鸟嘌呤核苷酸交换因子(GEF)诱导而释放GDP并与GTP结合，结果是Ras被由此“开启”，从而转化为Ras活性形式，其募集并活化各类下游效应子，进行信号传递，能够将细胞表面的信号传送至细胞质中，从而控制众多关键的细胞过程如分化、存活和增殖(Zhi Tan等人，Mini-Reviews in Medicinal Chemistry,2016,16,345-357)。Ras, the rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the GTPase protein family. Specifically, under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, differentiation and other functions. These regulatory functions of Ras are performed through the conversion between the GDP-bound state and the GTP-bound state, a "molecular switch" (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401). Ras bound to GDP is an inactive form and is in a dormant or off state. At this time, the signaling system is turned off. It will be activated when it is exposed to some growth-promoting stimuli. For example, it can be induced by guanine nucleotide exchange factor (GEF). GDP is released and combined with GTP. As a result, Ras is "turned on" and converted into the active form of Ras, which recruits and activates various downstream effectors for signal transmission and can transmit signals on the cell surface to the cytoplasm. Controls numerous key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).
Ras具有GTP酶活性，其可以裂解GTP的末端磷酸而将其转化为GDP，即将其自身转化为非活性状态。但是Ras的内源性GTP酶活性非常低，将GTP-Ras转化为GDP-Ras需要外源性蛋白GAP(GTP酶激活蛋白)。GAP与Ras相互作用并促进GTP向GDP的转化。因此，任何影响Ras与GAP相互作用或者影响GTP向GDP转化的Ras基因突变，都会导致Ras长时间处于活化状态，由此向细胞持续传达生长和分裂的信号，刺激细胞不断增殖，最终导致肿瘤形成和发展。Ras has GTPase activity, which can cleave the terminal phosphate of GTP and convert it into GDP, that is, convert itself into an inactive state. However, the endogenous GTPase activity of Ras is very low, and the exogenous protein GAP (GTPase activating protein) is required to convert GTP-Ras into GDP-Ras. GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation that affects the interaction between Ras and GAP or the conversion of GTP to GDP will cause Ras to remain active for a long time, thus continuously transmitting growth and division signals to cells, stimulating continuous cell proliferation, and ultimately leading to tumor formation. And development.
在人类肿瘤相关的基因中，存在三种遍在表达的Ras基因H-RAS、K-RAS和N-RAS，其分别编码高度同源的、约21KDa的HRas、NRas、KRas蛋白。1982年，研究人员首次发现Ras在癌细胞系中突变活化(Chang,E.H.等人，Proceedings of the National Academy of Sciences of the United States of America,1982,79(16),4848-4852)。随后在不同癌症类型中进行的大型基因组测序研究揭示，Ras蛋白在超过30％的癌症类型中发生突变，尤其在胰腺癌(>90％)、结肠癌(45％)和肺癌(35％)中的突变率最高。转基因和基因工程小鼠模型也已经揭示，突变的Ras蛋白足以驱动并引发多种类型的癌症，且Ras致癌基因对于多种癌症类型的肿瘤的维持和进展也是至关重要的，例如在Ras突变癌症细胞系和癌症动物模型中，已经显示RNA干预能够减缓肿瘤的生长。这些研究使得Ras肿瘤蛋白成为药学领域中广为接受的非常有吸引力的抗癌药物靶点。Among human tumor-related genes, there are three ubiquitously expressed Ras genes, H-RAS, K-RAS and N-RAS, which respectively encode highly homologous HRas, NRas and KRas proteins of approximately 21KDa. In 1982, researchers first discovered that Ras was mutated and activated in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large genome sequencing studies in different cancer types revealed that the Ras protein is mutated in more than 30% of cancer types, especially in pancreatic cancer (>90%), colon cancer (45%), and lung cancer (35%) has the highest mutation rate. Transgenic and genetically engineered mouse models have also revealed that mutated Ras proteins are sufficient to drive and initiate multiple types of cancer, and that the Ras oncogene is also critical for tumor maintenance and progression in multiple cancer types, such as in Ras mutations. RNA intervention has been shown to slow tumor growth in cancer cell lines and cancer animal models. These studies have made the Ras tumor protein a very attractive anti-cancer drug target that is widely accepted in the pharmaceutical field.
研究表明，Ras突变最常见于KRas，约85％的Ras突变驱动的癌症中可以观察到KRas突变；绝大部分Ras突变发生在密码子G12、G13和Q61上，其中约80％的KRas突变又发 生于密码子12的甘氨酸处，例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变等。KRas突变常见于胰腺癌、肺腺癌、结直肠癌、胆囊癌、甲状腺癌和胆管癌，也可见于25％的非小细胞肺癌患者中(McCormick,F.等人，Clinical Cancer Research 21(8),1797-1801,2015)。因此，KRas突变蛋白已经成为Ras药物靶点研究中最重要的分支，对于其抑制剂的开发也被视为抗癌/肿瘤药物开发中非常具有前景的研发方向。Research shows that Ras mutations are most common in KRas, and KRas mutations can be observed in about 85% of cancers driven by Ras mutations; the vast majority of Ras mutations occur in codons G12, G13, and Q61, of which about 80% of KRas mutations are hair Born at glycine in codon 12, such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation, etc. KRas mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma, and are also found in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21(8 ),1797-1801,2015). Therefore, KRas mutant protein has become the most important branch of Ras drug target research, and the development of its inhibitors is also regarded as a very promising research direction in the development of anti-cancer/tumor drugs.
但是，过去几十年针对Ras的药物研发显示，由于Ras蛋白表面光滑，缺少明显的用于结合小分子抑制剂的沟状或口袋装结构，而且其对鸟嘌呤底物的亲和力非常高(皮摩尔级)，使得其小分子抑制剂的开发陷入了难以解决的困境，由此Ras在业内长久以来被认为是“不可成药的”靶点。同时，目前仍然非常需要作为KRas抑制剂的更多结构类型或模式的化合物，提供更多的治疗选择，或者提供相对于现有Kras抑制剂而言进一步改进的抑制活性，从而为临床提供更强效的治疗药物。However, drug development for Ras in the past few decades has shown that due to the smooth surface of Ras protein, it lacks obvious grooves or pocket structures for binding small molecule inhibitors, and its affinity for guanine substrates is very high (Pi). molar level), causing the development of its small molecule inhibitors to fall into an insurmountable dilemma. As a result, Ras has long been considered an "undruggable" target in the industry. At the same time, there is still a great need for compounds with more structural types or patterns as KRas inhibitors to provide more treatment options, or to provide further improved inhibitory activity relative to existing Kras inhibitors, thereby providing stronger clinical benefits. effective therapeutic drugs.
本发明解决了这些和其他需求。本发明提供了具有KRas突变蛋白抑制活性的新结构抑制剂化合物。这些本发明化合物因具有改进的结构模式，相比现有技术已有的KRas突变蛋白抑制剂，具有增强的抑制KRas突变蛋白的活性以及对相关肿瘤抑制活性，具有良好的药代动力学性质，从而具有良好的成药性，比如能够以方便的方式给药后更容易在体内吸收，且毒副作用减少，具有改善的耐药性和安全性，以及降低的药物相互作用风险。The present invention addresses these and other needs. The present invention provides novel structural inhibitor compounds with KRas mutein inhibitory activity. Because these compounds of the present invention have improved structural patterns, compared with existing KRas mutant protein inhibitors in the prior art, they have enhanced activity in inhibiting KRas mutant proteins and related tumor inhibitory activities, and have good pharmacokinetic properties. Therefore, it has good drug-forming properties, such as being more easily absorbed in the body after administration in a convenient manner, with reduced toxic and side effects, improved drug resistance and safety, and reduced risk of drug interactions.
发明简述Brief description of the invention
本发明提供了本文如下所定义的具有结构式(I)的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：
The invention provides compounds of structural formula (I), their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof as defined herein below:
其中各个基团的定义如发明详述部分所定义。The definitions of each group are as defined in the detailed description of the invention.
本发明还提供了包含本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物以及任选的药学可接受的赋形剂或载体的药物组合物。The invention also provides a compound comprising a compound of the invention or its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate and optional pharmaceutically acceptable excipients or Carrier for pharmaceutical compositions.
本发明还提供了用作药物的本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。The invention also provides a compound of the invention or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof for use as a medicament.
本发明还提供了本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，用作Ras突变蛋白、尤其是KRas突变蛋白(例如G12C突变、G12D 突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增型细胞的抑制剂。The invention also provides the compounds of the invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates for use as Ras mutein, especially KRas mutein ( For example, G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and inhibitor of KRAS amplified cells.
本发明还提供了用于治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增介导的疾病的本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，或包含其的药物组合物。The invention also provides a method for treating and/or preventing mutations caused by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and Compounds of the invention, or stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing the same, for diseases mediated by KRAS amplification.
本发明还提供了本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物、或包含其的药物组合物用于治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增介导的疾病的用途。The invention also provides compounds of the invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing the same for the treatment and/or Or the use of preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification.
本发明还提供了本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物、或包含其的药物组合物在制备用于治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增介导的疾病的药物中的用途。The present invention also provides the compounds of the present invention or their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing them for use in the treatment of and/or prevent diseases mediated by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification Uses in medicines.
本发明还提供了治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增介导的疾病的方法，包括向有需要的对象施用治疗有效量的本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物、或包含其的药物组合物。The present invention also provides treatment and/or prevention of mutations caused by Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification. A method of increasing mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof substances, or pharmaceutical compositions containing them.
本发明还提供了一种治疗肿瘤或癌症的方法，其包括向有需要的患者施用本发明化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物、或包含其的药物组合物。The present invention also provides a method for treating tumors or cancer, which includes administering a compound of the present invention or a stereoisomer, tautomer, stable isotope variant, or pharmaceutically acceptable salt thereof to a patient in need thereof or solvates, or pharmaceutical compositions containing the same.
本发明还提供了本发明的化合物或其药学上可接受的盐或溶剂合物在研究中作为KRas抑制剂、特别是作为抑制KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变及Q61H突变蛋白)及KRAS扩增的研究工具化合物的用途。The present invention also provides the compounds of the present invention or their pharmaceutically acceptable salts or solvates in research as KRas inhibitors, especially as inhibitors of KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, Use of tool compounds for research on G12R mutations, G12S mutations, G13D mutations and Q61H mutant proteins) and KRAS amplification.
本发明还提供了药物组合，其包含本发明化合物其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物和一种或多种其他药物活性剂。The invention also provides pharmaceutical combinations comprising a compound of the invention as a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof and one or more other pharmaceutically active agent.
本发明还提供了用于制备本发明化合物的方法。The invention also provides methods for preparing the compounds of the invention.
发明详述Detailed description of the invention
定义definition
除非另外指出，说明书和权利要求书中使用的各个术语具有以下所示含义。在特定的术语或短语没有特别定义的情况下，应该按照本领域的普通含义理解。在冲突的情况下，以本 说明书(包括定义)为准。Unless otherwise indicated, each term used in the specification and claims has the meaning indicated below. Where a particular term or phrase is not specifically defined, it should be understood according to its ordinary meaning in the art. In case of conflict, this The instructions (including definitions) shall prevail.
在本文所公开的化合物的化学结构和名称发生冲突的情况下，以化学结构为准。In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure shall control.
本文所用的术语“Ras突变”或“Ras突变蛋白”是指其中一个或多个密码子发生突变的Ras基因所编码和表达的蛋白，典型地包括但不限于Ras的密码子12位的甘氨酸、密码子13位的甘氨酸或密码子61位的谷氨酰胺发生突变的Ras蛋白，例如突变的HRas、NRas或KRas。这些残基位于Ras的活性位点，其突变可损害Ras的固有的或GAP-催化的GTP酶活性，导致与GTP结合的Ras持续存在。The term "Ras mutation" or "Ras mutant protein" used herein refers to the protein encoded and expressed by the Ras gene in which one or more codons are mutated, typically including but not limited to glycine at position 12 of the codon of Ras, Ras proteins with mutations in glycine at codon 13 or glutamine at codon 61, such as mutated HRas, NRas or KRas. These residues are located in the active site of Ras, and their mutations can impair the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the persistence of GTP-bound Ras.
对本发明的目的而言，“Ras突变”或“Ras突变蛋白”以及描述抑制活性时所针对的“Ras”可互换使用，且一般地是指突变的HRas、NRas或KRas，例如但不限于KRas-G12C(密码子G12处甘氨酸向半胱氨酸的突变)、KRas-G12D(密码子G12处甘氨酸向天冬氨酸的突变)、HRas-G12D、NRas-G12D、KRas-G12V(密码子G12处甘氨酸向缬氨酸的突变)、KRas-G13D(密码子G13处甘氨酸向天冬氨酸的突变)；特别地是指KRas突变蛋白，更特别地是指KRas-G12C突变蛋白、KRas-G12D突变蛋白、KRas-G12V突变蛋白、KRas-G12A突变蛋白、KRas-G12R突变蛋白、KRas-G12S突变蛋白、KRas-G13D突变蛋白及KRas-Q61H突变蛋白。For the purposes of the present invention, "Ras mutant" or "Ras mutein" and "Ras" with respect to which inhibitory activity is described are used interchangeably and generally refer to mutated HRas, NRas or KRas, such as, but not limited to KRas-G12C (mutation of glycine to cysteine at codon G12), KRas-G12D (mutation of glycine to aspartate at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12 from glycine to aspartate) Mutation of glycine to valine at G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); specifically refers to the KRas mutant protein, and more particularly refers to the KRas-G12C mutant protein, KRas- G12D mutant protein, KRas-G12V mutant protein, KRas-G12A mutant protein, KRas-G12R mutant protein, KRas-G12S mutant protein, KRas-G13D mutant protein and KRas-Q61H mutant protein.
本文所用的术语“治疗”是指给患有所述疾病、或者具有所述疾病的症状的受试者、例如哺乳动物、例如人施用一种或多种本文所述的本发明化合物或其药学上可接受的盐或溶剂合物，用以治愈、缓解、减轻或影响所述疾病或所述疾病的症状。优选地，治疗是治愈性或改善性的。The term "treatment" as used herein refers to the administration of one or more compounds of the present invention or pharmaceuticals thereof as described herein to a subject, such as a mammal, such as a human, suffering from the disease, or having symptoms of the disease. Acceptable salts or solvates of the above are used to cure, alleviate, reduce or affect the disease or the symptoms of the disease. Preferably, the treatment is curative or ameliorative.
本文所用的术语“预防”在本领域中是众所周知的，是给怀疑患上或易感于如本文所定义的Ras突变介导的疾病、尤其是癌症或肿瘤的受试者、例如哺乳动物、例如人施用一种或多种本文所述的化合物或其药学上可接受的盐或溶剂合物，使得罹患所定义疾病的风险降低，或预防疾病的发作。术语“预防”包含在诊断或确定任何临床和/或病理症状以前使用本发明的化合物。The term "prevention" as used herein is well known in the art and refers to a subject, such as a mammal, suspected of suffering from or susceptible to a Ras mutation-mediated disease, in particular a cancer or tumor, as defined herein. For example, administration of one or more compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, to a human results in a reduced risk of developing a defined disease, or prevents the onset of a disease. The term "prophylaxis" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological symptoms.
本文所用的术语“抑制”和“降低”或这些术语的任何变体，是指生物活性剂的能力，其通过直接或间接与靶点相互作用，降低目标靶点的信号传导活性，且是指目标靶点活性的任何可以测量的减少或完全抑制。例如，与正常情况相比，可以是活性(例如KRas活性)降低量约、至多约或至少约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％、99％或更多、或其中可衍生的任何范围。As used herein, the terms "inhibit" and "reduce" or any variations of these terms, refer to the ability of a biologically active agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target, and refers to Any measurable reduction or complete inhibition of the activity of a target of interest. For example, the activity (e.g., KRas activity) may be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% compared to normal conditions. %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.
本文所用的术语“Ras突变介导的疾病”是指Ras突变对所述疾病的发生和发展起到促进作用，或抑制Ras突变将降低疾病的发生率、减少或消除疾病病状的疾病。对于本发明而言，“Ras突变介导的疾病”优选指的是KRas突变介导的疾病，更进一步优选KRas突变介导的癌症或肿瘤。The term "Ras mutation-mediated disease" as used herein refers to a disease in which a Ras mutation promotes the occurrence and development of the disease, or in which inhibition of the Ras mutation will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease. For the purposes of the present invention, "Ras mutation-mediated disease" preferably refers to a disease mediated by a KRas mutation, and more preferably a cancer or tumor mediated by a KRas mutation.
本文所用的术语“癌症”或“肿瘤”是指异常的细胞生长和增殖，无论是恶性的还是良性的，和所有的癌前期细胞和癌细胞和组织。对本发明的各个方面而言，所述癌症或肿瘤包 括但不限于肺腺癌、肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤(CNS)、原发性CNS淋巴瘤、脊柱肿瘤、脑干神经胶质瘤或垂体腺瘤。The term "cancer" or "tumor" as used herein refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. For various aspects of the invention, the cancer or tumor mass Including but not limited to lung adenocarcinoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer , fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer , Penile cancer, Prostate cancer, Chronic or acute leukemia, Lymphocytic lymphoma, Bladder cancer, Kidney or ureter cancer, Renal cell carcinoma, Renal pelvis cancer, Central nervous system tumors (CNS), Primary CNS lymphoma, Spinal tumors , brainstem glioma or pituitary adenoma.
对于本发明的各个方面，优选地，所述癌症或肿瘤与Ras突变、尤其是KRas突变及扩增相关，包括但不限于上述肿瘤类型以及其优选范围。本发明特别优选的肿瘤包括肺癌、肺腺癌、结肠癌、直肠癌、胰腺癌、子宫内膜癌、胆管癌、白血病和卵巢癌。For various aspects of the invention, preferably, the cancer or tumor is associated with Ras mutations, especially KRas mutations and amplifications, including but not limited to the above-mentioned tumor types and preferred ranges thereof. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, cholangiocarcinoma, leukemia and ovarian cancer.
本文所用的术语“受试者”、“个体”或“患者”是指脊椎动物。在某些实施方案中，脊椎动物为哺乳动物。哺乳动物包括但不限于农场动物(如牛)、运动动物、宠物(如豚鼠、猫、狗、兔子和马)、灵长类动物、小鼠和大鼠。在某些实施方案中，哺乳动物是人类。As used herein, the terms "subject," "individual," or "patient" refer to a vertebrate animal. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cattle), sporting animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, the mammal is a human.
本文所用的术语“治疗有效量”是指通常足以对需要治疗的所述“Ras突变介导的疾病”如癌症或肿瘤患者产生有益治疗效果的量或剂量。本领域技术人员可以通过常规方法、结合常规影响因素来确定本发明中活性成分的有效量或剂量。The term "therapeutically effective amount" as used herein refers to an amount or dosage generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment of said "Ras mutation-mediated disease" such as cancer or tumors. Those skilled in the art can determine the effective amount or dosage of the active ingredients in the present invention through conventional methods and combined with conventional influencing factors.
本文所用的术语“药物组合”是指本发明化合物可与其它活性剂组合用于实现本发明的目的。所述其他活性剂可以是一种或多种另外的本发明化合物，或可以是与本发明化合物相容即不会相互不利影响、或具有互补活性的第二种或另外的(例如第三种)化合物，例如这些活性剂已知调节其他生物活性通路，或者调节本发明化合物所涉及生物活性通路中的不同组分，或甚至是与本发明化合物的生物靶点相重叠。这类活性剂以达到预期目的的有效量适宜地组合存在。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，当分别施用时可以同时或相继进行。所述相继施用在时间上可以是接近或隔远的。The term "pharmaceutical combination" as used herein means that the compounds of the invention may be combined with other active agents for carrying out the purposes of the invention. The other active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., a third) compound that is compatible with the compound of the invention, that is, does not adversely affect each other, or has complementary activity. ) compounds, for example, these active agents are known to modulate other biologically active pathways, or modulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention. Such active agents are suitably present in combination in an amount effective to achieve the intended purpose. The other active agents may be co-administered with the compound of the invention in a single pharmaceutical composition, or may be administered separately from the compound of the invention in separate discrete units, and when administered separately may be administered simultaneously or sequentially. The sequential administrations may be close or distant in time.
本文所用的术语“药学上可接受的”意指当向动物例如人类适量施用时不会产生不利、过敏或其它不良反应的分子实体和组合物。The term "pharmaceutically acceptable" as used herein means molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered in appropriate amounts to animals, such as humans.
本文所用的术语“药学上可接受的盐”是指保留了母体化合物的生物学有效性和性质并且在生物学或其它方面不是不可取的那些盐，包括酸加成盐和碱加成盐。“药学上可接受的酸加成盐”可由具有碱性基团的化合物与无机酸或有机酸形成，无机酸例如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等，有机酸可以选自脂族、脂环族、芳香族、芳脂族、杂环类、羧酸类和磺酸类有机酸，如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、水杨酸等。“药学上可接受的碱加成盐”包括衍生自无机碱如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝的盐等的那些，以及衍生自药学上可接受有机无毒碱的盐，包括但不 限于伯胺、仲胺和叔胺、取代铵，包括天然存在的取代胺、环状胺和碱性离子交换树脂，如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、氨丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、三乙醇胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。The term "pharmaceutically acceptable salts" as used herein refers to those salts, including acid addition salts and base addition salts, which retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable. "Pharmaceutically acceptable acid addition salts" can be formed from compounds with basic groups and inorganic acids or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids can be selected from Aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, apple Acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, naphthalene Acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, as well as those derived from pharmaceutically acceptable base addition salts. Accepts salts from organic nontoxic bases, including but not Limited to primary, secondary and tertiary amines, substituted ammoniums, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, Ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, seaweed Pamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.
本文所用的术语“异构体”是指化合物在结构上可能存在的任何立体异构体、对映体混合物、包括外消旋物、非对映异构体混合物、几何异构体、阻旋异构体和/或互变异构体。所述异构体立体化学的确定和分离方法为本领域技术人员所熟知(S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；和Eliel,E.和Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994)。The term "isomer" as used herein refers to any stereoisomer or enantiomeric mixture that may exist in the structure of a compound, including racemates, diastereomeric mixtures, geometric isomers, and antirotation Isomers and/or tautomers. Methods for determining the stereochemistry and separation of such isomers are well known to those skilled in the art (S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994).
本发明的某些化合物包含至少一个不对称中心，且由此产生立体异构体，故本发明涵盖本文所定义化合物的所有可能的异构体形式，及其药学可接受的盐或溶剂合物，另有指示除外。Certain compounds of the present invention contain at least one asymmetric center and thus produce stereoisomers. Therefore, the present invention encompasses all possible isomeric forms of the compounds defined herein, as well as pharmaceutically acceptable salts or solvates thereof. , unless otherwise instructed.
本文化合物结构式或结构片段中使用的表示立体中心即手性中心的绝对构型，相应地在本发明所提供的化合物或中间体的命名中以R或S表示关于该手性中心的绝对构型；在有些本发明化合物定义中也可以使用轴手性表示化合物构型，这些构型的确定使用本领域技术人员所熟知的Cahn-Ingold-Prelog规则，如下图两个示例结构中轴手性绝对构型描述如下：
used in the structural formula or structural fragment of the compound in this article It represents the absolute configuration of the stereocenter, that is, the chiral center. Correspondingly, in the naming of the compounds or intermediates provided by the present invention, R or S represents the absolute configuration of the chiral center; in some definitions of the compounds of the present invention, it is also Axial chirality can be used to represent the configuration of a compound. The determination of these configurations uses the Cahn-Ingold-Prelog rule, which is well known to those skilled in the art. The absolute configuration of the axial chirality in the two example structures shown below is described as follows:
应当理解的是，当本领域技术人员基于本文所示化合物结构能够判断该化合物存在且仅存在一对手性异构体、且判断基于本领域常规方法可以容易地拆分时，则本文对该化合物外消旋体的公开(无论是结构式还是化学名)，均应视为已经分别公开了该化合物的各个异构体。It should be understood that when those skilled in the art can judge that the compound exists and only has one pair of chiral isomers based on the compound structure shown herein, and judge that it can be easily separated based on conventional methods in the art, then the compound herein The disclosure of a racemate (whether it is a structural formula or a chemical name) shall be deemed to have separately disclosed each isomer of the compound.
本文所涉及结构片段中使用的指示与其交叉的键是结构片段连接于分子其余部分的键。used in the structural fragments covered in this article The bond indicating its intersection is the bond connecting the structural fragment to the rest of the molecule.
本文所涉及环状结构片段中以横跨化学键示出的取代基，例如中的-(R3)m，是指该一个或多个R3取代基可以取代在环中任意化学上可行的一个或多个取代位点，包括Z。 The substituents in the cyclic structural fragments referred to herein are shown as spanning the chemical bond, for example -(R 3 ) m means that one or more R 3 substituents can substitute for one or more substitution sites in the ring that are chemically feasible, including Z.
本发明的化合物包括本发明化合物的未标记形式及其同位素标记形式。化合物的同位素标记形式是仅在一个或多个原子被相应的同位素富集原子替换不同的化合物。可以并入本发明化合物中的同位素的实例包括例如氢、碳、氮、氧、氟、氯和碘的同位素，例如2H、3H、11C、13C、14C、15N、18O、17O、35S、18F、37Cl和125I。此类同位素标记的化合物可用作例如生物测定中的探针、分析工具或用作治疗剂。在某些实施方案中，本发明的化合物以未标记的形式提供。Compounds of the invention include unlabeled forms of compounds of the invention and isotopically labeled forms thereof. Isotopically labeled forms of compounds are compounds that differ only in the replacement of one or more atoms by the corresponding isotopically enriched atom. Examples of isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O , 17 O, 35 S, 18 F, 37 Cl and 125 I. Such isotopically labeled compounds may be used, for example, as probes in biological assays, analytical tools, or as therapeutic agents. In certain embodiments, the compounds of the invention are provided in unlabeled form.
本文所用的术语“溶剂合物”是指包含化学计量的或非化学计量的溶剂的化合物的溶剂加成形式，包括本发明化合物的任何溶剂化形式，包括例如与水的溶剂合物，例如水合物，或与有机溶剂的溶剂合物，例如甲醇、乙醇或乙腈，即分别作为甲醇化物、乙醇化物或乙腈化物；或为任何多晶型物的形式。应当理解的是，本发明化合物的这类溶剂合物还包括本发明化合物的药学上可接受盐的溶剂合物。The term "solvate" as used herein refers to solvent addition forms of compounds containing stoichiometric or non-stoichiometric solvents, including any solvated form of the compounds of the present invention, including, for example, solvates with water, such as hydrates or as a solvate with an organic solvent such as methanol, ethanol or acetonitrile, i.e. as a methanolate, ethanolate or acetonitrile respectively; or in the form of any polymorphic form. It is to be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.
本文所用的术语“代谢物”意指化合物经由体内代谢生成的产物。这类产物可例如源自所施用化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、去酯化、酶促剪切等。代谢物产物的鉴定和分析以本领域技术人员熟知的方式进行。The term "metabolite" as used herein means the product of a compound metabolized in the body. Such products may, for example, result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Identification and analysis of metabolite products is performed in a manner well known to those skilled in the art.
本文所用的术语“药学上可接受的赋形剂”或“药学上可接受的载体”是指一种或多种相容性固体或液体填料或凝胶物质，适合于人使用，且具有足够的纯度和足够低的毒性，其实例包括但不限于纤维素及其衍生物(如羧甲基纤维素钠、醋酸纤维素等)、明胶、滑石、固体润滑剂(如硬脂酸镁)、硫酸钙、植物油、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温类)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂等。The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid filler or gel materials suitable for human use and having sufficient purity and sufficiently low toxicity, examples of which include but are not limited to cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), Calcium sulfate, vegetable oil, polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers agents, antioxidants, preservatives, etc.
本文所用的术语“卤素”或“卤代”意指F、Cl、Br或I。此外，本文定义基团时使用的术语“被卤素取代的”基团旨在包括单卤代或多卤代基团，其中一个或多个相同或不同的卤素取代相应基团中的一个或多个氢。The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-substituted" group as used herein in defining a group is intended to include mono- or polyhalogenated groups in which one or more of the same or different halogens replaces one or more of the corresponding groups. A hydrogen.
本文所用的术语“烷基”意指由碳原子和氢原子组成的直链或支链的单价饱和烃基团。具体地，烷基具有1-10个，例如1至8个、1至6个、1至5个、1至4个、1至3个或1至2个碳原子。例如，如本文中所使用，术语“C1-6烷基”指具有1至6个碳原子的直链或支链的饱和烃基团，其实例例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基戊基等。The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1 to 10, for example 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include methyl, ethyl, propyl (including n- Propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2 -Methylpentyl etc.
本文所用的术语“烷氧基”意指通过氧原子与分子其余部分相连的本文定义的烷基。具体地，烷氧基具有1-10个，例如1至8个、1至6个、1至5个、1至4个、1至3个或1至2个碳原子。例如，如本文中所使用，术语“C1-6烷氧基”指通过氧原子与分子其余部分相连的具有1至6个碳原子的直链或支链的饱和烃基团，其实例例如-O-甲基、-O-乙基、-O-丙基(包括-O-正丙基和-O-异丙基)、-O-丁基(包括-O-正丁基、-O-异丁基、-O-仲丁基或-O-叔丁基)、-O-戊基(包括-O-正戊基、-O-异戊基、-O-新戊基)、-O-正己基、2-甲基戊基-O-等。 The term "alkoxy" as used herein means an alkyl group as defined herein attached to the remainder of the molecule through an oxygen atom. Specifically, the alkoxy group has 1 to 10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 alkoxy" refers to a straight or branched saturated hydrocarbon group of 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom, examples of which are, for example, - O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O- Isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O -n-hexyl, 2-methylpentyl-O-, etc.
如本文中所使用的术语“任选被卤素取代的C1-6烷基”指上文所述的C1-6烷基，其中一个或多个(例如1、2、3、4或5个)氢原子任选被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C1-6烷基”的实例有例如-CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl、-CH2CH2CF3或-CF(CF3)2等。The term "C 1-6 alkyl optionally substituted by halogen" as used herein refers to the C 1-6 alkyl groups described above, in which one or more (e.g. 1, 2, 3, 4 or 5 ) hydrogen atoms are optionally replaced by halogens. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of "halogen-substituted C 1-6 alkyl" include -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3 or -CF (CF 3 ) 2 , etc.
本文所用的术语“烯基”指由碳原子和氢原子组成的包含至少一个双键的直链或支链的不饱和烃基团。具体地，烯基具有2-8个，例如2至6个、2至5个、2至4个或2至3个碳原子。例如，如本文中所使用，术语“C2-6烯基”指具有2至6个碳原子的直链或支链的烯基，例如乙烯基、丙烯基、烯丙基、丁烯基、戊烯基等，烯基中与分子其余部分相连的碳原子可以是饱和的，也可以是烯键碳原子。The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond. Specifically, the alkenyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 alkenyl" refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, Pentenyl, etc., the carbon atom in the alkenyl group connected to the rest of the molecule can be saturated or it can be an olefinic carbon atom.
本文所用的术语“炔基”指由碳原子和氢原子组成的包含至少一个叁键的直链或支链的不饱和烃基团。具体地，炔基具有2-8个，例如2至6个、2至5个、2至4个或2至3个碳原子。例如，如本文中所使用，术语“C2-6炔基”指具有2至6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、炔丙基、丁炔基等，炔基中与分子其余部分相连的碳原子可以是饱和的，也可以是炔键碳原子。The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Specifically, the alkynyl group has 2 to 8, such as 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, propargyl, butynyl Etc., the carbon atom in the alkynyl group attached to the rest of the molecule can be saturated or it can be an alkyne bonded carbon atom.
如本文中所使用的术语“环烷基”意指具有指定环碳原子数的单环、稠合多环、桥接多环或螺环非芳族饱和单价烃环结构。环烷基可具有3至12个碳原子(即C3-12环烷基)，例如3至10个、3至8个、3至7个、3至6个、5至6个碳原子。适合的环烷基的实例包括但不限于单环结构，如环丙基、环丁基、环戊基、环己基、环庚基或环辛基；或多环(例如双环)结构，包括螺环、稠合或桥连系统，如双环[1.1.1]戊基、双环[2.2.1]庚基、螺[3.4]辛烷基、双环[3.1.1]己烷基、双环[3.1.1]庚基或双环[3.2.1]辛基等。例如，如本文中所使用的术语“C3-6环烷基”是指单环环丙基、环丁基、环戊基或环己基。The term "cycloalkyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring carbon atoms. Cycloalkyl groups can have 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or polycyclic (eg bicyclic) structures including spiro Ring, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1]heptyl or bicyclo[3.2.1]octyl, etc. For example, the term "C 3-6 cycloalkyl" as used herein refers to monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
本文所用的术语“杂环烷基”意指包括一或多个(例如1、2、3或4个)独立地选自O、N、P、Se及S的杂原子及指定环原子数的单环、稠合多环、螺环或桥接多环非芳族饱和或不饱和环结构，或其N-氧化物，或其S-氧化物或S-二氧化物。在多环杂环烷基的情况下，与分子其余部分相连的环结构为非芳族环即可，即便与该非芳族环进一步稠合、螺合或桥接的环是芳族环，该杂环体系在本文仍定义为杂环烷基。杂环烷基可具有3至12个环成员(可称为3-12元杂环烷基)，例如3至10个环成员，3至8个环成员，3至7个环成员，4至7个环成员、4至6个环成员、5至7个环成员、5至6个环成员、6至10个环成员、6至12个环成员，例如5至7元单环杂环烷基如5-7元单环饱和杂环烷基，或6至12元多环杂环烷基。杂环烷基通常含有至少1个、至多4个(例如1个、2个、3个或4个)杂原子，例如含有1至3个独立选自N、O、S的杂原子的5-7元单环杂环烷基如5-7元单环饱和杂环烷基，或含有1至4个独立地选自N、O、P、Se和S的杂原子的6-12元多环杂环烷基。适合的杂环烷基的实例包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁基、吡咯烷基(例如1-吡咯烷基、2-吡咯烷基及3-吡咯烷基)、四氢呋喃基(例如1-四氢呋喃基、2-四氢呋喃基及3-四氢呋喃 基)、四氢噻吩基(例如1-四氢噻吩基、2-四氢噻吩基及3-四氢噻吩基)、哌啶基(例如1-哌啶基、2-哌啶基、3-哌啶基及4-哌啶基)、四氢吡喃基(例如4-四氢吡喃基)、四氢噻喃基(例如4-四氢噻喃基)、吗啉基(例如吗啉代)、硫吗啉基、二噁烷基、哌嗪基或氮杂环庚烷基、二氮杂环庚烷基例如1,4-二氮杂环庚基、3,6-二氮杂-双环[3.1.1]庚基或3-氮杂-双环[3.2.1]辛基。杂环烷基中与化合物其余部分连接的原子可以是碳原子，也可以是杂原子，只要化学上可行即可。As used herein, the term "heterocycloalkyl" is meant to include one or more (eg, 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of O, N, P, Se, and S and the specified number of ring atoms. Monocyclic, fused polycyclic, spirocyclic or bridged polycyclic non-aromatic saturated or unsaturated ring structures, or their N-oxides, or their S-oxides or S-dioxides. In the case of polycyclic heterocycloalkyl, it is sufficient that the ring structure connected to the rest of the molecule is a non-aromatic ring, even if the ring further fused, spiro or bridged with the non-aromatic ring is an aromatic ring. Heterocyclic systems are still defined herein as heterocycloalkyl. Heterocycloalkyl groups may have 3 to 12 ring members (can be referred to as 3-12 membered heterocycloalkyl groups), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, 5 to 7 ring members, 5 to 6 ring members, 6 to 10 ring members, 6 to 12 ring members, such as 5 to 7 membered monocyclic heterocycloalkanes Such as 5-7 membered monocyclic saturated heterocycloalkyl group, or 6 to 12 membered polycyclic heterocycloalkyl group. Heterocycloalkyl groups generally contain at least 1 and up to 4 (eg 1, 2, 3 or 4) heteroatoms, such as 5- containing 1 to 3 heteroatoms independently selected from N, O, S 7-membered monocyclic heterocycloalkyl such as 5-7-membered monocyclic saturated heterocycloalkyl, or 6-12-membered polycyclic ring containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S Heterocycloalkyl. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl). -pyrrolidinyl), tetrahydrofuranyl (such as 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl) base), tetrahydrothienyl (such as 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3- Piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4-tetrahydropyranyl), tetrahydrothiopyranyl (such as 4-tetrahydrothiopyranyl), morpholinyl (such as morpholine generation), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepanyl such as 1,4-diazepanyl, 3,6-diaza - Bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl. The atom in the heterocycloalkyl group attached to the remainder of the compound may be a carbon atom or a heteroatom, as long as this is chemically feasible.
对本发明化合物而言，示例性的杂环烷基包括但不限于以下： 应当理解，具有不对称中心的结构涵盖其外消旋的和/或单一的对映异构形式，例如可代表和/或 For compounds of the present invention, exemplary heterocycloalkyl groups include, but are not limited to, the following: It is to be understood that structures having asymmetric centers encompass their racemic and/or single enantiomeric forms, e.g. representative and / or
优选的杂环烷基例如 Preferred heterocycloalkyl groups are for example
本文所用的术语“羟基”是指-OH基团。The term "hydroxy" as used herein refers to the -OH group.
本文所用的术语“氰基”是指-CN基团。The term "cyano" as used herein refers to the -CN group.
本文所用的术语“任选取代的”，除非另外指出，表示基团可以是未取代的或被一个或多个(例如1、2、3、4或5或更多，或其中可衍生的任何范围)对该基团所列的取代基取代，其中所述取代基可以相同或不同。在一个实施方案中，任选取代的基团具有1个取代基。在另一个实施方案中，任选取代的基团具有2个相同或不同的取代基。在另一个实施方案中，任选取代的基团具有3个相同或不同的取代基。在另一个实施方案中，任选取代的基团具有4个相同或不同的取代基。在另一个实施方案中，任选取代的基团具有5个相同或不同的取代基。As used herein, the term "optionally substituted", unless otherwise indicated, means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5 or more, or any derivative thereof range) is substituted with the substituents listed for this group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents that may be the same or different. In another embodiment, the optionally substituted group has 3 substituents that may be the same or different. In another embodiment, an optionally substituted group has 4 substituents that may be the same or different. In another embodiment, an optionally substituted group has 5 substituents that may be the same or different.
本文定义的许多基团都是任选被取代的，该定义部分所给出的取代基列表仅仅是示例性的，不意欲限制本说明书和权利要求书中其他部分所定义的取代基。Many of the groups defined herein are optionally substituted, and the list of substituents given in this definitions section is exemplary only and is not intended to limit the substituents defined elsewhere in the specification and claims.
除非另有规定，本发明化合物定义中的Cn-n+m或Cn-Cm包括n至n+m个碳的各种情况，例如C1-6包括C1、C2、C3、C4、C5和C6，也包括n至n+m中的任何一个范围，例如C0-6包括C1、C2、C3、C4、C5、C6、C0-1、C0-2、C0-3、C0-4、C0-5、C1-2、C1-3、C1-4、C2-3等，C1-6包括C1-2、C1-3、C1-4、C2-6、C3-6等。同理，本发明化合物定义中的n元至n+m元表示环原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、12元环等，也包括n至n+m元的任何一个范围，例如3-12元环包括3-6元环、3-8元环、3-9元环、4-10元环、4-7元环、4-5元环、5-6元环、5-7元环、5-8元环、5-9元环、6-7元环、6-8元环、6-10元环和6至12元环等。Unless otherwise specified, C n-n+m or C n -C m in the definition of the compound of the present invention includes various situations of n to n+m carbons, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , also includes any range from n to n+m, for example, C 0-6 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 0- 1. C 0-2 , C 0-3 , C 0-4 , C 0-5 , C 1-2 , C 1-3 , C 1-4 , C 2-3, etc., C 1-6 includes C 1 -2 , C 1-3 , C 1-4 , C 2-6 , C 3-6 , etc. In the same way, n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is n to n+m. For example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring. , 12-membered rings, etc., also include any range from n to n+m members, for example, 3-12-membered rings include 3-6-membered rings, 3-8-membered rings, 3-9-membered rings, 4-10-membered rings, 4-7-membered ring, 4-5-membered ring, 5-6-membered ring, 5-7-membered ring, 5-8-membered ring, 5-9-membered ring, 6-7-membered ring, 6-8-membered ring, 6- 10-membered rings and 6 to 12-membered rings, etc.
有机合成领域普通技术人员均理解，本发明化合物结构上携带的各个基团，无论是未取代的还是被所定义的各种取代基所取代，均以使得化合物分子在化学上可行且稳定为前提，其中取代基的类型和数量由基团中原子的数量和化学价决定。Those of ordinary skill in the field of organic synthesis understand that each group carried on the structure of the compound of the present invention, whether unsubstituted or substituted by various defined substituents, is based on the premise that the compound molecule is chemically feasible and stable. , where the type and number of substituents are determined by the number and chemical valency of atoms in the group.
如在本说明书和随后的权利要求书中所使用的，词语“包含”和该词语的变体如“包括”和“含有”，意指“包括但不限于”，并且不意图排除例如其他添加剂、成分、整数或步骤。当将要素描述为包括多个成分、步骤或条件时，应理解的是，该要素也可以被描述为包括该多个成分、步骤或条件的任何组合，或“由多个或组合的成分、步骤或条件组成”或“基本上由多个或组合的成分、步骤或条件组成”。As used in this specification and the claims that follow, the word "comprises" and variations of this word such as "includes" and "contains" mean "including but not limited to" and are not intended to exclude, for example, other additives , ingredient, integer or step. When an element is described as including a plurality of ingredients, steps or conditions, it will be understood that the element may also be described as including any combination of such multiple ingredients, steps or conditions, or as "consisting of a plurality or combination of ingredients, "consisting essentially of a plurality or combination of ingredients, steps or conditions".
应理解，当本文描述本发明化合物、包含其的药物组合物、药物组合、药盒以及相关的用途和方法时所涉及的剂量，是基于游离形式的重量，不包括其任何盐、水合物或溶剂化物，除非说明书中指出该剂量基于盐、水合物或溶剂化物的重量。It is to be understood that when the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits and related uses and methods are described herein, the dosages referred to are based on the weight of the free form, excluding any salts, hydrates or salts thereof. Solvates, unless the instructions state that the dosage is based on the weight of the salt, hydrate, or solvate.
本发明解决的问题Problems solved by the invention
如上所述，能够抑制Ras突变蛋白、尤其KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS野 生扩增型细胞的化合物能够用于治疗或预防由所述突变蛋白介导的疾病(例如癌症或肿瘤)。因此，在该领域，已经开发出多种结构类型的Ras抑制剂。但是，现有的KRas抑制剂仍然存在需要解决的问题，包括例如很多抑制剂的抗肿瘤活性不能令人满意、或具有毒副作用导致耐药性差、或药代动力学性质不足以允许通过方便的方式给药即“成药性”差，或因为对细胞色素P450酶系的抑制作用而导致不期望的药物相互作用，等等。进一方面，即便是对于具有良好抗肿瘤活性的抑制剂，人们仍期望能够通过结构优化，来进一步提高其在体内对靶蛋白的选择性抑制活性、进一步改进其耐药性(更少的毒副作用或更好的安全性)且进一步改善其药代动力学性质，以便为临床上提供更多更好的治疗选择。As mentioned above, it is possible to inhibit Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS mutant protein. Compounds that generate expanded cells can be used to treat or prevent diseases (eg, cancer or tumors) mediated by the mutant protein. Therefore, in this field, various structural types of Ras inhibitors have been developed. However, existing KRas inhibitors still have problems that need to be solved, including, for example, the anti-tumor activity of many inhibitors is unsatisfactory, or they have toxic side effects leading to poor drug resistance, or their pharmacokinetic properties are not sufficient to allow convenient delivery. The way of administration means that the "drugability" is poor, or the inhibition of the cytochrome P450 enzyme system may lead to undesirable drug interactions, etc. Furthermore, even for inhibitors with good anti-tumor activity, people still expect to further improve their selective inhibitory activity against target proteins in vivo and further improve their drug resistance (less toxicity) through structural optimization. side effects or better safety) and further improve its pharmacokinetic properties to provide more and better treatment options for clinical use.
解决问题的方法way of solving the problem
本发明人通过广泛且深入的研究，已经开发出一组对Ras突变蛋白、尤其KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS扩增细胞具有明显抑制活性的化合物。本发明人通过结构改造和活性验证，发现在所述KRas抑制剂结构的苯并嘧啶环及喹唑啉的若干特定位点，进行特定类型的取代基修饰，所实施的若干取代位点和取代基类型的特定组合，获得了相比现有技术抑制剂进一步提高的对对KRas突变蛋白的抑制活性，而且这样修饰得到的化合物具有良好的安全性，具有减少的药物相互作用风险，还具有良好的、甚至是进一步改善的药代动力学性质，使得能够以方便的方式给药。Through extensive and in-depth research, the inventors have developed a group of Ras mutant proteins, especially KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein). ) and KRAS amplified cells have significant inhibitory activity. Through structural modification and activity verification, the inventor found that specific types of substituent modifications were carried out at several specific sites of the benzopyrimidine ring and quinazoline of the KRas inhibitor structure. The implemented several substitution sites and substitutions The specific combination of base types has further improved the inhibitory activity against KRas mutant protein compared with the existing technology inhibitors, and the compound obtained by such modification has good safety, reduced risk of drug interaction, and good performance. The even further improved pharmacokinetic properties enable administration in a convenient manner.
本发明主要提供有效的Ras抑制剂、具体地KRas抑制剂(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增型抑制剂)化合物；含有此类化合物作为活性成分的药物组合物；作为药物、用于治疗或预防由Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)介导或得益于Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)抑制的肿瘤或癌症的所述化合物；使用所述化合物用于治疗或预防由Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)介导或得益于Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)抑制的疾病如肿瘤或癌症的方法；以及所述化合物在制备用于治疗或预防由Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)介导或得益于Ras、具体地KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)抑制的疾病如肿瘤或癌症的药物中的用途。The present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification inhibitor) compounds; Pharmaceutical compositions containing such compounds as active ingredients; as medicaments, for the treatment or prevention of mutations caused by Ras, in particular KRas (e.g. G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations and KRAS amplifications) or cancer; use of said compound for the treatment or prevention of mutations caused by Ras, specifically KRas (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplifications). diseases such as tumors or cancers that are mediated by or benefit from inhibition of Ras, specifically KRas (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation, and KRAS amplification) Methods; and the preparation of said compounds for use in the treatment or prevention of mutations caused by Ras, specifically KRas (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplifications) Drugs that mediate or benefit from the inhibition of Ras, specifically KRas (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, Q61H mutations, and KRAS amplification), such as tumors or cancers use in.
本发明由此提供以下技术方案。The present invention therefore provides the following technical solutions.
本发明化合物Compounds of the present invention
本申请通篇使用的术语“发明的化合物”和“本发明的化合物”等，除非另外限定，涵盖本文各个实施方案及其优选实施方案中定义的化合物或其各个具体实施方式、包括其异构体，包括阻转异构体、对映体混合物、特别是外消旋体、非对映异构体混合物、几何异构体、互变异构体、溶剂化物、代谢物、前药、同位素变体和盐(例如药学上可接受的盐)。The terms "compounds of the invention" and "compounds of the invention" and the like are used throughout this application, unless otherwise limited, to encompass the compounds defined in each embodiment and its preferred embodiments herein or each embodiment thereof, including isomers thereof. Forms, including atropisomers, enantiomeric mixtures, especially racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopes Variations and salts (e.g., pharmaceutically acceptable salts).
因此，本发明化合物的上述各类异构体和衍生物由此均涵盖在本发明范围内，其各自的含义、制备及具体示例如上文“定义”部分所定义，或为本领域技术所熟知。然而，优选地为本发明化合物和/或其药学上可接受的盐或溶剂合物。Therefore, the above-mentioned various isomers and derivatives of the compounds of the present invention are therefore encompassed within the scope of the present invention, and their respective meanings, preparations and specific examples are as defined in the "Definitions" section above, or are well known to those skilled in the art. . However, preference is given to compounds of the invention and/or pharmaceutically acceptable salts or solvates thereof.
本发明还涵盖本发明化合物的N-氧化物，只要这些化合物含有碱性氮原子如存在于含氮杂环中的氮原子且化学和生物学上可行。本发明的某些化合物可以以多晶型或无定形形式存在，故它们也落入本发明的范围内。The invention also encompasses N-oxides of the compounds of the invention, provided these compounds contain basic nitrogen atoms such as those present in nitrogen-containing heterocycles and are chemically and biologically feasible. Certain compounds of the invention may exist in polymorphic or amorphous forms and thus fall within the scope of the invention.
本发明提供如下化合物实施方案：The present invention provides the following compound embodiments:
实施方案1：式(I)的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，
Embodiment 1: Compounds of formula (I), their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,
其中：in:
M选自N或C-R7；M is selected from N or CR 7 ;
X选自C和S，p选自0和1，条件是p为0时X为S，p为1时X为C；X is selected from C and S, p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C;
Y选自O、S和Se；Y is selected from O, S and Se;
W选自OH和NH2；W is selected from OH and NH 2 ;
B选自包含1至3个独立地选自N、O、P、Se和S的杂原子的5-7元单环杂环烷基，和包含1至4个独立地选自N、O、P、Se和S的杂原子的6-12元多环杂环烷基，条件是各自通过氮杂原子连接至分子的嘧啶环部分；B is selected from 5-7 membered monocyclic heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from N, O, P, Se, and S, and containing 1 to 4 heteroatoms independently selected from N, O, 6-12 membered polycyclic heterocycloalkyl groups of heteroatoms of P, Se and S, provided that each is connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom;
Q选自其中Q is selected from in
Z选自N、C、O、S和Se； Z is selected from N, C, O, S and Se;
k选自0或1；k is selected from 0 or 1;
m和n各自独立地选自0至2的整数；m and n are each independently selected from an integer from 0 to 2;
R1选自-C1-6烷基和-(CH2)n-C3-6环烷基，各自独立地任选被卤素或C1-6烷氧基取代；R 1 is selected from -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen or C 1-6 alkoxy;
R2选自H、-C1-6烷基和-(CH2)n-C3-6环烷基，其中的C1-6烷基或C3-6环烷基各自独立地任选被卤素或C1-6烷氧基取代，R 2 is selected from H, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl or C 3-6 cycloalkyl is independently optional Substituted by halogen or C 1-6 alkoxy,
或者连接于同一碳原子上的两个R2与它们所连接的碳原子一起形成C3-4环烷基；Or two R 2 connected to the same carbon atom together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
R3选自H、卤素、-CN、-OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基、-C2-6烯基、-C2- 6炔基和-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素、CN或C1-6烷氧基取代，R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 -6 alkynyl and - (CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3 Each -6 cycloalkyl group is independently optionally substituted by halogen, CN or C 1-6 alkoxy group,
或者连接于同一个碳原子上的两个R3形成＝C(Rc)2、任选被卤素取代的螺C3-6环烷基或任选被卤素取代的螺4-7元杂环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，Or two R 3 connected to the same carbon atom form =C(R c ) 2 , spiro C 3-6 cycloalkyl optionally substituted by halogen or spiro 4-7 membered heterocycle optionally substituted by halogen Alkyl, wherein R c is each independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen,
或者连接于相邻环碳原子上的R1和R3或连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基；Or R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
或者连接在非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基；Or two R 3 's connected to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;
R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基和-(CH2)n-C3-6环烷基，其中的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代；R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally optionally replaced by halogen, CN, -C 1-6 alkoxy or -O-CON (C 1-6 alkyl) 2 substitution;
R5选自H和卤素；R 5 is selected from H and halogen;
R6选自H、卤素、-C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-Se-C1-6烷基和-C2-6炔基，各自独立地任选被卤素取代；R 6 is selected from H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl and -C 2-6 alkynyl, Each independently optionally substituted by halogen;
R7选自H、卤素、CN和-C1-6烷基，其中-C1-6烷基任选被卤素或CN取代；R 7 is selected from H, halogen, CN and -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by halogen or CN;
R8选自-OH、卤素、-CN、-B(OH)2、-C1-6烷基、-O-C1-6烷基、-CONH(C1-6烷基)、-CON(C1-6烷基)2、-CON(C1-6烷基)(C2-6烯基)、-CON(C1-6烷基)(C2- 6炔基)、-PO(C1-6烷基)2、-PO(C1-6烷基)(C2-6烯基)、-PO(C1-6烷基)(C2-6炔基)、-SO-N(C1-6烷基)2、-SO-N(C1-6烷基)(C2-6烯基)、-SO-N(C1-6烷基)(C2-6炔基)、-SO2-N(C1-6烷基)2、-SO2-N(C1-6烷基)(C2-6烯基)和-SO2-N(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基或C2-6炔基任选被卤素或CN取代；R 8 is selected from -OH, halogen, -CN, -B(OH) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl), -CON(C 1-6 alkyl)(C 2- 6 alkynyl), -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl), -PO(C 1-6 alkyl)(C 2-6 alkynyl), -SO-N (C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N(C 1-6 alkyl)(C 2-6 alkynyl ), -SO 2 -N(C 1-6 alkyl) 2 , -SO 2 -N(C 1-6 alkyl)(C 2-6 alkenyl) and -SO 2 -N(C 1-6 alkyl) Base) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted by halogen or CN;
R9和R10各自独立地选自H、卤素和任选被卤素取代的C1-6烷基；R 9 and R 10 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted by halogen;
R11选自H、卤素、任选被卤素取代的-C1-6烷基、任选被卤素取代的-O-C1-6烷基和任选 被卤素取代的-C2-6炔基；和R 11 is selected from H, halogen, -C 1-6 alkyl optionally substituted by halogen, -OC 1-6 alkyl optionally substituted by halogen, and optionally -C 2-6 alkynyl substituted by halogen; and
t选自1至4的整数。t is selected as an integer from 1 to 4.
实施方案1.1：实施方案1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Embodiment 1.1: The compound of formula (I) of Embodiment 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein
R3选自H、卤素、-CN、-OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基、-C2-6烯基、-C2- 6炔基和-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素、CN或C1-6烷氧基取代，R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 -6 alkynyl and - (CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3 Each -6 cycloalkyl group is independently optionally substituted by halogen, CN or C 1-6 alkoxy group,
或者连接于同一个碳原子上的两个R3形成＝C(Rc)2、螺C3-6环烷基或螺4-7元杂环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，Or two R 3 connected to the same carbon atom form =C(R c ) 2 , spiro C 3-6 cycloalkyl or spiro 4-7 membered heterocycloalkyl, wherein R c is each independently selected from H , halogen and -C 1-6 alkyl optionally substituted by halogen,
或者连接于相邻环碳原子上的R1和R3或连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基；Or R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
或者连接在非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基；Or two R 3 's connected to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;
R11选自H、卤素、任选被卤素取代的-C1-6烷基和任选被卤素取代的-O-C1-6烷基。R 11 is selected from H, halogen, -C 1-6 alkyl optionally substituted by halogen, and -OC 1-6 alkyl optionally substituted by halogen.
实施方案1.2：实施方案1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其为下式(I-1)，
Embodiment 1.2: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, which is the following formula (I- 1),
其中：in:
X选自C和S，p选自0和1，条件是p为0时X为S，p为1时X为C；X is selected from C and S, p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C;
Y选自O、S和Se；Y is selected from O, S and Se;
W选自OH和NH2；W is selected from OH and NH 2 ;
B选自包含1至3个独立地选自N、O、P、Se和S的杂原子的5-7元单环杂环烷基，和包含1至4个独立地选自N、O、P、Se和S的杂原子的6-12元多环杂环烷基，条件是各自通过氮杂原子连接至分子的嘧啶环部分；B is selected from 5-7 membered monocyclic heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from N, O, P, Se, and S, and containing 1 to 4 heteroatoms independently selected from N, O, 6-12 membered polycyclic heterocycloalkyl groups of heteroatoms of P, Se and S, provided that each is connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom;
Q选自其中 Q is selected from in
Z选自N、C、O、S和Se；Z is selected from N, C, O, S and Se;
k选自0或1；k is selected from 0 or 1;
m和n各自独立地选自0至2的整数；m and n are each independently selected from an integer from 0 to 2;
R1选自-C1-6烷基和-(CH2)n-C3-6环烷基，各自独立地任选被卤素或C1-6烷氧基取代；R 1 is selected from -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen or C 1-6 alkoxy;
R2选自H、-C1-6烷基和-(CH2)n-C3-6环烷基，其中的C1-6烷基或C3-6环烷基各自独立地任选被卤素或C1-6烷氧基取代，R 2 is selected from H, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl or C 3-6 cycloalkyl is independently optional Substituted by halogen or C 1-6 alkoxy,
或者连接于同一碳原子上的两个R2与它们所连接的碳原子一起形成C3-4环烷基；Or two R 2 connected to the same carbon atom together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
R3选自H、卤素、-OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基和-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基或C3-6环烷基各自独立地任选被卤素或C1-6烷氧基取代，R 3 is selected from H, halogen, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl , wherein each occurrence of C 1-6 alkyl or C 3-6 cycloalkyl is independently optionally substituted by halogen or C 1-6 alkoxy,
或者连接于相邻环碳原子上的R1和R3或连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基；Or R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
或者连接在非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基；Or two R 3 's connected to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;
R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基和-(CH2)n-C3-6环烷基，其中的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代；R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally optionally replaced by halogen, CN, -C 1-6 alkoxy or -O-CON (C 1-6 alkyl) 2 substitution;
R5选自H和卤素；R 5 is selected from H and halogen;
R6选自H、卤素、-C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-Se-C1-6烷基和-C2-6炔基，各自独立地任选被卤素取代；R 6 is selected from H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl and -C 2-6 alkynyl, Each independently optionally substituted by halogen;
R7选自H、卤素、CN和-C1-6烷基，其中-C1-6烷基任选被卤素或CN取代；R 7 is selected from H, halogen, CN and -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by halogen or CN;
R8选自-OH、卤素、-CN、-B(OH)2、-C1-6烷基、-O-C1-6烷基、-CONH(C1-6烷基)、-CON(C1-6烷基)2、-CON(C1-6烷基)(C2-6烯基)、-CON(C1-6烷基)(C2- 6炔基)、-PO(C1-6烷基)2、-PO(C1-6烷基)(C2-6烯基)、-PO(C1-6烷基)(C2-6炔基)、-SO-N(C1-6烷基)2、-SO-N(C1-6烷基)(C2-6烯基)、-SO-N(C1-6烷基)(C2-6炔基)、-SO2-N(C1-6烷基)2、-SO2-N(C1-6烷基)(C2-6烯基)和-SO2-N(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基或C2-6炔基任选被卤素或CN取代；R 8 is selected from -OH, halogen, -CN, -B(OH) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl), -CON(C 1-6 alkyl)(C 2- 6 alkynyl), -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl), -PO(C 1-6 alkyl)(C 2-6 alkynyl), -SO-N (C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N(C 1-6 alkyl)(C 2-6 alkynyl ), -SO 2 -N(C 1-6 alkyl) 2 , -SO 2 -N(C 1-6 alkyl)(C 2-6 alkenyl) and -SO 2 -N(C 1-6 alkyl) Base) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted by halogen or CN;
R9和R10各自独立地选自H、卤素和任选被卤素取代的C1-6烷基；和R 9 and R 10 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted by halogen; and
t选自1至4的整数。t is selected as an integer from 1 to 4.
实施方案2.1：实施方案1或1.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中p为1且X为C，即X所在的稠合双环部分为 Embodiment 2.1: The compound of formula (I) of Embodiment 1 or 1.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein p is 1 and X is C, that is, the fused bicyclic part where X is located is
实施方案2.1.1：实施方案2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R5为H；或R5为卤素，选自F、Cl、Br、I；优选R5为卤素，最优选F。Embodiment 2.1.1: The compound of formula (I) of Embodiment 2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 5 is H ; Or R 5 is halogen, selected from F, Cl, Br, I; preferably R 5 is halogen, most preferably F.
实施方案2.1.2：实施方案2.1或2.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为H；或R6为卤素，选自F、Cl、Br、I。Embodiment 2.1.2: The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is H; or R 6 is halogen, selected from F, Cl, Br, and I.
实施方案2.1.3：实施方案2.1或2.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为-C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-Se-C1-6烷基，任选被卤素取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2Cl、-CH2F、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-O-CH3、-O-CH2CH3、-SCH3、-S-CH2CH3、-SeCH3。Embodiment 2.1.3: The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl, optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C( CH 3 ) 3 , -CH 2 Cl , -CH 2 F , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -O-CH 3 , -O-CH 2 CH 3 , -SCH 3 , -S-CH 2 CH 3 , -SeCH 3 .
实施方案2.1.4：实施方案2.1或2.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为-C2-6炔基，任选被卤素取代，例如但不限于优选 Embodiment 2.1.4: The compound of formula (I) of Embodiment 2.1 or 2.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 2-6 alkynyl, optionally substituted by halogen, such as but not limited to preferred
实施方案2.1.5：实施方案2.1至2.1.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R9和R10各自为H；或者R9和R10各自为卤素，优选F。Embodiment 2.1.5: The compound of formula (I) according to any one of embodiments 2.1 to 2.1.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 9 and R 10 are each H; or R 9 and R 10 are each halogen, preferably F.
实施方案2.1.6：实施方案2.1至2.1.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R9和R10之一为H，另一个选自卤素，优选F；优选R10为H且R9选自卤素，优选F，如以上所示例。Embodiment 2.1.6: The compound of formula (I) according to any one of embodiments 2.1 to 2.1.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Object, wherein one of R 9 and R 10 is H and the other is selected from halogen, preferably F; preferably R 10 is H and R 9 is selected from halogen, preferably F, as exemplified above.
实施方案2.1.7：实施方案2.1至2.1.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中W为-OH。Embodiment 2.1.7: The compound of formula (I) according to any one of embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -OH.
实施方案2.1.8：实施方案2.1至2.1.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中W为-NH2。Embodiment 2.1.8: The compound of formula (I) according to any one of embodiments 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -NH 2 .
实施方案2.1.9：实施方案2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位 素变体、药学上可接受的盐或溶剂合物，其中X所在的稠合双环部分为其中R5位卤素，优选F，R6选自-C1-6烷基、-C2-6炔基和卤素，优选选自-C1-6烷基和-C2-6炔基，例如 Embodiment 2.1.9: The compound of formula (I) of Embodiment 2.1, its stereoisomers, tautomers, and stable isotopes peptide variants, pharmaceutically acceptable salts or solvates, in which the fused bicyclic part where X is located is Wherein R is halogen at position 5 , preferably F, R 6 is selected from -C 1-6 alkyl, -C 2-6 alkynyl and halogen, preferably selected from -C 1-6 alkyl and -C 2-6 alkynyl, For example
实施方案2.2：实施方案1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中p为0且X为S，即X所在的稠合双环部分为 Embodiment 2.2: Compounds of formula (I) of Embodiment 1, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein p is 0 and X is S, that is, the fused bicyclic part where X is located is
实施方案2.2.1：实施方案2.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R5为H；或R5为卤素，选自F、Cl、Br、I；优选R5为卤素，最优选F。Embodiment 2.2.1: The compound of formula (I) of Embodiment 2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 5 is H ; Or R 5 is halogen, selected from F, Cl, Br, I; preferably R 5 is halogen, most preferably F.
实施方案2.2.2：实施方案2.2或2.2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为H；或R6为卤素，选自F、Cl、Br、I。Embodiment 2.2.2: The compound of formula (I) of Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is H; or R 6 is halogen, selected from F, Cl, Br, and I.
实施方案2.2.3：实施方案2.2或2.2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为-C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-Se-C1-6烷基，任选被卤素取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2Cl、-CH2F、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-O-CH3、-O-CH2CH3、-SCH3、-S-CH2CH3、-SeCH3。Embodiment 2.2.3: The compound of formula (I) of Embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl, optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C( CH 3 ) 3 , -CH 2 Cl , -CH 2 F , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -O-CH 3 , -O-CH 2 CH 3 , -SCH 3 , -S-CH 2 CH 3 , -SeCH 3 .
实施方案2.2.4：实施方案2.2或2.2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R6为-C2-6炔基，任选被卤素取代，例如但不限于优选 Embodiment 2.2.4: The compound of formula (I) of embodiment 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 6 is -C 2-6 alkynyl, optionally substituted by halogen, such as but not limited to preferred
实施方案2.2.5：实施方案2.2至2.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R9和R10各自为H；或者R9和R10各自为卤素，优选F。Embodiment 2.2.5: The compound of formula (I) according to any one of embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 9 and R 10 are each H; or R 9 and R 10 are each halogen, preferably F.
实施方案2.2.6：实施方案2.2至2.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R9和R10之一为H，另一个选自卤素；优选R10为H且R9选自卤素，如以上所示例。Embodiment 2.2.6: The compound of formula (I) according to any one of embodiments 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein one of R 9 and R 10 is H and the other is selected from halogen; preferably R 10 is H and R 9 is selected from halogen, as exemplified above.
实施方案2.2.7：实施方案2.2至2.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中W为-OH。Embodiment 2.2.7: The compound of formula (I) according to any one of embodiments 2.2 to 2.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -OH.
实施方案2.2.8：实施方案2.2至2.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中W为-NH2。Embodiment 2.2.8: The compound of formula (I) according to any one of embodiments 2.2 to 2.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, where W is -NH 2 .
实施方案2.2.9：实施方案2.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中X所在的稠合双环部分为例如 Embodiment 2.2.9: The compound of formula (I) of Embodiment 2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein The combined double ring part is For example
实施方案3.1：实施方案1至2.2.9任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为包含1至3个独立地选自N、O、P、Se和S的杂原子的5-7元单环杂环烷基，通过氮杂原子连接至分子的嘧啶环部分，例如但不限于其中各个环中的各个Z可以均为C，或其中至多两个为选自N、O、P、Se和S的杂原子，例如含有1-3个氮原子的5-7元杂环烷基、含有1个氮原子和1-2个选自O、P、Se和S的杂原子的5-7元杂环烷基、含有2个氮原子和1个选自O、P、Se和S的杂原子的5-7元杂环烷基、含有1个氮原子和1个O原子的5-7元杂环烷基，例如但不限于 各自被1-4个R8取代，优选被1-2个R8取代，更优选R8取代在环碳原子上。Embodiment 3.1: The compound of formula (I) according to any one of embodiments 1 to 2.2.9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is a 5-7 membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O, P, Se and S, linked to the pyrimidine ring portion of the molecule through a nitrogen heteroatom, such as but not limited to Each Z in each ring can be C, or at most two of them are heteroatoms selected from N, O, P, Se and S, such as a 5-7-membered heterocycloalkyl group containing 1-3 nitrogen atoms. , a 5-7 membered heterocycloalkyl group containing 1 nitrogen atom and 1-2 heteroatoms selected from O, P, Se and S, containing 2 nitrogen atoms and 1 heteroatom selected from O, P, Se and S 5-7 membered heterocycloalkyl of heteroatoms, 5-7 membered heterocycloalkyl containing 1 nitrogen atom and 1 O atom, such as but not limited to Each is substituted by 1-4 R8 , preferably by 1-2 R8 , more preferably R8 is substituted on the ring carbon atom.
实施方案3.1.1：实施方案3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为被1-2个R8取代，优选在N的间位被R8取代，例如但不限于 Embodiment 3.1.1: The compound of formula (I) of Embodiment 3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Substituted by 1-2 R 8 , preferably substituted by R 8 at the meta position of N, such as but not limited to
实施方案3.1.1.1：实施方案3.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上的取代基R8呈立体异构形式，例如R或S构型，只有化学上可行即可。Embodiment 3.1.1.1: The compound of formula (I) of Embodiment 3.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B The substituent R 8 is in stereoisomeric form, such as R or S configuration, only if it is chemically feasible.
实施方案3.1.2：实施方案3.1至3.1.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8各自独立地选自-OH、卤素、CN、-C1-6烷基和-OC1-6烷基，其中的-C1-6烷基任选被卤素或CN取代；优选连接在同一环碳原子上的两个R8之一为-OH且另一个为任选被卤素或CN取代的-C1-6烷基，优选甲基；更优选在与分子其余部分(例如嘧啶环)连接的N原子的间位环碳院子上连接两个R8，其中之一为-OH且另一个为-C1-6烷基，优选甲基，例如B为优选 Embodiment 3.1.2: The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein The substituents R 8 carried on B are each independently selected from -OH, halogen, CN, -C 1-6 alkyl and -OC 1-6 alkyl, in which -C 1-6 alkyl is optionally replaced by halogen or CN substitution; preferably one of the two R 8 attached to the same ring carbon atom is -OH and the other is -C 1-6 alkyl optionally substituted by halogen or CN, preferably methyl; more preferably in the same molecule The meta-ring carbon yard of the N atom connected to the remaining part (such as the pyrimidine ring) is connected to two R 8 , one of which is -OH and the other is -C 1-6 alkyl, preferably methyl, for example, B is preferred
实施方案3.1.3：实施方案3.1至3.1.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8选自-CONH(C1- 6烷基)、-CON(C1-6烷基)2、-CON(C1-6烷基)(C2-6烯基)、-CON(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代；优选-CON(C1-6烷基)2，例如-CON(CH3)2，例如B为 Embodiment 3.1.3: Compounds of formula (I), stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof according to embodiments 3.1 to 3.1.1.1, wherein The substituent R 8 carried on B is selected from -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl ) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl) ), -CON(C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally replaced by halogen or CN Substitution; preferably -CON(C 1-6 alkyl) 2 , for example -CON(CH 3 ) 2 , for example B is
实施方案3.1.4：实施方案3.1至3.1.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8选自-PO(C1-6烷基)2、-PO(C1-6烷基)(C2-6烯基)和-PO(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代。 Embodiment 3.1.4: The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein The substituent R 8 carried on B is selected from -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl) and -PO(C 1-6 alkyl) ) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN.
实施方案3.1.5：实施方案3.1至3.1.1.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8选自-SO-N(C1-6烷基)2、-SO-N(C1-6烷基)(C2-6烯基)、-SO-N(C1-6烷基)(C2-6炔基)、-SO2-N(C1-6烷基)2、-SO2-N(C1-6烷基)(C2-6烯基)和-SO2-N(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代；优选-SO-N(C1-6烷基)(C2-6炔基)或-SO2-N(C1-6烷基)(C2-6炔基)，例如-SO2-N(CH3)(C≡CH)，例如B为 Embodiment 3.1.5: The compound of formula (I) of embodiments 3.1 to 3.1.1.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein The substituent R 8 carried on B is selected from -SO-N(C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N( C 1-6 alkyl) (C 2-6 alkynyl), -SO 2 -N (C 1-6 alkyl) 2 , -SO 2 -N (C 1-6 alkyl) (C 2-6 alkene base) and -SO 2 -N(C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optional Substituted by halogen or CN; preferably -SO-N(C 1-6 alkyl)(C 2-6 alkynyl) or -SO 2 -N(C 1-6 alkyl)(C 2-6 alkynyl), For example -SO 2 -N(CH 3 )(C≡CH), for example, B is
实施方案3.1.6：实施方案3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为被1-2个R8取代，优选在N的间位被R8取代，R8各自独立地选自-OH、卤素、CN、-C1-6烷基和-OC1-6烷基，其中的-C1-6烷基任选被卤素或CN取代；优选连接在同一环碳原子上的两个R8之一为-OH且另一个为任选被卤素或CN取代的-C1-6烷基，优选甲基；更优选在与分子其余部分(例如嘧啶环)连接的N原子的间位环碳院子上连接两个R8，其中之一为-OH且另一个为-C1-6烷基，优选甲基，例如B为优选 Embodiment 3.1.6: The compound of formula (I) of Embodiment 3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Substituted by 1-2 R 8 , preferably substituted by R 8 at the meta position of N, each R 8 is independently selected from -OH, halogen, CN, -C 1-6 alkyl and -OC 1-6 alkyl, The -C 1-6 alkyl group is optionally substituted by halogen or CN; preferably one of the two R 8 attached to the same ring carbon atom is -OH and the other is -C 1 optionally substituted by halogen or CN -6 alkyl, preferably methyl; more preferably two R 8 , one of which is -OH and the other is -C, is attached to the meta-ring carbon yard of the N atom attached to the rest of the molecule (e.g., pyrimidine ring) 1-6 alkyl, preferably methyl, for example B is preferred
实施方案3.1.6.1：实施方案3.1.6的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上的取代基R8呈立体异构形式，例如R或S构型，只有化学上可行即可。Embodiment 3.1.6.1: The compound of formula (I) of Embodiment 3.1.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B The substituent R 8 is in stereoisomeric form, such as R or S configuration, only if it is chemically feasible.
实施方案3.2：实施方案1至2.2.9任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为包含1至4个独立地选自N、O、P、Se和S的杂原子的6-12元多环杂环烷基(例如6-10元、6-9元、6-8元、6-7元多环杂环烷基)，通过氮杂原子连接至分子的嘧啶环部分，例如含有1-4个氮原子、含有1个氮原子和1-3个选自O、S、P和Se的杂原子、含有2个氮原子和1-2个选自O、S、P和Se的杂原子，含有3个氮原子和1个选自O、S、P和Se的杂原子，例如但不限于 各自被1-4个R8取代，优选被1-2个R8取代，更优选R8取代在环碳原子上。Embodiment 3.2: The compound of formula (I) according to any one of embodiments 1 to 2.2.9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, Wherein B is a 6-12 membered polycyclic heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from N, O, P, Se and S (such as 6-10 member, 6-9 member, 6-8 member membered, 6-7 membered polycyclic heterocycloalkyl), connected to the pyrimidine ring part of the molecule through a nitrogen heteroatom, for example, containing 1-4 nitrogen atoms, containing 1 nitrogen atom and 1-3 selected from O, S , heteroatoms of P and Se, containing 2 nitrogen atoms and 1-2 heteroatoms selected from O, S, P and Se, containing 3 nitrogen atoms and 1 heteroatom selected from O, S, P and Se atoms, such as but not limited to Each is substituted by 1-4 R8 , preferably by 1-2 R8 , more preferably R8 is substituted on the ring carbon atom.
实施方案3.2.1：实施方案3.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为被1个R8取代，例如但不限于 Embodiment 3.2.1: The compound of formula (I) of Embodiment 3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Replaced by 1 R 8 such as but not limited to
实施方案3.2.2：实施方案3.2或3.2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8各自独立地选自-CONH(C1-6烷基)、-CON(C1-6烷基)2、-CON(C1-6烷基)(C2-6烯基)、-CON(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代；优选-CON(C1-6烷基)2，例如-CON(CH3)2，例如B为 Embodiment 3.2.2: The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein The substituents R 8 carried on B are each independently selected from -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2- 6 alkenyl), -CON (C 1-6 alkyl) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally Halogen or CN substitution; preferably -CON(C 1-6 alkyl) 2 , for example -CON(CH 3 ) 2 , for example B is
实施方案3.2.3：实施方案3.2或3.2.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8选自-PO(C1-6烷基)2、-PO(C1-6烷基)(C2-6烯基)和-PO(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代。Embodiment 3.2.3: The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein The substituent R 8 carried on B is selected from -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl) and -PO(C 1-6 alkyl) ) (C 2-6 alkynyl), in which -C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN.
实施方案3.2.4：实施方案3.2或3.2.1的式(I)化合物、其立体异构体、互变异构体、稳定 的同位素变体、药学上可接受的盐或溶剂合物，其中B上携带的取代基R8选自-SO-N(C1-6烷基)2、-SO-N(C1-6烷基)(C2-6烯基)、-SO-N(C1-6烷基)(C2-6炔基)、-SO2-N(C1-6烷基)2、-SO2-N(C1- 6烷基)(C2-6烯基)和-SO2-N(C1-6烷基)(C2-6炔基)，其中的-C1-6烷基、C2-6烯基和C2-6炔基任选被卤素或CN取代；优选-SO-N(C1-6烷基)(C2-6炔基)或-SO2-N(C1-6烷基)(C2-6炔基)，例如-SO2-N(CH3)(C≡CH)，例如B为 Embodiment 3.2.4: The compound of formula (I) of Embodiment 3.2 or 3.2.1, its stereoisomers, tautomers, and stable Isotopic variants, pharmaceutically acceptable salts or solvates, wherein the substituent R 8 carried on B is selected from -SO-N(C 1-6 alkyl) 2 , -SO-N(C 1-6 Alkyl) (C 2-6 alkenyl), -SO-N (C 1-6 alkyl) (C 2-6 alkynyl), -SO 2 -N (C 1-6 alkyl) 2 , -SO 2 -N(C 1-6 alkyl)(C 2-6 alkenyl) and -SO 2 -N(C 1-6 alkyl)(C 2-6 alkynyl ) , where -C 1-6 alkyl Base, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by halogen or CN; preferably -SO-N (C 1-6 alkyl) (C 2-6 alkynyl) or -SO 2 -N (C 1-6 alkyl) (C 2-6 alkynyl), for example -SO 2 -N(CH 3 ) (C≡CH), for example B is
实施方案4.1：实施方案1至3.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为 Embodiment 4.1: The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
实施方案4.2：实施方案1至3.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为例如 Embodiment 4.2: The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is For example
实施方案4.2.1：实施方案4.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R1为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.2.1: The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )( CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.2.2：实施方案4.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R1为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.2.2: The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - (CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.2.3：实施方案4.2至4.2.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R2为H。Embodiment 4.2.3: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 2 is H.
实施方案4.2.4：实施方案4.2至4.2.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中至少一个R2为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.2.4: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Materials, wherein at least one R 2 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3. -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , - CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3. -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.2.5：实施方案4.2至4.2.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中至少一个R2为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.2.5: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof Materials, wherein at least one R 2 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.2.6：实施方案4.2至4.2.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中两个R2与它们所连接的碳原子一起形成环丙基或环丁基。Embodiment 4.2.6: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which the two R 2s , together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl.
实施方案4.2.7：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为H。Embodiment 4.2.7: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
实施方案4.2.8：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构 体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为卤素，选自F、Cl、Br、I；优选F。Embodiment 4.2.8: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers and tautomers isotopes, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 3 is halogen, selected from F, Cl, Br, I; F is preferred.
实施方案4.2.9：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-OH。Embodiment 4.2.9: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
实施方案4.2.10：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.2.10: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.2.11：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-O-CH(CH3)2、-O-CH2F、-O-CH2Cl、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3。Embodiment 4.2.11: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 .
实施方案4.2.12：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.2.12: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.2.13：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.2.13: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.2.14：实施方案4.2.8至4.2.13任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中存在至少一个R3；优选存在一个R3，更优选所述一个R3与R1相邻，例如所述一个R3选自卤素如F、-C1-6烷基如甲基、-C1-6烷氧基如甲氧基。Embodiment 4.2.14: The compound of formula (I) according to any one of embodiments 4.2.8 to 4.2.13, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or Solvate, in which there is at least one R 3 ; preferably there is one R 3 , more preferably the one R 3 is adjacent to R 1 , for example, the one R 3 is selected from halogen such as F, -C 1-6 alkyl such as Methyl, -C 1-6 alkoxy such as methoxy.
实施方案4.2.15：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于相邻环碳原子上的R1和R3与它们所连接的碳原子一起形成C3-4环烷基。Embodiment 4.2.15: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates A substance in which R 1 and R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
实施方案4.2.16：实施方案4.2至4.2.6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基。Embodiment 4.2.16: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
实施方案4.2.17：实施方案4.2至4.2.16任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为H。Embodiment 4.2.17: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof thing, where R 4 is H.
实施方案4.2.18：实施方案4.2至4.2.16任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-C1-6烷基，任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH(CH3)CH2-OCH3、-CH2CH(CH3)-OCH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH(CH3)F、-CH(CH3)CH2F、-CH2CH(CH3)F、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2、-CH2CN、-CH2CH2CN、 Embodiment 4.2.18: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate substance, wherein R 4 is -C 1-6 alkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 , such as but not limited to - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , - C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , - CH(CH 3 )CH 2 -OCH 3 , -CH 2 CH(CH 3 )-OCH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH(CH 3 )F, -CH(CH 3 )CH 2 F, -CH 2 CH(CH 3 )F, -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 , -CH 2 CN, -CH 2 CH 2 CN,
实施方案4.2.19：实施方案4.2至4.2.16任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-C2-6烯基或-C2-6炔基，例如但不限于乙烯基、丙烯基、乙炔基，各自任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代。Embodiment 4.2.19: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not limited to vinyl, propenyl, ethynyl, each optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 substituted.
实施方案4.2.20：实施方案4.2至4.2.16任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-(CH2)n-C3-6环烷基，任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代，例如但不限于 Embodiment 4.2.20: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 replace, such as but not limited to
实施方案4.2.21：实施方案4.2至4.2.16任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为甲基。Embodiment 4.2.21: The compound of formula (I) according to any one of embodiments 4.2 to 4.2.16, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is methyl.
实施方案4.2.22：实施方案4.2的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R1为-C1-6烷基，R2为H，R3选自卤素、C1-6烷基和C1-6烷氧基，且R4为C1-6烷基，例如Q为例如 Embodiment 4.2.22: The compound of formula (I) of Embodiment 4.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 1 is - C 1-6 alkyl, R 2 is H, R 3 is selected from halogen, C 1-6 alkyl and C 1-6 alkoxy, and R 4 is C 1-6 alkyl, for example, Q is For example
实施方案4.3：实施方案1至3.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为 Embodiment 4.3: The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
实施方案4.3.1：实施方案4.3的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中k为0，则Q为例如优选 Embodiment 4.3.1: The compound of formula (I) of Embodiment 4.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein k is 0, Then Q is For example preferred
实施方案4.3.2：实施方案4.3的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中k为1，则Q为例如 Embodiment 4.3.2: The compound of formula (I) of Embodiment 4.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein k is 1, Then Q is For example
实施方案4.3.3：实施方案4.3至4.3.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R1为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2；优选-CH3。Embodiment 4.3.3: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 ; preferably -CH 3 .
实施方案4.3.4：实施方案4.3至4.3.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R1为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.3.4: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.3.5：实施方案4.3至4.3.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于相邻环碳原子上的R1和R3与它们所连接的碳原子一起形成C3-4环烷基，相应的结构片段例如但不限于 Embodiment 4.3.5: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 1 and R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group, and the corresponding structural fragments are such as but not limited to
实施方案4.3.6：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为H。Embodiment 4.3.6: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
实施方案4.3.7：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为卤素，选自F、Cl、Br、I，优选F。Embodiment 4.3.7: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is halogen, selected from F, Cl, Br, I, preferably F.
实施方案4.3.7.1：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为CN。Embodiment 4.3.7.1: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is CN.
实施方案4.3.8：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-OH。Embodiment 4.3.8: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
实施方案4.3.9：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.3.9: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.3.9.1：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-C2-6烯基或-C2-6炔基，任选被卤素、CN或-C1-6烷氧基取代；例如但不限于各自任选被卤素、CN或-C1-6烷氧基取代的乙烯基、丙烯基、乙炔基。Embodiment 4.3.9.1: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -C 2-6 alkenyl or -C 2-6 alkynyl, optionally substituted by halogen, CN or -C 1-6 alkoxy; for example, but not limited to, each is optionally substituted by halogen, CN Or -C 1-6 alkoxy substituted vinyl, propenyl, ethynyl.
实施方案4.3.10：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-O-CH(CH3)2、-O-CH2F、-O-CH2Cl、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3。Embodiment 4.3.10: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 .
实施方案4.3.11：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.3.11: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.3.12：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.3.12: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.3.13：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基，优选环丙基；相应的环例如但不限于 Embodiment 4.3.13: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates substance, wherein two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group, preferably cyclopropyl; the corresponding ring is such as but not limited to
实施方案4.3.13.1：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、F、Cl、Br、I、任选被卤素取代的-C1-6烷基；例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2。Embodiment 4.3.13.1: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein two R 3 attached to the same carbon atom form =C(R c ) 2 , wherein each R c is independently selected from H, F, Cl, Br, I, -C optionally substituted by halogen 1-6 alkyl; for example but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 .
实施方案4.3.13.2：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于同一个碳原子上的两个R3形成螺C3-6环烷基或螺4-7元杂环烷基，例如但不限于螺环丙基、螺环丁基、螺环戊基、螺氮杂环丁烷、螺氮杂环戊烷。 Embodiment 4.3.13.2: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, in which two R 3 connected to the same carbon atom form a spiro C 3-6 cycloalkyl group or a spiro 4-7 membered heterocycloalkyl group, such as but not limited to spiro cyclopropyl, spiro cyclobutyl, spiro cycloalkyl Cyclopentyl, spiroazetidine, spiroazetidine.
实施方案4.3.14：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基。Embodiment 4.3.14: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 's attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group.
实施方案4.3.14.1：实施方案4.3至4.3.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3选自卤素、CN、OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基、-C2-6炔基、-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素或-OC1-6烷基取代；Embodiment 4.3.14.1: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is selected from halogen, CN, OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkynyl, -(CH 2 ) n -C 3-6 cycloalkyl, wherein each occurrence of C 1-6 alkyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is independently optionally replaced by halogen or -OC 1- 6Alkyl substitution;
或者连接于同一环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基，Or two R 3 attached to the same ring carbon atom together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group,
或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；优选地，Or two R 3 attached to the same carbon atom form =C(R c ) 2 , where each R c is independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen, such as but Not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; preferably,
R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2。R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 connected to the same carbon atom form =C(R c ) 2 , where R c is each independently selected from H, halogen and any -C 1-3 alkyl substituted by halogen is selected, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 .
实施方案4.3.14.2：实施方案4.3.14.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3所连接的环碳原子与R1所连接的环碳原子相邻且与环N-R4不相邻，例如 Embodiment 4.3.14.2: The compound of formula (I) of Embodiment 4.3.14.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 3 The attached ring carbon atom is adjacent to the ring carbon atom to which R 1 is attached and not adjacent to ring NR 4 , e.g.
实施方案4.3.15：实施方案4.3至4.3.14.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为H。Embodiment 4.3.15: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof thing, where R 4 is H.
实施方案4.3.16：实施方案4.3至4.3.14.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-C1-6烷基，任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH(CH3)CH2-OCH3、-CH2CH(CH3)-OCH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH(CH3)F、-CH(CH3)CH2F、-CH2CH(CH3)F、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2、-CH2CN、-CH2CH2CN、 Embodiment 4.3.16: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -C 1-6 alkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 , such as but not limited to - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , - C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , - CH(CH 3 )CH 2 -OCH 3 , -CH 2 CH(CH 3 )-OCH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH(CH 3 )F, -CH(CH 3 )CH 2 F, -CH 2 CH(CH 3 )F, -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 , -CH 2 CN, -CH 2 CH 2 CN,
优选地，R4为-C1-3烷基，例如甲基；Preferably, R 4 is -C 1-3 alkyl, such as methyl;
优选地，R4为被一个或多个氘取代的-C1-3烷基，例如-CD3。Preferably, R 4 is -C 1-3 alkyl substituted by one or more deuteriums, such as -CD 3 .
实施方案4.3.17：实施方案4.3至4.3.14.2任一项的式(I)化合物、其立体异构体、互变异 构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-C2-6烯基或-C2-6炔基，例如但不限于乙烯基、丙烯基、乙炔基，各自任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代。Embodiment 4.3.17: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers and tautomers Conformations, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 4 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not limited to vinyl, propenyl, Ethynyl, each optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 .
实施方案4.3.18：实施方案4.3至4.3.14.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为-(CH2)n-C3-6环烷基，任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代，例如但不限于 Embodiment 4.3.18: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen, CN, -C 1-6 alkoxy or -O-CON(C 1-6 alkyl) 2 replace, such as but not limited to
实施方案4.3.19：实施方案4.3至4.3.14.2任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R4为甲基。Embodiment 4.3.19: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.14.2, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 4 is methyl.
实施方案4.3.20：实施方案4.3的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Z选自C、Se和O，R1为-C1-6烷基，R3选自H、卤素、C1-6烷基和C1-6烷氧基，且R4为C1-6烷基；优选Z选自C。Embodiment 4.3.20: The compound of formula (I) of Embodiment 4.3, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, wherein Z is selected from C , Se and O, R 1 is -C 1-6 alkyl, R 3 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy, and R 4 is C 1-6 alkyl; Preferably Z is selected from C.
实施方案4.3.21：实施方案4.3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Z选自C，R1为-C1-6烷基，R3选自卤素、CN、OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基、-C2-6炔基、-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素或-OC1-6烷基取代，Embodiment 4.3.21: The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is selected From C, R 1 is -C 1-6 alkyl, R 3 is selected from halogen, CN, OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, - C 2-6 alkynyl, -(CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is each independently optionally substituted by halogen or -OC 1-6 alkyl,
或者连接于同一环碳原子上的两个R3与它们所连接的碳原子一起形成任选被卤素取代的螺C3-4环烷基，Or two R 3 attached to the same ring carbon atom together with the carbon atom to which they are attached form a spiro C 3-4 cycloalkyl group optionally substituted by halogen,
或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；且Or two R 3 attached to the same carbon atom form =C(R c ) 2 , where each R c is independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen, such as but Not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; and
R4为C1-6烷基；R 4 is C 1-6 alkyl;
优选地，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、 ＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3。Preferably, R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 connected to the same carbon atom form =C(R c ) 2 , wherein R c is each independently selected from H, Halogen and -C 1-3 alkyl optionally substituted by halogen, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; R 4 is -C 1-3 alkyl or -C 1-3 alkyl substituted by one or more deuteriums , such as methyl, -CD 3 .
实施方案4.3.21.1：实施方案4.3至4.3.21任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q部分中连接至Y的亚甲基的两个氢原子任选被氘代替。Embodiment 4.3.21.1: The compound of formula (I) according to any one of embodiments 4.3 to 4.3.21, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which the two hydrogen atoms in the Q moiety connected to the methylene group of Y are optionally replaced by deuterium.
实施方案4.3.22：实施方案4.3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q的示例包括但不限于 Embodiment 4.3.22: The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q Examples include but are not limited to
优选 preferred
实施方案4.3.23：实施方案4.3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为其中R3和R4各自如实施方案1所定义，优选如实施方案4.3.6至4.3.19相应所定义；更优选地，其中R4为任选被-O-C1-6烷基或卤素取代的-C1-6烷基，优选-C1-3烷基；R3选自卤素、CN、任选被卤素取代的-C1-6烷基、任选被卤素取代的-C2-6炔基和任选被卤素取代的-O-C1-6烷基，或者连接于同一个 碳原子上的两个R3形成＝C(Rc)2或任选被卤素取代的螺C3-6环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，且m选自1或2；R3的具体示例包括但不限于氟、氟代甲基、二氟甲基、甲基、甲氧基、乙炔基、氰基、氟代亚甲基、二氟代亚甲基、亚甲基、二氟、螺环丙基、双甲基；Embodiment 4.3.23: The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q is wherein R 3 and R 4 are each as defined in Embodiment 1, preferably as defined correspondingly in Embodiments 4.3.6 to 4.3.19; more preferably, wherein R 4 is optionally substituted by -OC 1-6 alkyl or halogen -C 1-6 alkyl, preferably -C 1-3 alkyl; R 3 is selected from halogen, CN, -C 1-6 alkyl optionally substituted by halogen, -C 2- optionally substituted by halogen 6 alkynyl and -OC 1-6 alkyl optionally substituted by halogen, or connected to the same Two R on carbon atoms form =C(R c ) 2 or spiro C 3-6 cycloalkyl optionally substituted by halogen, wherein R c is each independently selected from H, halogen and optionally substituted by halogen -C 1-6 alkyl, and m is selected from 1 or 2; specific examples of R 3 include but are not limited to fluorine, fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, Fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl;
最优选地，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；Most preferably, R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 attached to the same carbon atom form =C(R c ) 2 , where each R c is independently selected from H , halogen and -C 1-3 alkyl optionally substituted by halogen, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; R 4 is -C 1-3 alkyl or -C 1-3 alkyl substituted by one or more deuteriums, such as methyl, -CD 3 ;
其中与Y连接的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
实施方案4.3.23：实施方案4.3.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为其中R3和R4各自如实施方案1所定义，优选如实施方案4.3.6至4.3.19相应所定义；更优选地，其中R4为任选被-O-C1-6烷基或卤素取代的-C1-6烷基，优选-C1-3烷基；R3选自卤素、CN、任选被卤素取代的-C1-6烷基、任选被卤素取代的-C2-6炔基和任选被卤素取代的-O-C1-6烷基，或者连接于同一个碳原子上的两个R3形成＝C(Rc)2或任选被卤素取代的螺C3-6环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，且m选自1或2；R3的具体示例包括但不限于氟、氟代甲基、二氟甲基、甲基、甲氧基、乙炔基、氰基、氟代亚甲基、二氟代亚甲基、亚甲基、二氟、螺环丙基、双甲基；Embodiment 4.3.23: The compound of formula (I) of Embodiment 4.3.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q is wherein R 3 and R 4 are each as defined in Embodiment 1, preferably as defined correspondingly in Embodiments 4.3.6 to 4.3.19; more preferably, wherein R 4 is optionally substituted by -OC 1-6 alkyl or halogen -C 1-6 alkyl, preferably -C 1-3 alkyl; R 3 is selected from halogen, CN, -C 1-6 alkyl optionally substituted by halogen, -C 2- optionally substituted by halogen 6 alkynyl and -OC 1-6 alkyl optionally substituted by halogen, or two R 3 connected to the same carbon atom to form =C(R c ) 2 or spiro C 3- optionally substituted by halogen 6 cycloalkyl, wherein R c is each independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen, and m is selected from 1 or 2 ; specific examples of R include but are not limited to fluorine, Fluoromethyl, difluoromethyl, methyl, methoxy, ethynyl, cyano, fluoromethylene, difluoromethylene, methylene, difluoro, spirocyclopropyl, dimethyl base;
最优选地，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；Most preferably, R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 attached to the same carbon atom form =C(R c ) 2 , where each R c is independently selected from H , halogen and -C 1-3 alkyl optionally substituted by halogen, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; R 4 is -C 1-3 alkyl or -C 1-3 alkyl substituted by one or more deuteriums, such as methyl, -CD 3 ;
其中与Y连接的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
实施方案4.4：实施方案1至3.2.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为 Embodiment 4.4: The compound of formula (I) according to any one of embodiments 1 to 3.2.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Q is
实施方案4.4.1：实施方案4.4的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q选自 Embodiment 4.4.1: The compound of formula (I) of Embodiment 4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q is selected from
实施方案4.4.2：实施方案4.4或4.4.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R2为H。Embodiment 4.4.2: The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R2 is H.
实施方案4.4.3：实施方案4.4或4.4.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中至少一个R2为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.4.3: The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein At least one R 2 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 - O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , - CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.4.4：实施方案4.4或4.4.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中至少一个R2为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.4.4: The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein At least one R 2 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.4.5：实施方案4.4或4.4.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中两个R2与它们所连接的碳原子一起形成环丙基或环丁基，例如Q为例如 Embodiment 4.4.5: The compound of formula (I) of Embodiment 4.4 or 4.4.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Two R 2 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, for example Q is For example
实施方案4.4.6：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为H。Embodiment 4.4.6: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, where R 3 is H.
实施方案4.4.7：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为卤素，选自F、Cl、Br、I；优选F。 Embodiment 4.4.7: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is halogen, selected from F, Cl, Br, I; F is preferred.
实施方案4.4.8：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-OH。Embodiment 4.4.8: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OH.
实施方案4.4.9：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2。Embodiment 4.4.9: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -C 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F , -CH 2 Cl , -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F , -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF(CF 3 ) 2 .
实施方案4.4.10：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C1-6烷基，任选被卤素或C1-6烷氧基取代，例如但不限于-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-O-CH(CH3)2、-O-CH2F、-O-CH2Cl、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3。Embodiment 4.4.10: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 1-6 alkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F , -O-CH 2 Cl , -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F , -O-CH 2 CHF 2 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 .
实施方案4.4.11：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-(CH2)n-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.4.11: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -(CH 2 ) n -C 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.4.12：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R3为-O-C3-6环烷基，任选被卤素或C1-6烷氧基取代，例如但不限于 Embodiment 4.4.12: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof substance, wherein R 3 is -OC 3-6 cycloalkyl, optionally substituted by halogen or C 1-6 alkoxy, such as but not limited to
实施方案4.4.13：实施方案4.4.7至4.4.12任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中存在至少一个R3；优选存在一个R3。Embodiment 4.4.13: The compound of formula (I) according to any one of embodiments 4.4.7 to 4.4.12, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or Solvates in which at least one R 3 is present; preferably one R 3 is present.
实施方案4.4.14：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基。Embodiment 4.4.14: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3 attached to adjacent ring carbon atoms together with the carbon atoms to which they are attached form a C 3-4 cycloalkyl group.
实施方案4.4.15：实施方案4.4至4.4.5任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中连接于非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基，例如Q为 Embodiment 4.4.15: The compound of formula (I) according to any one of embodiments 4.4 to 4.4.5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof A substance in which two R 3's attached to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group, for example Q is
实施方案4.4.16：实施方案4.4的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Z选自C、Se和O，两个R2与它们所连接的碳原子一起形成环丙基或环丁基，且R3选自H、卤素、C1-6烷基和C1-6烷氧基。Embodiment 4.4.16: The compound of formula (I) of Embodiment 4.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Z is selected from C , Se and O, two R 2 together with the carbon atoms to which they are attached form cyclopropyl or cyclobutyl, and R 3 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy.
实施方案5.1：实施方案1至4.4.15任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Y为O。Embodiment 5.1: The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is O.
实施方案5.2：实施方案1至4.4.15任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Y为S。Embodiment 5.2: The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is S.
实施方案5.3：实施方案1至4.4.15任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Y为Se。Embodiment 5.3: The compound of formula (I) according to any one of embodiments 1 to 4.4.15, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, where Y is Se.
实施方案6a：实施方案1至5.3任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中M是N。Embodiment 6a: The compound of formula (I) of any one of embodiments 1 to 5.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M It's N.
实施方案6b：实施方案1至5.3任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中M是C-R7。Embodiment 6b: The compound of formula (I) according to any one of embodiments 1 to 5.3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein M It's CR 7 .
实施方案6.1：实施方案6b的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R7为H。Embodiment 6.1: The compound of formula (I) of Embodiment 6b, wherein R 7 is H, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof.
实施方案6.2：实施方案6b的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R7为卤素，选自F、Cl、Br和I；优选F或Cl。Embodiment 6.2: The compound of formula (I) of Embodiment 6b, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 7 is halogen, preferably From F, Cl, Br and I; preferably F or Cl.
实施方案6.3：实施方案6b的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R7为CN。Embodiment 6.3: The compound of formula (I) of Embodiment 6b, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 7 is CN.
实施方案6.4：实施方案6b的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R7为-C1-6烷基，任选被卤素或CN取代；例如但不限于-CH3、-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CN、-CH2CH2CN。 Embodiment 6.4: Compounds of formula (I) according to Embodiment 6b, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 7 is -C 1 -6 alkyl, optionally substituted by halogen or CN; for example but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3 , -CCl 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 CN.
实施方案7a：实施方案1至6.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R11为H。Embodiment 7a: The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is H.
实施方案7b：实施方案1至6.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R11为卤素，优选F。Embodiment 7b: The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is halogen, preferably F.
实施方案7c：实施方案1至6.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R11为任选被卤素取代的-C1-6烷基，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OCH3、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CH2Cl、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CF(CF3)2，优选-CH3。Embodiment 7c: The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 1-6 alkyl optionally substituted by halogen, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 -OCH 3 , -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -C 2 F 5 , -C 2 Cl 5 , -CF (CF 3 ) 2 , preferably -CH 3 .
实施方案7d：实施方案1至6.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R11为任选被卤素取代的-O-C1-6烷基，例如但不限于-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-O-CH(CH3)2、-O-CH2F、-O-CH2Cl、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3，优选-O-CH3。Embodiment 7d: A compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates thereof, wherein R 11 is -OC 1-6 alkyl optionally substituted by halogen, such as but not limited to -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 F, -O-CH 2 Cl, -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F, -O-CH 2 CHF 2 , -O- CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 , preferably -O-CH 3 .
实施方案7e：实施方案1至6.4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R11为任选被卤素取代的-C2-6炔基，优选乙炔基。Embodiment 7e: The compound of formula (I) according to any one of embodiments 1 to 6.4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R 11 is -C 2-6 alkynyl optionally substituted by halogen, preferably ethynyl.
实施方案7：实施方案1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其具有以下子通式：



Embodiment 7: The compound of formula (I) of Embodiment 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, which has the following subgeneral formula:



其中各个取代基具有前述各个相应实施方案所定义的含义。Wherein each substituent has the meaning defined in each corresponding embodiment mentioned above.
实施方案7.1：实施方案7的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中：Embodiment 7.1: The compound of formula (I) of Embodiment 7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, wherein:
Y为O；Y is O;
B选自 B is selected from
Z选自C、Se和O，优选O或C；Z is selected from C, Se and O, preferably O or C;
W为-OH；W is -OH;
R1为C1-6烷基，优选甲基；R 1 is C 1-6 alkyl, preferably methyl;
R2为H，或连接在同一碳原子上的两个R2一起形成环丙基，R 2 is H, or two R 2 connected to the same carbon atom together form a cyclopropyl group,
R3选自H、C1-6烷基、-OC1-6烷基和卤素，优选C1-6烷基、-OC1-6烷基和卤素，例如甲基、乙基、甲氧基、乙氧基和F；或R 3 is selected from H, C 1-6 alkyl, -OC 1-6 alkyl and halogen, preferably C 1-6 alkyl, -OC 1-6 alkyl and halogen, such as methyl, ethyl, methoxy radical, ethoxy and F; or
对于式(I-A-2)、(I-B-2)、(I-C-2)或(I-D-2)，R3选自卤素、CN、任选被卤素取代的-C1-6烷基、任选被卤素取代的-C2-6炔基和任选被卤素取代的-O-C1-6烷基，或者连接于同一个碳原子上的两个R3形成＝C(Rc)2或任选被卤素取代的螺C3-6环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基；优选地，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；For formula (IA-2), (IB-2), (IC-2) or (ID-2), R 3 is selected from halogen, CN, -C 1-6 alkyl optionally substituted by halogen, optionally -C 2-6 alkynyl substituted by halogen and -OC 1-6 alkyl optionally substituted by halogen, or two R 3 connected to the same carbon atom to form =C(R c ) 2 or optionally Spiro C 3-6 cycloalkyl substituted by halogen, wherein R c is each independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen; preferably, R 3 is -C 1-3 Alkyl, substituted by halogen; or two R 3 attached to the same carbon atom form =C(R c ) 2 , wherein R c is each independently selected from H, halogen and -C 1 optionally substituted by halogen -3 Alkyl group, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ;
R4选自H和C1-6烷基，优选C1-6烷基，例如甲基或乙基；更优选，R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；R 4 is selected from H and C 1-6 alkyl, preferably C 1-6 alkyl, such as methyl or ethyl; more preferably, R 4 is -C 1-3 alkyl or substituted by one or more deuterium -C 1-3 alkyl, such as methyl, -CD 3 ;
R5选自H和卤素，优选卤素，例如F；R 5 is selected from H and halogen, preferably halogen, such as F;
R6选自卤素、C1-6烷基和C2-6炔基，优选F、乙基或乙炔基；R 6 is selected from halogen, C 1-6 alkyl and C 2-6 alkynyl, preferably F, ethyl or ethynyl;
R7选自H、卤素、CN和卤素取代的C1-6烷基，优选H、F、Cl、CN、CF3； R 7 is selected from H, halogen, CN and halogen-substituted C 1-6 alkyl, preferably H, F, Cl, CN, CF 3 ;
R8选自-OH、卤素、-CN、-C1-6烷基、-OC1-6烷基和-CON(C1-6烷基)2；R 8 is selected from -OH, halogen, -CN, -C 1-6 alkyl, -OC 1-6 alkyl and -CON(C 1-6 alkyl) 2 ;
R9和R10各自独立地为H或卤素，例如各自独立地为H或F，或均为H，或均为卤素，例如F；R 9 and R 10 are each independently H or halogen, such as each independently H or F, or both are H, or both are halogen, such as F;
R11选自H、卤素、任选被卤素取代的C1-6烷基、任选被卤素取代的C1-6烷氧基和任选被卤素取代的-C2-6炔基；优选H、卤素、C1-6烷基、C1-6烷氧基和-C2-6炔基；R 11 is selected from H, halogen, C 1-6 alkyl optionally substituted by halogen, C 1-6 alkoxy optionally substituted by halogen, and -C 2-6 alkynyl optionally substituted by halogen; preferably H, halogen, C 1-6 alkyl, C 1-6 alkoxy and -C 2-6 alkynyl;
n选自0、1和2，k选自0和1，m和t各自独立地选自1或2，优选2；n is selected from 0, 1 and 2, k is selected from 0 and 1, m and t are each independently selected from 1 or 2, preferably 2;
其中与Y连接的Q的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group of Q connected to Y are optionally replaced by deuterium.
实施方案8：实施方案7或7.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其具有以下子通式：







Embodiment 8: The compound of formula (I) of Embodiment 7 or 7.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, which have the following substructure Mode:







优选地，其中Preferably, where
R8选自-OH和-C1-6烷基，优选其中之一为-OH，另一个为C1-6烷基，例如-CH3；R 8 is selected from -OH and -C 1-6 alkyl, preferably one of them is -OH and the other is C 1-6 alkyl, such as -CH 3 ;
Y为O；Y is O;
R9为H；R 9 is H;
R5选自卤素，优选F；且 R5 is selected from halogen, preferably F; and
R6选自C1-6烷基和C2-6炔基，优选乙基或乙炔基；R 6 is selected from C 1-6 alkyl and C 2-6 alkynyl, preferably ethyl or ethynyl;
对于式(I-A’-2)、(I-B’-2)、(I-C’-2)或(I-D’-2)，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如但不限于＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；For formula (I-A'-2), (I-B'-2), (I-C'-2) or (I-D'-2), R 3 is -C 1-3 alkyl, represented by Halogen substitution; or two R 3 attached to the same carbon atom form =C(R c ) 2 , where each R c is independently selected from H, halogen and -C 1-3 alkyl optionally substituted by halogen , for example but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; R 4 is -C 1-3 alkyl or is replaced by one or Multiple deuterium-substituted -C 1-3 alkyl groups, such as methyl, -CD 3 ;
R11选自H、卤素、C1-6烷基和C1-6烷氧基；R 11 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy;
k选自0，m选自1或2；k is selected from 0, m is selected from 1 or 2;
其中与Y连接的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
实施方案8.1：实施方案8的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中各个子通式中的B结构片段为 Embodiment 8.1: The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein in each subgeneral formula The B structure fragment is
实施方案8.2：实施方案8的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中各个子通式中的B结构片段可替换为优选由此相应得到子通式(I-A”)、(I-A”’-1)、(I-A”’-2)、(I-A”’-3)、(I-A”’-4)、(I-B”’)、(I-B”’-1)、(I-B”’-2)、(I-B”’-3)、(I-B”’-4)、(I-C”’)、(I-C”’-1)、(I-C”’-2)、(I-C”’-3)、(I-C”’-4)、(I-D”’)、(I-D”’-1)、(I-D”’-2)、(I-D”’-3)、(I-D”’-4)的化合物，例如



Embodiment 8.2: The compound of formula (I) of Embodiment 8, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein in each subgeneral formula The B structure fragment can be replaced by preferred From this, the sub-general formulas (IA”), (IA”'-1), (IA”’-2), (IA”’-3), (IA”’-4), (IB”’), (IB"'-1), (IB"'-2), (IB"'-3), (IB"'-4), (IC"'), (IC"'-1), (IC"' -2), (IC”'-3), (IC”’-4), (ID”’), (ID”’-1), (ID”’-2), (ID”’-3), (ID”'-4) compounds, such as



实施方案9：实施方案7或7.1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其具有以下子通式：


Embodiment 9: The compound of formula (I) of Embodiment 7 or 7.1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, which have the following substructure Mode:


优选R8为-CON(C1-6烷基)2，优选-CON(CH3)2。Preferably R 8 is -CON(C 1-6 alkyl) 2 , preferably -CON(CH 3 ) 2 .
实施方案10：化合物，选自下文实施例1-185的化合物或其药学上可接受的盐或溶剂合物。 Embodiment 10: A compound selected from the compounds of Examples 1-185 below or a pharmaceutically acceptable salt or solvate thereof.
需要说明的是，本发明的化合物涵盖以上各个独立的实施方案或各个具体实施方案，还涵盖上述各个实施方案或具体实施方案的任何组合或亚组合构成的实施方案，也涵盖以上任何优选或例举的实施方案的任何组合所构成的实施方案。It should be noted that the compounds of the present invention cover each of the above independent embodiments or each specific embodiment, and also cover any combination or sub-combination of the above each embodiment or specific embodiment, and also cover any of the above preferences or examples. Any combination of the above-mentioned embodiments constitutes an embodiment.
发明的有益效果Beneficial effects of the invention
如前文所述，已知Ras突变蛋白、尤其KRas突变蛋白在肿瘤发生以及多种其它疾病中发挥作用。我们已令人惊讶地发现，具有上述结构特征的本发明化合物在携带由KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS野生扩增的细胞系中能够强效抑制细胞增殖，从而在预防、遏制和/或治疗相关肿瘤疾病方面具有潜在的、作为抗增殖、促凋亡和/或抗侵袭药物的价值。特别地，预期本发明化合物可用于预防或治疗那些Ras突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)或KRAS野生扩增介导的或得益于Ras突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)或KRAS野生扩增抑制的疾病或病症，例如本文所定义的癌症或肿瘤。As mentioned above, Ras mutant proteins, especially KRas mutant proteins, are known to play a role in tumorigenesis and various other diseases. We have surprisingly found that the compounds of the present invention with the above structural characteristics carry the KRas mutant protein (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS wild-amplified cell lines can potently inhibit cell proliferation, thus having potential value as anti-proliferation, pro-apoptosis and/or anti-invasive drugs in the prevention, containment and/or treatment of related tumor diseases. In particular, the compounds of the present invention are expected to be useful in the prevention or treatment of those Ras mutant proteins (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H mutant proteins) or KRAS wild-type amplification mediated Diseases or conditions that are caused by or benefit from suppression of Ras mutations (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H mutations) or KRAS wild amplification, such as cancers as defined herein or tumors.
具体地，经研究发现，本发明的化合物能够实现以下一种或多种技术效果：Specifically, it has been found through research that the compounds of the present invention can achieve one or more of the following technical effects:
·高的突变蛋白抑制活性：本发明的化合物、尤其是本文上下文具体示例的化合物，在KRAS突变细胞(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增细胞增殖抑制实验中显示出增殖抑制活性，IC50值在0.0001-10μM范围内，优选在0.0001-1μM范围内；例如0.0001～1μM、0.001～1μM、0.0001～0.5μM、0.001～0.5μM、0.0001～0.1μM、0.001～0.5μM、0.001～0.1μM；High mutant protein inhibitory activity: The compounds of the invention, especially the compounds specifically exemplified in this context, have a high inhibitory activity in KRAS mutant cells (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification cell proliferation inhibition experiments show proliferation inhibitory activity, the IC50 value is in the range of 0.0001-10μM, preferably in the range of 0.0001-1μM; for example, 0.0001~1μM, 0.001~1μM, 0.0001~0.5μM, 0.001~ 0.5μM, 0.0001～0.1μM, 0.001～0.5μM, 0.001～0.1μM;
·具有良好的药代动力学性质，例如具有较长的t1/2，从而例如可以加大给药间隔，更长的半衰期，使患者具有更好的依从性；具有安全性/活性综合效应最佳的AUC0-t数据，具有更好的成药性，更高的生物利用度，如活性实施例3所验证；和/或·Have good pharmacokinetic properties, such as a longer t 1/2 , which can, for example, increase the dosing interval and a longer half-life, allowing patients to have better compliance; and have a comprehensive safety/activity effect The best AUC 0-t data, with better druggability and higher bioavailability, as verified by Active Example 3; and/or
·具有明显令人满意的安全性，药物相互作用的风险降低，对于药物代谢关键CYP亚型没有显著抑制作用，如活性实施例4所验证。·It has an obviously satisfactory safety profile, reduced risk of drug interactions, and no significant inhibitory effect on key CYP subtypes of drug metabolism, as verified by Active Example 4.
·良好的药代动力学性质带来更便捷的口服给药模式，显示出良好的药效作用，如活性实施例7所验证。·Good pharmacokinetic properties bring a more convenient oral administration mode and show good pharmacodynamic effects, as verified by Active Example 7.
基于以上本发明化合物的有益效果，本发明还提供以下各个方面的技术方案。Based on the above beneficial effects of the compounds of the present invention, the present invention also provides technical solutions in the following aspects.
用于治疗或用作药物的本发明化合物Compounds of the invention for use in therapy or as medicaments
一方面，本发明提供了本发明化合物、优选其药学上可接受的盐或溶剂合物，用作药物。 In one aspect, the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
另一方面，本发明提供了本发明化合物、优选其药学上可接受的盐或溶剂合物用作KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS野生扩增型细胞抑制剂。In another aspect, the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, for use as a KRas mutant protein (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations and Q61H mutant protein) and KRAS wild-amplified cellular inhibitors.
另一方面，本发明提供本发明化合物、优选其药学上可接受的盐或溶剂合物，用于治疗和/或预防Ras突变蛋白、具体地KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS扩增介导的或得益于Ras突变、具体地KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS扩增抑制的疾病或病症。On the other hand, the invention provides compounds of the invention, preferably pharmaceutically acceptable salts or solvates thereof, for the treatment and/or prevention of Ras muteins, in particular KRas muteins (e.g. G12C mutations, G12D mutations, G12V mutations , G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification mediated or benefiting from Ras mutation, specifically KRas mutant protein (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and diseases or conditions that inhibit KRAS amplification.
在具体的实施方式中，本发明提供用于治疗和/或预防Ras突变蛋白、具体地KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS扩增对所述疾病的发生和发展起到促进作用或抑制Ras突变蛋白、具体地KRas突变蛋白(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变蛋白)及KRAS扩增将降低疾病的发生率、减少或消除疾病病状的疾病的本发明化合物，所述疾病例如肿瘤或癌症，包括但不限于：肺癌、肺腺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤(CNS)、原发性CNS淋巴瘤、脊柱肿瘤、脑干神经胶质瘤或垂体腺瘤。In specific embodiments, the present invention provides for the treatment and/or prevention of Ras mutant proteins, in particular KRas mutant proteins (e.g., G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations, and Q61H Mutated proteins) and KRAS amplification play a role in promoting the occurrence and development of the disease or inhibiting Ras mutant proteins, specifically KRas mutant proteins (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutant protein) and KRAS amplification will reduce the incidence of disease, reduce or eliminate disease symptoms, such as tumors or cancers, including but not limited to: lung cancer, lung adenocarcinoma, bone Cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervix Cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia , lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma .
本发明尤其提供可用于治疗患有胰腺癌、结肠癌、直肠癌、肺腺癌、肺癌、胆管癌、子宫内膜癌、卵巢癌、白血病；最优选选自胰腺癌、结肠癌、直肠癌、肺腺癌、胆管癌的患者的式(I)化合物或其异构体、它们药学上可接受的盐或溶剂合物。In particular, the present invention provides a method for treating patients with pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, and leukemia; most preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, Compounds of formula (I) or isomers thereof, their pharmaceutically acceptable salts or solvates for patients with lung adenocarcinoma and cholangiocarcinoma.
药物组合物及其施用Pharmaceutical compositions and their administration
另一方面，本发明提供药物组合物，其包含以上定义的式(I)化合物、优选其药学上可接受的盐或溶剂合物，以及可药用载体或赋形剂。本发明的药物组合物可用于治疗或预防由Ras突变、尤其KRas突变介导的疾病，例如KRas G12C、KRas G12D、KRas G12V、KRas G12A、KRas G12R、KRas G12S、KRas G13D突变或KRas Q61H突变、及KRAS扩增介导的疾病，例如肿瘤或癌症。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, preferably a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S, KRas G13D mutations or KRas Q61H mutations, and diseases mediated by KRAS amplification, such as tumors or cancers.
上述本发明药物组合物，可以通过本领域技术人员已知的技术来配制，如在Remington’s Pharmaceutical Sciences第20版中公开的技术。例如，可配制为片剂、粉末、胶囊、锭剂、颗粒、溶液、分散剂、混悬剂、糖浆、喷雾、栓剂、凝胶、乳剂、贴剂等。所述组合物可含有药物制剂中的常规组分，例如稀释剂(例如葡萄糖、乳糖或甘露醇)、载体、pH调节剂、缓冲剂、 甜味剂、填充剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、加香剂、调味剂、其它已知添加剂以及其它活性剂。合适的载体和赋形剂为本领域技术人员熟知并详述于例如Ansel,Howard C.,等,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004中。The pharmaceutical composition of the present invention described above can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th Edition. For example, it can be formulated into tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The composition may contain conventional components found in pharmaceutical preparations, such as diluents (such as glucose, lactose or mannitol), carriers, pH adjusters, buffers, Sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents , flavoring agents, other known additives and other active agents. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004.
本发明药物组合物的给药和施用均符合良好的医学实践。在此背景下需要考虑的因素包括所治疗特定障碍、所治疗的特定哺乳动物、个体患者的临床情况、障碍的起因、药剂递送位置、施用方法、施用安排以及医生从业者熟知的其它因素。本发明化合物或药物组合物的最佳剂量水平和给药频率可由本领域技术人员通过药学研究领域的标准试验确定。The administration and administration of the pharmaceutical compositions of the invention are in accordance with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of agent delivery, the method of administration, the schedule of administration, and other factors well known to the medical practitioner. The optimal dosage level and frequency of administration of the compounds or pharmaceutical compositions of the present invention can be determined by those skilled in the art through standard experiments in the field of pharmaceutical research.
本发明的组合物可采取任意合适方式施用，包括口服、局部(包括颊和舌下)、直肠、阴道、透皮、胃肠外、皮下、腹膜内、肺内、皮内、鞘内、吸入和硬膜外和鼻内，和如需局部治疗，也可采取病灶内施用。胃肠外输注包括肌肉、静脉内、动脉内、腹膜内或皮下施用。在一些实施方案中，本发明的药物组合物通过口服施用。The compositions of the present invention may be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation and epidural and intranasal, and if local treatment is required, intralesional administration may also be used. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, pharmaceutical compositions of the invention are administered orally.
对于70kg的人类对象，本发明化合物的适合的剂量范围可由本领域技术人员常规确定，例如可以为1-1000mg/天。For a 70 kg human subject, a suitable dosage range for the compounds of the invention can be routinely determined by those skilled in the art and may, for example, be 1-1000 mg/day.
当本文描述药物或其药学上可接受的盐的剂量时，应理解，该剂量基于游离碱的重量，不包括其任何水合物或溶剂化物，除非说明书中指出该剂量基于盐、水合物或溶剂合物的重量。When dosages of a drug or a pharmaceutically acceptable salt thereof are described herein, it is to be understood that the dosage is based on the weight of the free base, excluding any hydrates or solvates thereof, unless the instructions indicate that the dosage is based on the weight of a salt, hydrate, or solvent The weight of the compound.
治疗方法和用途Treatment methods and uses
如上所述，本发明的化合物及其各种具体实施方案的化合物、尤其是实施例中具体制备和表征的化合物，显示出对Ras突变、尤其是KRas突变、例如KRas G12C、KRas G12D、KRas G12V、KRas G12A、KRas G12R、KRas G12S或KRas G13D突变、或KRas Q61H，及KRAS扩增型细胞的抑制作用。As mentioned above, the compounds of the invention and the compounds of its various embodiments, especially the compounds specifically prepared and characterized in the examples, show resistance to Ras mutations, especially KRas mutations, such as KRas G12C, KRas G12D, KRas G12V , KRas G12A, KRas G12R, KRas G12S or KRas G13D mutations, or KRas Q61H, and the inhibitory effect of KRAS amplified cells.
因此，另一方面，本发明提供了一种抑制细胞中Ras突变、尤其是KRas突变、优选KRas G12D突变的方法，包括使细胞与本发明的化合物、优选其药学上可接受的盐或溶剂合物相接触以抑制细胞中Ras突变、尤其是KRas突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增的活性。Therefore, on the other hand, the invention provides a method for inhibiting Ras mutation, especially KRas mutation, preferably KRas G12D mutation in a cell, comprising combining the cell with a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof. Contact with each other to inhibit the activity of Ras mutations, especially KRas mutations (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification in cells.
基于同样的性质，本发明还相应地提供一种抑制哺乳动物中异常细胞生长的方法，包括给所述哺乳动物施用治疗有效量的本发明的化合物、优选其药学上可接受的盐或溶剂合物、或包含本发明的化合物、优选其药学上可接受的盐或溶剂合物的药物组合物。Based on the same properties, the present invention also correspondingly provides a method for inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof. or a pharmaceutical composition comprising a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof.
另一方面，本发明提供了用于治疗和/或预防由Ras突变、尤其是KRas突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增介导的疾病的方法，包括向有需要的对象施用治疗有效量的本发明化合物、 优选其药学上可接受的盐或溶剂合物、或包含本发明化合物优选药学上可接受的盐或溶剂合物的药物组合物。In another aspect, the invention provides a method for treating and/or preventing mutations caused by Ras mutations, especially KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations) and Methods for KRAS amplification-mediated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, A pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of the present invention, preferably a pharmaceutically acceptable salt or solvate thereof, is preferred.
另一方面，本发明提供了本发明的化合物、优选其药学上可接受的盐或溶剂合物、或包含本发明的化合物、优选其药学上可接受的盐或溶剂合物的药物组合物的用途，用于抑制细胞中Ras突变、尤其是KRas突变、优选KRas G12C、KRas G12D、KRas G12V、KRas G12A、KRas G12R、KRas G12S或KRas G13D、或KRas Q61H突变，及KRAS扩增介导的疾病。In another aspect, the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof. Use for inhibiting Ras mutations in cells, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations, and diseases mediated by KRAS amplification .
另一方面，本发明提供了本发明的化合物、优选其药学上可接受的盐或溶剂合物、或包含本发明的化合物、优选其药学上可接受的盐或溶剂合物的药物组合物在制备用于治疗和/或预防由Ras突变、尤其是KRas突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增介导的疾病的药物中的用途。In another aspect, the invention provides a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, in Preparation for the treatment and/or prevention of diseases mediated by Ras mutations, especially KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations and Q61H mutations) and KRAS amplifications uses in medicines.
对上述本发明提供的各个方法和用途技术方案而言，所述异常细胞生长或由Ras突变、尤其KRas突变、优选KRas G12C、KRas G12D、KRas G12V、KRas G12A、KRas G12R、KRas G12S或KRas G13D、或KRas Q61H突变，及KRAS扩增介导的疾病尤其指的是癌症或肿瘤。示例性的所述癌症或肿瘤包括但不限于肺癌、肺腺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤(CNS)、原发性CNS淋巴瘤、脊柱肿瘤、脑干神经胶质瘤或垂体腺瘤。For each method and use technical solution provided by the above-mentioned invention, the abnormal cell growth may be caused by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D , or KRas Q61H mutation, and diseases mediated by KRAS amplification particularly refer to cancer or tumors. Exemplary such cancers or tumors include, but are not limited to, lung cancer, lung adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area cancer , stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal gland cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors (CNS), primary idiopathic CNS lymphoma, spinal tumors, brainstem glioma, or pituitary adenoma.
对上述本发明提供的各个方法和用途技术方案而言，所述异常细胞生长或由Ras突变、尤其KRas突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增介导的疾病优选选自胰腺癌、结肠癌、直肠癌、肺腺癌、肺癌、胆管癌、子宫内膜癌、卵巢癌、白血病；最优选选自胰腺癌、结肠癌、直肠癌、肺腺癌、胆管癌。For each method and use technical solution provided by the present invention, the abnormal cell growth may be caused by Ras mutation, especially KRas mutation (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation and Q61H mutation) and KRAS amplification-mediated diseases are preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, Colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.
因此，在该方面的优选实施方案中，本发明提供了用于通过抑制KRas突变或扩增而治疗或预防癌症或肿瘤的上述各项方法和用途技术方案。在更进一步优选的实施方案中，本发明提供了通过抑制KRas突变或扩增而治疗或预防胰腺癌、结肠癌、直肠癌、肺腺癌和胆管癌的上述各项方法和用途技术方案。Therefore, in a preferred embodiment of this aspect, the present invention provides each of the above methods and uses for treating or preventing cancer or tumors by inhibiting KRas mutation or amplification. In a further preferred embodiment, the present invention provides the above methods and application technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and cholangiocarcinoma by inhibiting KRas mutation or amplification.
本发明还提供了本发明的化合物、优选其药学上可接受的盐或溶剂合物在研究中作为KRas抑制剂(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增抑制剂)的研究工具化合物的用途。因此，本发明涉及本发明化合物、优选其药学上可接受的盐或溶剂合物作为KRas抑制剂的体外用途，特别地涉及本发明化合物、优选其药学上可接受的盐或溶剂合物作为KRas抑制剂起效的研究 工具化合物的体外用途。本发明同样涉及抑制KRas(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变、Q61H突变及KRAS扩增)的方法，特别是体外方法，该方法包括将本发明的化合物、优选其药学上可接受的盐或溶剂合物施用于样品(例如生物样品)。。应理解，术语“体外”在该特定上下文中以“活的人体或动物体外”的含义使用，其具体包括用细胞、细胞或亚细胞提取物和/或人工环境中的生物分子进行的实验，例如可以在烧瓶、试管、培养皿、微量滴定板等中提供的水溶液或培养基。The invention also provides compounds of the invention, preferably pharmaceutically acceptable salts or solvates thereof, in studies as KRas inhibitors (e.g. G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutations, Q61H mutations and KRAS amplification inhibitors). Therefore, the present invention relates to the in vitro use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a KRas inhibitor, and in particular to the use of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, as a KRas inhibitor. Studies on the effectiveness of inhibitors In vitro uses of tool compounds. The present invention also relates to methods for inhibiting KRas (such as G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, G13D mutation, Q61H mutation and KRAS amplification), especially in vitro methods, the method comprising The compound, preferably a pharmaceutically acceptable salt or solvate thereof, is administered to a sample (eg, a biological sample). . It is understood that the term "in vitro" is used in this particular context in the sense of "in vitro in living humans or animals", which specifically includes experiments with cells, cellular or subcellular extracts and/or biomolecules in artificial environments, For example, an aqueous solution or culture medium may be provided in a flask, test tube, petri dish, microtiter plate, etc.
药物组合drug combination
本发明的化合物可以作为唯一的活性成分进行施用，也可以与另外的药物或疗法组合进行施用。The compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies.
因此，另一方面，本发明提供了药物组合，其包含本发明的化合物、优选其药学上可接受的盐或溶剂合物以及其他活性剂，或由二者组成。该药物组合用于抑制哺乳动物中异常细胞生长，或用于治疗和/或预防由Ras突变、优选KRas突变(例如G12C突变、G12D突变、G12V突变、G12A突变、G12R突变、G12S突变、G13D突变和Q61H突变)及KRAS扩增介导的疾病。Thus, in another aspect, the invention provides pharmaceutical combinations comprising or consisting of a compound of the invention, preferably a pharmaceutically acceptable salt or solvate thereof, and other active agents. The pharmaceutical combination is used to inhibit abnormal cell growth in mammals, or to treat and/or prevent mutations caused by Ras mutations, preferably KRas mutations (such as G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, G13D mutations). and Q61H mutations) and KRAS amplification-mediated diseases.
所述其他活性剂可以是一种或多种另外的本发明化合物，或可以是与本发明化合物相容即不会相互不利影响、或具有互补活性的第二种或另外的(例如第三种)化合物，例如这些活性剂可以是已知调节其他生物活性通路的化合物，或者可以是调节本发明化合物所涉及生物活性通路中的不同组分的化合物，或甚至是与本发明化合物的生物靶点相重叠的化合物。The other active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., a third) compound that is compatible with the compound of the invention, that is, does not adversely affect each other, or has complementary activity. ) compounds, for example, these active agents can be compounds known to modulate other biologically active pathways, or can be compounds that modulate different components in the biologically active pathways involved in the compounds of the present invention, or even biological targets related to the compounds of the present invention. Overlapping compounds.
在一个具体的实施方案中，可以与本发明化合物组合使用的其他活性剂包括但不限于化疗剂、治疗性抗体和放疗，例如烷化剂、抗代谢物、细胞周期抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂、抗激素类药物、血管生成抑制剂、细胞毒性剂。In a specific embodiment, other active agents that may be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiotherapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, Topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents.
与本发明组合使用的其他活性剂可以与本发明的化合物通过相同或不同的施用途径同时、分别或依次地进行施用。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，例如组合产品,优选为药盒形式，当分别施用时可以同时或相继进行，所述相继施用在时间上可以是接近或隔远的。它们可以由相同或不同的制造商制备和/或配制。而且，本发明的化合物和其他活性剂可以(i)在将组合产品发送给医师之前(例如在包含本发明的化合物和另外的药物的药盒的情形中)；(ii)在临施用前由医师自身(或在医师指导下)；(iii)由患者自身、例如在本发明的化合物和其他活性剂的依次施用期间一起加入组合治疗中。Other active agents used in combination with the invention may be administered simultaneously, separately or sequentially with the compounds of the invention by the same or different routes of administration. The other active agents may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered separately from the compound of the present invention in different discrete units, such as a combination product, preferably in the form of a kit, and when administered separately may be simultaneously or Performed sequentially, the successive administrations may be close or distant in time. They may be prepared and/or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other active agents may be administered (i) before the combination product is sent to the physician (for example, in the case of a kit containing a compound of the present invention and an additional drug); (ii) immediately before administration. The physician himself (or under the direction of the physician); (iii) the patient himself, for example, during the sequential administration of a compound of the invention and other active agents together in the combination therapy.
本发明的化合物还可以与抗肿瘤疗法组合，所述抗肿瘤疗法包括但不限于手术、辐射治疗、移植(例如干细胞移植、骨髓移植)、肿瘤免疫疗法和化疗等。The compounds of the present invention can also be combined with anti-tumor therapies, including but not limited to surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
因此，另一方面，本发明还提供了药盒，其包含两种或多种单独的药物组合物，其中至少一种包含本发明的化合物或其药学上可接受的盐或溶剂合物，以及分别容纳所述组合物的装置，如容器、分装瓶或分立的箔包装，例如用于包装片剂、胶囊等的泡罩包装，还包括使 用说明书。本发明的药盒特别适用于施用不同的剂型，如口服剂型和胃肠外剂型，或者适合于以不同的剂量间隔施用不同的组合物。Accordingly, in another aspect, the invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and Devices for separately containing the compositions, such as containers, portion bottles or discrete foil packages, such as blister packs for packaging tablets, capsules, etc., also including Use instructions. The kit of the invention is particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, or for administering different compositions at different dosage intervals.
对于上述本发明的药物组合物、药物组合或药盒的技术方案而言，其中所涉及的异常细胞生长或由Ras突变、尤其KRas突变、优选KRas G12C、KRas G12D、KRas G12V、KRas G12A、KRas G12R、KRas G12S或KRas G13D、或KRas Q61H突变，及KRAS扩增介导的疾病如上文对于本发明方法和用途所定义。For the technical solutions of the above-mentioned pharmaceutical compositions, pharmaceutical combinations or kits of the present invention, the abnormal cell growth involved may be caused by Ras mutations, especially KRas mutations, preferably KRas G12C, KRas G12D, KRas G12V, KRas G12A, KRas G12R, KRas G12S or KRas G13D, or KRas Q61H mutations, and KRAS amplification-mediated diseases are as defined above for the methods and uses of the invention.
对于上述本发明化合物、药物组合物、方法、用途、药物组合及药盒而言，优选本文实施例的化合物。For the compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits of the invention described above, the compounds of the examples herein are preferred.
本发明化合物的制备方法Preparation methods of compounds of the present invention
另一方面，本发明还提供了本发明所定义化合物的制备方法。On the other hand, the present invention also provides methods for preparing the compounds defined in the present invention.
本发明的化合物可以通过多种方法、包括下文给出的通用方法、实施例中公开的方法或与之类似的方法制备。The compounds of the present invention can be prepared by a variety of methods, including the general methods given below, the methods disclosed in the examples, or methods similar thereto.
用于制备有机化合物和官能团转化和操作的标准合成方法和操作是本领域已知的并且可以在标准教科书中找到，例如Smith M.B.,“March’s Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”,第7版,Wiley,2013)。对于各通用合成方案的各个反应步骤而言，适当的反应条件是本领域技术人员已知的或可以常规确定的。用于合成本发明化合物的方法步骤可以在本身已知的反应条件(包括具体提及的那些条件)下、在不存在或通常在存在溶剂或稀释剂(包括例如对所用试剂而言是惰性的且可溶解所用试剂的溶剂或稀释剂)的情况下、在不存在或存在催化剂、缩合剂或中和剂(例如离子交换剂，如阳离子交换剂，例如H+形式)的情况下、根据反应和/或反应物的性质在降低的、正常的或升高的温度(例如约-100℃至约190℃，包括例如约-78℃至约150℃，例如约0℃至约125℃、室温、-20至40℃或回流温度)下、在大气压力下或在密闭容器中、当适宜时在加压下、和/或在惰性气氛例如氩气或氮气气氛下进行。Standard synthetic methods and procedures for the preparation of organic compounds and functional group transformations and manipulations are known in the art and can be found in standard textbooks, such as Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Vol. Edition, Wiley, 2013). Appropriate reaction conditions for the individual reaction steps of each general synthetic scheme are known to or can be routinely determined by those skilled in the art. The process steps for the synthesis of the compounds of the invention may be carried out under reaction conditions known per se, including those specifically mentioned, in the absence or usually in the presence of solvents or diluents, including e.g. inert to the reagents used. and can dissolve the reagents used), in the absence or presence of catalysts, condensing agents or neutralizing agents (such as ion exchangers, such as cation exchangers, such as H + form), according to the reaction and/or the properties of the reactants at reduced, normal or elevated temperatures (e.g., from about -100°C to about 190°C, including, for example, from about -78°C to about 150°C, such as from about 0°C to about 125°C, room temperature , -20 to 40° C. or reflux temperature), under atmospheric pressure or in a closed container, under pressure when appropriate, and/or under an inert atmosphere such as argon or nitrogen.
如果没有特别说明，在制备化合物中使用的原料和试剂是商购可获得的，或文献中已知的化合物，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的标准方法由本领域技术人员制得。除非在方法描述中另有说明，否则可以适用的溶剂是本领域技术人员熟知的适用于所涉及具体反应类型的那些常规溶剂，例如水、酯类、醚类、液体芳族烃类、醇类、腈类、卤化烃类、酰胺类、碱类、羧酸酐类、环状、直链或支链烃类，或这些溶剂的混合物。该类溶剂混合物也可用于后处理，例如通过色谱法或分配进行的后处理。If not specifically stated, the raw materials and reagents used in the preparation of the compounds are commercially available, or compounds known in the literature, or can be obtained by the methods below, methods similar to the methods given below, or known in the art. Standard methods are prepared by those skilled in the art. Unless otherwise stated in the process description, suitable solvents are those conventional solvents known to those skilled in the art to be suitable for the specific reaction type involved, for example water, esters, ethers, liquid aromatic hydrocarbons, alcohols , nitriles, halogenated hydrocarbons, amides, bases, carboxylic anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for work-up, for example by chromatography or partitioning.
如果需要，合成反应流程中的原料和中间体可以采用常规技术进行分离和纯化，所述技术包括但不限于过滤、蒸馏、结晶、色谱法等。如果中间体和终产物以固体形式获得，则纯化也可以通过重结晶或陈化来进行。所述材料可以采用包括物理常数和波谱数据在内的常规方法表征。反应混合物以常规方式后处理，例如通过与水混合，分离各相，并在适当时通过色谱法纯化粗产物来进行。 If necessary, the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging. The materials can be characterized using conventional methods including physical constants and spectral data. The reaction mixture is worked up in a customary manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography.
本领域技术人员能认识到本发明化合物中是否存在立体中心。在反应的所有阶段，所形成的异构体的混合物可被分离成单个异构体，例如非对映异构体或对映异构体，或者分离成任何所需的异构体混合物，例如外消旋物或非对映异构体的混合物，参见例如E.L.Eliel,S.H.Wilen和L.N.Mander的“Stereochemistry of Organic Compounds”(Wiley-Interscience,1994)。One skilled in the art will recognize the presence or absence of stereogenic centers in the compounds of the present invention. At all stages of the reaction, the mixture of isomers formed can be separated into the individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, e.g. Racemates or mixtures of diastereomers, see for example "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).
在制备本发明化合物的过程中产生立体异构体混合物的情况下，本发明化合物的单个立体异构体可以通过拆分获得，例如，通过从作为立体异构体混合物获得的本发明化合物开始，使用众所周知的方法，例如形成非对映体对，通过与旋光酸成盐，然后分级结晶和再生游离碱，或通过手性制备型色谱法；或者，可以使用具有既定立体化学的原料或中间体、或者可以使用任何已知的手性拆分方法获得光学纯的或对映体富集的合成中间体，然后可以在上述合成过程的各个阶段将其原样用于后续步骤。In the case where a mixture of stereoisomers is produced during the preparation of a compound of the invention, the individual stereoisomers of the compound of the invention can be obtained by resolution, for example, by starting from a compound of the invention obtained as a mixture of stereoisomers, Well-known methods are used, such as formation of diastereomeric pairs by salt formation with optically active acids followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography; alternatively, starting materials or intermediates with established stereochemistry can be used , or any known chiral resolution method can be used to obtain optically pure or enantiomerically enriched synthetic intermediates, which can then be used as such in subsequent steps at various stages of the above synthetic process.
在某些特定情况下，可能有必要使用适当的保护基团保护特定的反应基团，以避免干扰其他反应性基团的反应。适合的保护基和采用这样的适合保护基进行保护和脱保护的方法是本领域技术人员众所周知的；其实例可以见于T.Greene和P.Wuts,Protective Groups in Organic Synthesis(第3版),John Wiley&Sons,NY(1999)中。In some specific cases, it may be necessary to protect specific reactive groups with appropriate protecting groups to avoid interfering with the reactions of other reactive groups. Suitable protecting groups and methods for protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples may be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
下文仅举例说明合成本发明化合物的通用合成方案。本领域普通技术人员已知的其他路线以及其他反应物和中间体也可以用于得到本发明的化合物。The following merely illustrates a general synthetic scheme for the synthesis of the compounds of the present invention. Other routes as well as other reactants and intermediates known to those of ordinary skill in the art may also be used to obtain the compounds of the invention.
为了清楚起见，在以下所述的示例性合成方案中，如无特别说明，各个中间体化合物结构式中出现的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Y、Z、n、m和t如上文对本发明化合物所定义，其中PG代表可由本领域技术人员基于有机化学知识确定的适合保护基。For the sake of clarity, in the exemplary synthesis scheme described below, unless otherwise specified, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R appearing in the structural formula of each intermediate compound 8 , R9 , R10 ,
合成方案ASynthesis Plan A
本发明化合物的合成可以根据以下方案或其适当的变体制备。
The synthesis of the compounds of the present invention can be prepared according to the following schemes or appropriate variations thereof.
在步骤A中，化合物1商购可得、或可以按照本文实施例所使用的方法或与其类似的方法得到。使化合物1通过芳香亲核取代反应引入片段B-(R8)t，得到化合物2。典型的芳香亲核取代条件为本领域熟知，例如DIEA/THF等。In step A, compound 1 is commercially available or can be obtained according to the method used in the examples herein or a method similar thereto. Compound 1 is introduced into fragment B-(R 8 ) t through an aromatic nucleophilic substitution reaction to obtain compound 2. Typical aromatic nucleophilic substitution conditions are well known in the art, such as DIEA/THF, etc.
在步骤B中，使化合物2与相应的胺类化合物、在例如DIEA/二氧六环等条件下反应，得到化合物3或者4。其中相应的胺类化合物商购可得，或可以按照本文实施例所使用的方法或与其类似的方法得到，还可以按照有机化学领域相关文献方法得到。后者在步骤C中通过Suzuki-Miyaura偶联反应引入萘或者苯并噻吩类化合物，得到化合物5或者6或者7或者8。在步骤D中，将化合物5～8脱除所带保护基，得到通式I-A-1、I-B-1、I-A-4和I-B-4的化合物。In step B, compound 2 is reacted with the corresponding amine compound under conditions such as DIEA/dioxane to obtain compound 3 or 4. The corresponding amine compounds are commercially available, or can be obtained according to the methods used in the examples herein or methods similar to them, or can be obtained according to the methods of relevant literature in the field of organic chemistry. The latter introduces naphthalene or benzothiophene compounds through Suzuki-Miyaura coupling reaction in step C to obtain compounds 5 or 6 or 7 or 8. In step D, the protective groups of compounds 5 to 8 are removed to obtain compounds of general formulas I-A-1, I-B-1, I-A-4 and I-B-4.
典型的Suzuki-Miyaura偶联条件为本领域众所周知的，且本领域技术人员了解用于促进这类交叉偶联反应的多种条件，典型条件例如Pd(dtbpf)Cl2/K3PO4/二氧六环/水，或者Pd(OAc)2/rac-BIDIME/K2CO3/甲苯；适合的钯催化剂还包括XantPhos Pd G2、A Pd G3、氯化双(三苯膦)钯(II)、Pd(dppf)Cl2、Pd2dba3、四苯膦钯和乙酸钯(II)等；如果需要，适合的配体可以包括三环己膦和三苯膦等；适合的碱还包括氟化钾、碳酸铯、碳酸钠、叔丁醇钾和磷酸钾一水合物等。Typical Suzuki-Miyaura coupling conditions are well known in the art, and those skilled in the art are aware of a variety of conditions for promoting such cross-coupling reactions, typical conditions such as Pd(dtbpf)Cl 2 /K 3 PO 4 /di Oxygen/water, or Pd(OAc) 2 /rac-BIDIME/K 2 CO 3 /toluene; suitable palladium catalysts also include XantPhos Pd G2, A Pd G3, bis(triphenylphosphine)palladium(II) chloride, Pd(dppf)Cl 2 , Pd 2 dba 3 , tetraphenylphosphine palladium and palladium acetate (II), etc.; if necessary, suitable ligands may include Tricyclohexylphosphine, triphenylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide, potassium phosphate monohydrate, etc.
需要说明的是，步骤D中保护基的脱除，可以根据分子所携带的保护基进行调整，可以是一步反应，也可以是多步反应。例如，当化合物W为OH，所携带保护基PG为TIPS时，可通过例如CsF等试剂进行脱除。It should be noted that the removal of the protecting group in step D can be adjusted according to the protecting group carried by the molecule, and can be a one-step reaction or a multi-step reaction. For example, when compound W is OH and the protective group PG carried is TIPS, it can be removed by reagents such as CsF.
本发明的通式为I-A-2、I-B-2、I-A-3、I-B-3的化合物的合成可由本领域技术人员参照上述方案类似地进行。 The synthesis of the compounds of the present invention with the general formulas IA-2, IB-2, IA-3, and IB-3 can be carried out similarly by those skilled in the art with reference to the above scheme.
合成方案BSynthesis Plan B
本发明的通式I-A和I-B化合物的合成还可以根据以下方案或其适当的变体制备。
The synthesis of the compounds of general formulas IA and IB of the present invention can also be prepared according to the following schemes or appropriate variations thereof.
在步骤A中，化合物2可以按照合成方案A所述的方法步骤得到。使化合物2通过卤素交换反应、在例如KF/DMSO或KF/MsOH/DABCO/DMSO等条件下进行氟代，得到化合物9。化合物9再依次经过步骤B的Suzuki-Miyaura偶联反应、步骤C的芳香亲核取代反应及步骤D的保护基脱除反应，得到最终化合物I-A-1、I-B-1、I-A-4和I-B-4。此方案中涉及的Suzuki-Miyaura偶联反应、亲核取代反应及保护基脱除反应的典型条件为本领域熟知，且可参照合成方案A中所述相关反应条件类似进行。In step A, compound 2 can be obtained according to the method steps described in synthetic scheme A. Compound 2 is fluorinated through a halogen exchange reaction under conditions such as KF/DMSO or KF/MsOH/DABCO/DMSO to obtain compound 9. Compound 9 then undergoes the Suzuki-Miyaura coupling reaction in step B, the aromatic nucleophilic substitution reaction in step C, and the protecting group removal reaction in step D to obtain the final compounds I-A-1, I-B-1, I-A-4 and I-B- 4. The typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protecting group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.
本发明的通式为I-A-2、I-B-2、I-A-3、I-B-3的化合物的合成可由本领域技术人员参照上述方案进行。The synthesis of the compounds of the general formulas I-A-2, I-B-2, I-A-3 and I-B-3 of the present invention can be carried out by those skilled in the art with reference to the above scheme.
本发明的通式为I-C和I-D的化合物的合成可由本领域技术人员采用适合的原料、参照上述方案进行，或通过以下方案C所示进行。The synthesis of the compounds of the general formulas I-C and I-D of the present invention can be carried out by those skilled in the art using suitable raw materials and referring to the above scheme, or as shown in Scheme C below.
合成方案CSynthesis Scheme C
本发明的通式I-C和I-D化合物的合成根据以下方案或其适当的变体制备。
The synthesis of compounds of general formulas IC and ID of the present invention is prepared according to the following schemes or appropriate variations thereof.
化合物9可以商业化购得、可参照文献报道或本发明提供合成方案及适当变体获得。在步骤A中，化合物9在例如缩合剂BOP等条件下，通过缩合反应引入片段B-(R8)t，得到化合物10。在步骤B中，化合物10通过Suzuki-Miyaura偶联反应引入萘或者苯并噻吩类化合物，得到化合物11或者12。在步骤C中，化合物11或者12中硫醚经氧化得到亚砜或砜、或亚砜和砜的混合物，得到化合13或者14。后在在步骤D中通过芳香亲核取代反应引入Y-Q基团得到化合物15或者16。在步骤E中，化合物15或者16脱除可能带有的保护基得到通式为I-C或者I-D的化合物。此方案中涉及的Suzuki-Miyaura偶联反应、亲核取代反应及保护基脱除反应的典型条件为本领域熟知，且可参照合成方案A中所述相关反应条件类似进行。Compound 9 can be purchased commercially, and can be obtained by referring to literature reports or the synthesis scheme and appropriate variations provided by this invention. In step A, compound 9 introduces fragment B-(R 8 ) t through a condensation reaction under conditions such as condensation agent BOP to obtain compound 10. In step B, compound 10 is introduced into naphthalene or benzothiophene compounds through Suzuki-Miyaura coupling reaction to obtain compound 11 or 12. In step C, the thioether in compound 11 or 12 is oxidized to obtain sulfoxide or sulfone, or a mixture of sulfoxide and sulfone, to obtain compound 13 or 14. Then, in step D, the YQ group is introduced through aromatic nucleophilic substitution reaction to obtain compound 15 or 16. In step E, compound 15 or 16 removes possible protective groups to obtain a compound of general formula IC or ID. The typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and protecting group removal reaction involved in this scheme are well known in the art, and can be carried out similarly with reference to the relevant reaction conditions described in Synthesis Scheme A.
合成实施例Synthesis Example
以下结合实施例对本发明作进一步的说明。需要说明的是，下述实施例是示例性的，不应视为对本发明保护范围的限制。The present invention will be further described below in conjunction with the examples. It should be noted that the following examples are exemplary and should not be regarded as limiting the scope of the present invention.
本文在对实施方案和随后的具体实施例的描述中，使用了以下缩写：In the description of the embodiments and the specific examples that follow, the following abbreviations are used herein:
ACN(乙腈)；Boc(叔丁氧基羰基)；BOP(六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷)；CDCl3(氘代氯仿)；cataCXium A Pd G3(甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II))；DABCO(1,4-二氮杂二环[2.2.2]辛烷)；DCM(二氯甲烷)；DIEA或者DIPEA(N,N-二异丙基乙胺)；DMF(N,N-二甲基甲酰胺)；DMSO(二甲亚砜)；DMSO-d6(六氘代二甲亚砜)；EA或EtOAc(乙酸乙酯)；EDTA-K2(乙二胺四乙酸二钾盐)；EtOH(乙醇)；FCC(快速柱层析)； g(克)；h(小时)；HCl(氯化氢)；HCl-MeOH或者HCl/MeOH(氯化氢甲醇溶液)；HLM(人肝微粒体)；H2O(水)；H2SO4(硫酸)；IV(静脉给药)；K2CO3(碳酸钾)；LCMS(液质联机)；LC-MS/MS(液谱-质谱-质谱联机)；MeOH(甲醇)；Methanol-d4(四氘代甲醇)；mg(毫克)；MHz(兆赫兹)；min(分钟)；mL(毫升)；mmol(毫摩尔)；MOM(甲氧基甲基醚)；MsOH(甲磺酸)；MTBE(甲基叔丁基醚)；m/z(质荷比)；N2(氮气)；NaCl(氯化钠)；NaH(氢化钠)；NaHCO3(碳酸氢钠)；Na2SO3(亚硫酸钠)；Na2SO4(硫酸钠)；NCS(氯代丁二酰亚胺)；NH4Cl(氯化铵)；NMR(核磁共振)；PdCl2(dtbpf)或者Pd(dtbpf)Cl2(1,1'-二(二叔丁基膦)二茂铁二氯化钯)；PdCl2(dppf)或者Pd(dppf)Cl2(1,1'-双二苯基膦二茂铁二氯化钯)；Pd(OAc)(醋酸钯)；Pd(PPh3)4(四三苯基膦钯)；PE(石油醚)；PO或po(口服给药)；POCl3(三氯氧磷)；r.t.(室温)；Selectfluor(1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐)；SiO2(硅胶)；TEA(三乙胺)；TFA(三氟乙酸)；THF(四氢呋喃)；TIPS(三异丙基甲硅烷基)；TLC(薄层色谱)；TsOH(对甲苯磺酸)；TsOH·H2O(对甲苯磺酸一水合物)；μL(微升)；μM(微摩尔浓度)；μmol(微摩尔)。ACN (acetonitrile); Boc (tert-butoxycarbonyl); BOP (benzotriazole-1-oxytris(dimethylamino)phosphorus hexafluorophosphate); CDCl 3 (deuterated chloroform); cataCXium A Pd G 3 (Methanesulfonate[n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)); DABCO(1,4-diaza Bicyclo[2.2.2]octane); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMSO (dimethylformamide) Methyl sulfoxide); DMSO-d 6 (hexadeuterated dimethyl sulfoxide); EA or EtOAc (ethyl acetate); EDTA-K2 (ethylenediaminetetraacetic acid dipotassium salt); EtOH (ethanol); FCC (fast column chromatography); g (grams); h (hours); HCl (hydrogen chloride); HCl-MeOH or HCl/MeOH (hydrogen chloride in methanol solution); HLM (human liver microsomes); H 2 O (water); H 2 SO 4 (sulfuric acid) ; IV (intravenous administration); K 2 CO 3 (potassium carbonate); LCMS (liquid mass spectrometry); LC-MS/MS (liquid spectrometry-mass spectrometry-mass spectrometry); MeOH (methanol); Methanol-d 4 (tetrahydrofuran) Deuterated methanol); mg (milligram); MHz (megahertz); min (minutes); mL (ml); mmol (millimol); MOM (methoxymethyl ether); MsOH (methane sulfonic acid); MTBE (Methyl tert-butyl ether); m/z (mass-to-charge ratio); N 2 (nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO 3 (sodium bicarbonate); Na 2 SO 3 ( Sodium sulfite); Na 2 SO 4 (sodium sulfate); NCS (chlorosuccinimide); NH 4 Cl (ammonium chloride); NMR (nuclear magnetic resonance); PdCl 2 (dtbpf) or Pd(dtbpf)Cl 2 (1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride); PdCl 2 (dppf) or Pd(dppf)Cl 2 (1,1'-bisdiphenylphosphine ferrocene dichloride) Palladium chloride); Pd(OAc) (palladium acetate); Pd(PPh 3 ) 4 (tetrakis triphenylphosphine palladium); PE (petroleum ether); PO or po (oral administration); POCl 3 (trichloroxy Phosphorus); rt (room temperature); Selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) salt); SiO 2 (silica gel); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIPS (triisopropylsilyl); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); TsOH·H 2 O (p-toluenesulfonic acid monohydrate); μL (microliter); μM (micromolar concentration); μmol (micromol).
在如下实施例中，给出了所合成目标化合物的名称及其结构。名称与结构之间出现任何偏差并非有意，在这种情况下，结构为决定性的。In the following examples, the name of the synthesized target compound and its structure are given. Any deviation between name and structure is not intentional and in this case structure is decisive.
下列实施例中未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。除非另外说明，否则液体的比为体积比。Experimental methods without specifying specific conditions in the following examples usually follow the conventional conditions for this type of reaction, or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless stated otherwise, ratios of liquids are by volume.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得、依据现有技术的方法制得或根据与本申请公开的类似的方法制得。Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.
在下列实施例中，1H-NMR谱是用Bruker(400MHz)记录，化学位移以相对于氘代溶剂峰(CDCl3:δ＝7.26ppm；CD3OD:δ＝3.31ppm；DMSO-d6:δ＝2.50ppm)的δ(ppm)表示；液质联用是用Aglient 1260液相色谱+Aglient G6125B质谱LCMS液质联用仪记录。气相色谱质谱联用仪使用Shimadzu GCMS-QP2010SE进行检测。In the following examples, 1 H-NMR spectra were recorded with a Bruker (400 MHz), and chemical shifts were expressed relative to the deuterated solvent peak (CDCl 3 : δ = 7.26 ppm; CD 3 OD: δ = 3.31 ppm; DMSO-d 6 :δ=2.50ppm) expressed in δ (ppm); the liquid mass spectrometry was recorded using Aglient 1260 liquid chromatography + Aglient G6125B mass spectrometry LCMS liquid mass spectrometry instrument. The gas chromatography mass spectrometer used Shimadzu GCMS-QP2010SE for detection.
中间体A
Intermediate A
7-溴-2,4-二氯-8-氟喹唑啉
7-bromo-2,4-dichloro-8-fluoroquinazoline
步骤A：7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮Step A: 7-Bromo-8-fluoroquinazoline-2,4(1H,3H)-dione
在室温条件下，将2-氨基-4-溴-3-氟苯甲酸(10.0g,42.7mmol)和尿素(25.7g,427.3mmol)混合在一起，升温到200℃，搅拌2h。反应逐渐由固态转变为液态，然后再继续转变为固态，LCMS监测反应结束后，用热水(250mL)洗涤，过滤收集固体，得到7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(12g,粗品)。LCMS(ESI,m/z):258.9(M+H)。At room temperature, 2-amino-4-bromo-3-fluorobenzoic acid (10.0g, 42.7mmol) and urea (25.7g, 427.3mmol) were mixed together, heated to 200°C, and stirred for 2 hours. The reaction gradually changed from solid state to liquid state, and then continued to change to solid state. After the reaction was monitored by LCMS, it was washed with hot water (250 mL), and the solid was collected by filtration to obtain 7-bromo-8-fluoroquinazoline-2,4(1H ,3H)-diketone (12g, crude product). LCMS(ESI,m/z):258.9(M+H).
步骤B：7-溴-2,4-二氯-8-氟喹唑啉Step B: 7-bromo-2,4-dichloro-8-fluoroquinazoline
在室温条件下，将DIPEA(13.5mL,77.2mmol)加入到7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(4.0g,15.4mmol)和POCl3(35.9mL,386.0mmol)的混合液中，升温到100℃搅拌5h。LCMS监测反应结束后，浓缩除去大部分溶剂和碱，加入ACN(10mL)稀释。室温搅拌下，将所得稀释液慢慢滴加到水中，析出固体，过滤，烘干后，得到黄色固体7-溴-2,4-二氯-8-氟喹唑啉(3.8g,收率83％)。LCMS(ESI,m/z):296.8(M+H)。DIPEA (13.5 mL, 77.2 mmol) was added to 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.0 g, 15.4 mmol) and POCl 3 (35.9 mL, 386.0 mmol), the temperature was raised to 100°C and stirred for 5 hours. After monitoring the reaction with LCMS, concentrate to remove most of the solvent and alkali, and add ACN (10 mL) to dilute. With stirring at room temperature, the obtained dilution was slowly added dropwise to the water to precipitate the solid, filtered, and dried to obtain a yellow solid 7-bromo-2,4-dichloro-8-fluoroquinazoline (3.8g, yield 83%). LCMS(ESI,m/z):296.8(M+H).
中间体B
Intermediate B
7-溴-2,4-二氯-6,8-二氟喹唑啉
7-Bromo-2,4-dichloro-6,8-difluoroquinazoline
步骤A：4-溴-3,5-二氟-2-(3-(2,2,2-三氯乙酰基)脲基)苯甲酸甲酯Step A: Methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate
室温下，在置有搅拌子的圆底烧瓶中加入2-氨基-4-溴-3,5-二氟苯甲酸甲酯(10g,37.6mmol)和THF(100mL)。室温搅拌下向体系中滴加2,2,2-三氯乙酰异氰酸酯(8.5g,45.1mmol)。所得混合物室温搅拌2小时，减压浓缩，得到棕色固体4-溴-3,5-二氟-2-(3-(2,2,2-三氯乙酰基)脲基)苯甲酸甲酯(粗品)，直接用于下一步。LCMS(ESI,m/z):452.8(M+H)。At room temperature, 2-amino-4-bromo-3,5-difluorobenzoic acid methyl ester (10 g, 37.6 mmol) and THF (100 mL) were added to a round-bottomed flask equipped with a stirrer. 2,2,2-trichloroacetyl isocyanate (8.5g, 45.1mmol) was added dropwise to the system with stirring at room temperature. The resulting mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester ( crude product) and used directly in the next step. LCMS(ESI,m/z):452.8(M+H).
步骤B：7-溴-6,8-二氟喹唑啉-2,4-二醇Step B: 7-bromo-6,8-difluoroquinazoline-2,4-diol
室温下，将上步所得4-溴-3,5-二氟-2-(3-(2,2,2-三氯乙酰基)脲基)苯甲酸甲酯加入置有搅拌子的圆底烧瓶中加入，再加入NH3(100mL,7M MeOH溶液)。将所得混合物在室温搅拌2小时，LCMS监测反应完全。减压浓缩，将所得固体用甲基叔丁基醚打浆，过滤，得到淡黄色固体7-溴-6,8-二氟喹唑啉-2,4-二醇(14g,粗品)，无需进一步纯化，直接用于下一步。LCMS(ESI,m/z):277.0(M+H)。At room temperature, add 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoic acid methyl ester obtained in the previous step to a round bottom equipped with a stirrer. The flask was added, followed by NH3 (100 mL, 7M MeOH solution). The resulting mixture was stirred at room temperature for 2 hours and the reaction was monitored by LCMS to be complete. Concentrate under reduced pressure, beat the obtained solid with methyl tert-butyl ether, and filter to obtain a light yellow solid 7-bromo-6,8-difluoroquinazoline-2,4-diol (14g, crude product) without further processing. Purified and used directly in the next step. LCMS(ESI,m/z):277.0(M+H).
步骤C：7-溴-2,4-二氯-6,8-二氟喹唑啉 Step C: 7-bromo-2,4-dichloro-6,8-difluoroquinazoline
在置有搅拌子的圆底烧瓶中加入7-溴-6,8-二氟喹唑啉-2,4-二醇(14g,粗品)、POCl3(112mL)。室温下搅拌下，向体系中滴加DIEA(28mL)。滴加完毕后，将体系升温至110℃搅拌反应过夜。将反应液减压浓缩至约30mL，倒入水(600mL)中，析出沉淀过滤收集，干燥后，得到黄色固体7-溴-2,4-二氯-6,8-二氟喹唑啉(11g,粗品)，直接用于后续反应。LCMS(ESI,m/z):312.9(M+H)。Add 7-bromo-6,8-difluoroquinazoline-2,4-diol (14g, crude product) and POCl 3 (112mL) into a round-bottomed flask equipped with a stirrer. While stirring at room temperature, DIEA (28 mL) was added dropwise to the system. After the dropwise addition was completed, the system was heated to 110°C and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure to about 30 mL, poured into water (600 mL), and the precipitated precipitate was filtered and collected. After drying, a yellow solid 7-bromo-2,4-dichloro-6,8-difluoroquinazoline ( 11g, crude product), which was directly used in subsequent reactions. LCMS(ESI,m/z):312.9(M+H).
根据上述合成方法制备以下中间体：
The following intermediates are prepared according to the above synthetic method:
中间体G
Intermediate G
7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇
7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
步骤A：4,6-二氯-5-氟烟酰氯Step A: 4,6-dichloro-5-fluoronicotinic acid chloride
在室温搅拌下，将氯化亚砜(2.25mL,31mmol)缓慢加入到4,6-二氯-5-氟烟酸(5.0g,23.4mmol)的DCM(100mL)溶液中，后加入DMF(175mg,2.4mmol)。将所得反应液在50℃下搅拌2h。TLC监测反应完全后，浓缩，加入少量甲苯带蒸后，得到黄色固体4,6-二氯-5-氟烟酰氯(4.5g,收率83％)，直接用于后续反应。 Under stirring at room temperature, thionyl chloride (2.25 mL, 31 mmol) was slowly added to a solution of 4,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.4 mmol) in DCM (100 mL), and then DMF ( 175 mg, 2.4 mmol). The resulting reaction solution was stirred at 50°C for 2 h. After TLC monitoring, the reaction was completed, concentrated, and a small amount of toluene was added and steamed to obtain a yellow solid 4,6-dichloro-5-fluoronicotinic acid chloride (4.5g, yield 83%), which was directly used in subsequent reactions.
步骤B：(4,6-二氯-5-氟烟酰基)氨基甲酰亚胺硫代甲酯Step B: (4,6-Dichloro-5-fluoronicotinoyl)carbaimidothiomethyl ester
在0℃搅拌下，将4,6-二氯-5-氟烟碱酰氯(4.5g,19.8mmol)与乙二醇二甲醚(20ml)的混合溶液缓慢滴加入2-甲基异硫脲硫酸(15g,49.5mmol)与1M NaOH水溶液(70ml)的混合溶液中，保持温度搅拌1h。将析出的固体沉淀物过滤、干燥，得到产物(4,6-二氯-5-氟烟酰基)氨基甲酰亚胺硫代甲酯(5.0g,收率90％)。LCMS(m/z):282.1(M+H)。While stirring at 0°C, slowly add 2-methylisothiourea to the mixed solution of 4,6-dichloro-5-fluoronicotinic acid chloride (4.5g, 19.8mmol) and ethylene glycol dimethyl ether (20ml). into a mixed solution of sulfuric acid (15g, 49.5mmol) and 1M NaOH aqueous solution (70ml), maintaining the temperature and stirring for 1h. The precipitated solid precipitate was filtered and dried to obtain the product (4,6-dichloro-5-fluoronicotinoyl)carbaimidothiomethyl ester (5.0 g, yield 90%). LCMS(m/z):282.1(M+H).
步骤C：7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇Step C: 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
将(4,6-二氯-5-氟烟酰基)氨基甲酰亚胺硫代甲酯(5.0g,17.8mmol)溶于DMF(40mL)中，加热至120℃搅拌反应3h。LCMS监测反应完全后，冷至室温，加入水(200mL)。将析出的固体过滤、干燥，得到产物7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(3.6g,收率82％)。LCMS(m/z):245.6(M+H)。Dissolve (4,6-dichloro-5-fluoronicotinoyl)carbaimidothiomethyl ester (5.0g, 17.8mmol) in DMF (40mL), heat to 120°C and stir for 3 hours. After the reaction was monitored by LCMS, it was cooled to room temperature and water (200 mL) was added. The precipitated solid was filtered and dried to obtain the product 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.6 g, yield 82%). LCMS(m/z):245.6(M+H).
中间体I
Intermediate I
7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇
7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
步骤A：2,6-二氯-3-氟吡啶-4-胺Step A: 2,6-Dichloro-3-fluoropyridin-4-amine
在室温下，将Selectfluor(68g,180mmol)加入到2,6-二氯吡啶-4-胺(25g,154mmol)的甲醇/水(V/V＝5:1,300mL)溶液中。所得混合物在50℃下搅拌48h，减压浓缩，乙酸乙酯稀释，依次用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤浓缩，所得粗品经FCC(SiO2，EA/PE＝0-10％)纯化，得到白色固体2,6-二氯-3-氟吡啶-4-胺(10g)。LCMS(m/z):180.9(M+H)。Selectfluor (68 g, 180 mmol) was added to a solution of 2,6-dichloropyridin-4-amine (25 g, 154 mmol) in methanol/water (V/V = 5:1, 300 mL) at room temperature. The resulting mixture was stirred at 50°C for 48 h, concentrated under reduced pressure, diluted with ethyl acetate, washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. After filtration and concentration, the obtained crude product was purified by FCC (SiO 2 , EA/PE=0-10%) to obtain 2,6-dichloro-3-fluoropyridin-4-amine (10g) as a white solid. LCMS(m/z):180.9(M+H).
步骤B：(叔丁氧基羰基)(2,6-二氯-3-氟吡啶-4-基)氨基甲酸叔丁基酯Step B: (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester
室温搅拌下，将4-二甲氨基吡啶(307mg,2.75mmol)、二碳酸二叔丁酯(30g,138mmol)加入到2,6-二氯-3-氟吡啶-4-胺(10g,55mmol)的四氢呋喃(100mL)溶液中。所得混合物加热至60℃搅拌16h，TLC监测反应完成，浓缩，得粗品，经甲醇打浆，得到白色固体(叔丁氧基羰 基)(2,6-二氯-3-氟吡啶-4-基)氨基甲酸叔丁基酯(16g)。LCMS(m/z):381.2(M+H)。Under stirring at room temperature, 4-dimethylaminopyridine (307mg, 2.75mmol) and di-tert-butyl dicarbonate (30g, 138mmol) were added to 2,6-dichloro-3-fluoropyridin-4-amine (10g, 55mmol). ) in tetrahydrofuran (100 mL). The resulting mixture was heated to 60°C and stirred for 16 hours. TLC monitored the completion of the reaction. It was concentrated to obtain a crude product, which was slurried with methanol to obtain a white solid (tert-butoxycarbonyl). (2,6-dichloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (16 g). LCMS(m/z):381.2(M+H).
步骤C：4-((叔丁氧基羰基)氨基)-2,6-二氯-5-氟烟酸叔丁酯Step C: 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester
干冰乙醇浴下，将LDA(2.0M，63mL，126mmol)缓慢加入到(叔丁氧基羰基)(2,6-二氯-3-氟吡啶-4-基)氨基甲酸叔丁基酯(16g,42mmol)的THF(200mL)溶液中，所得混合物保持温度搅拌1h。TLC监测反应完成，加入适量醋酸淬灭反应，用EA稀释，水洗，无水硫酸钠干燥。过滤，浓缩后所得粗品经FCC(SiO2,EA/PE＝0-20％)纯化，得到4-((叔丁氧基羰基)氨基)-2,6-二氯-5-氟烟酸叔丁酯(13g)。Under a dry ice ethanol bath, slowly add LDA (2.0M, 63mL, 126mmol) to (tert-butoxycarbonyl)(2,6-dichloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (16g , 42 mmol) in a solution of THF (200 mL), and the resulting mixture was stirred at temperature for 1 h. TLC monitored the completion of the reaction, added an appropriate amount of acetic acid to quench the reaction, diluted with EA, washed with water, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product obtained was purified by FCC (SiO 2 , EA/PE = 0-20%) to obtain 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert. Butyl ester (13g).
步骤D：4-氨基-2,6-二氯-5-氟烟酸·盐酸盐Step D: 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride
室温条件下将浓盐酸(30ml)加入到4-((叔丁氧基羰基)氨基)-2,6-二氯-5-氟烟酸叔丁酯(13g,34mmol)的二氧六环(90mL)溶液中。所得混合物在室温下搅拌3h。LCMS监测反应完成后，浓缩得到4-氨基-2,6-二氯-5-氟烟酸·盐酸盐(8g)。LCMS(m/z):224.9(M+H)。Concentrated hydrochloric acid (30 ml) was added to dioxane (13 g, 34 mmol) of 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester (13 g, 34 mmol) at room temperature. 90mL) solution. The resulting mixture was stirred at room temperature for 3 h. After the reaction was monitored by LCMS, it was concentrated to obtain 4-amino-2,6-dichloro-5-fluoronicotinic acid hydrochloride (8 g). LCMS(m/z):224.9(M+H).
步骤E：5,7-二氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4-醇Step E: 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol
将4-氨基-2,6-二氯-5-氟烟酸(8g,30.8mmol)与氯化亚砜(200mL)的混合溶液在50℃下搅拌3h。然后浓缩，将残留物溶解在丙酮中(50mL)得到溶液1。在室温下将硫氰酸铵(7g,92mmol)与丙酮溶液(160mL)的混合溶液滴入溶液1中，所得反应液在室温下继续搅拌1h。LCMS监测反应完成后，将反应液倒入水中，过滤，滤饼干燥后，得到5,7-二氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4(3H)-酮(5g)。LCMS(m/z):265.9(M+H)。A mixed solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (8g, 30.8mmol) and thionyl chloride (200mL) was stirred at 50°C for 3h. It was then concentrated and the residue was dissolved in acetone (50 mL) to give solution 1. A mixed solution of ammonium thiocyanate (7g, 92mmol) and acetone solution (160mL) was dropped into solution 1 at room temperature, and the resulting reaction solution was continued to stir at room temperature for 1 hour. After LCMS monitors the completion of the reaction, pour the reaction solution into water, filter, and dry the filter cake to obtain 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidine-4(3H) -Ketone (5g). LCMS(m/z):265.9(M+H).
步骤F：5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇Step F: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
在室温下,将5,7-二氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4-醇(5g,18.8mmol)、甲醇(380mL)、氢氧化钠水溶液(0.1M,380mL,380mmol)及碘甲烷(5.3g,380mmol)的混合溶液搅拌2h。LCMS监测反应完成后，将反应液倒入1000ml水中，用浓盐酸酸化至pH～6。将溶液过滤，滤饼干燥后，得到产物5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(4g).LCMS(m/z):279.9(M+H)。At room temperature, 5,7-dichloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol (5g, 18.8mmol), methanol (380mL), aqueous sodium hydroxide solution ( A mixed solution of 0.1 M, 380 mL, 380 mmol) and methyl iodide (5.3 g, 380 mmol) was stirred for 2 h. After LCMS monitoring of the completion of the reaction, pour the reaction solution into 1000 ml of water and acidify it to pH ~ 6 with concentrated hydrochloric acid. The solution was filtered and the filter cake was dried to obtain the product 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (4g). LCMS (m /z):279.9(M+H).
步骤G：7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇Step G: 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
将5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(6.0g,22mmol)、甲醇钠(10.3g,330mmol)、DMA(100mL)与甲醇(10mL)的混合物在50℃搅拌16h。LCMS监测反应完成后，加水稀释，用浓盐酸调节到pH～3，过滤，收集滤饼，干燥后，得产品7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(5.5g)。LCMS(m/z):276.0(M+H)。5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (6.0g, 22mmol), sodium methoxide (10.3g, 330mmol), DMA (100 mL) and methanol (10 mL) were stirred at 50 °C for 16 h. After LCMS monitors the reaction, add water to dilute it, adjust to pH ~ 3 with concentrated hydrochloric acid, filter, collect the filter cake, and dry it to obtain the product 7-chloro-8-fluoro-5-methoxy-2-(methylthio) Pyrido[4,3-d]pyrimidin-4-ol (5.5g). LCMS(m/z):276.0(M+H).
中间体J
Intermediate J
5-溴-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇
5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
步骤A：2-氯-3-氟-5-碘吡啶-4-胺Step A: 2-Chloro-3-fluoro-5-iodopyridin-4-amine
室温条件下，将2-氯-3-氟-4-氨基吡啶(25.0g,171mmol)溶解到250mL乙腈中。然后把NIS(35.4g,205mmol)和对甲苯磺酸一水合物(3.24g,17.1mmol)分别加入上面体系中。所得混合物加热到70℃，搅拌反应过夜。LCMS监测反应结束，冷却到室温，将反应液倒入水(500mL)中淬灭，乙酸乙酯萃取(800mL×3)。合并有机相，分别用饱和NaHCO3水洗，饱和Na2S2O3水洗，食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到的粗产品经FCC(SiO2，EA/PE＝0-50％)纯化，得到白色固体2-氯-3-氟-5-碘吡啶-4-胺(42g,收率90％)。LCMS(m/z):272.9(M+H)。1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),6.69(s,2H)。19F NMR(376MHz,DMSO-d6)δ-138.90。Dissolve 2-chloro-3-fluoro-4-aminopyridine (25.0 g, 171 mmol) in 250 mL acetonitrile at room temperature. Then NIS (35.4g, 205mmol) and p-toluenesulfonic acid monohydrate (3.24g, 17.1mmol) were added to the above system respectively. The resulting mixture was heated to 70°C and the reaction was stirred overnight. LCMS monitored the end of the reaction, cooled to room temperature, poured the reaction solution into water (500 mL) to quench, and extracted with ethyl acetate (800 mL × 3). The organic phases were combined, washed with saturated NaHCO 3 , saturated Na 2 S 2 O 3 , and brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was subjected to FCC (SiO 2 , EA/PE=0-50 %) was purified to obtain 2-chloro-3-fluoro-5-iodopyridin-4-amine as a white solid (42g, yield 90%). LCMS(m/z):272.9(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 6.69 (s, 2H). 19 F NMR (376MHz, DMSO-d 6 ) δ-138.90.
步骤B：4-氨基-6-氯-5-氟烟酸乙酯Step B: 4-Amino-6-chloro-5-fluoronicotinic acid ethyl ester
室温条件下，将2-氯-3-氟-5-碘吡啶-4-胺(40g,147mmol)溶解到400mL无水乙醇中。用CO置换体系，反复三次。后将Pd(PPh3)2Cl2(10.3g,14.7mmol)和TEA(95.0g,735mmol)加入反应瓶中，置换CO气体三次。所得混合物在CO气体氛围中，加热到80℃反应过夜。LCMS监测反应结束，冷却到室温，将反应液用硅藻土过滤。滤液浓缩至干，得到得粗品经FCC(SiO2，EA/PE＝0-50％)纯化，得到白色固体4-氨基-6-氯-5-氟烟酸乙酯(30g,收率93％)。LCMS(m/z):219.0(M+H)。Dissolve 2-chloro-3-fluoro-5-iodopyridin-4-amine (40 g, 147 mmol) into 400 mL of absolute ethanol at room temperature. Replace the system with CO and repeat three times. Then, Pd(PPh 3 ) 2 Cl 2 (10.3g, 14.7mmol) and TEA (95.0g, 735mmol) were added to the reaction bottle, and CO gas was replaced three times. The resulting mixture was heated to 80°C for reaction overnight in a CO gas atmosphere. LCMS monitored the end of the reaction, cooled to room temperature, and filtered the reaction solution through diatomaceous earth. The filtrate was concentrated to dryness, and the obtained crude product was purified by FCC (SiO 2 , EA/PE=0-50%) to obtain white solid 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (30g, yield 93% ). LCMS(m/z):219.0(M+H).
步骤C：4-(双(叔丁氧基羰基)氨基)-6-氯-5-氟烟酸乙酯Step C: 4-(Bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid ethyl ester
室温搅拌下，将Boc2O(65.9g,302mmol)滴加到4-氨基-6-氯-5-氟烟酸乙酯(30.0g,137mmol)和DMAP(3.4g,27.5mmol)的无水二氯甲烷(600mL)溶液中。滴加完成后加热到45℃反应过夜。向体系中加入咪唑(9.33g,137mmol)，搅拌半小时后，加入饱和氯化铵溶液洗涤(300mL×3)，分液，有机相再用饱和食盐水(300mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩至干，得得到黄色固体4-(双(叔丁氧基羰基)氨基)-6-氯-5-氟烟酸乙酯(45.9g,收率80％)。LCMS(m/z):419.1(M+H)。Under stirring at room temperature, Boc 2 O (65.9g, 302mmol) was added dropwise to the anhydrous solution of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (30.0g, 137mmol) and DMAP (3.4g, 27.5mmol). Dichloromethane (600mL) solution. After the dropwise addition is completed, the mixture is heated to 45°C for overnight reaction. Add imidazole (9.33g, 137mmol) to the system, stir for half an hour, add saturated ammonium chloride solution for washing (300mL×3), separate the liquids, and wash the organic phase with saturated brine (300mL×2). Dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a yellow solid 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid ethyl ester (45.9g, yield 80%) . LCMS(m/z):419.1(M+H).
步骤D：4-(双(叔丁氧基羰基)氨基)-2-溴-6-氯-5-氟烟酸乙酯Step D: 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester
将4-(双(叔丁氧基羰基)氨基)-6-氯-5-氟烟酸乙酯(45.0g,107mmol)的无水THF(450mL)溶液用干冰乙腈浴冷却到-40℃。此温度下搅拌滴加TMPMgCl-LiCl的THF溶液(161mL,161mmol,1M)。加毕后，保持此温度继续搅拌4h，再滴加二溴四氯乙烷(42.0g，129mmol)的 THF(100mL)溶液。在-40℃下继续搅拌4h。加入500mL饱和氯化铵溶液淬灭，再用EtOAc萃取(500mL×3)。合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩，得到的粗产品经FCC(SiO2，EA/DCM＝0-50％)纯化，得到白色固体4-(双(叔丁氧基羰基)氨基)-2-溴-6-氯-5-氟烟酸乙酯(17.0g，收率32％)。LCMS(m/z):497.0(M+H)。A solution of 4-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid ethyl ester (45.0 g, 107 mmol) in anhydrous THF (450 mL) was cooled to -40°C using a dry ice acetonitrile bath. At this temperature, a solution of TMPMgCl-LiCl in THF (161 mL, 161 mmol, 1 M) was added dropwise with stirring. After the addition is completed, keep stirring at this temperature for 4 hours, and then add dibromotetrachloroethane (42.0g, 129mmol) dropwise. THF (100 mL) solution. Continue stirring at -40 °C for 4 h. Add 500 mL saturated ammonium chloride solution to quench, and then extract with EtOAc (500 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was purified by FCC (SiO 2 , EA/DCM=0-50%) to obtain a white solid 4-(bis(tert-butoxy) Carbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester (17.0 g, yield 32%). LCMS(m/z):497.0(M+H).
步骤E：4-氨基-2-溴-6-氯-5-氟烟酸乙酯·HClStep E: 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester·HCl
室温条件下，将4-(双(叔丁氧基羰基)氨基)-2-溴-6-氯-5-氟烟酸乙酯(28.0g,56.3mmol)溶解到4M盐酸-二氧六环(500mL)中。室温下搅拌1h,LCMS监测反应完成，体系浓缩干，得到的粗产品白色固体4-氨基-2-溴-6-氯-5-氟烟酸乙酯·HCl(19.1g,粗品)。LCMS(m/z):296.9(M+H)。Dissolve 4-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester (28.0g, 56.3mmol) into 4M hydrochloric acid-dioxane at room temperature. (500mL). Stir at room temperature for 1 hour, LCMS monitors that the reaction is complete, and the system is concentrated to dryness to obtain the crude product white solid 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid ethyl ester·HCl (19.1 g, crude product). LCMS(m/z):296.9(M+H).
步骤F：4-氨基-2-溴-6-氯-5-氟烟酸Step F: 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid
室温条件下，把1N NaOH(45.0mL,45.0mmol)加入到4-氨基-2-溴-6-氯-5-氟烟酸乙酯·HCl(5.00g,15.0mmol)的MeOH/THF(V:V＝1:1,100mL)溶液中。所得混合物室温下搅拌1h，TLC监测反应结束，将反应液浓缩除去有机溶剂，残留物用1M HCl调pH＝5-6，用EA萃取(80mL×3)。合并有机相后用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到白色固体产物4-氨基-2-溴-6-氯-5-氟烟酸(1.90g,收率47％)。LCMS(m/z):269.0(M+H)。At room temperature, 1N NaOH (45.0 mL, 45.0 mmol) was added to MeOH/THF (V :V=1:1,100mL) solution. The resulting mixture was stirred at room temperature for 1 hour. TLC monitored the end of the reaction. The reaction solution was concentrated to remove the organic solvent. The residue was adjusted to pH=5-6 with 1M HCl and extracted with EA (80 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the white solid product 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid (1.90 g, yield 47%). LCMS(m/z):269.0(M+H).
步骤G：5-溴-7-氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4-醇Step G: 5-Bromo-7-chloro-8-fluoro-2-mercaptopyrido[4,3-d]pyrimidin-4-ol
室温条件下，把4-氨基-2-溴-6-氯-5-氟烟酸(1.90g,7.05mmol)溶解到二氯亚砜(40mL,551mmol)。催化量DMF(2滴)加入反应体系后，升温到80℃搅拌反应4h。反应液直接浓缩干得中间体酰氯。室温下，将所得酰氯用无水丙酮(50mL)搅拌溶解，缓慢加入硫氰酸铵(2.15g,28.2mmol)。所得混合物室温搅拌反应3h，大量固体产生。反应结束后，反应液慢慢倒入搅拌的水(400mL)中，析出固体，搅拌15min后过滤，滤饼烘干得5-溴-7-氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4-醇(1.55g,收率71％)。LCMS(m/z):309.8(M+H)。Dissolve 4-amino-2-bromo-6-chloro-5-fluoronicotinic acid (1.90g, 7.05mmol) into sulfoxide dichloride (40mL, 551mmol) at room temperature. After adding a catalytic amount of DMF (2 drops) to the reaction system, the temperature was raised to 80°C and the reaction was stirred for 4 hours. The reaction solution is directly concentrated to dryness to obtain the intermediate acid chloride. At room temperature, the obtained acid chloride was stirred and dissolved with anhydrous acetone (50 mL), and ammonium thiocyanate (2.15 g, 28.2 mmol) was slowly added. The resulting mixture was stirred and reacted at room temperature for 3 hours, and a large amount of solid was produced. After the reaction, the reaction solution was slowly poured into stirring water (400 mL) to precipitate a solid. After stirring for 15 minutes, it was filtered and the filter cake was dried to obtain 5-bromo-7-chloro-8-fluoro-2-mercaptopyrido[4 ,3-d]pyrimidin-4-ol (1.55g, yield 71%). LCMS(m/z):309.8(M+H).
步骤H：5-溴-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇Step H: 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
室温条件下，将0.1M NaOH(100mL,10.0mmol)和碘甲烷(1.42g,9.98mmol)依次加入到5-溴-7-氯-8-氟-2-巯基吡啶并[4,3-d]嘧啶-4-醇(1.55g,4.99mmol)的甲醇(50mL)溶液中。所得混合物室温搅拌反应2h。反应结束后，将反应液慢慢倒入搅拌的水(400mL)中。再用1M HCl调pH中性，析出白色固体，搅拌约15min后过滤，滤饼烘干得5-溴-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(1.5g,收率93％)。LCMS(m/z):323.8(M+H)。At room temperature, 0.1M NaOH (100mL, 10.0mmol) and methyl iodide (1.42g, 9.98mmol) were added successively to 5-bromo-7-chloro-8-fluoro-2-mercaptopyrido[4,3-d ]pyrimidin-4-ol (1.55g, 4.99mmol) in methanol (50mL). The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was slowly poured into stirring water (400 mL). Then adjust the pH to neutral with 1M HCl, and precipitate a white solid. Stir for about 15 minutes and then filter. The filter cake is dried to obtain 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3- d] Pyrimidine-4-ol (1.5g, yield 93%). LCMS(m/z):323.8(M+H).
中间体K
Intermediate K
7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-醇
7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol
步骤A：7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-醇Step A: 7-Chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol
室温条件下，将5-溴-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(500mg,1.54mmol)，Pd(PPh3)2Cl2(216mg，0.31mmol)和CuI(147mg，0.77mmol)溶解到10mL无水THF中。体系氮气置换三次，加入三异丙基硅基乙炔(562mg,3.08mmol)和TEA(779mg,7.70mmol)，再次氮气置换三次。所得混合物，加热到50℃反应16h。LCMS监测反应结束，冷却到室温，将反应液用硅藻土过滤。滤液浓缩干得到得粗品经FCC(SiO2，EA/PE＝0-50％)纯化，得到白色固体7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-醇(330mg，收率46％)。LCMS(m/z):426.0(M+H)。At room temperature, 5-bromo-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (500mg, 1.54mmol), Pd(PPh 3 ) 2 Cl 2 (216 mg, 0.31 mmol) and CuI (147 mg, 0.77 mmol) were dissolved in 10 mL of dry THF. The system was replaced with nitrogen three times, triisopropylsilyl acetylene (562 mg, 3.08 mmol) and TEA (779 mg, 7.70 mmol) were added, and nitrogen was replaced three times again. The resulting mixture was heated to 50°C and reacted for 16 hours. LCMS monitored the end of the reaction, cooled to room temperature, and filtered the reaction solution through diatomaceous earth. The filtrate was concentrated to dryness to obtain a crude product which was purified by FCC (SiO 2 , EA/PE=0-50%) to obtain a white solid 7-chloro-8-fluoro-2-(methylthio)-5-((triisopropyl) Silyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol (330 mg, yield 46%). LCMS(m/z):426.0(M+H).
中间体A-I
Intermediate AI
1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇
1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
步骤A：1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
将7-溴-2,4-二氯-8-氟喹唑啉(1.40g，4.73mmol)、DIEA(6.6mL，37.8mmol)的DCM(20mL)溶液冷至0℃。搅拌下，将3-甲基哌啶-3-醇·盐酸盐(789mg，5.20mmol)分批加入到上述体系中。所得体系继续搅拌2h，缓慢升至室温，LCMS监测反应完成。加入DCM(20mL)稀释，饱和氯化铵水溶液(30mL)洗涤，饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩，FCC(SiO2,EA/PE＝0-100％)纯化得到淡黄色固体1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3- 醇(1.42g，收率80％)。LCMS(m/z):374.0,375.9(M+H).A solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.40 g, 4.73 mmol), DIEA (6.6 mL, 37.8 mmol) in DCM (20 mL) was cooled to 0°C. Under stirring, 3-methylpiperidin-3-ol hydrochloride (789 mg, 5.20 mmol) was added to the above system in batches. The resulting system continued to stir for 2 h, slowly rose to room temperature, and LCMS monitored the completion of the reaction. DCM (20 mL) was added to dilute, washed with saturated aqueous ammonium chloride solution (30 mL), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify with FCC (SiO 2 , EA/PE=0-100%) to obtain light yellow solid 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3- Methylpiperidine-3- Alcohol (1.42g, yield 80%). LCMS(m/z):374.0,375.9(M+H).
中间体A-II
Intermediate A-II
5-(7-溴-2-氯-8-氟喹唑啉-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂-2-甲酰胺5-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1, 5-a][1,4]diaza-2-carboxamide
中间体A-II的合成参照中间体A-I合成所述，在步骤A中使用N,N-二甲基-5,6,7,8-四氢-4H-吡唑并[1,5-a][1,4]二氮杂-2-甲酰胺(参照文献WO2022132200进行制备)代替3-甲基哌啶-3-醇·盐酸盐。LCMS(m/z):467.0(M+H)The synthesis of intermediate A-II is as described in the synthesis of intermediate A-I. In step A, N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a is used ][1,4]diaza-2-carboxamide (prepared with reference to document WO2022132200) instead of 3-methylpiperidin-3-ol·hydrochloride. LCMS(m/z):467.0(M+H)
中间体B-I
Intermediate BI
1-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
中间体B-I的合成参照中间体A-I合成所述，在步骤A中使用7-溴-2,4-二氯-6,8-二氟喹唑啉(中间体B)代替7-溴-2,4-二氯-8-氟喹唑啉(中间体A)。LCMS(m/z):392.0(M+H).The synthesis of Intermediate B-I is as described in the synthesis of Intermediate A-I. In step A, 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (Intermediate B) is used instead of 7-bromo-2. 4-Dichloro-8-fluoroquinazoline (Intermediate A). LCMS(m/z):392.0(M+H).
根据上述合成方案制备以下中间体

Prepare the following intermediates according to the above synthetic scheme

中间体B-I-AF
Intermediate BI-AF
(R)-1-(7-溴-2,6,8-三氟喹唑啉-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
步骤A：(R)-1-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将DIPEA(39.9mL,229mmol)加入到7-溴-2,4-二氯-6,8-二氟喹唑啉(18.0g,57mmol)、(R)-3-甲基哌啶-3-醇·盐酸盐(8.69g,57mmol)和THF(200mL)的混合液中，室温条件下搅拌反应2h。TLC和LCMS监测反应结束，浓缩除去THF，加入乙腈(15mL)，将乙腈和化合物的混合液慢慢倒入搅拌的水(600mL)中，产生絮状不溶物，过滤并将滤饼烘干后得到 黄色固体(R)-1-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(21.7g,收率96％)。LCMS(m/z):393.9(M+H)。At room temperature, DIPEA (39.9 mL, 229 mmol) was added to 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (18.0 g, 57 mmol) and (R)-3-methylpiperzoline. into a mixture of din-3-ol·hydrochloride (8.69g, 57mmol) and THF (200mL), and stirred for 2 h at room temperature. TLC and LCMS monitored the end of the reaction, concentrated to remove THF, added acetonitrile (15mL), slowly poured the mixture of acetonitrile and the compound into stirring water (600mL) to produce flocculent insoluble matter, filtered and dried the filter cake. get Yellow solid (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (21.7g, yield 96% ). LCMS(m/z):393.9(M+H).
步骤B：(R)-1-(7-溴-2,6,8-三氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，依次将(R)-1-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(12.0g,30.6mmol)、KF(17.8g,306mmol)、DABCO(137mg,1.22mmol)、MsOH(117mg,1.22mmol)加入到DMSO(60mL)中，并升温至65℃搅拌10h。LCMS监测反应结束后，反应液恢复至室温。然后慢慢倒入搅拌的水(600mL)中，产生絮状不溶物，过滤并将滤饼烘干得到黄色固体(R)-1-(7-溴-2,6,8-三氟喹唑啉-4-基)-3-甲基哌啶-3-醇(11.3g,收率98％)。LCMS(m/z):378.0(M+H)。中间体B-III-AF
At room temperature, (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (12.0g, 30.6mmol), KF (17.8g, 306mmol), DABCO (137mg, 1.22mmol), and MsOH (117mg, 1.22mmol) were added to DMSO (60mL), and the temperature was raised to 65°C and stirred for 10h. After the reaction was monitored by LCMS, the reaction solution returned to room temperature. Then slowly pour into stirring water (600mL) to produce flocculent insoluble matter, filter and dry the filter cake to obtain a yellow solid (R)-1-(7-bromo-2,6,8-trifluoroquinazole) Phin-4-yl)-3-methylpiperidin-3-ol (11.3 g, yield 98%). LCMS(m/z):378.0(M+H). Intermediate B-III-AF
(S)-4-(7-溴-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇
(S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
步骤A：(S)-4-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step A: (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine- 6-alcohol
室温条件下，将DIPEA(1.55mL,8.92mmol)加入到7-溴-2,4-二氯-6,8-二氟喹唑啉(700mg,2.23mmol)，(S)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·盐酸盐(374mg,2.23mmol)和THF(12mL)的混合液中，所得混合物室温条件下搅拌反应2h。TLC和LCMS监测反应结束，浓缩除去THF，加入乙腈(2mL)，慢慢倒入搅拌的水(50mL)中，絮状不溶物产生，过滤并将滤饼烘干后得到棕黄色固体(S)-4-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(720mg,收率79％)。LCMS(m/z):409.9(M+H)。At room temperature, DIPEA (1.55mL, 8.92mmol) was added to 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (700mg, 2.23mmol), (S)-6-methyl -In a mixture of 1,4-oxazepan-6-ol hydrochloride (374 mg, 2.23 mmol) and THF (12 mL), the resulting mixture was stirred and reacted at room temperature for 2 h. TLC and LCMS monitored the end of the reaction, concentrated to remove THF, added acetonitrile (2mL), and slowly poured it into stirring water (50mL). Flocculated insoluble matter was produced. Filter and dry the filter cake to obtain a brown solid (S). -4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (720 mg, Yield 79%). LCMS(m/z):409.9(M+H).
步骤B：(S)-4-(7-溴-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step B: (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine-6- alcohol
室温条件下，依次将(S)-4-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(700mg,1.71mmol)，KF(995mg,17.1mmol)，MsOH(16mg,171umol),DABCO(19mg,171umol)，加入到DMSO(10mL)中，并升温至65℃搅拌18h。LCMS监测反应结束，反应液恢复至室温。然后慢慢倒入搅拌的水(60mL)中，黄色絮状不溶物产生，过滤并将滤饼烘干得到黄色固体(S)-4-(7-溴-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(600mg,收率89％)。LCMS(m/z):392.0(M+H)。 At room temperature, (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol (700mg, 1.71mmol), KF (995mg, 17.1mmol), MsOH (16mg, 171umol), DABCO (19mg, 171umol) were added to DMSO (10mL), and the temperature was raised to 65°C and stirred for 18h. . LCMS monitored the end of the reaction, and the reaction solution returned to room temperature. Then slowly pour into stirring water (60mL), yellow flocculent insoluble matter is produced, filter and dry the filter cake to obtain yellow solid (S)-4-(7-bromo-2,6,8-trifluoroquine) Zozolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (600 mg, yield 89%). LCMS(m/z):392.0(M+H).
中间体E-I-AF
Intermediate EI-AF
(R)-1-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-3-甲基-3-哌啶醇
(R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol
步骤A：(R)-1-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-3-甲基-3-哌啶醇Step A: (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol
在0℃下，将DIEA(4.5mL,27.24mmol)加入到7-溴-2,4,6-三氯-8-氟喹唑啉(3.0g,3.03mmol)、(R)-3-甲基-3-哌啶醇·盐酸盐(1.38g,9.08mmol)和THF(50mL)的混合溶液中，所得混合物室温搅拌2h。TLC监测反应完成，反应液浓缩后得到油状物，加入乙腈(5mL)溶解。将此溶液倒入H2O(300mL)中，棕黄色固体析出，过滤，H2O(100mL)洗滤饼。烘干滤饼得到棕色固体(R)-1-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-3-甲基-3-哌啶醇(3.7g，9.04mmol,收率99％)。At 0°C, DIEA (4.5 mL, 27.24 mmol) was added to 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (3.0 g, 3.03 mmol), (R)-3-methyl into a mixed solution of methyl-3-piperidinol hydrochloride (1.38g, 9.08mmol) and THF (50mL), and the resulting mixture was stirred at room temperature for 2h. TLC monitored the completion of the reaction, and the reaction solution was concentrated to obtain an oily substance, which was added to acetonitrile (5 mL) to dissolve. Pour this solution into H 2 O (300 mL), a brown solid precipitates, filter, and wash the filter cake with H 2 O (100 mL). The filter cake was dried to obtain a brown solid (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.7g , 9.04mmol, yield 99%).
步骤B：(R)-1-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-3-甲基-3-哌啶醇Step B: (R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol
室温条件下，将(R)-1-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-3-甲基-3-哌啶醇(3.7g,9.04mmol)加入到DABCO(102mg,904μmol)、KF(5.25g,90.45mmol)、MsOH(87mg,904μmol)和DMSO(50mL)的混合溶液中，所得混合物加热至65℃搅拌16h。LCMS监测反应完成，冷却后将反应液倒入H2O(400mL)中，棕黄色固体析出，过滤，H2O(100mL)洗滤饼。烘干滤饼，得到棕色固体(R)-1-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-3-甲基-3-哌啶醇(3.0g,收率84％)。LCMS(m/z):393.9(M+H)。At room temperature, (R)-1-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.7g, 9.04 mmol) was added to a mixed solution of DABCO (102 mg, 904 μmol), KF (5.25 g, 90.45 mmol), MsOH (87 mg, 904 μmol) and DMSO (50 mL), and the resulting mixture was heated to 65°C and stirred for 16 h. LCMS monitored the completion of the reaction. After cooling, the reaction solution was poured into H 2 O (400 mL). A brown solid precipitated, filtered, and the filter cake was washed with H 2 O (100 mL). Dry the filter cake to obtain brown solid (R)-1-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-3-methyl-3-piperidinol (3.0 g, yield 84%). LCMS(m/z):393.9(M+H).
中间体E-III-AF
Intermediate E-III-AF
(S)-4-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇
(S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxaazepan-6-ol
步骤A：(S)-6-甲基-1,4-氧杂环己烷-6-醇盐酸盐Step A: (S)-6-Methyl-1,4-oxane-6-ol hydrochloride
室温条件下，将HCl-二噁烷(4M)(10mL,10V)加入到(S)-6-羟基-6-甲基-1,4-氧杂环戊烯-4-羧酸叔丁酯(1.00g,4.32mmol)中并在室温下搅拌1h。LCMS监测反应结束，反应液浓缩后得到白色固体(S)-6-甲基-1,4-氧杂环己烷-6-醇盐酸盐(840mg,粗品)。LCMS(m/z):132.1(M+H)。At room temperature, add HCl-dioxane (4M) (10mL, 10V) to (S)-6-hydroxy-6-methyl-1,4-oxolane-4-carboxylic acid tert-butyl ester (1.00g, 4.32mmol) and stirred at room temperature for 1h. LCMS monitored the completion of the reaction, and the reaction solution was concentrated to obtain (S)-6-methyl-1,4-oxane-6-ol hydrochloride (840 mg, crude product) as a white solid. LCMS(m/z):132.1(M+H).
步骤B：(S)-4-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇Step B: (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxane-6- alcohol
室温条件下，将DIPEA(1.56g,12.1mmol)加入到7-溴-2,4,6-三氯-8-氟喹唑啉(1.00g,3.03mmol)、(S)-6-甲基-1,4-氧杂环己烷-6-醇盐酸盐(655mg,12.1mmol)和THF(20mL)的混合液并在室温条件下搅拌1h。LCMS监测反应结束，将反应液倒入饱和NH4Cl水溶液(50mL)中，EA(30mL×3)萃取。收集有机相，饱和NaCl水溶液(70mL)洗涤，无水Na2SO4干燥，过滤，浓缩得到白色固体(S)-4-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(1.2g,收率93％)。LCMS(m/z):425.9(M+H)。At room temperature, DIPEA (1.56g, 12.1mmol) was added to 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.00g, 3.03mmol), (S)-6-methyl -A mixture of 1,4-oxane-6-ol hydrochloride (655 mg, 12.1 mmol) and THF (20 mL) was stirred at room temperature for 1 h. LCMS monitored the completion of the reaction, and the reaction solution was poured into saturated NH 4 Cl aqueous solution (50 mL), and extracted with EA (30 mL × 3). The organic phase was collected, washed with saturated NaCl aqueous solution (70 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a white solid (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4- Quinazolinyl)-6-methyl-1,4-oxan-6-ol (1.2 g, yield 93%). LCMS(m/z):425.9(M+H).
步骤C:(S)-4-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇Step C: (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxane-6- alcohol
室温条件下，将MsOH(27.0mg,0.282mmol)加入到(S)-4-(7-溴-2,6-二氯-8-氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(1.20g,2.82mmol)、KF(1.64g,28.2mmol)、DABCO(31.7mg,0.282mmol)和DMSO(30mL)的混合溶液中，将反应液升温至100℃并搅拌1h。LCMS监测反应结束，将反应液缓慢滴加入水(150mL)中析出固体，过滤，滤饼用EA(100mL)溶解后用无水Na2SO4干燥，过滤，有机液浓缩得到黄色固体(S)-4-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(1.0g,收率87％)。LCMS(m/z):409.9(M+H)。At room temperature, MsOH (27.0 mg, 0.282 mmol) was added to (S)-4-(7-bromo-2,6-dichloro-8-fluoro-4-quinazolinyl)-6-methyl- In a mixed solution of 1,4-oxane-6-ol (1.20g, 2.82mmol), KF (1.64g, 28.2mmol), DABCO (31.7mg, 0.282mmol) and DMSO (30mL), the reaction was The liquid was heated to 100°C and stirred for 1 hour. LCMS monitors the end of the reaction. The reaction solution is slowly added dropwise to water (150 mL) to precipitate the solid, which is filtered. The filter cake is dissolved in EA (100 mL) and dried over anhydrous Na 2 SO 4. It is filtered and the organic liquid is concentrated to obtain a yellow solid (S). -4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol (1.0g, collected rate 87%). LCMS(m/z):409.9(M+H).
中间体G-I-A
Intermediate GIA
(3R)-1-(7-氯-8-氟-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine din-3-ol
步骤A：(3R)-1-(7-氯-8-氟-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3- Methylpiperidin-3-ol
室温条件下，将DIPEA(2.37g,18.3mmol)加入到7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(1.50g,6.11mmol)、(R)-3-甲基哌啶-3-醇·盐酸盐(1.06g,7.02mmol)、BOP(5.40g,12.2mmol)和DMF(20mL)的混合液中。将反应体系升温至45℃搅拌18h。TLC监测反应结束，反应液恢复至室温后缓慢倒入搅拌着的H2O(200mL)中，固体析出，过滤，H2O(100mL)洗滤饼，烘干滤饼，得到棕色固体(3R)-1-(7-氯-8-氟-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(2.0g,收率98％)。At room temperature, DIPEA (2.37g, 18.3mmol) was added to 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.50g, 6.11mmol). ), (R)-3-methylpiperidin-3-ol hydrochloride (1.06g, 7.02mmol), BOP (5.40g, 12.2mmol) and DMF (20mL). The reaction system was heated to 45°C and stirred for 18 h. TLC monitors the end of the reaction. After returning to room temperature, the reaction solution is slowly poured into stirring H 2 O (200 mL). The solid precipitates and is filtered. The filter cake is washed with H 2 O (100 mL) and dried to obtain a brown solid (3R )-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine- 3-alcohol (2.0g, yield 98%).
中间体G-II
Intermediate G-II
4-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane- 6-alcohol
步骤A：4-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step A: 4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxaazepine Cycloheptan-6-ol
室温搅拌下，向溶有7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(0.57g,2.33mmol)的DMF(8.0mL)中依次加入6-甲基-1,4-氧氮杂环庚烷-6-醇盐酸盐(0.55g,3.2mmol)、DIPEA(1.4mL,8.16mmol)、苯并三氮唑-1-基氧基三(二甲氨基)磷鎓六氟磷酸盐(3.14g,7.00mmol)。所得混合物加热至45℃搅拌6h，反应结束后，向反应体系中加水(30mL)淬灭反应，用乙酸乙酯(30.0mL×3)萃取。合并有机相，无水硫酸钠干燥，减压浓缩，残留物经过FCC(SiO2，EA/PE～0-50％)纯化，得到淡黄色固体4-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧杂环己烷-6-醇(0.77g,收率92％)，LCMS(m/z)＝359.0(M+H)。Under stirring at room temperature, 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (0.57g, 2.33mmol) was dissolved in DMF (8.0mL). Add 6-methyl-1,4-oxazepan-6-ol hydrochloride (0.55g, 3.2mmol), DIPEA (1.4mL, 8.16mmol), and benzotriazol-1-yl in sequence. Oxytris(dimethylamino)phosphonium hexafluorophosphate (3.14g, 7.00mmol). The resulting mixture was heated to 45°C and stirred for 6 h. After the reaction was completed, water (30 mL) was added to the reaction system to quench the reaction, and extracted with ethyl acetate (30.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by FCC (SiO 2 , EA/PE ~ 0-50%) to obtain a light yellow solid 4-(7-chloro-8-fluoro-2- (Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxan-6-ol (0.77g, yield 92%), LCMS (m/z)=359.0(M+H).
中间体G-II-A
Intermediate G-II-A
(S)-4-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxaza Cycloheptan-6-ol
中间体G-II-A的合成参照中间体G-II所述方案进行，在步骤A中使用(S)-6-甲基-1,4-氧杂环庚烷-6-醇·盐酸盐代替6-甲基-1,4-氧氮杂环庚烷-6-醇·盐酸盐。The synthesis of intermediate G-II-A is carried out according to the protocol described in intermediate G-II. In step A, (S)-6-methyl-1,4-oxepan-6-ol·hydrochloric acid is used The salt replaces 6-methyl-1,4-oxazepan-6-ol·hydrochloride.
中间体I-I-A
Intermediate IIA
(S)-4-(7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
(S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1 ,4-Oxaazepan-6-ol
步骤A：(S)-4-(7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step A: (S)-4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl 1,4-Oxaazepan-6-ol
室温条件下，将DIEA(1.4g,11mmol)加入到7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(1.0g,3.6mmol)、(S)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·盐酸盐(770mg,4.64mmol)、BOP(2.4g,5.4mmol)和DMF(15mL)的混合溶液中。将反应体系升温至50℃搅拌2h。LCMS监测反应结束，反应液恢复至室温后缓慢倒入搅拌着的H2O(100mL)中，固体析出，过滤并将滤饼烘干后，得到棕黄色固体(S)-4-(7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(900mg,收率64％)。LCMS(m/z):389.0(M+H)。DIEA (1.4g, 11mmol) was added to 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol ( 1.0g, 3.6mmol), (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride (770mg, 4.64mmol), BOP (2.4g, 5.4mmol) and DMF (15 mL). The reaction system was heated to 50°C and stirred for 2 h. LCMS monitors the end of the reaction. After the reaction solution returns to room temperature, it is slowly poured into stirring H 2 O (100 mL). The solid precipitates. After filtering and drying the filter cake, a brown solid (S)-4-(7- Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol (900 mg, yield 64%). LCMS(m/z):389.0(M+H).
中间体I-II-A
Intermediate I-II-A
(R)-1-(7-氯-8-氟-5-甲氧基-2-甲硫基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇 (R)-1-(7-chloro-8-fluoro-5-methoxy-2-methylthiopyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3 -alcohol
中间体I-II-A的合成参照中间体I-I-A所述方案进行，在步骤A中使用(R)-6-甲基哌啶-3-醇·盐酸盐代替(S)-6-甲基-1,4-氧杂环庚烷-6-醇·盐酸盐。The synthesis of intermediate I-II-A is carried out according to the protocol described in intermediate I-I-A. In step A, (R)-6-methylpiperidin-3-ol·hydrochloride is used instead of (S)-6-methyl. -1,4-oxepane-6-ol hydrochloride.
中间体K-I-A
Intermediate KIA
(R)-1-(7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine-4- methyl)-3-methylpiperidin-3-ol
步骤A：(R)-1-(7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine -4-yl)-3-methylpiperidin-3-ol
室温条件下，将7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-醇(200mg,0.47mmol)溶于POCl3(2mL)，加入DIPEA(360mg,2.35mmol)。所得体系加热至100℃反应3h，减压浓缩干。冷至室温，加入5mL无水THF，后加入(R)-3-甲基-3-羟基哌啶·盐酸盐(107mg,0.704mmol)和DIPEA(360mg,2.35mmol)。所得混合物室温搅拌反应2h，LCMS监测反应完。反应液浓缩干，得到的粗产品经FCC(SiO2，EA/PE＝0-50％)纯化，得到白色固体(R)-1-(7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(200mg，收率81％)。LCMS(m/z):523.2(M+H)。At room temperature, 7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-ol ( 200 mg, 0.47 mmol) was dissolved in POCl 3 (2 mL), and DIPEA (360 mg, 2.35 mmol) was added. The resulting system was heated to 100°C for 3 hours, and then concentrated to dryness under reduced pressure. Cool to room temperature, add 5 mL of anhydrous THF, and then add (R)-3-methyl-3-hydroxypiperidine hydrochloride (107 mg, 0.704 mmol) and DIPEA (360 mg, 2.35 mmol). The resulting mixture was stirred and reacted at room temperature for 2 h, and LCMS monitored the completion of the reaction. The reaction solution was concentrated to dryness, and the crude product obtained was purified by FCC (SiO 2 , EA/PE=0-50%) to obtain a white solid (R)-1-(7-chloro-8-fluoro-2-(methylthio) )-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, yield 81%) . LCMS(m/z):523.2(M+H).
中间体K-II-A
Intermediate K-II-A
(S)-4-(7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(S)-4-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidine-4- methyl)-6-methyl-1,4-oxazepan-6-ol
中间体K-II-A的合成参照中间体K-I-A所述方案进行，在步骤A中使用(S)-6-甲基-1,4- 氧杂环庚烷-6-醇·盐酸盐代替(R)-3-甲基-3-羟基哌啶·盐酸盐。The synthesis of intermediate K-II-A is carried out according to the protocol described for intermediate KIA. In step A, (S)-6-methyl-1,4- Oxeptan-6-ol·hydrochloride was used instead of (R)-3-methyl-3-hydroxypiperidine·hydrochloride.
中间体a
Intermediate a
(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇
(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol
步骤A：1-(叔丁基)2-乙基2-甲基-3-氧吡咯烷-1,2-二甲酸酯Step A: 1-(tert-butyl)2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate
冰浴条件下，将CH3I(5.52g,38.87mmol)滴加到1-(叔丁基)2-乙基3-氧吡咯烷-1,2-二甲酸酯(5.0g,19.43mmol)，K2CO3(8.06g,58.30mmol)和无水ACN(50mL)的混合溶液中。滴加完成后，反应液升温至40℃并搅拌过夜。TLC(PE:EA＝5:1,Rf＝0.6)监测反应结束后，把反应液倒入饱和NH4Cl水溶液(200mL)中，EA(100mL×3)萃取。有机相用饱和NaCl水溶液(50mL)洗涤，收集有机相浓缩后经FCC(SiO2，EA/PE＝0-15％)得到无色油状液体(1-(叔丁基)2-乙基2-甲基-3-氧吡咯烷-1,2-二甲酸酯(3.8g,收率72％)。1H NMR(400MHz,CDCl3)δ4.29–4.08(m,2H),3.95–3.78(m,1H),3.77–3.66(m,1H),2.83–2.71(m,1H),2.70–2.57(m,1H),1.66–1.57(m,3H),1.51–1.41(m,9H),1.30–1.20(m,3H).LCMS(m/z):294.0(M+Na)。Under ice bath conditions, CH 3 I (5.52g, 38.87mmol) was added dropwise to 1-(tert-butyl)2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (5.0g, 19.43mmol) ), a mixed solution of K 2 CO 3 (8.06g, 58.30mmol) and anhydrous ACN (50mL). After the dropwise addition was completed, the reaction solution was heated to 40°C and stirred overnight. After the reaction was monitored by TLC (PE:EA=5:1, Rf=0.6), the reaction solution was poured into saturated NH 4 Cl aqueous solution (200 mL), and extracted with EA (100 mL × 3). The organic phase was washed with saturated NaCl aqueous solution (50 mL). The organic phase was collected and concentrated and then passed through FCC (SiO 2 , EA/PE = 0-15%) to obtain a colorless oily liquid (1-(tert-butyl) 2-ethyl 2- Methyl-3-oxopyrrolidine-1,2-dicarboxylate (3.8g, yield 72%). 1 H NMR (400MHz, CDCl 3 ) δ4.29–4.08 (m, 2H), 3.95–3.78 (m,1H),3.77–3.66(m,1H),2.83–2.71(m,1H),2.70–2.57(m,1H),1.66–1.57(m,3H),1.51–1.41(m,9H) ,1.30–1.20(m,3H).LCMS(m/z):294.0(M+Na).
步骤B：1-(叔丁基)2-乙基3-羟基-2-甲基吡咯烷-1,2-二甲酸酯Step B: 1-(tert-butyl)2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate
冰浴搅拌下，向1-(叔丁基)2-乙基2-甲基-3-氧吡咯烷-1,2-二甲酸酯(1.0g，3.69mmol)的MeOH(10mL)溶液中加人NaBH4(150mg，4.06mmol),所得混合物在室温下继续搅拌0.5h。反应结束后向体系中加入过量的氯化铵饱和水溶液，用乙酸乙酯EA(50mL×3)萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，所得粗品经FCC(SiO2，EA/PE＝0-20％)纯化，得到无色液体1-(叔丁基)2-乙基3-羟基-2-甲基吡咯烷-1,2-二甲酸酯(926mg，收率92％)。LCMS(m/z):296.0(M+Na)。Under stirring in an ice bath, add 1-(tert-butyl)2-ethyl 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (1.0g, 3.69mmol) in MeOH (10mL). NaBH 4 (150 mg, 4.06 mmol) was added, and the resulting mixture was stirred at room temperature for 0.5 h. After the reaction, an excess of saturated aqueous ammonium chloride solution was added to the system, and the mixture was extracted with ethyl acetate EA (50 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product obtained is purified by FCC (SiO 2 , EA/PE = 0-20%) to obtain colorless liquid 1-(tert-butyl) 2 -Ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate (926 mg, yield 92%). LCMS (m/z): 296.0 (M+Na).
步骤C：1-(叔丁基)2-乙基3-甲氧基-2-甲基吡咯烷-1,2-二甲酸酯Step C: 1-(tert-butyl)2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate
室温条件下，向1-(叔丁基)2-乙基3-羟基-2-甲基吡咯烷-1,2-二甲酸酯(580mg，2.12mmol)的THF(3mL)溶液中加人NaH(255mg，60％w/w，6.37mmol),将所得混合物在室温下继续搅拌0.5h。之后向反应体系中加入CH3I(904mg，6.36mmol)，继续反应3h。反应结束后向体系中加入过量的氯化铵饱和水溶液，用乙酸乙酯EA(15mL×3)萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，所得粗品经FCC(SiO2，EA/PE＝0-30％)纯化，得到无色液体1-(叔丁基)2-乙基3-甲氧基-2-甲基吡咯烷-1,2-二甲酸酯(200mg,收率34％)。LCMS(m/z):310.0(M+Na)。 To a solution of 1-(tert-butyl)2-ethyl 3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate (580 mg, 2.12 mmol) in THF (3 mL) was added at room temperature. NaH (255 mg, 60% w/w, 6.37 mmol), and the resulting mixture was stirred at room temperature for 0.5 h. Then CH 3 I (904 mg, 6.36 mmol) was added to the reaction system, and the reaction was continued for 3 h. After the reaction, an excess of saturated aqueous ammonium chloride solution was added to the system, and the mixture was extracted with ethyl acetate EA (15 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product obtained is purified by FCC (SiO 2 , EA/PE = 0-30%) to obtain colorless liquid 1-(tert-butyl) 2 -Ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate (200 mg, yield 34%). LCMS (m/z): 310.0 (M+Na).
步骤D：(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇Step D: (3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol
向配有磁力搅拌子的反应管中加入1-(叔丁基)2-乙基3-甲氧基-2-甲基吡咯烷-1,2-二甲酸酯(200mg，0.70mmol)，再向反应体系中加入LiAlH4(3.5mL，1M THF溶液，3.5mmol)。所得混合物加热至70℃回流搅拌3h，反应结束后用十水合硫酸钠淬灭反应，再用无水硫酸钠干燥反应体系。过滤除去不溶物，滤液减压浓缩，得无色液体(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(110mg，收率99％)，无需纯化直接用于后续反应。LCMS(m/z):160.1(M+H)。Add 1-(tert-butyl)2-ethyl 3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate (200 mg, 0.70 mmol) to the reaction tube equipped with a magnetic stirrer. LiAlH 4 (3.5 mL, 1 M THF solution, 3.5 mmol) was then added to the reaction system. The resulting mixture was heated to 70°C and stirred under reflux for 3 hours. After the reaction was completed, the reaction was quenched with sodium sulfate decahydrate, and the reaction system was dried with anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain colorless liquid (3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (110 mg, yield 99%), which was used directly without purification. Subsequent reactions. LCMS(m/z):160.1(M+H).
中间体b
Intermediate b
化合物3-甲基-4-氧代哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(120g)经SFC(SFC150,Waters)拆分(分离柱：DAICEL250*50mm,10μm；流动相：CO2/MeOH＝90/10；流速：120mL/min),得到首先洗脱出来的异构体1，为化合物b(52.8g,相对保留时间较小)。手性分析方法-b(Waters UPCC,分析柱：Daicel100*3mm3μm；流动相A：CO2，流动相B：MeOH；流速：1.5mL/min；柱温：35℃；反压：1800psi；梯度：0-8.0min A/B＝90/10)，Rt＝0.682min。1H NMR(400MHz,Chloroform-d)δ4.59–4.42(m,1H),4.26–3.98(m,1H),3.73(s,3H),3.42–3.24(m,1H),3.16–3.01(m,1H),2.93–2.63(m,1H),2.58–2.40(m,1H),1.49(s,9H),1.31(s,3H)。LCMS(m/z):216.1(M-56+H)。随后洗脱出来的异构体2，为化合物b-1(52.4g,相对保留时间较大)。手性分析方法-b，Rt＝1.035min。1H NMR(400MHz,Chloroform-d)δ4.60–4.41(m,1H),4.24–3.94(m,1H),3.73(s,3H),3.42–3.24(m,1H),3.17–3.00(m,1H),2.93–2.64(m,1H),2.56–2.40(m,1H),1.49(s,9H),1.31(s,3H)。Compound 3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (120g) was separated by SFC (SFC150, Waters) (separation column: DAICEL 250*50mm, 10μm; mobile phase: CO 2 /MeOH=90/10; flow rate: 120mL/min), the isomer 1 that eluted first was obtained, which was compound b (52.8g, relatively small retention time). Chiral analysis method-b (Waters UPCC, analytical column: Daicel 100*3mm3μm; mobile phase A: CO 2 , mobile phase B: MeOH; flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-8.0min A/B＝90/10), Rt=0.682min. 1 H NMR (400MHz, Chloroform-d) δ4.59–4.42(m,1H),4.26–3.98(m,1H),3.73(s,3H),3.42–3.24(m,1H),3.16–3.01( m,1H),2.93–2.63(m,1H),2.58–2.40(m,1H),1.49(s,9H),1.31(s,3H). LCMS(m/z):216.1(M-56+H). The isomer 2 that subsequently eluted was compound b-1 (52.4 g, relatively large retention time). Chiral analysis method-b, Rt=1.035min. 1 H NMR (400MHz, Chloroform-d) δ4.60–4.41(m,1H),4.24–3.94(m,1H),3.73(s,3H),3.42–3.24(m,1H),3.17–3.00( m,1H),2.93–2.64(m,1H),2.56–2.40(m,1H),1.49(s,9H),1.31(s,3H).
中间体c
Intermediate c
(3S)-(1,3,4-三甲基哌啶-3-基)甲醇
(3S)-(1,3,4-trimethylpiperidin-3-yl)methanol
步骤A：(S)-3-甲基-4-亚甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯Step A: (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylate-1-(tert-butyl)ester-3-methyl ester
冰浴条件下，将叔丁醇钾的THF溶液(5.25mL,1M,5.25mmol)滴加到甲基三苯基溴化磷(1.89g,5.25mmol)的甲苯(10mL)溶液中，所得体系在冰浴下搅拌0.5h。将(R)-3-甲基-4-氧代哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(1.00g,3.50mmol)的甲苯(5mL)溶液滴加到上述体系中，保持温度反应1h。后缓慢升至110℃后保持温度搅拌反应过夜。TLC监测反应完成，冷却至室温，减压浓缩至干，得到粗产品，通过FCC(SiO2，EA/PE＝0-100％)纯化，得到无色油状产物(S)-3-甲基-4-亚甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(750mg,收率75％)。LCMS(m/z):214.1(M-56+H),292.1(M+Na)。Under ice bath conditions, a solution of potassium tert-butoxide in THF (5.25mL, 1M, 5.25mmol) was added dropwise to a solution of methyltriphenylphosphonium bromide (1.89g, 5.25mmol) in toluene (10mL), and the resulting system Stir under ice bath for 0.5h. A solution of (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl ester (1.00g, 3.50mmol) in toluene (5mL) Add dropwise to the above system and maintain the temperature for 1 hour. Afterwards, the temperature was slowly raised to 110°C and the reaction was stirred overnight while maintaining the temperature. TLC monitors the completion of the reaction, cools to room temperature, and concentrates to dryness under reduced pressure to obtain a crude product, which is purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a colorless oily product (S)-3-methyl- 4-Methylenepiperidine-1,3-dicarboxylic acid-1-(tert-butyl)ester-3-methyl ester (750 mg, yield 75%). LCMS (m/z): 214.1 (M-56+H), 292.1 (M+Na).
步骤B：(3S)-3,4-二甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯Step B: (3S)-3,4-dimethylpiperidine-1,3-dicarboxylate-1-(tert-butyl)ester-3-methyl ester
室温氮气保护下，将Pd/C(500mg,10％w/w,0.47mmol)加入到(S)-3-甲基-4-亚甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(750mg,2.78mmol)的甲醇(20mL)溶液中。用氢气球置换体系，后在氢气氛围中搅拌反应过夜。TLC监测反应结束后，用硅藻土过滤，滤液浓缩得到粗产品，通过FCC(SiO2，EA/PE＝0-50％)纯化，得到无色油状产物(3S)-3,4-二甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(600mg,收率79％)。LCMS(m/z):216.1(M-56+H),294.1(M+Na)。1H NMR(400MHz,甲醇-d4)δ4.08–4.02(m,0.23H),3.98(dd,J＝13.7,1.5Hz,1H),3.91–3.78(m,1.23H),3.72(s,0.69H),3.67(s,3H),3.21–2.76(m,2.46H),2.20–2.06(m,0.23H),1.81–1.29(m,14.9H),1.20(s,3H),1.07(s,0.69H),1.02(d,J＝6.6Hz,3H),0.86(d,J＝6.8Hz,0.69H)。Under nitrogen protection at room temperature, Pd/C (500 mg, 10% w/w, 0.47 mmol) was added to (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylic acid-1- (tert-butyl)ester-3-methyl ester (750 mg, 2.78 mmol) in methanol (20 mL). The system was replaced with a hydrogen balloon, and the reaction was stirred overnight in a hydrogen atmosphere. After TLC monitoring of the reaction, filter through diatomaceous earth, and concentrate the filtrate to obtain a crude product, which is purified by FCC (SiO 2 , EA/PE = 0-50%) to obtain a colorless oily product (3S)-3,4-dimethyl. Piperidine-1,3-dicarboxylic acid-1-(tert-butyl)ester-3-methyl ester (600 mg, yield 79%). LCMS (m/z): 216.1 (M-56+H), 294.1 (M+Na). 1 H NMR (400MHz, methanol-d 4 ) δ4.08–4.02 (m, 0.23H), 3.98 (dd, J = 13.7, 1.5Hz, 1H), 3.91–3.78 (m, 1.23H), 3.72 (s ,0.69H),3.67(s,3H),3.21–2.76(m,2.46H),2.20–2.06(m,0.23H),1.81–1.29(m,14.9H),1.20(s,3H),1.07 (s, 0.69H), 1.02 (d, J = 6.6Hz, 3H), 0.86 (d, J = 6.8Hz, 0.69H).
步骤C：(3S)-(1,3,4-三甲基哌啶-3-基)甲醇Step C: (3S)-(1,3,4-trimethylpiperidin-3-yl)methanol
室温下，将LiAlH4-THF(1M,5.26mmol,5.26mL)滴加入(3S)-3,4-二甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(500mg,1.75mmol)的THF(5mL)溶液中，所得体系加热到70℃搅拌3h。LCMS监测反应结束后，加入Na2SO4·10H2O淬灭反应直到没有气体产生为止，反应液通过硅藻土过滤，得到的滤液低温(35℃)减压浓缩，得到无色液体(3S)-(1,3,4-三甲基哌啶-3-基)甲醇(250mg,收率91％)。LC-MS(m/z):158.2(M+H)。At room temperature, LiAlH 4 -THF (1M, 5.26mmol, 5.26mL) was added dropwise to (3S)-3,4-dimethylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)ester- In a solution of 3-methyl ester (500 mg, 1.75 mmol) in THF (5 mL), the resulting system was heated to 70°C and stirred for 3 h. After the reaction was monitored by LCMS, Na 2 SO 4 ·10H 2 O was added to quench the reaction until no gas was produced. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated under reduced pressure at low temperature (35°C) to obtain a colorless liquid (3S )-(1,3,4-trimethylpiperidin-3-yl)methanol (250 mg, yield 91%). LC-MS(m/z):158.2(M+H).
中间体d
Intermediate d
(3S)-(4-氟-1,3-二甲基哌啶-3-基)甲醇
(3S)-(4-Fluoro-1,3-dimethylpiperidin-3-yl)methanol
步骤A：(S)-4-氟-3-甲基-3,6-二氢吡啶-1,3(2H)-二羧酸-1-(叔丁基)酯-3-甲基酯Step A: (S)-4-Fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid-1-(tert-butyl)ester-3-methyl ester
冰浴条件下，将BAST(19.57g,16.3mL,88.46mmol)滴入到(R)-3-甲基-4-氧代哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(8.0g,29.49mmol)和DCM(40mL)的混合溶液中，滴加完毕后恢复室温搅拌过夜。TLC监测反应结束后，将反应液缓慢倒入半饱和的NaHCO3(100mL)溶液中，用DCM(100mL×3)萃取。合并有机相浓缩后通过FCC(SiO2,EA/PE＝0-10％)纯化，得到无色油状物(S)-4-氟-3-甲基-3,6-二氢吡啶-1,3(2H)-二羧酸-1-(叔丁基)酯-3-甲基酯(1.0g,收率12％)。LCMS(m/z):218.1(M-56+H)。Under ice bath conditions, BAST (19.57g, 16.3mL, 88.46mmol) was dropped into (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) into a mixed solution of ester 3-methyl ester (8.0 g, 29.49 mmol) and DCM (40 mL). After the dropwise addition is completed, return to room temperature and stir overnight. After the reaction was monitored by TLC, the reaction solution was slowly poured into a semisaturated NaHCO 3 (100 mL) solution, and extracted with DCM (100 mL × 3). The combined organic phases were concentrated and purified by FCC (SiO 2 , EA/PE=0-10%) to obtain a colorless oily substance (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1. 3(2H)-dicarboxylic acid-1-(tert-butyl)ester-3-methyl ester (1.0g, yield 12%). LCMS(m/z):218.1(M-56+H).
步骤B：(S)-(4-氟-1,3-二甲基-1,2,3,6-四氢吡啶-3-基)甲醇Step B: (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol
室温条件下，将LiAH4(4.02mL,4.02mmol,1MTHF溶液)加到(S)-4-氟-3-甲基-3,6-二氢吡啶-1,3(2H)-二羧酸-1-(叔丁基)酯-3-甲基酯(500mg,1.83mmol)中并升温至70℃搅拌1h。LCMS监测反应结束后，在冰浴条件下，缓慢将Na2SO4·10H2O加入反应液中淬灭LiAH4，直到反应不再生成气体为止，再加入无水硫酸钠干燥溶液，过滤，收集母液浓缩，得到无色油状液体(S)-(4-氟-1,3-二甲基-1,2,3,6-四氢吡啶-3-基)甲醇(284mg,收率98％)。LCMS(m/z):160.1(M+H)。At room temperature, add LiAH 4 (4.02 mL, 4.02 mmol, 1MTHF solution) to (S)-4-fluoro-3-methyl-3,6-dihydropyridine-1,3(2H)-dicarboxylic acid -1-(tert-butyl) ester-3-methyl ester (500 mg, 1.83 mmol) and heated to 70°C and stirred for 1 h. After the reaction is monitored by LCMS, under ice bath conditions, slowly add Na 2 SO 4 ·10H 2 O to the reaction solution to quench LiAH 4 until the reaction no longer generates gas, then add anhydrous sodium sulfate dry solution and filter. The mother liquor was collected and concentrated to obtain colorless oily liquid (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydropyridin-3-yl)methanol (284 mg, yield 98%) ). LCMS(m/z):160.1(M+H).
步骤C：(3S)-(4-氟-1,3-二甲基哌啶-3-基)甲醇Step C: (3S)-(4-fluoro-1,3-dimethylpiperidin-3-yl)methanol
室温氮气保护下，将Pd/C(5％w/w,374mg,0.176mmol)加入到(S)-(4-氟-1,3-二甲基-1,2,3,6-四氢吡啶-3-基)甲醇(280mg,1.76mmol)和EA:MeOH＝1:1(20mL)的混合溶液中，所的混合物氢气置换，后在60psi H2压力下室温反应2h。TLC监测反应结束后，反应液经硅藻土过滤，EA(50ml)洗涤，有机相浓缩，得到无色油状液体(3S)-(4-氟-1,3-二甲基哌啶-3-基)甲醇(220mg,收率78％)。LCMS(m/z):162(M+H)。Under nitrogen protection at room temperature, Pd/C (5% w/w, 374 mg, 0.176 mmol) was added to (S)-(4-fluoro-1,3-dimethyl-1,2,3,6-tetrahydro In a mixed solution of pyridin-3-yl)methanol (280 mg, 1.76 mmol) and EA:MeOH = 1:1 (20 mL), the mixture was replaced with hydrogen, and then reacted at room temperature under 60 psi H 2 pressure for 2 hours. After the reaction was monitored by TLC, the reaction solution was filtered through diatomaceous earth, washed with EA (50 ml), and the organic phase was concentrated to obtain a colorless oily liquid (3S)-(4-fluoro-1,3-dimethylpiperidine-3- base) methanol (220 mg, yield 78%). LCMS(m/z):162(M+H).
中间体e
Intermediate e
(S,E)–(4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲醇
(S,E)–(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol
步骤A：(S,E)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯及(S,Z)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯Step A: (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester and (S,Z )-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester
将(氟亚甲基)三苯基膦四氟硼酸盐(10.56g,27.64mmol)溶解到无水THF(50mL)中,氮气置换三次。在干冰乙醇条件下，把反应液的温度降至-70℃，将叔丁醇钾-四氢呋喃(27.64mL,1M,27.64mmol)溶液逐滴地滴加到反应体系中。保持温度继续搅拌1h。后将(R)-3-甲基-4-氧代哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯(5.0g,18.43mmol)的无水四氢呋喃(15mL)溶液滴加到反应体系中。滴加完成后，所得混合物缓慢升至室温搅拌过夜。TLC监测反应结束后，将反应液缓慢倒入水(100mL)中，用乙酸乙酯萃取3次。有机相合并后，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩干，得到粗产品。粗产物通过FCC(SiO2，EA/PE＝0-15％)纯化，得到无色油状产物(S,E)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯(1.98g,收率37％)。LCMS(m/z):232.1(M-56+H)。1H NMR(400MHz,Chloroform-d)δ6.55(d,J＝84.7,1H),4.35(d,J＝13.2Hz,1H),4.10–3.82(m,1H),3.69(s,3H),3.00–2.85(m,1H),2.76(d,J＝13.1Hz,1H),2.71–2.60(m,1H),2.31–2.08(m,1H),1.46(s,9H),1.29(s,3H)；及无色油状产物(S,Z)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯(600mg,收率11％)。LCMS(m/z):232.1(M-56+H)。1H NMR(400MHz,Chloroform-d)δ6.43(d,J＝83.7,1H),3.86–3.75(m,1H),3.71(s,3H),3.62–3.47(m,1H),3.42–3.29(m,2H),2.24–2.06(m,2H),1.46(s,9H),1.43–1.39(m,3H)。(Fluoromethylene)triphenylphosphine tetrafluoroborate (10.56g, 27.64mmol) was dissolved in anhydrous THF (50mL) and replaced with nitrogen three times. Under dry ice ethanol conditions, lower the temperature of the reaction solution to -70°C, and add potassium tert-butoxide-tetrahydrofuran (27.64mL, 1M, 27.64mmol) solution dropwise to the reaction system. Maintain temperature and continue stirring for 1 hour. Then (R)-3-methyl-4-oxopiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.0g, 18.43mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) solution was added dropwise to the reaction system. After the dropwise addition was completed, the resulting mixture was slowly raised to room temperature and stirred overnight. After TLC monitoring of the reaction, the reaction solution was slowly poured into water (100 mL), and extracted three times with ethyl acetate. After the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a crude product. The crude product was purified by FCC (SiO 2 , EA/PE=0-15%) to obtain the colorless oily product (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3- Dicarboxylic acid-1-tert-butyl ester-3-methyl ester (1.98g, yield 37%). LCMS(m/z):232.1(M-56+H). 1 H NMR(400MHz,Chloroform-d)δ6.55(d,J＝84.7,1H),4.35(d,J＝13.2Hz,1H),4.10–3.82(m,1H),3.69(s,3H) ,3.00–2.85(m,1H),2.76(d,J＝13.1Hz,1H),2.71–2.60(m,1H),2.31–2.08(m,1H),1.46(s,9H),1.29(s ,3H); and colorless oily product (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl Ester (600 mg, yield 11%). LCMS(m/z):232.1(M-56+H). 1 H NMR (400MHz, Chloroform-d) δ6.43 (d, J = 83.7, 1H), 3.86–3.75 (m, 1H), 3.71 (s, 3H), 3.62–3.47 (m, 1H), 3.42– 3.29(m,2H),2.24–2.06(m,2H),1.46(s,9H),1.43–1.39(m,3H).
步骤B：(S,E)-4-(氟亚甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐Step B: (S,E)-4-(Fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride
室温条件下，将4M HCl-二氧六环(10mL)加入到(S,E)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯(600mg,2.09mmol)中，保持室温搅拌1h。浓缩除去酸溶液，得到白色固体(S,E)-4-(氟亚甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐(572mg,收率100％)。LCMS(m/z):188.1(M+H)。At room temperature, add 4M HCl-dioxane (10 mL) to (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert. Butyl ester-3-methyl ester (600 mg, 2.09 mmol) was stirred at room temperature for 1 h. The acid solution was concentrated and removed to obtain (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (572 mg, yield 100%) as a white solid. LCMS(m/z):188.1(M+H).
步骤C：(S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-羧酸甲酯Step C: (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
室温条件下，将(S,E)-4-(氟亚甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐(370mg,1.98mmol)溶解至甲醇(5mL)中，滴加三乙胺至反应液pH～10,搅拌10分钟，后滴加冰醋酸至反应液pH～4。 将甲醛水溶液(481.15mg,5.93mmol)加入反应液中，在室温下搅拌30min。将氰基硼氢化钠(136.62mg,2.17mmol)加入反应液中，在室温下搅拌2h。LCMS监测反应结束后，减压浓缩除去溶剂，无水四氢呋喃带蒸两遍后，得到白色固体(S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-羧酸甲酯(380mg,收率96％)。LCMS(m/z):202.1(M+H)。Dissolve (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (370 mg, 1.98 mmol) into methanol (5 mL) at room temperature. , add triethylamine dropwise until the pH of the reaction solution is ~10, stir for 10 minutes, and then add glacial acetic acid dropwise until the pH of the reaction solution is ~4. Formaldehyde aqueous solution (481.15 mg, 5.93 mmol) was added to the reaction solution, and stirred at room temperature for 30 min. Sodium cyanoborohydride (136.62 mg, 2.17 mmol) was added to the reaction solution, and stirred at room temperature for 2 h. After monitoring the reaction with LCMS, the solvent was concentrated under reduced pressure and evaporated twice with anhydrous tetrahydrofuran to obtain a white solid (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3. -Carboxylic acid methyl ester (380 mg, yield 96%). LCMS(m/z):202.1(M+H).
步骤D：(S,E)–(4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲醇Step D: (S,E)–(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol
在冰浴条件下，将1M的LiAlH4-THF溶液(2.83mL,107.5mg,2.83mmol)滴加到(E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-羧酸甲酯(380mg,1.89mmol)的无水四氢呋喃(5mL)溶液中。所得混合物在室温下搅拌20min。LCMS监测反应结束后，反应液用十水合硫酸钠淬灭，直到没有气泡产生。加入约5g无水硫酸钠除水。反应液用硅藻土过滤，滤饼用无水四氢呋喃洗涤三遍。收集滤液，浓缩至干，得无色油状产物(S,E)–(4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲醇(300mg,收率92％)。LCMS(m/z):174.1(M+H)。Under ice bath conditions, 1M LiAlH 4 -THF solution (2.83 mL, 107.5 mg, 2.83 mmol) was added dropwise to (E)-4-(fluoromethylene)-1,3-dimethylpiperidine- A solution of methyl 3-carboxylate (380 mg, 1.89 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at room temperature for 20 min. After the reaction was monitored by LCMS, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. Add about 5g anhydrous sodium sulfate to remove water. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with anhydrous tetrahydrofuran. Collect the filtrate and concentrate to dryness to obtain colorless oily product (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (300 mg, yield 92% ). LCMS(m/z):174.1(M+H).
中间体f
Intermediate f
((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲醇
((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol
步骤A：(S,E)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯及(S,Z)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯Step A: (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester and (S,Z )-4-(Fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-methyl ester
步骤A的合成参照中间体e步骤A合成所述进行。The synthesis of step A is carried out as described in the synthesis of step A of intermediate e.
步骤B：(3S,4S)-4-(氟甲基)-3-甲基哌啶-1,3-二羧酸酯-1-(叔丁基)-3-甲基酯Step B: (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl)-3-methyl ester
室温氮气保护下，将湿Pd/C(400mg,10％w/w)加入到(S,E)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯及(S,Z)-4-(氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-叔丁基酯-3-甲基酯混合物(850mg,2.96mmol)的甲醇(10mL)溶液中。用氢气球置换体系，在氢气氛围中搅拌反应过夜。TLC监测反应结束后，用硅藻土过滤，滤液浓缩至干，得到粗产品，通过FCC(SiO2，EA/PE＝0-10％)纯化，得到无色油状产物(3S,4S)-4-(氟甲基)-3-甲基哌啶-1,3-二羧酸酯-1-(叔丁 基)-3-甲基酯(600mg,收率70％)。LCMS(m/z):234.1(M-56+H),312.1(M+Na)。1H NMR(400MHz,甲醇-d4)δ4.76–4.70(m,0.5H),4.64–4.52(m,1H),4.46–4.41(m,0.5H),4.23(d,J＝13.7Hz,1H),4.08–3.99(m,1H),3.67(s,3H),3.06–2.86(m,1H),2.86–2.70(m,1H),1.95–1.81(m,1H),1.80–1.68(m,2H),1.46(s,9H),1.27(s,3H).19F NMR(376MHz,甲醇-d4)δ221.80.Under nitrogen protection at room temperature, wet Pd/C (400 mg, 10% w/w) was added to (S,E)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid -1-tert-butyl ester-3-methyl ester and (S,Z)-4-(fluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-tert-butyl ester -A solution of the 3-methyl ester mixture (850 mg, 2.96 mmol) in methanol (10 mL). The system was replaced with a hydrogen balloon, and the reaction was stirred overnight in a hydrogen atmosphere. After TLC monitoring of the reaction, filter through diatomaceous earth and concentrate the filtrate to dryness to obtain a crude product, which is purified by FCC (SiO 2 , EA/PE=0-10%) to obtain a colorless oily product (3S, 4S)-4 -(Fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1-(tert-butyl methyl)-3-methyl ester (600 mg, yield 70%). LCMS (m/z): 234.1 (M-56+H), 312.1 (M+Na). 1 H NMR (400MHz, methanol-d4) δ4.76–4.70 (m, 0.5H), 4.64–4.52 (m, 1H), 4.46–4.41 (m, 0.5H), 4.23 (d, J = 13.7Hz, 1H),4.08–3.99(m,1H),3.67(s,3H),3.06–2.86(m,1H),2.86–2.70(m,1H),1.95–1.81(m,1H),1.80–1.68( m,2H),1.46(s,9H),1.27(s,3H). 19 F NMR(376MHz, methanol-d4)δ221.80.
步骤C：(3S,4S)-4-(氟甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐Step C: (3S,4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride
室温下，将3M盐酸-二氧六环(10mL,30mmol)滴加到(3S,4S)-4-(氟甲基)-3-甲基哌啶-1,3-二羧酸酯-1-(叔丁基)-3-甲基酯(600mg,2.07mmol)的乙酸乙酯(10mL)溶液中，所得混合物在室温搅拌反应1h。LCMS监测反应完成，减压浓缩，得到白色固体(3S,4S)-4-(氟甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐(500mg,粗品)。LCMS(m/z):190.1(M+H)。At room temperature, 3M hydrochloric acid-dioxane (10 mL, 30 mmol) was added dropwise to (3S, 4S)-4-(fluoromethyl)-3-methylpiperidine-1,3-dicarboxylate-1 -(tert-butyl)-3-methyl ester (600 mg, 2.07 mmol) was dissolved in ethyl acetate (10 mL), and the resulting mixture was stirred and reacted at room temperature for 1 h. LCMS monitored the completion of the reaction, and concentrated under reduced pressure to obtain a white solid (3S, 4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (500 mg, crude product). LCMS(m/z):190.1(M+H).
步骤D：(3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯Step D: (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
室温下，将(3S,4S)-4-(氟甲基)-3-甲基哌啶-3-羧酸甲酯盐酸盐(500mg,上步粗品)溶于甲醇(10mL)，加入甲醛水溶液(2mL,35～40％w/w,～24mmol)，室温搅拌2h。分批加入氰基硼氢化钠(696mg,11.1mmol)，所得混合物室温搅拌反应2h。LCMS监测反应结束，饱和NH4Cl水溶液加入反应液中，用乙酸乙酯提取产物三次，合并有机相浓缩得到粗产品，通过FCC(SiO2，EA/PE＝0-100％)纯化，得到无色油状产物(3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯(200mg，收率44％)。LCMS(m/z):204.1(M+H)。Dissolve (3S, 4S)-4-(fluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (500 mg, crude product from the previous step) in methanol (10 mL) at room temperature, and add formaldehyde Aqueous solution (2mL, 35~40% w/w, ~24mmol), stirred at room temperature for 2h. Sodium cyanoborohydride (696 mg, 11.1 mmol) was added in batches, and the resulting mixture was stirred and reacted at room temperature for 2 h. LCMS monitors the end of the reaction, adds saturated NH 4 Cl aqueous solution to the reaction solution, extracts the product three times with ethyl acetate, combines the organic phases and concentrates to obtain a crude product, which is purified by FCC (SiO 2 , EA/PE=0-100%) to obtain free The color oily product (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester (200 mg, yield 44%). LCMS(m/z):204.1(M+H).
步骤E：((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲醇Step E: ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol
在室温条件下，将LiAlH4-THF(1.7mL,1M,1.7mmol)慢慢滴加到(3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯(200mg,0.869mmol)的无水THF(2mL)溶液中，所得混合物室温搅拌反应0.5小时。TLC监测反应结束，冰浴冷却，加入十水硫酸钠淬灭反应直至无气泡产生。补加适量的乙酸乙酯，无水硫酸钠干燥，过滤浓缩至干，得到无色油状粗产物((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲醇(100mg,收率58％)。LCMS(m/z):176.1(M+H)。At room temperature, LiAlH 4 -THF (1.7mL, 1M, 1.7mmol) was slowly added dropwise to (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3- In a solution of methyl carboxylate (200 mg, 0.869 mmol) in anhydrous THF (2 mL), the resulting mixture was stirred and reacted at room temperature for 0.5 hours. TLC monitored the reaction to completion, cooled it in an ice bath, and added sodium sulfate decahydrate to quench the reaction until no bubbles were generated. Add an appropriate amount of ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain a colorless oily crude product ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine- 3-yl)methanol (100 mg, yield 58%). LCMS(m/z):176.1(M+H).
中间体g
Intermediate g
(S)-(1,3-二甲基-4-亚甲基哌啶-3-基)甲醇
(S)-(1,3-Dimethyl-4-methylenepiperidin-3-yl)methanol
步骤A：(S)-(1,3-二甲基-4-亚甲基哌啶-3-基)甲醇 Step A: (S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol
室温下,将LiAlH4(0.7mL,2.5M THF溶液，1.75mmol)滴加到(S)-3-甲基-4-亚甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(150mg,0.56mmol)和THF(2mL)的混合体系中，滴加完毕后，加热至70℃搅拌3h。TLC监测反应结束后,加入Na2SO4·10H2O淬灭反应，再加入无水硫酸钠干燥，乙酸乙酯稀释，反应液过滤硅藻土除去固体，滤液浓缩后得到无色油状液体(S)-(1,3-二甲基-4-亚甲基哌啶-3-基)甲醇(120mg,收率80％)，直接用于后续反应。At room temperature, LiAlH 4 (0.7 mL, 2.5 M THF solution, 1.75 mmol) was added dropwise to (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylic acid-1-(tert. In a mixed system of butyl ester-3-methyl ester (150 mg, 0.56 mmol) and THF (2 mL), after the dropwise addition was completed, the mixture was heated to 70°C and stirred for 3 hours. After the reaction was monitored by TLC, Na 2 SO 4 ·10H 2 O was added to quench the reaction, then anhydrous sodium sulfate was added to dry it, and it was diluted with ethyl acetate. The reaction solution was filtered through diatomaceous earth to remove the solid, and the filtrate was concentrated to obtain a colorless oily liquid ( S)-(1,3-dimethyl-4-methylenepiperidin-3-yl)methanol (120 mg, yield 80%), was directly used in subsequent reactions.
中间体h
Intermediate h
((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇
((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol
步骤A：(S)-4-(二氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯Step A: (S)-4-(Difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester
将(R)-3-甲基-4-氧哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯(10.0g,36.86mmol)和2-((二氟甲基)磺酰基)吡啶(10.68g,55.29mmol)溶解到无水DMF(100mL)中,氮气置换三次。将体系用干冰乙醇浴冷却，滴加1摩尔的叔丁醇钾四氢呋喃溶液(66.34mL,66.34mmol)。所得混合液保持温度搅拌2h，后缓慢升至室温后继续搅拌3h。LCMS监测反应结束后，用饱和氯化铵水溶液(50mL)淬灭反应，加入水(200mL)、DCM/MeOH(100mL,v/v＝10/1)萃取5次。LiCl水溶液(100mL,4％w/w)洗涤3次，饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤浓缩干。所得粗品经FCC(SiO2,EA/PE＝0-20％)纯化后，得到淡黄色油状产物(5.2g,收率46％)。LCMS(m/z):250.1(M-56+H)。(R)-3-Methyl-4-oxopiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (10.0g, 36.86mmol) and 2-((di Fluoromethyl)sulfonyl)pyridine (10.68g, 55.29mmol) was dissolved in anhydrous DMF (100mL) and replaced with nitrogen three times. The system was cooled in a dry ice ethanol bath, and 1 mole of potassium tert-butoxide solution in tetrahydrofuran (66.34 mL, 66.34 mmol) was added dropwise. The resulting mixture was kept at temperature and stirred for 2 h, then slowly rose to room temperature and continued to stir for 3 h. After monitoring the reaction with LCMS, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), and water (200 mL) and DCM/MeOH (100 mL, v/v=10/1) were added for extraction 5 times. Wash three times with LiCl aqueous solution (100 mL, 4% w/w), wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate to dryness. After the crude product was purified by FCC (SiO 2 , EA/PE=0-20%), a light yellow oily product (5.2g, yield 46%) was obtained. LCMS(m/z):250.1(M-56+H).
步骤B：(3S,4S)-4-(二氟甲基)-3-甲基哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯Step B: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester
室温条件下，将(S)-4-(二氟亚甲基)-3-甲基哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯(6.20g,20.31mmol)溶解到甲醇(150mL)中，用氮气置换三次。加入钯碳(2.16g,10％w/w)，用氢气置换三次。在15Psi的氢气氛围下30℃搅拌4h。LCMS监测反应结束后，反应液用硅藻土过滤，滤饼用甲醇洗涤三遍。收集滤液，浓缩干,得到无色油状产物(3S,4S)-4-(二氟甲基)-3-甲基哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯(5.53g,收率89％)。LCMS(m/z):252.1(M-56+H)。At room temperature, (S)-4-(difluoromethylene)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (6.20g , 20.31 mmol) was dissolved in methanol (150 mL), and replaced with nitrogen three times. Palladium on carbon (2.16g, 10% w/w) was added and replaced with hydrogen three times. Stir at 30°C for 4 hours under a hydrogen atmosphere of 15 Psi. After the reaction was monitored by LCMS, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with methanol. Collect the filtrate and concentrate to dryness to obtain the colorless oily product (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3 -Methyl ester (5.53g, yield 89%). LCMS(m/z):252.1(M-56+H).
步骤C：(3S,4S)-4-(二氟甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐Step C: (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride
室温条件下，将(3S,4S)-4-(二氟甲基)-3-甲基哌啶-1,3-二羧酸-1-(叔丁基)-3-甲基酯(5.53g,17.99mmol)溶解于4M HCl/dioxane(60mL)中，所得混合液室温搅拌1h，浓缩除去酸溶液，得到白色固体(3S,4S)-4-(二氟甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐(4.38g,收率100％)。LCMS(m/z):208.1(M+H)。 At room temperature, (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylic acid-1-(tert-butyl)-3-methyl ester (5.53 g, 17.99mmol) was dissolved in 4M HCl/dioxane (60mL). The resulting mixture was stirred at room temperature for 1 h. The acid solution was concentrated to remove the acid solution to obtain a white solid (3S,4S)-4-(difluoromethyl)-3-methyl. Piperidine-3-carboxylic acid methyl ester hydrochloride (4.38g, yield 100%). LCMS(m/z):208.1(M+H).
步骤D：(3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯Step D: (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylic acid methyl ester
室温下，将(3S,4S)-4-(二氟甲基)-3-甲基哌啶-3-羧酸甲酯·盐酸盐(3.58g,14.69mmol),溶解至甲醇(40mL)中，加入甲醛水溶液(3.58g,37％w/w，44.07mmol)。所得混合物在室温下搅拌30min。加入氰基硼氢化钠(1.11g,17.63mmol)，所得混合液在室温下搅拌1.5h。LCMS监测反应结束后，将体系浓缩干，加入乙酸乙酯溶解粗产物，硅藻土过滤。所得滤液经FCC(SiO2,MeOH/DCM(含0.3％DIEA)＝0-4％)纯化后，得到无色油状产物(3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯(3.0g,收率92％)。LCMS(m/z):222.1(M+H)。Dissolve (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.58g, 14.69mmol) into methanol (40mL) at room temperature. , add formaldehyde aqueous solution (3.58g, 37% w/w, 44.07mmol). The resulting mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (1.11g, 17.63mmol) was added, and the resulting mixture was stirred at room temperature for 1.5h. After the reaction was monitored by LCMS, the system was concentrated to dryness, ethyl acetate was added to dissolve the crude product, and filtered through diatomaceous earth. After the obtained filtrate was purified by FCC (SiO 2 , MeOH/DCM (containing 0.3% DIEA) = 0-4%), the colorless oily product (3S, 4S)-4-(difluoromethyl)-1,3- was obtained. Dimethylpiperidine-3-carboxylic acid methyl ester (3.0g, yield 92%). LCMS(m/z):222.1(M+H).
步骤E：(3S,4S)-(4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇Step E: (3S,4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol
在冰浴条件下，将1M的LiAlH4-THF(17.63mL,17.63mmol)滴加到(3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-羧酸甲酯(3.0g,13.56mmol)的无水THF(30mL)溶液中。所得混合液在0℃搅拌15min。LCMS监测反应结束后，加入十水合的硫酸钠淬灭反应，直到没有气泡产生。加入约8g无水硫酸钠。硅藻土过滤，滤饼用无水四氢呋喃洗涤3次。收集滤液，浓缩干，得到无色固体产物(3S,4S)-(4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(2.6g,收率99％)。LCMS(m/z):194.1(M+H)。Under ice bath conditions, 1M LiAlH 4 -THF (17.63 mL, 17.63 mmol) was added dropwise to (3S, 4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3- A solution of methyl carboxylate (3.0 g, 13.56 mmol) in anhydrous THF (30 mL). The resulting mixture was stirred at 0°C for 15 min. After the reaction was monitored by LCMS, sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated. Add about 8g anhydrous sodium sulfate. Filter through diatomaceous earth, and wash the filter cake three times with anhydrous tetrahydrofuran. Collect the filtrate and concentrate to dryness to obtain the colorless solid product (3S, 4S)-(4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (2.6g, yield 99%) ). LCMS(m/z):194.1(M+H).
中间体i
Intermediate i
(3S)-(4-甲氧基-1,3-二甲基哌啶-3-基)甲醇
(3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol
步骤A：(3R)-4-羟基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯Step A: (3R)-4-Hydroxy-3-methylpiperidine-1,3-dicarboxylate 1-(tert-butyl)ester 3-methyl ester
冰浴条件下，将NaBH4(279mg,7.37mmol)分批加入到(R)-3-甲基-4-氧哌啶-1-羧酸叔丁酯-3-羧酸甲酯(2.0g，7.37mmol)和MeOH(50mL)的混合溶液中，冰浴条件下搅拌10min，TLC显示原料消失。然后把反应液倒入NH4Cl(100mL)中，EA(100mL×3)萃取，收集的有机相用饱和NaCl水溶液(30mL)洗涤，有机相浓缩后，得到的粗品经FCC(SiO2，EA/PE＝0％～40％)纯化，得到无色油状液体(3R)-4-羟基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(1.7g,收率85％)。LCMS(m/z):218.1(M+H-56)。1H NMR(400MHz,Chloroform-d)δ4.05–3.93(m,1H),3.78–3.70(m,3H),3.69–3.59(m,2H),3.35–3.22(m,1H),3.20–3.10(m,1H),1.97–1.82(m,1H),1.77–1.63(m,1H),1.54–1.40(m,9H),1.29–1.18(m,3H)。 Under ice bath conditions, NaBH 4 (279 mg, 7.37 mmol) was added in portions to (R)-3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (2.0g , 7.37 mmol) and MeOH (50 mL) in a mixed solution, stirred for 10 min under ice bath conditions, TLC showed that the raw material disappeared. Then the reaction solution was poured into NH 4 Cl (100 mL), and extracted with EA (100 mL × 3). The collected organic phase was washed with saturated NaCl aqueous solution (30 mL). After the organic phase was concentrated, the crude product obtained was subjected to FCC (SiO 2 , EA /PE=0%~40%) and purified to obtain colorless oily liquid (3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-methyl Ester (1.7g, yield 85%). LCMS(m/z):218.1(M+H-56). 1 H NMR(400MHz,Chloroform-d)δ4.05–3.93(m,1H),3.78–3.70(m,3H),3.69–3.59(m,2H),3.35–3.22(m,1H),3.20– 3.10(m,1H),1.97–1.82(m,1H),1.77–1.63(m,1H),1.54–1.40(m,9H),1.29–1.18(m,3H).
步骤B：(3R)-4-甲氧基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯Step B: (3R)-4-Methoxy-3-methylpiperidine-1,3-dicarboxylate 1-(tert-butyl)ester 3-methyl ester
冰浴条件下，将NaH(439mg,10.94mmol,60％)加入到(3R)-4-羟基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(1.0g,3.66mmol)和DMF(10mL)的混合溶液中，并搅拌20分钟。后将CH3I(1.56g,10.94mmol)加入到上述反应液中，在冰浴条件下继续搅拌3h。TLC监测反应结束后，把反应液倒入饱和NH4Cl水溶液(80mL)中，加入EA(50mL×3)萃取，收集的有机相用饱和NaCl水溶液(20mL)洗涤，浓缩后的粗品经FCC(SiO2，EA/PE＝0～40％)纯化，得到白色固体(3R)-4-甲氧基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(1.0g,收率95％)。LCMS(m/z):232.1(M+H-56)。1H NMR(400MHz,Chloroform-d3)δ3.98–3.78(m,1H),3.75–3.61(m,4H),3.56–3.47(m,1H),3.46–3.36(m,1H),3.34(s,1H),3.30(s,2H),3.19–2.86(m,1H),1.89–1.56(m,2H),1.45(s,9H),1.16(s,3H)。Under ice bath conditions, NaH (439 mg, 10.94 mmol, 60%) was added to (3R)-4-hydroxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3- into a mixed solution of methyl ester (1.0 g, 3.66 mmol) and DMF (10 mL), and stirred for 20 minutes. Then, CH 3 I (1.56 g, 10.94 mmol) was added to the above reaction solution, and stirring was continued for 3 h under ice bath conditions. After the reaction was monitored by TLC, the reaction solution was poured into saturated NH 4 Cl aqueous solution (80 mL), and EA (50 mL × 3) was added for extraction. The collected organic phase was washed with saturated NaCl aqueous solution (20 mL), and the concentrated crude product was subjected to FCC ( SiO 2 , EA/PE=0～40%) was purified to obtain white solid (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3 -Methyl ester (1.0g, yield 95%). LCMS(m/z):232.1(M+H-56). 1 H NMR (400MHz, Chloroform-d 3 ) δ3.98–3.78(m,1H),3.75–3.61(m,4H),3.56–3.47(m,1H),3.46–3.36(m,1H),3.34 (s,1H),3.30(s,2H),3.19–2.86(m,1H),1.89–1.56(m,2H),1.45(s,9H),1.16(s,3H).
步骤C：(3S)-(4-甲氧基-1,3-二甲基哌啶-3-基)甲醇Step C: (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol
室温条件下，将LiAH4(2.04mL,2.04mmol,1M in THF)加到(3R)-4-甲氧基-3-甲基哌啶-1,3-二羧酸1-(叔丁基)酯3-甲基酯(200mg,0.696mmol)中并升温至70℃搅拌2h。LCMS监测反应结束后，在冰浴条件下，缓慢将Na2SO4·10H2O加入反应液中淬灭LiAH4，直到反应不再生成气体为止，加入少量EA稀释，再加入无水硫酸钠干燥，过滤，收集母液浓缩，得到无色液体(3S)-(4-甲氧基-1,3-二甲基哌啶-3-基)甲醇(120mg,收率99％)。LCMS(m/z):174.1(M+H)。1H NMR(400MHz,Chloroform-d3)δ3.95–3.53(m,4H),3.30(s,2H),3.27(s,1H),3.13–2.55(m,2H),2.16(s,1H),2.13(s,2H),2.04–1.81(m,3H),0.89(s,1H),0.83(s,2H)。LiAH 4 (2.04 mL, 2.04 mmol, 1 M in THF) was added to (3R)-4-methoxy-3-methylpiperidine-1,3-dicarboxylic acid 1-(tert-butyl) at room temperature. ) ester 3-methyl ester (200 mg, 0.696 mmol) and heated to 70°C and stirred for 2 h. After monitoring the reaction with LCMS, slowly add Na 2 SO 4 ·10H 2 O to the reaction solution to quench LiAH 4 under ice bath conditions until the reaction no longer generates gas. Add a small amount of EA to dilute, and then add anhydrous sodium sulfate. Dry, filter, collect the mother liquor and concentrate to obtain colorless liquid (3S)-(4-methoxy-1,3-dimethylpiperidin-3-yl)methanol (120 mg, yield 99%). LCMS(m/z):174.1(M+H). 1 H NMR (400MHz, Chloroform-d 3 ) δ3.95–3.53(m,4H),3.30(s,2H),3.27(s,1H),3.13–2.55(m,2H),2.16(s,1H ),2.13(s,2H),2.04–1.81(m,3H),0.89(s,1H),0.83(s,2H).
中间体j
Intermediate j
(S)-(4,6-二甲基-6-氮杂螺[2.5]辛-4-基)甲醇
(S)-(4,6-dimethyl-6-azaspiro[2.5]oct-4-yl)methanol
步骤A：(4S)-1,1-二氯-4-甲基-6-氮杂螺[2.5]辛烷-4,6-二羧酸-6-叔丁基-4-甲基酯Step A: (4S)-1,1-dichloro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic acid-6-tert-butyl-4-methyl ester
室温下，将TEBAC(25.4mg,0.11mmol)加入到(S)-3-甲基-4-亚甲基哌啶-1,3-二羧酸-1-(叔丁基)酯-3-甲基酯(250mg,0.93mmol)，氢氧化钠(7.5mL,50％wt)和CHCl3(25mL)的混合溶液中，加完后加热到80℃搅拌过夜。LCMS监测反应结束后，加入水(50mL)、DCM(50mL×3)萃取。有机相用饱和食盐水洗涤,收集有机相浓缩并进一步FCC(SiO2，EA/PE＝0-25％)纯化，得到无色液体(4S)-1,1-二氯-4-甲基-6-氮杂螺[2.5]辛烷-4,6-二羧酸-6-叔丁基-4-甲基酯(320mg, 收率98％)。LC-MS(m/z):296.0(M-56)。TEBAC (25.4 mg, 0.11 mmol) was added to (S)-3-methyl-4-methylenepiperidine-1,3-dicarboxylic acid-1-(tert-butyl)ester-3- at room temperature. To a mixed solution of methyl ester (250 mg, 0.93 mmol), sodium hydroxide (7.5 mL, 50% wt) and CHCl 3 (25 mL), heat to 80°C and stir overnight. After the reaction was monitored by LCMS, water (50 mL) and DCM (50 mL × 3) were added for extraction. The organic phase was washed with saturated brine, collected, concentrated and further purified by FCC (SiO 2 , EA/PE=0-25%) to obtain colorless liquid (4S)-1,1-dichloro-4-methyl- 6-Azaspiro[2.5]octane-4,6-dicarboxylic acid-6-tert-butyl-4-methyl ester (320mg, Yield 98%). LC-MS(m/z):296.0(M-56).
步骤B：(S)-(4,6-二甲基-6-氮杂螺[2.5]辛-4-基)甲醇Step B: (S)-(4,6-dimethyl-6-azaspiro[2.5]oct-4-yl)methanol
室温下，将LiAlH4(1M,2.2mmol,2.2mL)滴入(4S)-1,1-二氯-4-甲基-6-氮杂螺[2.5]辛烷-4,6-二羧酸-6-叔丁基-4-甲基酯(130mg,0.37mmol)和THF(2mL)的混合溶液中，滴加完成后将体系加热到70℃搅拌过夜。LCMS监测反应结束后，加入Na2SO4·10H2O淬灭反应直到没有气体产生为止，反应液通过硅藻土过滤，得到的滤液低温(35℃)浓缩，得到无色液体(S)-(4,6-二甲基-6-氮杂螺[2.5]辛-4-基)甲醇(40mg,收率62％)。LC-MS(m/z):170.1(M+H)。At room temperature, LiAlH 4 (1M, 2.2mmol, 2.2mL) was dropped into (4S)-1,1-dichloro-4-methyl-6-azaspiro[2.5]octane-4,6-dicarboxylic into a mixed solution of acid-6-tert-butyl-4-methyl ester (130 mg, 0.37 mmol) and THF (2 mL). After the dropwise addition was completed, the system was heated to 70°C and stirred overnight. After the reaction is monitored by LCMS, Na 2 SO 4 ·10H 2 O is added to quench the reaction until no gas is generated. The reaction solution is filtered through diatomaceous earth, and the obtained filtrate is concentrated at low temperature (35°C) to obtain a colorless liquid (S)- (4,6-Dimethyl-6-azaspiro[2.5]oct-4-yl)methanol (40 mg, yield 62%). LC-MS (m/z): 170.1 (M+H).
参照上述合成方案或者适当变体制备了以下中间体：
The following intermediates were prepared with reference to the above synthetic scheme or appropriate variations:
中间体e-d3
Intermediate e-d3
(S,E)-(4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲醇
(S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methanol
步骤A：(S,E)-4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-甲酸甲酯Step A: (S,E)-4-(Fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidine-3-carboxylic acid methyl ester
室温下，将碳酸钾(5.55g，40.2mmol)加入到(S,E)-4-(氟亚甲基)-3-甲基哌啶-3-羧酸甲酯盐酸盐(3.00g,13.4mmol)、氘代碘甲烷(2.33g,16.1mmol)和ACN(100mL)的混合溶液中，加完后加热至90℃搅拌过夜。LCMS监测反应结束后，过滤,用EA(50mL)淋洗滤饼。收集滤液浓缩并进一步FCC(SiO2，EA/PE＝0-20％)纯化，得到无色液体(S,E)-4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-甲酸甲酯(1.9g,收率69％)。LC-MS(m/z):205.1(M+H)。At room temperature, potassium carbonate (5.55g, 40.2mmol) was added to (S,E)-4-(fluoromethylene)-3-methylpiperidine-3-carboxylic acid methyl ester hydrochloride (3.00g, 13.4 mmol), deuterated methyl iodide (2.33 g, 16.1 mmol) and ACN (100 mL). After adding, heat to 90°C and stir overnight. After monitoring the reaction with LCMS, filter and rinse the filter cake with EA (50 mL). The filtrate was collected, concentrated and further purified by FCC (SiO 2 , EA/PE=0-20%) to obtain a colorless liquid (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl -d 3 ) Piperidine-3-carboxylic acid methyl ester (1.9g, yield 69%). LC-MS(m/z):205.1(M+H).
步骤B：(S,E)-(4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲醇Step B: (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methanol
冰浴下，将LiAlH4(1M-THF,9.3mmol,9.3mL)滴入(S,E)-4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-甲酸甲酯(1.9g,9.3mmol)和THF(50mL)的混合溶液中，加完后在0℃冰浴搅拌0.5h。LCMS监测反应结束后，用Na2SO4·10H2O淬灭反应直到没有气体产生为止，反应液通过硅藻土过滤，得到的滤液低温(35℃)浓缩，得到无色液体4-氟亚甲基-3-甲基-1-甲基-D3-哌啶-3-甲醇(1.3g,79％收率)。LC-MS(m/z):177.1(M+H)。Under ice bath, add LiAlH 4 (1M-THF, 9.3mmol, 9.3mL) dropwise into (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piper into a mixed solution of methyl helidine-3-carboxylate (1.9g, 9.3mmol) and THF (50mL). After adding, stir in an ice bath at 0°C for 0.5h. After monitoring the reaction with LCMS, the reaction was quenched with Na 2 SO 4 ·10H 2 O until no gas was produced. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was concentrated at low temperature (35°C) to obtain a colorless liquid 4-fluoride. Methyl-3-methyl-1-methyl-D3-piperidine-3-methanol (1.3 g, 79% yield). LC-MS(m/z):177.1(M+H).
中间体e-d5
Intermediate e-d5
(S,E)-(4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)亚甲基-d2-醇
(S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methylene-d 2 -ol
步骤A：(S,E)-(4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)亚甲基-d2-醇Step A: (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methylene-d 2 -ol
在冰浴条件下，将LiAlD4粉末(271.28mg,6.46mmol)加入到(S,E)-4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-甲酸甲酯(1.10g,5.39mmol)的无水四氢呋喃(15mL)溶液中。所得混合物在室温下搅拌15min。LCMS监测反应结束后，反应液用十水合硫酸钠淬灭，直到没有气泡产生。再向反应液中加入约5克的无水硫酸钠除水。反应液用硅藻土过滤，滤饼用无水四氢呋喃洗涤 三遍。收集滤液，浓缩至干，得到无色油状产物(S,E)-(4-(氟亚甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)亚甲基-d2-醇(951mg,收率99％)。该产品没有经过纯化直接用于下一步反应。LCMS(m/z):179.1(M+H)。LiAlD 4 powder (271.28 mg, 6.46 mmol) was added to (S,E)-4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidine under ice bath conditions. -A solution of methyl 3-formate (1.10 g, 5.39 mmol) in anhydrous tetrahydrofuran (15 mL). The resulting mixture was stirred at room temperature for 15 min. After the reaction was monitored by LCMS, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. Then add about 5 grams of anhydrous sodium sulfate to the reaction solution to remove water. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with anhydrous tetrahydrofuran. Three times. The filtrate was collected and concentrated to dryness to obtain the colorless oily product (S,E)-(4-(fluoromethylene)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)ylidene. Methyl- d2 -ol (951 mg, yield 99%). This product was used directly in the next reaction without purification. LCMS(m/z):179.1(M+H).
参照上述方法合成下列中间体h-d3及h-d5。Refer to the above method to synthesize the following intermediates h-d3 and h-d5.
中间体h-d3
Intermediate h-d3
((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲醇((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methanol
中间体h-d5
Intermediate h-d5
((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲-d2-醇((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methan-d 2 -ol
实施例1
Example 1
1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇

1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine) -7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

步骤A：1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazoline -4-yl)-3-methylpiperidin-3-ol
将((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲醇(191mg，1.20mmol)和氢化钠(64mg,60％w/w,1.60mmol)的THF(10mL)溶液在0℃下搅拌15min，然后一次性加入1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇(300mg，0.80mmol)。所得体系继续搅拌1.5h，缓慢升至室温。LCMS监测反应完成，体系中加入饱和氯化铵水溶液(20mL)，乙酸乙酯萃取(15mL×2)。合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥。过滤，减压浓缩，粗品经FCC(SiO2，MeOH/DCM＝0-20％)纯化，得到黄色固体1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(283mg，收率71％)。LCMS(m/z):497.0,499.1(M+H)。((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (191 mg, 1.20 mmol) and sodium hydride (64 mg, 60% w/w, 1.60 mmol) were mixed The THF (10 mL) solution was stirred at 0°C for 15 min, and then 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ( 300mg, 0.80mmol). The resulting system continued to stir for 1.5 h and slowly rose to room temperature. LCMS monitored the completion of the reaction, added saturated aqueous ammonium chloride solution (20 mL) to the system, and extracted with ethyl acetate (15 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The crude product is purified by FCC (SiO 2 , MeOH/DCM=0-20%) to obtain a yellow solid 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (283 mg, yield 71%). LCMS(m/z):497.0,499.1(M+H).
步骤B：1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene- 1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl piperidin-3-ol
氮气保护下，将1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(200mg，0.40mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(349mg，0.64mmol)、Pd(dtbpf)Cl2(26mg，0.04mmol)、K3PO4(256mg，1.21mmol)的1,4-二氧六环/水(V/V＝4:1,6mL)溶液加热至100℃，搅拌反应1.5h。LCMS监测反应完成，体系冷至室温，经硅藻土过滤，滤液减压浓缩。所得粗品经FCC(SiO2，EA/PE＝0-100％)纯化，得到棕色固体1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(243mg，收率66％)。LCMS(m/z):915.4(M+H)。Under nitrogen protection, 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quin Zozolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.40 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(( 1 of triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (349 mg, 0.64 mmol), Pd(dtbpf)Cl 2 (26 mg, 0.04 mmol), K 3 PO 4 (256 mg, 1.21 mmol) , 4-dioxane/water (V/V=4:1, 6mL) solution was heated to 100°C and stirred for 1.5h. LCMS monitored the completion of the reaction. The system was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a brown solid 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl) )-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -(yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (243 mg, yield 66%). LCMS(m/z):915.4(M+H).
步骤C：1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step C: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
将1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(240mg，0.26mmol)和氟化铯(398mg，2.6mmol)的DMF(2mL)溶液，加热至50℃，搅拌反应1.5h。LCMS监测反应完成，过滤除去氟化铯固体，滤液经Pre-HPLC(C18E,ACN/(0.1％NH4HCO3/H2O)＝45-95％)纯化，得到白色固体1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(97mg，收率61％)。1H NMR(400MHz,DMSO-d6)δ7.91–7.72(m,2H),7.44–7.34(m,1H),7.30–7.23(m,1H),7.21–7.15(m,1H),7.10–7.02(m,1H),5.28(d,J＝54.1Hz,1H),4.14–3.93(m,3H),3.91–3.71(m,2H),3.16– 3.06(m,2H),3.04–2.98(m,1H),2.88–2.78(m,1H),2.18–1.95(m,4H),1.87–1.57(m,6H),1.15(d,J＝6.2Hz,3H),1.02–0.96(m,3H).19F NMR(376MHz,DMSO-d6)δ-111.75,-129.31,-172.02.LCMS(m/z):603.1(M+H)。1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperdine A solution of din-3-ol (240 mg, 0.26 mmol) and cesium fluoride (398 mg, 2.6 mmol) in DMF (2 mL) was heated to 50°C and stirred for 1.5 h. LCMS monitors the completion of the reaction, and the cesium fluoride solid is removed by filtration. The filtrate is purified by Pre-HPLC (C18E, ACN/(0.1% NH 4 HCO 3 /H 2 O) = 45-95%) to obtain a white solid 1-(7- (8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H) -(yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (97 mg, yield 61%). 1 H NMR (400MHz, DMSO-d 6 ) δ7.91–7.72(m,2H),7.44–7.34(m,1H),7.30–7.23(m,1H),7.21–7.15(m,1H),7.10 –7.02(m,1H),5.28(d,J＝54.1Hz,1H),4.14–3.93(m,3H),3.91–3.71(m,2H),3.16– 3.06(m,2H),3.04–2.98(m,1H),2.88–2.78(m,1H),2.18–1.95(m,4H),1.87–1.57(m,6H),1.15(d,J＝6.2 Hz, 3H), 1.02–0.96 (m, 3H). 19 F NMR (376MHz, DMSO-d 6 ) δ-111.75, -129.31, -172.02. LCMS (m/z): 603.1 (M+H).
实施例2
Example 2
1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇
1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrroli Azine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
步骤A：1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
向化合物1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(17mg,0.028mmol)中加入甲醇(1mL)。在N2条件下，将Pd/C(6.0mg,0.003mmol)加入到反应体系中，用H2(15psi)将反应液置换三次，保持H2氛围室温度搅拌3小时。LCMS监测反应完全。反应液通过硅藻土过滤，滤液再经过滤头过滤，浓缩，冻干后得到白色固体1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-((((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(7.0mg，收率41％)。1H NMR(400MHz,DMSO-d6)δ7.91(dd,J＝8.5,6.6Hz,1H),7.73(dd,J＝9.1,6.0Hz,1H),7.38–7.24(m,3H),6.96–6.89(m,1H),5.27(d,J＝54.5Hz,1H),4.80–4.53(m,1H),4.13–4.07(m,1H),4.05–3.95(m,2H),3.90–3.78(m,1H),3.52(d,J＝13.0Hz,1H),3.12–3.05(m,2H),3.03–2.99(m,1H),2.88–2.76(m,1H),2.41–2.29(m,2H),2.15–1.98(m,4H),1.85–1.61(m,6H),1.15(d,J＝14.4Hz,3H),1.05–0.92(m,1H),0.76–0.67(m,3H).19F NMR(376MHz,DMSO-d6)δ-128.38,-172.12.LCMS(m/z):607.3(M+H)。To the compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Methanol (1 mL) was added to riazine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (17 mg, 0.028 mmol). Under N 2 conditions, Pd/C (6.0 mg, 0.003 mmol) was added to the reaction system, the reaction solution was replaced three times with H 2 (15 psi), and the H 2 atmosphere chamber temperature was maintained for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was filtered through a filter head, concentrated, and lyophilized to obtain a white solid 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- Fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiper Din-3-ol (7.0 mg, yield 41%). 1 H NMR (400MHz, DMSO-d 6 ) δ7.91 (dd, J = 8.5, 6.6 Hz, 1H), 7.73 (dd, J = 9.1, 6.0Hz,1H),7.38–7.24(m,3H),6.96–6.89(m,1H),5.27(d,J＝54.5Hz,1H),4.80–4.53(m,1H),4.13–4.07(m ,1H),4.05–3.95(m,2H),3.90–3.78(m,1H),3.52(d,J＝13.0Hz,1H),3.12–3.05(m,2H),3.03–2.99(m,1H ),2.88–2.76(m,1H),2.41–2.29(m,2H),2.15–1.98(m,4H),1.85–1.61(m,6H),1.15(d,J＝14.4Hz,3H), 1.05–0.92(m,1H),0.76–0.67(m,3H). 19 F NMR (376MHz, DMSO-d 6 )δ-128.38,-172.12. LCMS (m/z): 607.3(M+H).
实施例3
Example 3
1-(2-((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐
1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol formate
步骤A：1-(7-溴-2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: 1-(7-bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3 -Methylpiperidin-3-ol
在冰浴条件下，将(R)-(1,2-二甲基吡咯烷-2-基)甲醇(100mg,0.8mmol)溶解到无水四氢呋喃(5mL)中，缓慢加入钠氢(40mg,60％w/w,1.0mmol)到反应体系中，保持温度搅拌反应半小时。将1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇(200mg,0.53mmol)加入到反应体系中，所得混合物在室温条件下继续搅拌反应2小时。LCMS监测反应结束后，将体系倒入冰水(50mL)中淬灭反应，再用乙酸乙酯萃取3次。合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩干，所得的粗产品经过FCC(SiO2，MeOH/DCM＝10-30％)纯化，得黄色油状产物1-(7-溴-2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇(170mg,收率68％)。LCMS(m/z):469.0(M+H)。Dissolve (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (100 mg, 0.8 mmol) in anhydrous tetrahydrofuran (5 mL) under ice bath conditions, and slowly add sodium hydrogen (40 mg, 60% w/w, 1.0 mmol) into the reaction system, maintaining the temperature and stirring for half an hour. 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.53 mmol) was added to the reaction system, and the resulting mixture was at room temperature. Continue to stir the reaction under these conditions for 2 hours. After the reaction was monitored by LCMS, the system was poured into ice water (50 mL) to quench the reaction, and then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product obtained was purified by FCC (SiO 2 , MeOH/DCM=10-30%) to obtain the yellow oily product 1-(7-bromo- 2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol ( 170 mg, yield 68%). LCMS(m/z):469.0(M+H).
步骤B：1-(2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-(三异丙基硅氧烷基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triiso Propylsilyl)ethynyl)-3-(triisopropylsiloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
在N2保护下，将化合物1-(7-溴-2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇(140mg,0.28mmol)和(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(238mg,0.42mmol)溶于1,4-二氧六环/水(V/V＝4:1,6mL)中。然后在N2条件下加入Pd(dtbpf)Cl2(34mg,0.028mmol)和磷酸钾(126mg,0.56mmol)。所得混合物在110℃下搅拌反应2小时。LCMS监测反应完成，将体系减压浓缩干，所得粗产品通过 FCC(MeOH/DCM＝0-10％)纯化，得到黄色固体1-(2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-(三异丙基硅氧烷基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg,收率56％)。LCMS(m/z):885.5(M+H)。Under N protection, compound 1-(7-bromo-2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazoline-4 -yl)-3-methylpiperidin-3-ol (140 mg, 0.28 mmol) and (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl) Silyl)oxy)naphth-1-yl)boronic acid (238 mg, 0.42 mmol) was dissolved in 1,4-dioxane/water (V/V = 4:1, 6 mL). Then Pd(dtbpf)Cl 2 (34 mg, 0.028 mmol) and potassium phosphate (126 mg, 0.56 mmol) were added under N 2 conditions. The resulting mixture was stirred and reacted at 110°C for 2 hours. LCMS monitors the completion of the reaction, and the system is concentrated to dryness under reduced pressure, and the crude product obtained is passed FCC (MeOH/DCM=0-10%) purification gave a yellow solid 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro- 7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triisopropylsiloxy)naphthalen-1-yl)quinazolin-4-yl)- 3-Methylpiperidin-3-ol (150 mg, yield 56%). LCMS(m/z):885.5(M+H).
步骤C：1-(2-((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐Step C: 1-(2-((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -(yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·formate
室温搅拌下，将1-(2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-(三异丙基硅氧烷基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(130mg,0.15mmol)溶解到无水DMF(2mL)中，加入氟化铯(223mg,1.5mmol)。升温至50℃搅拌反应2小时，LCMS监测反应完成。过滤除去不溶物，滤液经过pre-HPLC(C18E,ACN/(0.1％FA/H2O)＝45-95％)纯化，得到白色固体1-(2-((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐(41mg,收率48％)。1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.96(dd,J＝9.2,5.9Hz,1H),7.83(dd,J＝32.3,8.6Hz,1H),7.51–7.41(m,1H),7.36(d,J＝2.6Hz,1H),7.26–7.16(m,1H),7.09(dd,J＝11.7,2.6Hz,1H),4.27–4.15(m,2H),4.13–3.96(m,1H),3.93–3.75(m,3H),3.54–3.26(m,2H),2.97–2.88(m,1H),2.71–2.61(m,1H),2.33(s,3H),2.15–1.90(m,2H),1.76–1.58(m,6H),1.16(d,J＝7.2Hz,3H),1.07(d,J＝1.5Hz,3H).19F NMR(376MHz,DMSO-d6)δ-110.52,-128.59～-129.23.LCMS(m/z):573.2(M+H)。Under stirring at room temperature, 1-(2-(((R)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-8-(( Triisopropylsilyl)ethynyl)-3-(triisopropylsiloxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol ( 130 mg, 0.15 mmol) was dissolved in anhydrous DMF (2 mL), and cesium fluoride (223 mg, 1.5 mmol) was added. The temperature was raised to 50°C and the reaction was stirred for 2 hours, and LCMS monitored the completion of the reaction. Insoluble matter was removed by filtration, and the filtrate was purified by pre-HPLC (C18E, ACN/(0.1% FA/H 2 O) = 45-95%) to obtain a white solid 1-(2-((R)-1,2-di Methylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3- Methylpiperidin-3-ol·formate (41 mg, yield 48%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.19 (s, 1H), 7.96 (dd, J＝9.2, 5.9Hz, 1H), 7.83 (dd, J＝32.3, 8.6Hz, 1H), 7.51– 7.41(m,1H),7.36(d,J＝2.6Hz,1H),7.26–7.16(m,1H),7.09(dd,J＝11.7,2.6Hz,1H),4.27–4.15(m,2H) ,4.13–3.96(m,1H),3.93–3.75(m,3H),3.54–3.26(m,2H),2.97–2.88(m,1H),2.71–2.61(m,1H),2.33(s, 3H), 2.15–1.90 (m, 2H), 1.76–1.58 (m, 6H), 1.16 (d, J = 7.2Hz, 3H), 1.07 (d, J = 1.5Hz, 3H). 19 F NMR (376MHz , DMSO-d 6 )δ-110.52,-128.59～-129.23.LCMS (m/z): 573.2 (M+H).
实施例4
Example 4
1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐
1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidine-2- (yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate
步骤A：1-(7-溴-8-氟-2-((3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperidin-3-ol
将(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(110mg，0.7mmol)溶入THF(1mL)中，再向反应体系中加入NaH(46.3mg，1.2mmol)。室温条件下搅拌30分钟，向反应体系中加入1-(7-溴-2-氯-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇(173mg，0.46mmol)，室温继续搅拌3h。LCMS监测反应结束后，用饱和氯化铵水溶液淬灭反应，DCM(15mL×3)萃取，无水硫酸钠干燥有机相，过滤、浓缩。所得粗品经FCC纯化(SiO2，MeOH/DCM＝0-30％)，得到淡黄色固体1-(7-溴-8-氟-2-((3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg，收率26％)。LCMS(m/z):497.0(M+H)。Dissolve (3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (110 mg, 0.7 mmol) in THF (1 mL), and then add NaH (46.3 mg, 1.2 mmol) to the reaction system ). Stir at room temperature for 30 minutes, and add 1-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (173 mg, 0.46 mmol) to the reaction system. ) and continue stirring at room temperature for 3 h. After monitoring the reaction with LCMS, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with DCM (15 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by FCC (SiO 2 , MeOH/DCM=0-30%) to obtain a light yellow solid 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethyl) pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 26%). LCMS(m/z):497.0(M+H).
步骤B：1-(8-氟-7-(7-氟-8-(三异丙基甲硅烷基)乙炔基)-3-(三异丙基甲硅烷基)氧基)萘-1-基)-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1- (yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
氮气保护下，向1-(7-溴-8-氟-2-((3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg，0.12mmol)的1,4-二氧六环/H2O(V/V＝4:1，1.0mL)溶液中依次加入(7-氟-8-(三异丙基硅基)乙炔基)-3-(三异甲基硅基)氧基)萘-1-基)硼酸(131mg，0.24mmol)，PdCl2(dtbpf)(7.8mg,0.012mmol),K3PO4(76.8mg,0.36mmol)之后110℃条件下反应3h。减压浓缩后粗品经FCC纯化(SiO2，MeOH/DCM＝0-30％)，得到淡黄色固体1-(8-氟-7-(7-氟-8-(三异丙基甲硅烷基)乙炔基)-3-(三异丙基甲硅烷基)氧基)萘-1-基)-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(80mg，收率73％)。LCMS(m/z):916.4(M+H)。Under nitrogen protection, 1-(7-bromo-8-fluoro-2-((3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazoline-4- ( 7 -Fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisomethylsilyl)oxy)naphth-1-yl)boronic acid (131 mg, 0.24 mmol), PdCl 2 (dtbpf) ( 7.8mg, 0.012mmol), K 3 PO 4 (76.8mg, 0.36mmol) and then reacted at 110°C for 3h. After concentration under reduced pressure, the crude product was purified by FCC (SiO 2 , MeOH/DCM=0-30%) to obtain a light yellow solid 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl) )Ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)-2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methyl Oxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (80 mg, yield 73%). LCMS(m/z):916.4(M+H).
步骤C：1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐Step C: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidine) -2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol formate
向1-(8-氟-7-(7-氟-8-(三异丙基甲硅烷基)乙炔基)-3-(三异丙基甲硅烷基)氧基)萘-1-基)-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(80.0mg,0.087mmol)的DMF(1mL)溶液中加入CsF(134mg,0.88mmol)。所得混合物在50℃下加热搅拌2h,冷至室温，过滤除去不溶物，滤液用Pre-HPLC(C18E,ACN/(0.1％FA/H2O)＝45-95％)纯化，得淡黄色固体1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·甲酸盐(30mg,收率57％)LCMS(m/z):603.0(M+H)。To 1-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl) -2-(3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (80.0 mg CsF (134 mg, 0.88 mmol) was added to a solution of DMF (1 mL). The resulting mixture was heated and stirred at 50°C for 2 hours, cooled to room temperature, filtered to remove insoluble matter, and the filtrate was purified by Pre-HPLC (C18E, ACN/(0.1% FA/H 2 O) = 45-95%) to obtain a light yellow solid. 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(3-methoxy-1,2-dimethylpyrrolidine-2- (yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol·formate (30 mg, yield 57%) LCMS (m/z): 603.0 (M+H) .
参照上述化合物的合成方法，还制备并表征了以下实施例：





Referring to the synthesis methods of the above compounds, the following examples were also prepared and characterized:





实施例32-A-1和32-A-2
Example 32-A-1 and 32-A-2
(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Sa)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇和(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇
(3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa )-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol and (3R)- 1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
步骤A：(R)-3-甲基-1-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇Step A: (R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-( (Triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol
室温条件下，依次将(R)-1-(7-溴-2,6,8-三氟喹唑啉-4-基)-3-甲基哌啶-3-醇(12.0g,31.9mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(22.5g,41.5mmol)、Pd(OAc)2(716mg,3.19mmol)、BIDIME(2.11g,6.38mmol)、K3PO4(27.1g,128mmol)加入到无水甲苯(150mL)中，N2置换三次后，升温至110℃搅拌过夜。LCMS和TLC监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂，收集母液，加入水(100mL)，EA(150mL×3)萃取，收集的有机相用饱和NaCl(50mL)洗涤，浓缩有机液得到的粗品经FCC(SiO2，EA/PE＝0-20％)纯化，得到黄色固体(3R)-3-甲基-1-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(16.0g,收率64％)。LCMS(m/z):794.3(M+H)。 At room temperature, (R)-1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (12.0g, 31.9mmol ), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (22.5g, 41.5 mmol), Pd(OAc) 2 (716mg, 3.19mmol), BIDIME (2.11g, 6.38mmol), K 3 PO 4 (27.1g, 128mmol) were added to anhydrous toluene (150mL), and after N 2 replacement three times, The temperature was raised to 110°C and stirred overnight. Monitor the end of the reaction with LCMS and TLC, return the reaction solution to room temperature, filter through diatomaceous earth to remove the palladium catalyst, collect the mother liquor, add water (100mL), extract with EA (150mL×3), and wash the collected organic phase with saturated NaCl (50mL) , the crude product obtained by concentrating the organic liquid was purified by FCC (SiO 2 , EA/PE=0-20%) to obtain a yellow solid (3R)-3-methyl-1-(2,6,8-trifluoro-7- (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl) Piperidin-3-ol (16.0 g, yield 64%). LCMS(m/z):794.3(M+H).
步骤B：(R)-3-甲基-1-(2,6,8-三氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇和(R)-3-甲基-1-(2,6,8-三氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇Step B: (R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-(triisopropylsilyl)ethynyl) -3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)piperidin-3-ol and (R)-3-methyl-1-(2, 6,8-Trifluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)quinazolin-4-yl)piperidin-3-ol
上述化合物(R)-3-甲基-1-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(16.0g)经SFC拆分(Waters SFC 150，分离柱250*50mm 10μm；流动相：CO2/MeOH(+0.1％7.0mol/l NH3/MeOH)＝75/25；流速：140mL/min)，得到首先洗脱出来的异构体1为中间体32-A-P1，(R)-3-甲基-1-(2,6,8-三氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(7.0g，相对保留时间较小)。手性分析方法SFC-32A，Rt＝2.539。随后洗脱出来的异构体2为中间体32-A-P2，(R)-3-甲基-1-(2,6,8-三氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(7.0g,相对保留时间较大)。手性分析方法SFC-32A，Rt＝3.978。The above compound (R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(( Triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidin-3-ol (16.0 g) was resolved by SFC (Waters SFC 150, separation column 250*50mm 10μm; mobile phase: CO 2 /MeOH (+0.1% 7.0mol/l NH 3 /MeOH) = 75/25; flow rate: 140mL/min), and the isomer 1 that eluted first was obtained as the intermediate 32-A-P1, (R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)) Ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)piperidin-3-ol (7.0 g, relatively small retention time). Chiral analysis method SFC-32A, Rt=2.539. The subsequently eluted isomer 2 is intermediate 32-A-P2, (R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro- 8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidine-3- Alcohol (7.0g, relatively large retention time). Chiral analysis method SFC-32A, Rt=3.978.
手性分析方法SFC-32A：Waters UPCC(CA-352)，分析柱：100*3mm3μm；流动相A：CO2，流动相B：MeOH(+0.1％DEA)；流速：1.5mL/min；柱温：35℃；反压：1800psi；梯度：0-8.0min A/B＝80/20。Chiral analysis method SFC-32A: Waters UPCC (CA-352), analytical column: 100*3mm3μm; mobile phase A: CO2, mobile phase B: MeOH (+0.1% DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-8.0min A/B＝ 80/20.
步骤C：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6, 8-Difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -(yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将NaH(30mg,60％,756umol)加入到(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(58mg,302umol)和THF(10mL)的混合溶液中并搅拌30min，再将((R)-3-甲基-1-(2,6,8-三氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(32-A-P1,200mg,252umol)一次加入到上述反应液中并搅拌2h，LCMS监测反应结束，将反应液倒入半饱和的NH4Cl溶液(30mL)中，EA(30mL×3)萃取，收集有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，浓缩有机相经FCC(SiO2，EA/PE＝0-80％)纯化，得到黄色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg,收率62％)。LCMS(m/z):484.2(M/2+H)。At room temperature, NaH (30 mg, 60%, 756umol) was added to (((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (58 mg ,302umol) and THF (10mL) mixed solution and stirred for 30min, then ((R)-3-methyl-1-(2,6,8-trifluoro-7-((Sa)-7-fluoro -8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidine-3 -Alcohol (32-A-P1, 200mg, 252umol) was added to the above reaction solution at one time and stirred for 2h. LCMS monitored the end of the reaction. Pour the reaction solution into a semisaturated NH 4 Cl solution (30mL), EA (30mL× 3) Extract, collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , concentrate the organic phase and purify it by FCC (SiO 2 , EA/PE=0-80%) to obtain yellow solid (R)-1- (2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-(( Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazoline-4- (150 mg, yield 62%). LCMS (m/z): 484.2 (M/2+H).
步骤D：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Sa)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- ((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将CsF(236mg,1.55mmol)加入到((R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Sa)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg,155umol)和DMF(3mL)的混合溶液中，升温至50℃反应1h，LCMS和TLC监测反应结束，经pre-HPLC(C18,CAN/(10mmol NH4HCO3/H2O)＝55-75％)纯化，得到白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶- 3-基)甲氧基)-7-((Sa)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg,收率59％)。LCMS(m/z):655.3(M+H).1H NMR(400MHz,甲醇-d4)δ7.97–7.78(m,1H),7.65(d,J＝9.8Hz,1H),7.40–7.23(m,2H),7.17–7.05(m,1H),6.39–5.93(m,1H),4.62–4.42(m,3H),4.32–4.18(m,1H),4.13–3.92(m,1H),3.57–3.46(m,1H),3.43–3.33(m,1H),3.26(s,1H),3.17–3.06(m,1H),3.02–2.89(m,1H),2.24(s,3H),2.19–2.09(m,1H),2.07–1.92(m,1H),1.87–1.69(m,6H),1.27(s,3H),1.21(s,3H).19F NMR(376MHz,甲醇-d4)δ-111.60,-118.56,-119.53,-121.59,-125.79。At room temperature, CsF (236 mg, 1.55 mmol) was added to ((R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine) -3-yl)methoxy)-6,8-difluoro-7-((Sa)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triiso In a mixed solution of propylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 155umol) and DMF (3 mL), raise the temperature React at 50°C for 1 hour, monitor the end of the reaction with LCMS and TLC, and purify through pre-HPLC (C18, CAN/(10mmol NH 4 HCO 3 /H 2 O) = 55-75%) to obtain a white solid (R)-1- (2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine- 3-yl)methoxy)-7-((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)- 3-Methylpiperidin-3-ol (60 mg, yield 59%). LCMS (m/z): 655.3 (M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.97–7.78 (m, 1H), 7.65 (d, J = 9.8Hz, 1H), 7.40– 7.23(m,2H),7.17–7.05(m,1H),6.39–5.93(m,1H),4.62–4.42(m,3H),4.32–4.18(m,1H),4.13–3.92(m,1H ),3.57–3.46(m,1H),3.43–3.33(m,1H),3.26(s,1H),3.17–3.06(m,1H),3.02–2.89(m,1H),2.24(s,3H ),2.19–2.09(m,1H),2.07–1.92(m,1H),1.87–1.69(m,6H),1.27(s,3H),1.21(s,3H). 19 F NMR (376MHz, methanol -d 4 )δ-111.60,-118.56,-119.53,-121.59,-125.79.
步骤E：(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step E: (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6, 8-Difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -(yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将NaH(30mg,60％,756umol)加入到(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(58mg,302umol)和THF(10mL)的混合溶液中并搅拌30min，再将(3R)-3-甲基-1-(2,6,8-三氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)哌啶-3-醇(32-A-P2，200mg，252umol)一次加入到上述反应液中并搅拌2h，LCMS监测反应结束后，将反应液倒入半饱和的NH4Cl溶液(30mL)中，EA(30mL×3)萃取，收集有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，浓缩有机相经FCC(SiO2，EA/PE＝0-80％)纯化，得到黄色固体(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg,收率62％)。LCMS(m/z):484.2(M/2+H)。At room temperature, NaH (30 mg, 60%, 756umol) was added to (((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (58 mg ,302umol) and THF (10mL) mixed solution and stirred for 30min, then (3R)-3-methyl-1-(2,6,8-trifluoro-7-((Ra)-7-fluoro- 8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)piperidine-3- Alcohol (32-A-P2, 200 mg, 252umol) was added to the above reaction solution at one time and stirred for 2 hours. After the reaction was monitored by LCMS, the reaction solution was poured into a semisaturated NH 4 Cl solution (30 mL), EA (30 mL × 3) Extract, collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , concentrate the organic phase and purify it by FCC (SiO 2 , EA/PE=0-80%) to obtain yellow solid (3R)-1- (2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6,8-difluoro-7-(( Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazoline-4- (150 mg, yield 62%). LCMS (m/z): 484.2 (M/2+H).
步骤F：(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step F: (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- ((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将CsF(236mg,1.55mmol)加入到(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-((Ra)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(150mg,155umol)和DMF(3mL)的混合溶液中，升温至50℃反应1h，LCMS和TLC监测反应结束，经pre-HPLC(C18,CAN/(10mmol NH4HCO3/H2O)＝55-75％)纯化，得到白色固体(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg,59％)。LCMS(m/z):655.3(M+H).1H NMR(400MHz,甲醇-d4)δ7.91–7.78(m,1H),7.62(d,J＝9.8Hz,1H),7.36–7.25(m,2H),7.18–7.09(m,1H),6.45–6.00(m,1H),4.62–4.48(m,3H),4.36–4.23(m,1H),4.14–4.04(m,1H),3.53–3.45(m,1H),3.41–3.34(m,1H),3.24(s,1H),3.14–3.06(m,1H),3.02–2.90(m,1H),2.23(s,3H),2.20–2.10(m,1H),2.05–1.92(m,1H),1.87–1.66(m,6H),1.25(s,3H),1.21(s,3H).19F NMR(376MHz,甲醇-d4)δ-111.63,-118.54,-119.85,-121.49,-126.12。At room temperature, CsF (236 mg, 1.55 mmol) was added to (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine- 3-yl)methoxy)-6,8-difluoro-7-((Ra)-7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl) methylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (150mg, 155umol) and DMF (3mL), and heat it to React at 50°C for 1 hour. LCMS and TLC monitor the end of the reaction. Purify by pre-HPLC (C18, CAN/(10mmol NH 4 HCO 3 /H 2 O) = 55-75%) to obtain a white solid (3R)-1-( 2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethynyl- 7-Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 59%). LCMS (m/z): 655.3 (M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.91–7.78 (m, 1H), 7.62 (d, J = 9.8Hz, 1H), 7.36– 7.25(m,2H),7.18–7.09(m,1H),6.45–6.00(m,1H),4.62–4.48(m,3H),4.36–4.23(m,1H),4.14–4.04(m,1H ),3.53–3.45(m,1H),3.41–3.34(m,1H),3.24(s,1H),3.14–3.06(m,1H),3.02–2.90(m,1H),2.23(s,3H ),2.20–2.10(m,1H),2.05–1.92(m,1H),1.87–1.66(m,6H),1.25(s,3H),1.21(s,3H). 19 F NMR (376MHz, methanol -d 4 )δ-111.63,-118.54,-119.85,-121.49,-126.12.
实施例32-1
Example 32-1
(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Sa)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇
(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Sa )-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温下，将(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Sa)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(45mg,69umol)溶于甲醇(20mL)，加入Pd/C(15mg,10wt％),H2气球置换两次并在室温搅拌4h，LCMS监测反应结束，反应液过滤头得到澄清的有机相，浓缩完全后，加入乙腈(2mL),再加入去离子水(20mL)，冻干得到白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((S)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(34mg,收率75％)。LCMS(m/z):659.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.75(d,J＝9.8Hz,1H),7.70–7.60(m,1H),7.27(d,J＝2.5Hz,1H),7.26–7.19(m,1H),7.01–6.94(m,1H),6.38–5.97(m,1H),4.62–4.46(m,2H),4.33–4.21(m,1H),4.12–4.01(m,1H),3.58–3.34(m,2H),3.14–3.03(m,1H),2.98–2.89(m,1H),2.63–2.34(m,2H),2.22(s,3H),2.19–2.13(m,1H),2.01–1.93(m,1H),1.87–1.69(m,7H),1.25(s,3H),1.21(s,3H),0.79(t,J＝7.4Hz,3H).19F NMR(376MHz,甲醇-d4)δ-118.19,-118.87,-118.95,-121.17,-121.30,-121.92,-124.72。At room temperature, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -((Sa)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (45mg, 69umol) was dissolved in methanol (20mL), added Pd/C (15mg, 10wt%), the H 2 balloon was replaced twice and stirred at room temperature for 4h. LCMS monitored the end of the reaction, and the reaction solution was filtered to obtain a clear organic phase. After complete concentration, add acetonitrile (2mL), then add deionized water (20mL), and freeze-dry to obtain a white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)- 1,3-dimethylpiperidin-3-yl)methoxy)-7-((S)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-di Fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (34 mg, yield 75%). LCMS(m/z):659.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.75 (d, J = 9.8 Hz, 1H), 7.70–7.60 (m, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.26–7.19 ( m,1H),7.01–6.94(m,1H),6.38–5.97(m,1H),4.62–4.46(m,2H),4.33–4.21(m,1H),4.12–4.01(m,1H), 3.58–3.34(m,2H),3.14–3.03(m,1H),2.98–2.89(m,1H),2.63–2.34(m,2H),2.22(s,3H),2.19–2.13(m,1H 19 F NMR ( 376MHz, methanol-d 4 )δ-118.19,-118.87,-118.95,-121.17,-121.30,-121.92,-124.72.
实施例32-2
Example 32-2
(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇
(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra )-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
室温下，将(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(45mg,69umol)溶于甲醇(20mL)，加入Pd/C(15mg,10％,14umol)，H2气球置换两次并在室温搅拌4h，LCMS监测反应结束，反应液过滤头得到澄清的有机相，浓缩完全后，加入乙腈(2mL),再加入去离子水(20mL)，冻干得到白色固体(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-((Ra)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(39mg,收率86％)。LCMS(m/z):659.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.79(dd,J＝9.9,1.8Hz,1H),7.70–7.59(m,1H),7.27(d,J＝2.7Hz,1H),7.26–7.19(m,1H),6.97(d,J＝2.6Hz,1H),6.40–6.02(m,1H),4.63–4.46(m,2H),4.29–4.17(m,1H),4.13–3.99(m,1H),3.54–3.36(m,2H),3.14–3.03(m,1H),3.00–2.88(m,1H),2.64–2.34(m,2H),2.22(s,3H),2.18–1.91(m,2H),1.90–1.68(m,7H),1.28(s,3H),1.21(s,3H),0.81(t,3H).19F NMR(376MHz,甲醇-d4)δ-118.09,-118.75,-118.85,-121.16,-121.27,-121.92,-124.72。



At room temperature, (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -((Ra)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (45mg, 69umol) was dissolved in methanol (20mL), added Pd/C (15mg, 10%, 14umol), the H 2 balloon was replaced twice and stirred at room temperature for 4h. LCMS monitored the end of the reaction, and the reaction solution was filtered to obtain clarified organic phase, after complete concentration, add acetonitrile (2mL), then add deionized water (20mL), and freeze-dry to obtain a white solid (3R)-1-(2-(((3S,4S)-4-(difluoromethyl) )-1,3-dimethylpiperidin-3-yl)methoxy)-7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8 -Difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (39 mg, yield 86%). LCMS(m/z):659.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.79 (dd, J＝9.9, 1.8Hz, 1H), 7.70–7.59 (m, 1H), 7.27 (d, J＝2.7Hz, 1H), 7.26– 7.19(m,1H),6.97(d,J＝2.6Hz,1H),6.40–6.02(m,1H),4.63–4.46(m,2H),4.29–4.17(m,1H),4.13–3.99( m,1H),3.54–3.36(m,2H),3.14–3.03(m,1H),3.00–2.88(m,1H),2.64–2.34(m,2H),2.22(s,3H),2.18– 1.91(m,2H),1.90–1.68(m,7H),1.28(s,3H),1.21(s,3H),0.81(t,3H). 19 F NMR (376MHz, methanol-d 4 )δ- 118.09,-118.75,-118.85,-121.16,-121.27,-121.92,-124.72.



实施例49
Example 49
(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl) -1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
步骤A：(R)-1-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温下，将DIPEA(717mg,5.55mmol)加入到2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(350mg,1.39mmol)和(R)-3-甲基哌啶-3-醇盐酸盐(210mg,1.39mmol)的THF(10mL)溶液中，并在室温搅拌1h。LCMS监测反应结束后，低温(35℃)浓缩除去THF。后加入EA(50mL)和水(20mL)，分液，水相用EA(50mL×3)萃取。合并有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，浓缩，得黄色固体(R)-1-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(450mg,收率98％)。LCMS(m/z):331.0(M+H)。DIPEA (717 mg, 5.55 mmol) was added to 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (350 mg, 1.39 mmol) and (R)-3-methyl at room temperature. piperidin-3-ol hydrochloride (210 mg, 1.39 mmol) in THF (10 mL) and stirred at room temperature for 1 h. After monitoring the reaction with LCMS, concentrate at low temperature (35°C) to remove THF. Then add EA (50 mL) and water (20 mL), separate the liquids, and extract the aqueous phase with EA (50 mL × 3). Combine the organic phases, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , and concentrate to obtain a yellow solid (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine- 4-yl)-3-methylpiperidin-3-ol (450 mg, yield 98%). LCMS(m/z):331.0(M+H).
步骤B：(R)-1-(7-氯-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step B: (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
冰浴条件下，将NaH(130mg,60％,3.26mmol)加入到(3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲醇(200mg,1.14mmol)的THF(10mL)溶液中并搅拌30min。保持冰浴，将(R)-1-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(360mg,1.09mmol)一次加入到上述反应液中并搅拌5h。LCMS监测反应结束后，将反应液倒入饱和NH4Cl溶液(50mL)中，EA(50mL×3)萃取。合并有机相，饱和NaCl溶液洗涤、无水Na2SO4干燥、过滤、浓缩，所得粗品经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-20％)纯化，得黄色固体(R)-1-(7-氯-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(180mg,收率35％)。LCMS(m/z):470.1(M+H)。Under ice bath conditions, NaH (130 mg, 60%, 3.26 mmol) was added to (3S, 4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (200 mg, 1.14 mmol) in THF (10 mL) and stirred for 30 min. Keep in ice bath, add (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (360 mg , 1.09mmol) was added to the above reaction solution in one go and stirred for 5h. After the reaction was monitored by LCMS, the reaction solution was poured into saturated NH 4 Cl solution (50 mL), and extracted with EA (50 mL × 3). Combine the organic phases, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate. The crude product obtained is purified by FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-20%) to obtain yellow color Solid (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (180 mg, yield 35%). LCMS(m/z):470.1(M+H).
步骤C：(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step C: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
氮气保护下，将(R)-1-(7-氯-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(80mg,0.17mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(185mg,0.34mmol)、Pd(dtbpf)Cl2(11mg,0.017mmol)和K3PO4(108mg,0.51mmol)的1,4-二氧六环/H2O(5.5mL,V/V＝4:1)溶液升温至100℃搅拌2h。 TLC监测反应结束后，将反应液倒入水中(50mL)，EA(50mL×3)萃取，合并有机相用饱和NaCl(20mL)洗涤。有机相减压浓缩，所得粗品经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-20％)纯化，得到黄色固体(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(60mg,收率38％)。Under nitrogen protection, (R)-1-(7-chloro-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (80 mg, 0.17mmol), (7-fluoro-8-((triiso Propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (185mg, 0.34mmol), Pd(dtbpf)Cl 2 (11mg, 0.017mmol) ) and K 3 PO 4 (108 mg, 0.51 mmol) in 1,4-dioxane/H 2 O (5.5 mL, V/V=4:1) solution was heated to 100°C and stirred for 2 hours. After TLC monitoring of the reaction, the reaction solution was poured into water (50 mL), extracted with EA (50 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL). The organic phase was concentrated under reduced pressure, and the crude product obtained was purified by FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-20%) to obtain a yellow solid (R)-1-(8-fluoro-7-( 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S )-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine -3-ol (60 mg, yield 38%).
步骤D：(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step D: (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将CsF(98mg,0.64mmol)加入到(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(60mg,0.064mmol)的DMF(3mL)溶液中。所得混合物升温至50℃反应1h，LCMS和TLC监测反应结束后，反应液经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-60％)纯化，得到淡黄色固体(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(35mg,收率88％)。LCMS(m/z):620.3(M+H)。At room temperature, CsF (98 mg, 0.64 mmol) was added to (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3- (60 mg, 0.064 mmol) in DMF (3 mL). The resulting mixture was heated to 50°C and reacted for 1 hour. After the reaction was monitored by LCMS and TLC, the reaction solution was purified by FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-60%) to obtain a light yellow solid (R )-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1 ,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (35 mg, yield 88% ). LCMS(m/z):620.3(M+H).
实施例50
Example 50
(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl) -1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
步骤A：(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4-醇Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol
室温氮气保护下，将Pd/C(5mg,10％)加入到(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(30mg,0.048mmol)的甲醇(20mL)溶液中。体系用H2气球置换三次，并在H2气球条件下室温搅拌过夜。LCMS监测反应结束，反应液过滤除去Pd/C后经Pre.HPLC，制备得到白色固体(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4-醇(10mg，收率33％)。LCMS(m/z):624.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.55(dd,J＝9.0,5.8Hz,1H),7.19–7.09(m,2H),6.96(dd,J＝9.0, 2.6Hz,1H),4.69–4.31(m,4H),4.14–3.78(m,4H),3.70–3.37(m,3H),3.10–2.82(m,2H),2.56–2.34(m,1H),2.32–2.10(m,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84–0.69(m,3H).1H NMR(400MHz,甲醇-d4)δ-76.94,-121.59,-149.95,-150.32。Under nitrogen protection at room temperature, add Pd/C (5 mg, 10%) to (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro- 2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl )-3-methylpiperidin-3-ol (30 mg, 0.048 mmol) in methanol (20 mL). The system was replaced with H balloon three times and stirred at room temperature under H balloon conditions overnight. LCMS monitors the end of the reaction. The reaction solution is filtered to remove Pd/C and then subjected to Pre.HPLC to prepare a white solid (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-Fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d] Pyrimidin-4-yl)-3-methylpiperidin-4-ol (10 mg, yield 33%). LCMS(m/z):624.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.55 (dd, J＝9.0, 5.8Hz, 1H), 7.19–7.09 (m, 2H), 6.96 (dd, J＝9.0, 2.6Hz,1H),4.69–4.31(m,4H),4.14–3.78(m,4H),3.70–3.37(m,3H),3.10–2.82(m,2H),2.56–2.34(m,1H) ,2.32–2.10(m,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84–0.69( m, 3H). 1 H NMR (400MHz, methanol-d 4 ) δ -76.94, -121.59, -149.95, -150.32.
实施例51
Example 51
(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl) -1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- alcohol
步骤A：(3R)-1-(7-氯-8-氟-5-甲氧基-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol
室温条件下，将DIPEA(2.11g,16.32mmol)加入到(R)-3-甲基哌啶-3-醇盐酸盐(949mg,6.26mmol)、7-氯-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(1.5g,5.44mmol)、BOP(4.81g,10.88mmol)和DMF(20mL)的混合液中。所得反应体系升温至45℃搅拌5h。LCMS监测反应结束后，反应液恢复至室温，缓慢倒入搅拌着的H2O(300mL)中。过滤，滤饼用水(100mL)洗，收集烘干，得到棕色固体(3R)-1-(7-氯-8-氟-5-甲氧基-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(2.0g,收率99％)。LCMS(m/z):373.0(M+H)。At room temperature, DIPEA (2.11g, 16.32mmol) was added to (R)-3-methylpiperidin-3-ol hydrochloride (949mg, 6.26mmol), 7-chloro-8-fluoro-5-methyl Mixture of oxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.5g, 5.44mmol), BOP (4.81g, 10.88mmol) and DMF (20mL) liquid. The resulting reaction system was heated to 45°C and stirred for 5 hours. After the reaction was monitored by LCMS, the reaction solution was returned to room temperature and slowly poured into stirring H 2 O (300 mL). Filter, wash the filter cake with water (100 mL), collect and dry to obtain brown solid (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4- Dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (2.0 g, yield 99%). LCMS(m/z):373.0(M+H).
步骤B：(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step B: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
氮气保护下，将(3R)-1-(7-氯-8-氟-5-甲氧基-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(300mg,0.60mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(391mg,0.72mmol)、cataCXium A Pd G3(43.7mg,0.06mmol)、K3PO4(382 mg,1.8mmol)和1,4-二氧六环/H2O(10mL，V/V＝4:1)的混合溶液升温至110℃搅拌2h。LCMS监测反应结束后，将反应液倒入水中(50mL)，EA(60mL×3)萃取，合并有机相用饱和NaCl(20mL)洗涤。有机相浓缩，所得粗品经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-20％)纯化，得到黄色固体(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(450mg,收率78％)。LCMS(m/z):835.4(M+H)。Under nitrogen protection, (3R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidine -4-yl)-3-methylpiperidin-3-ol (300mg, 0.60mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)ethynyl) Propylsilyl)oxy)naphthalen-1-yl)boronic acid (391 mg, 0.72 mmol), cataCXium A Pd G 3 (43.7 mg, 0.06 mmol), K 3 PO 4 (382 mg, 1.8 mmol) and 1,4-dioxane/H 2 O (10 mL, V/V = 4:1). The mixed solution was heated to 110°C and stirred for 2 hours. After the reaction was monitored by LCMS, the reaction solution was poured into water (50 mL), extracted with EA (60 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL). The organic phase was concentrated, and the crude product was purified by FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-20%) to obtain a yellow solid (R)-1-(8-fluoro-7-(7- Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methyl Thio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (450 mg, yield 78%). LCMS(m/z):835.4(M+H).
步骤C：(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step C: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphth-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将m-CPBA(129mg,0.75mmol)加入到(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(250mg,0.30mmol)的DCM(15mL)溶液中并在室温搅拌2h。TLC和LCMS监测反应结束后，依次加入DCM(50mL)及半饱和NaHCO3水溶液(20mL)洗涤。分液，水相再用DCM(60mL×3)萃取。合并有机相用饱和NaCl(30mL)洗涤，无水Na2SO4干燥，过滤，减压浓缩后，得到棕黄色固体(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(250mg,收率96％)。LCMS(m/z):867.3(M+H)。At room temperature, m-CPBA (129 mg, 0.75 mmol) was added to (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)- 3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl) -3-Methylpiperidin-3-ol (250 mg, 0.30 mmol) was dissolved in DCM (15 mL) and stirred at room temperature for 2 h. After TLC and LCMS monitored the reaction, DCM (50 mL) and half-saturated NaHCO 3 aqueous solution (20 mL) were added successively for washing. The liquids were separated, and the aqueous phase was extracted with DCM (60mL×3). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a brown solid (R)-1-(8-fluoro-7-(7-fluoro-8- ((Triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfonyl) Pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (250 mg, yield 96%). LCMS(m/z):867.3(M+H).
步骤D：(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step D: (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy yl)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxy pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将NaH(17mg,60％,0.41mmol)加入到((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲醇(29mg,0.17mmol)和THF(3mL)的混合溶液中并搅拌30min。再将(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(120mg,0.14mmol)一次加入到上述反应液中并搅拌3h。LCMS监测反应结束后，将反应液倒入饱和NH4Cl溶液(50mL)中。EA(50mL×3)萃取，合并有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，浓缩，所得粗品经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-40％)纯化，得到黄色固体(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(100mg,收率75％)。LCMS(m/z):962.5(M+H)。At room temperature, NaH (17 mg, 60%, 0.41 mmol) was added to ((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (29 mg, 0.17 mmol) and THF (3 mL) and stirred for 30 min. Then (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy) )naphthalen-1-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (120 mg , 0.14 mmol) was added to the above reaction solution at a time and stirred for 3 h. After the reaction was monitored by LCMS, the reaction solution was poured into saturated NH 4 Cl solution (50 mL). Extract with EA (50mL×3), wash the combined organic phases with saturated NaCl solution, dry over anhydrous Na 2 SO 4 and concentrate. The crude product obtained is subjected to FCC (SiO 2 , (EtOH: EA=1:3)/PE=0-40 %) was purified to obtain a yellow solid (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylmethyl) Silyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)- 5-Methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (100 mg, yield 75%). LCMS(m/z):962.5(M+H).
步骤E：(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step E: (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine -3-ol
室温条件下，将CsF(158mg,1.04mmol)加入到(R)-1-(8-氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(100mg,0.10mmol)的DMF(3mL)溶液 中，所得混合物升温至50℃反应1h，LCMS监测反应结束。反应液经Pre-HPLC，制备得到得到淡黄色固体(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(30mg,收率44％)。LCMS(m/z):650.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.93–7.78(m,1H),7.39–7.19(m,3H),4.79–4.43(m,5H),4.10–3.95(m,3H),3.89–3.82(m,1H),3.79–3.67(m,1H),3.58–3.47(m,1H),3.27–3.16(m,1H),3.13–3.06(m,1H),3.04–2.95(m,1H),2.38–2.24(m,3H),2.24–2.15(m,1H),2.12–2.01(m,1H),1.91–1.57(m,7H),1.38–1.28(m,1H),1.22–1.14(m,5H).1H NMR(400MHz,甲醇-d4)δ-112.10，-150.97，-151.99，-223.17。At room temperature, CsF (158 mg, 1.04 mmol) was added to (R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidine-3- (100 mg, 0.10 mmol) in DMF (3 mL) , the resulting mixture was heated to 50°C and reacted for 1 hour, and LCMS monitored the completion of the reaction. The reaction solution was prepared by Pre-HPLC to obtain a light yellow solid (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(( (3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol (30 mg, yield 44%). LCMS(m/z):650.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.93–7.78(m,1H),7.39–7.19(m,3H),4.79–4.43(m,5H),4.10–3.95(m,3H),3.89 –3.82(m,1H),3.79–3.67(m,1H),3.58–3.47(m,1H),3.27–3.16(m,1H),3.13–3.06(m,1H),3.04–2.95(m, 1H),2.38–2.24(m,3H),2.24–2.15(m,1H),2.12–2.01(m,1H),1.91–1.57(m,7H),1.38–1.28(m,1H),1.22– 1.14 (m, 5H). 1 H NMR (400MHz, methanol-d 4 ) δ -112.10, -150.97, -151.99, -223.17.
实施例52
Example 52
(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoromethyl) -1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- alcohol
步骤A：(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4-醇Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,4S)-4-(fluoro Methyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-ol
室温氮气保护下，将Pd/C(9.8mg,10％wt)加入到(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(20mg,0.031mmol)的甲醇(10mL)溶液中。所得体系用H2气球置换三次，并在H2气球条件下室温搅拌过夜。LCMS监测反应结束后，反应液过滤除去Pd/C，滤液浓缩后冻干，得到白色固体(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((3S,4S)-4-(氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-4-醇(9.3mg，收率46％)。LCMS(m/z):654.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.55(dd,J＝9.0,5.8Hz,1H),7.19–7.09(m,2H),6.96(dd,J＝9.0,2.6Hz,1H),4.69–4.31(m,4H),4.14–3.78(m,4H),3.70–3.37(m,3H),3.10–2.82(m,2H),2.56–2.34(m,1H),2.32–2.10(m,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84–0.69(m,3H).1H NMR(400MHz,甲醇-d4)δ-76.94,-121.59,-149.95,-150.32。Under nitrogen protection at room temperature, Pd/C (9.8 mg, 10% wt) was added to (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8- Fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3 -d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (20 mg, 0.031 mmol) in methanol (10 mL). The resulting system was replaced with H balloon three times and stirred at room temperature under H balloon conditions overnight. After monitoring the reaction by LCMS, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated and lyophilized to obtain a white solid (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) )-8-fluoro-2-(((3S,4S)-4-(fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-4-ol (9.3 mg, yield 46%). LCMS(m/z):654.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ7.55 (dd, J＝9.0, 5.8Hz, 1H), 7.19–7.09 (m, 2H), 6.96 (dd, J＝9.0, 2.6Hz, 1H), 4.69–4.31(m,4H),4.14–3.78(m,4H),3.70–3.37(m,3H),3.10–2.82(m,2H),2.56–2.34(m,1H),2.32–2.10(m ,4H),2.06–1.89(m,2H),1.80–1.47(m,7H),1.30–1.21(m,1H),1.14–1.01(m,6H),0.84–0.69(m,3H). 1 H NMR (400MHz, methanol-d 4 ) δ -76.94, -121.59, -149.95, -150.32.
实施例53
Example 53
(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
步骤A：(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio) Pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(3R)-1-(7-氯-8-氟-2-(甲硫基)-3,4-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(1.20g,3.48mmol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.38g,3.83mmol)、cataCXium A Pd G3(507mg,696μmol)、K3PO4(2.22g,10.4mmol)和1,4-二氧六环/H2O(V/V＝4/1,15mL)的混合溶液N2置换三次后，升温至110℃搅拌2h。LCMS监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂，收集母液，加入水(50mL)，EA(80mL×3)萃取。合并有机相用饱和NaCl水溶液(20mL)洗涤，浓缩后得到的粗品经FCC(SiO2,EA/PE＝0-40％)纯化，得到黄色固体(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(1.1g,收率61％)。LCMS(m/z):541.0(M+H)。At room temperature, (3R)-1-(7-chloro-8-fluoro-2-(methylthio)-3,4-dihydropyrido[4,3-d]pyrimidin-4-yl)- 3-Methylpiperidin-3-ol (1.20g, 3.48mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolane (1.38g, 3.83mmol), cataCXium A Pd G 3 (507mg, 696μmol), K 3 PO 4 (2.22g, The mixed solution of 10.4 mmol) and 1,4-dioxane/H 2 O (V/V=4/1, 15 mL) was replaced with N2 three times, then the temperature was raised to 110°C and stirred for 2 hours. LCMS monitored the end of the reaction, returned the reaction solution to room temperature, filtered through diatomaceous earth to remove the palladium catalyst, collected the mother liquor, added water (50 mL), and extracted with EA (80 mL × 3). The combined organic phases were washed with saturated NaCl aqueous solution (20 mL), and the crude product obtained after concentration was purified by FCC (SiO 2 , EA/PE=0-40%) to obtain a yellow solid (R)-1-(7-(8-ethyl) yl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)- 3-Methylpiperidin-3-ol (1.1 g, yield 61%). LCMS(m/z):541.0(M+H).
步骤B：(3R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step B: (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(methylsulfenic acid) Acyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将mCPBA(375mg,1.85mmol)加入到(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(500mg,925umol)和DCM(20mL)的溶液中并室温搅拌2h。TLC和LCMS监测反应结束，将反应液用DCM(100mL)稀释，加入半饱和NaHCO3水溶液(20mL)洗涤，DCM(60mL×3)萃取水相，合并有机相用饱和NaCl水溶液(30mL)洗涤，无水Na2SO4干燥，过滤，有机液浓缩，得到棕黄色固体(3R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(510mg,收率99％)。LCMS(m/z):557.2(M+H)。At room temperature, mCPBA (375 mg, 1.85 mmol) was added to (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)- In a solution of 8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (500 mg, 925umol) and DCM (20 mL) And stirred at room temperature for 2h. TLC and LCMS monitored the completion of the reaction. The reaction solution was diluted with DCM (100 mL), washed with half-saturated NaHCO 3 aqueous solution (20 mL), the aqueous phase was extracted with DCM (60 mL × 3), and the combined organic phases were washed with saturated NaCl aqueous solution (30 mL). Dry over anhydrous Na 2 SO 4 , filter, and concentrate the organic liquid to obtain a brown solid (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1) -yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (510 mg, yield 99% ). LCMS(m/z):557.2(M+H).
步骤C：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methyl piperidin-3-ol
在-40℃条件下，将NaHMDS(1.31mL,1M THF溶液,1.31mmol)滴加到(3R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(250mg,436umol)、((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(101mg,524umol)和 THF(10mL)的混合溶液中并搅拌2h，LCMS监测反应结束，将反应液倒入半饱和NH4Cl水溶液(50mL)中，EA(50mL×3)萃取。收集有机相，饱和NaCl水溶液(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩有机相经FCC(SiO2，(EtOH/EA＝1/3)/PE＝0-40％)纯化，得到黄色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(80mg,收率26％)。LCMS(m/z):686.3(M+H)。At -40°C, NaHMDS (1.31 mL, 1M THF solution, 1.31 mmol) was added dropwise to (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy) yl)naphth-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (250 mg ,436umol), ((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (101mg, 524umol) and into a mixed solution of THF (10 mL) and stirred for 2 h. LCMS monitored the completion of the reaction. The reaction solution was poured into a semisaturated NH 4 Cl aqueous solution (50 mL), and extracted with EA (50 mL × 3). The organic phase was collected, washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and the organic phase was concentrated and purified by FCC (SiO 2 , (EtOH/EA=1/3)/PE=0-40%). Obtained yellow solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methyl Piperidin-3-ol (80 mg, yield 26%). LCMS(m/z):686.3(M+H).
步骤D：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温下，将CF3COOH(15mL)加入到(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(80mg,117umol)中，并在室温下搅拌1h。LCMS监测反应结束，浓缩反应液除去酸液，EA(30mL)稀释，加入半饱和的NaHCO3水溶液(30mL)使pH调至碱性，EA(30mL×3)萃取，收集有机相，浓缩后经pre-HPLC(C18,CAN/(10mmol NH4HCO3/H2O)＝55-75％)，得到白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(19mg,收率25％)。LCMS(m/z):642.3(M+H)。1H NMR(400MHz,甲醇-d4)δ9.20(s,1H),7.67(dd,J＝9.1,5.8Hz,1H),7.33–7.28(m,1H),7.27–7.20(m,1H),7.13–7.00(m,1H),6.42–6.05(m,1H),4.59–4.51(m,3H),4.35–4.23(m,2H),3.73–3.56(m,1H),3.53–3.43(m,1H),3.13–3.04(m,1H),3.00–2.92(m,1H),2.55–2.43(m,1H),2.23(s,3H),2.19–2.11(m,2H),2.04–1.94(m,1H),1.87–1.76(m,6H),1.35–1.26(m,3H),1.22(s,3H),0.88–0.75(m,3H).19F NMR(376MHz,甲醇-d4)δ-118.98,-121.17,-121.72,-139.21。At room temperature, CF 3 COOH (15 mL) was added to (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3- (yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidine- 4-yl)-3-methylpiperidin-3-ol (80 mg, 117umol) and stirred at room temperature for 1 h. LCMS monitors the end of the reaction, concentrates the reaction solution to remove the acid, dilutes with EA (30 mL), adds half-saturated NaHCO 3 aqueous solution (30 mL) to adjust the pH to alkaline, extracts with EA (30 mL × 3), collects the organic phase, concentrates and pre-HPLC (C18,CAN/(10mmol NH 4 HCO 3 /H 2 O)=55-75%), obtained white solid (R)-1-(2-(((3S,4S)-4-(di Fluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridine And[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (19 mg, yield 25%). LCMS(m/z):642.3(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ9.20 (s, 1H), 7.67 (dd, J = 9.1, 5.8Hz, 1H), 7.33–7.28 (m, 1H), 7.27–7.20 (m, 1H) ),7.13–7.00(m,1H),6.42–6.05(m,1H),4.59–4.51(m,3H),4.35–4.23(m,2H),3.73–3.56(m,1H),3.53–3.43 (m,1H),3.13–3.04(m,1H),3.00–2.92(m,1H),2.55–2.43(m,1H),2.23(s,3H),2.19–2.11(m,2H),2.04 –1.94(m,1H),1.87–1.76(m,6H),1.35–1.26(m,3H),1.22(s,3H),0.88–0.75(m,3H). 19 F NMR (376MHz, methanol- d 4 )δ-118.98,-121.17,-121.72,-139.21.
参照上述化合物的合成方法，还制备并表征了以下实施例：








Referring to the synthesis methods of the above compounds, the following examples were also prepared and characterized:








实施例93-A
Example 93-A
(6S)-4-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂环-6-醇
(6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaheterocyclyl-6-ol
步骤A：(6S)-6-甲基-4-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-1,4-氧杂氮杂环庚烷-6-醇Step A: (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-( (Triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-1,4-oxaazepan-6-ol
室温条件下，依次将(S)-4-(7-溴-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(500mg,1.27mmol),(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(1.04g,1.91mmol)、Pd(OAc)2(29mg,127umol)、BIDIME(84mg,255umol)、K3PO4(812mg,3.82mmol)加入到无水甲苯(15mL)中，N2置换三次后，升温至110℃搅拌过夜。LCMS和TLC监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂和碱，浓缩有机液得到的粗品经FCC(SiO2,EA/PE＝0-20％)纯化，得到黄色固体(6S)-6-甲基-4-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-1,4-氧杂氮杂环庚烷-6-醇(780mg,收率76％)。LCMS(m/z):810.2(M+H)。At room temperature, (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine -6-ol (500mg, 1.27mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -Bio)boronic acid (1.04g, 1.91mmol), Pd(OAc) 2 (29mg, 127umol), BIDIME (84mg, 255umol), K 3 PO 4 (812mg, 3.82mmol) were added to anhydrous toluene (15mL), After N2 replacement three times, the temperature was raised to 110°C and stirred overnight. LCMS and TLC monitor the end of the reaction. Return the reaction solution to room temperature. Filter through diatomaceous earth to remove the palladium catalyst and alkali. The crude product obtained by concentrating the organic liquid is purified by FCC (SiO 2 , EA/PE = 0-20%) to obtain a yellow solid. (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-(triiso Propylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-1,4-oxazepan-6-ol (780 mg, yield 76%). LCMS(m/z):810.2(M+H).
步骤B：(6S)-4-(2-(((3S,4S)-4-((二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step B: (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-6 ,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl) Quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
室温条件下，将NaH(59mg,60wt％,1.48mmol)加入到((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(86mg,444umol)和THF(15mL)的混合溶液中并搅拌30分钟，再将(6S)-6-甲基-4- (2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-1,4-氧杂氮杂环庚烷-6-醇(300mg,370umol)一次加入到上述反应液中并搅拌1.5h，TLC和LCMS监测反应结束，将反应液倒入半饱和的NH4Cl(50mL)溶液中，EA(30mL×3)萃取，收集有机相后，饱和NaCl溶液洗涤，无水Na2SO4干燥，浓缩有机相经FCC(EA/PE＝0-90％)纯化，得到黄色固体(6S)-4-(2-(((3S,4S)-4-((二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(270mg,收率74％)。LCMS(m/z):964.3(M+H)。At room temperature, NaH (59 mg, 60 wt%, 1.48 mmol) was added to ((3S, 4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol (86 mg ,444umol) and THF (15mL) and stirred for 30 minutes, then (6S)-6-methyl-4- (2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene- 1-yl)quinazolin-4-yl)-1,4-oxazepan-6-ol (300mg, 370umol) was added to the above reaction solution at once and stirred for 1.5h. TLC and LCMS monitored the reaction. At the end, pour the reaction solution into a semi-saturated NH 4 Cl (50 mL) solution, extract with EA (30 mL × 3), collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , concentrate the organic phase and pass through FCC (EA/PE=0-90%) purification to obtain a yellow solid (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperdine) (ridin-3-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylmethyl) Silyl)oxy)naphth-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (270 mg, yield 74%). LCMS(m/z):964.3(M+H).
步骤C：(6S)-4-(2-((((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step C: (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol
室温条件下，将CsF(417mg,2.75mmol)加入到(6S)-4-(2-(((3S,4S)-4-((二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(270mg,275umol)和DMF(5mL)的混合溶液中，升温至50℃反应1h，LCMS和TLC监测反应结束，经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝50-70％)纯化，得到白色固体(6S)-4-(2-((((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(85mg,收率46％)。LCMS(m/z):964.3(M+H).1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.19–7.94(m,2H),7.55–7.45(m,1H),7.42(d,J＝2.6Hz,1H),7.21–7.10(m,1H),6.50–6.12(m,1H),5.38–5.18(m,1H),4.52–4.19(m,4H),4.11–3.86(m,4H),3.81–3.66(m,1H),3.62–3.45(m,2H),2.94–2.71(m,2H),2.11(s,3H),2.03–1.53(m,5H),1.20–1.13(m,3H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.19,-114.75–-116.33(m),-118.17–-119.09(m),-119.12–-119.84(m),-124.21–-125.19(m)。At room temperature, CsF (417 mg, 2.75 mmol) was added to (6S)-4-(2-(((3S,4S)-4-((difluoromethyl)-1,3-dimethylpiperidine) -3-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilane (yl)oxy)naphth-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (270 mg, 275umol) and DMF (5 mL) In the mixed solution, the temperature was raised to 50°C and reacted for 1 hour. LCMS and TLC monitored the end of the reaction. Purified by pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 50-70%), a white solid was obtained. (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8 -Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine- 6-alcohol (85 mg, yield 46%). LCMS (m/z): 964.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.19–7.94 ( m,2H),7.55–7.45(m,1H),7.42(d,J＝2.6Hz,1H),7.21–7.10(m,1H),6.50–6.12(m,1H),5.38–5.18(m, 1H),4.52–4.19(m,4H),4.11–3.86(m,4H),3.81–3.66(m,1H),3.62–3.45(m,2H),2.94–2.71(m,2H),2.11( s,3H),2.03–1.53(m,5H),1.20–1.13(m,3H),1.11(s,3H). 19 F NMR (376MHz, DMSO-d 6 )δ-110.19,-114.75–-116.33 (m),-118.17–-119.09(m),-119.12–-119.84(m),-124.21–-125.19(m).
实施例93
Example 93
(6S)-4-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇
(6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine-6 -alcohol
步骤A：(6S)-4-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇 Step A: (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine alkan-6-ol
室温下，将(6S)-4-(2-((((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(15mg,22umol)溶于甲醇(10mL)，加入Pd/C(5mg,10％,4.5umol),H2气球置换两次并在室温搅拌2h，LCMS监测反应结束，反应液过滤头得到澄清的有机相，浓缩完全后，加入乙腈(2mL),再加入去离子水(20mL)，冻干，得到白色固体(6S)-4-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(12mg,收率80％)。LCMS(m/z):675.2(M+H)。1H NMR(400MHz,DMSO-d6)δ8.36–8.18(m,1H),7.78(dd,J＝9.1,6.0Hz,1H),7.45–7.29(m,2H),7.10–6.95(m,1H),6.53–6.10(m,1H),5.37–5.19(m,1H),4.56–4.08(m,4H),4.04–3.68(m,4H),3.65–3.48(m,2H),2.92–2.74(m,2H),2.43–2.30(m,1H),2.10(s,3H),1.92–1.52(m,6H),1.17–1.08(m,6H),0.89–0.70(m,3H).19F NMR(376MHz,DMSO-d6)δ-115.01–-116.01(m),-118.28–-119.20(m).-118.57–-118.80(m),-119.36,-123.83。At room temperature, (6S)-4-(2-((((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)- 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine Cycloheptane-6-ol (15mg, 22umol) was dissolved in methanol (10mL), Pd/C (5mg, 10%, 4.5umol) was added, the H 2 balloon was replaced twice and stirred at room temperature for 2h. LCMS monitored the end of the reaction. Filter the reaction solution to obtain a clear organic phase. After complete concentration, add acetonitrile (2mL), then add deionized water (20mL), and freeze-dry to obtain a white solid (6S)-4-(2-(((3S,4S )-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) )-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (12 mg, yield 80%). LCMS (m/ z): 675.2 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.36–8.18 (m, 1H), 7.78 (dd, J = 9.1, 6.0Hz, 1H), 7.45–7.29 ( m,2H),7.10–6.95(m,1H),6.53–6.10(m,1H),5.37–5.19(m,1H),4.56–4.08(m,4H),4.04–3.68(m,4H), 3.65–3.48(m,2H),2.92–2.74(m,2H),2.43–2.30(m,1H),2.10(s,3H),1.92–1.52(m,6H),1.17–1.08(m,6H ),0.89–0.70(m,3H). 19 F NMR(376MHz, DMSO-d 6 )δ-115.01–-116.01(m),-118.28–-119.20(m).-118.57–-118.80(m), -119.36,-123.83.
实施例93-1及实施例93-2
Example 93-1 and Example 93-2
实施例93，(6S)-4-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(25mg)经Pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝60-80％)分离，得到首先洗脱出来的异构体1为实施例93-1(4.8mg，保留时间11.5min)，LCMS(m/z):675.2(M+H)；随后洗脱出来的异构体2为实施例93-2(8.4mg，保留时间12.8min)，LCMS(m/z):675.2(M+H)。


Example 93, (6S)-4-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptane-6-ol (25 mg) was separated by Pre-HPLC (C18, ACN/(10 mmol NH 4 HCO 3 /H 2 O) = 60-80%), and the isomer 1 that eluted first was obtained as an example. 93-1 (4.8 mg, retention time 11.5 min), LCMS (m/z): 675.2 (M+H); the isomer 2 that subsequently eluted was Example 93-2 (8.4 mg, retention time 12.8 min) ), LCMS(m/z):675.2(M+H).


实施例98-1和98-2
Examples 98-1 and 98-2
(6S)-4-(7-((Ra)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·三氟乙酸盐和(6S)-4-(7-((Sa)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·三氟乙酸盐
(6S)-4-(7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptane-6-ol·trifluoroacetate and (6S)-4-(7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8- Difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6 -Methyl-1,4-oxaazepan-6-ol trifluoroacetate
步骤A：(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step A: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,6,8-trifluoroquinazoline -4-yl)-6-methyl-1,4-oxaazepan-6-ol
室温条件下，依次将(S)-4-(7-溴-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(100mg,255umol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(138mg,382umol),Pd(OAc)2(6mg,26umol)、BIDIME(17mg,51umol)、K3PO4(162mg,765mmol)加入到无水甲苯(8mL)中，N2置换三次后，升温至105℃搅拌过夜。LCMS和TLC监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂，收集母液浓缩，得到的粗品经FCC(SiO2,EA/PE＝0-60％)纯化，得到黄色固体(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘 -1-基)-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(40mg,收率29％)。LCMS(m/z):546.1(M+H)。At room temperature, (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepine -6-ol (100mg, 255umol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (138mg, 382umol), Pd(OAc) 2 (6mg, 26umol), BIDIME (17mg, 51umol), K 3 PO 4 (162mg, 765mmol) were added to In anhydrous toluene (8 mL), after replacing with N2 three times, the temperature was raised to 105°C and stirred overnight. LCMS and TLC monitor the end of the reaction, return the reaction solution to room temperature, filter through diatomaceous earth to remove the palladium catalyst, collect the mother liquor and concentrate, and the crude product obtained is purified by FCC (SiO 2 , EA/PE=0-60%) to obtain a yellow solid ( 6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene -1-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (40 mg, yield 29% ). LCMS(m/z):546.1(M+H).
步骤B：(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step B: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-6,8-difluoro-2-(( (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4 -Oxaazepan-6-ol
室温条件下，将NaH(12mg,60％,293umol)加入到(S,E)-(4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲醇(15mg,88umol)和THF(5mL)的混合溶液中并搅拌30分钟，再将(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-2,6,8-三氟喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(40mg,73umol)一次加入到上述反应液中并搅拌1h，TLC监测反应结束，将反应液倒入半饱和的NH4Cl(30mL)溶液中，EA(30mL×3)萃取，收集有机相，饱和NaCl水溶液(30mL)洗涤，无水Na2SO4干燥，浓缩有机相经FCC(SiO2,EA/PE＝0-90％)纯化，得到黄色固体(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(30mg,收率59％)。At room temperature, NaH (12 mg, 60%, 293umol) was added to (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (15 mg, 88umol) and THF (5mL) and stirred for 30 minutes, then (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -(yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (40 mg, 73umol) was added to the above into the reaction solution and stir for 1 hour. TLC monitors the end of the reaction. Pour the reaction solution into a semi-saturated NH 4 Cl (30 mL) solution, extract with EA (30 mL × 3), collect the organic phase, and wash with saturated NaCl aqueous solution (30 mL). Dry with water Na 2 SO 4 , concentrate the organic phase and purify it by FCC (SiO 2 , EA/PE=0-90%) to obtain yellow solid (6S)-4-(7-(8-ethyl-7-fluoro-3) -(Methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiper (Din-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (30 mg, yield 59%).
步骤C：(6S)-4-(7-((Ra)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·三氟乙酸盐和(6S)-4-(7-((Sa)-8-乙基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇·三氟乙酸盐Step C: (6S)-4-(7-((Ra)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S, E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxa Azepan-6-ol trifluoroacetate and (6S)-4-(7-((Sa)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6 ,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl )-6-Methyl-1,4-oxaazepan-6-ol trifluoroacetate
室温下，将CF3COOH(10mL)加入到(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(30mg,43umol)中，并在室温下搅拌1h。LCMS监测反应结束，浓缩反应液除去酸液，EA(20mL)稀释，加入半饱和的NaHCO3溶液15mL，pH调至碱性，EA(20mL×3)萃取，收集有机相，浓缩后经pre-HPLC(C18,ACN/(0.1％TFA/H2O)＝35-45％)纯化，首先洗脱出来的异构体1为98-1(3mg,收率21％，保留时间8.20min)；随后洗脱出来的异构体2为98-2(2mg,收率14％，保留时间9.23min)。LCMS(m/z):655.2(M+H)。


Add CF 3 COOH (10 mL) to (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-6 at room temperature, 8-Difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl) -6-methyl-1,4-oxazepan-6-ol (30 mg, 43umol) and stirred at room temperature for 1 h. Monitor the end of the reaction with LCMS, concentrate the reaction solution to remove the acid, dilute with EA (20 mL), add 15 mL of semi-saturated NaHCO 3 solution, adjust the pH to alkaline, extract with EA (20 mL × 3), collect the organic phase, concentrate and pre- HPLC (C18, ACN/(0.1% TFA/H 2 O) = 35-45%) purification, the first eluted isomer 1 is 98-1 (3 mg, yield 21%, retention time 8.20 min); The isomer 2 that subsequently eluted was 98-2 (2 mg, yield 14%, retention time 9.23 min). LCMS(m/z):655.2(M+H).


实施例106
Example 106
(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-5-乙炔基-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
(R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy -d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-4-yl) -3-methylpiperidin-3-ol
步骤A：(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step A: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylthio) -5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(7-氯-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(200mg,0.38mmol)，2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(207mg,0.58mmol)、磷酸钾(243mg,1.14mmol)和Pd(dtbpf)Cl2(25mg,0.038mmol)加到置有磁子的反应瓶中，氮气置换三次，再加入二氧六环(4mL)和水(1mL)，加热至100℃搅拌过夜。LCMS监测反应结束，冷却到室温，加入30mL饱和氯化铵水溶液淬灭，再用EtOAc(30mL×3)萃取。合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩干，得到的粗产品经FCC(SiO2,EA/PE＝0-100％)纯化，得到白色固体(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(50mg,收率18％)。LCMS(m/z):721.0(M+H)。At room temperature, (R)-1-(7-chloro-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d ]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.38 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -base)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (207mg, 0.58mmol), potassium phosphate (243mg, 1.14mmol) and Pd (dtbpf) Cl 2 (25 mg, 0.038 mmol) was added to the reaction flask equipped with a magnet, replaced with nitrogen three times, then dioxane (4 mL) and water (1 mL) were added, heated to 100°C and stirred overnight. LCMS monitored the end of the reaction, cooled to room temperature, added 30 mL of saturated aqueous ammonium chloride solution to quench, and then extracted with EtOAc (30 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness. The crude product obtained is purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a white solid (R)-1-(7 -(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-((triisopropylsilyl) )ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50 mg, yield 18%). LCMS(m/z):721.0(M+H).
步骤B：(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step B: (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(methylsulfenic acid) Acyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将m-CBPA(21mg,85％含量,0.10mmol)加入到(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲硫基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(50mg,0.069mmol)的DCM(5mL)溶液中并室温搅拌反应1h。TLC监测反应结束，补加适量DCM后，分别用饱和NaHCO3和NaCl水溶液洗，无水硫酸钠干燥，过滤浓缩，得到粗产品白色固体(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(51mg,粗品)。LCMS(m/z):737.0(M+H)。At room temperature, m-CBPA (21 mg, 85% content, 0.10 mmol) was added to (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene) -1-yl)-8-fluoro-2-(methylthio)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3- Methyl piperidin-3-ol (50 mg, 0.069 mmol) was dissolved in DCM (5 mL) and stirred at room temperature for 1 h. TLC monitors the end of the reaction. After adding an appropriate amount of DCM, wash with saturated NaHCO 3 and NaCl aqueous solutions respectively, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product white solid (R)-1-(7-(8-ethyl- 7-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)-5-((triisopropylsilyl)ethynyl)pyridine And[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (51 mg, crude). LCMS(m/z):737.0(M+H).
步骤C：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step C: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-((triisopropylsilane (yl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(甲基亚磺酰基)-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(50mg)和((3S,4S)-4-(二氟甲 基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲-d2-醇(20mg,0.10mmol)溶解到2mL无水THF中。氮气保护下，冷却到-70℃，滴加入t-BuONa(0.1mL,2M in THF,0.2mmol)。所得混合物-70℃搅拌1h。加入饱和氯化铵水溶液(10mL)淬灭反应，用EtOAc(15mL×3)萃取，有机相合并，干燥浓缩，得粗产品白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(60mg，粗品)。LCMS(m/z):871.0(M+H)。Under room temperature conditions, (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(methyl Sulfinyl)-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (50 mg) and ( (3S,4S)-4-(difluoromethyl (20 mg, 0.10 mmol) was dissolved in 2 mL of dry THF. Under nitrogen protection, cool to -70°C, and add t-BuONa (0.1 mL, 2M in THF, 0.2 mmol) dropwise. The resulting mixture was stirred at -70°C for 1 h. Add saturated aqueous ammonium chloride solution (10mL) to quench the reaction, extract with EtOAc (15mL×3), combine the organic phases, dry and concentrate to obtain the crude product white solid (R)-1-(2-(((3S,4S) -4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-7-(8-ethyl-7-fluoro -3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl )-3-methylpiperidin-3-ol (60 mg, crude). LCMS(m/z):871.0(M+H).
步骤D：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step D: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl)pyrido [4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(60mg)溶解到4M HCl-Dioxane(5mL)中。室温搅拌1h，LCMS监测反应完成，停止反应，浓缩干，残留物用20mL饱和碳酸氢钠溶液中和，再用EtOAc萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，得到粗产品白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(57mg,粗品)。LCMS(m/z):827.3(M+H)。Under room temperature conditions, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidine-3- base)methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-((triisopropyl Silyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg) was dissolved in 4M HCl-Dioxane (5 mL). Stir at room temperature for 1 hour. LCMS monitors that the reaction is complete. Stop the reaction and concentrate to dryness. The residue is neutralized with 20 mL of saturated sodium bicarbonate solution and extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product white solid (R)-1-(2-(((3S,4S)-4-(difluoromethyl)- 3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl) -8-Fluoro-5-((triisopropylsilyl)ethynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (57 mg, crude product) . LCMS(m/z):827.3(M+H).
步骤E：(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-5-乙炔基-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇Step E: (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidine-4 -yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-((三异丙基硅基)乙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(57mg)和氟化铯(52mg,0.34mmol)溶于DMF(2mL)中，在60℃下搅拌1h。LCMS监测反应结束后，反应液过滤后，经pre-HPLC(C18,ACN/(0.1％NH4HCO3/H2O)＝40-60％)纯化，得到白色固体(R)-1-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-5-乙炔基-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇(5.0mg)。LCMS(m/z):671.4(M+H)。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.81–7.74(m,1H),7.40–7.31(m,2H),7.17–7.04(m,1H),6.46–6.11(m,1H),4.81–4.71(m,1H),4.64–4.23(m,1H),3.76–3.46(m,3H),3.25–3.18(m,1H),2.89–2.75(m,2H),2.24–1.40(m,10H),1.26–0.99(m,6H),0.82–0.71(m,3H).19F NMR(376MHz,DMSO-d6)δ-116.07,-119.07,-119.23,-138.45。

Under room temperature conditions, (R)-1-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidine-3- yl)methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-5-((triisopropylsilyl)ethynyl) Pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (57 mg) and cesium fluoride (52 mg, 0.34 mmol) were dissolved in DMF (2 mL) at 60°C. Stir for 1 hour. After the LCMS monitors the end of the reaction, the reaction solution is filtered and purified by pre-HPLC (C18, ACN/(0.1% NH 4 HCO 3 /H 2 O) = 40-60%) to obtain a white solid (R)-1-( 2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine -3-ol (5.0 mg). LCMS(m/z):671.4(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.96(s,1H),7.81–7.74(m,1H),7.40–7.31(m,2H),7.17–7.04(m,1H),6.46–6.11 (m,1H),4.81–4.71(m,1H),4.64–4.23(m,1H),3.76–3.46(m,3H),3.25–3.18(m,1H),2.89–2.75(m,2H) ,2.24–1.40(m,10H),1.26–0.99(m,6H),0.82–0.71(m,3H). 19 F NMR (376MHz, DMSO-d 6 )δ-116.07,-119.07,-119.23,- 138.45.

实施例110
Example 110
(6S)-4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇
(6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoro (Methylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepine-6 -alcohol
步骤A：(6S)-4-(6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step A: (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) yl)oxy)naphth-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazole Phin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
室温条件下，将NaH(40mg,60％,987umol)加入到(S,E)-(4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲醇(51mg,296umol)和THF(10mL)的混合溶液中并搅拌30分钟，再将(6S)-6-甲基-4-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)喹唑啉-4-基)-1,4-氧杂氮杂环庚烷-6-醇(200mg,247umol)一次加入到上述反应液中并搅拌1.5h，TLC监测反应结束，将反应液倒入半饱和的NH4Cl溶液(30mL)中，EA(30mL×3)萃取，收集有机相后，饱和NaCl溶液(30mL)洗涤，无水Na2SO4干燥，浓缩有机相，经FCC(SiO2,EA/PE＝0-90％)纯化，得到黄色固体(6S)-4-(6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基- 1,4-氧杂氮杂环庚烷-6-醇(110mg,收率46％)。LCMS(m/z):482.3(M/2+H)。At room temperature, NaH (40 mg, 60%, 987umol) was added to (S,E)-(4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methanol (51 mg, 296umol) and THF (10mL) and stirred for 30 minutes, then (6S)-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-8-(( Triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-1,4-oxaazepine Cycloheptane-6-ol (200mg, 247umol) was added to the above reaction solution at one time and stirred for 1.5h. TLC monitored the end of the reaction. Pour the reaction solution into a semisaturated NH 4 Cl solution (30mL), EA (30mL× 3) Extraction, collect the organic phase, wash with saturated NaCl solution (30 mL), dry with anhydrous Na 2 SO 4 , concentrate the organic phase, and purify by FCC (SiO 2 , EA/PE=0-90%) to obtain a yellow solid ( 6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy) )naphthalen-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazoline-4- base)-6-methyl- 1,4-Oxaazepan-6-ol (110 mg, yield 46%). LCMS(m/z):482.3(M/2+H).
步骤B：(6S)-4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇Step B: (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4 -(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepine alkan-6-ol
室温条件下，将CsF(173mg,1.14mmol)加入到(6S)-4-(6,8-二氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)-2-((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(110mg,114umol)和DMF(3mL)的混合溶液中，升温至50℃反应1h。LCMS和TLC监测反应结束，经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝50-70％)纯化，得到白色固体(6S)-4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(35mg,收率47％)。LCMS(m/z):651.2(M+H).1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.23–7.88(m,2H),7.60–7.35(m,2H),7.26–7.09(m,1H),6.97–6.44(m,1H),5.46–5.17(m,1H),4.70–4.50(m,1H),4.42–4.16(m,3H),4.14–3.86(m,4H),3.80–3.50(m,4H),2.79–2.62(m,2H),2.35–2.09(m,4H),2.04–1.76(m,2H),1.21–1.13(m,3H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.17,-117.83–-120.05(m),-124.89,-138.89。At room temperature, CsF (173 mg, 1.14 mmol) was added to (6S)-4-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)) -3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine Mixing of -3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (110mg, 114umol) and DMF (3mL) In the solution, the temperature was raised to 50°C and reacted for 1 hour. LCMS and TLC monitored the completion of the reaction, and purified by pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 50-70%) to obtain a white solid (6S)-4-(7-(8- Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethyl Piperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35 mg, yield 47%). LCMS(m/z):651.2(M+H). 1 H NMR(400MHz, DMSO-d 6 )δ10.23(s,1H),8.23–7.88(m,2H),7.60–7.35(m,2H) ),7.26–7.09(m,1H),6.97–6.44(m,1H),5.46–5.17(m,1H),4.70–4.50(m,1H),4.42–4.16(m,3H),4.14–3.86 (m,4H),3.80–3.50(m,4H),2.79–2.62(m,2H),2.35–2.09(m,4H),2.04–1.76(m,2H),1.21–1.13(m,3H) ,1.11(s,3H). 19 F NMR (376MHz, DMSO-d 6 )δ-110.17,-117.83–-120.05(m),-124.89,-138.89.
实施例110-1及实施例110-2
Example 110-1 and Example 110-2
实施例110，(6S)-4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧杂氮杂环庚烷-6-醇(34mg)经SFC拆分(Waters SFC 150，分离柱：250*25mm 10μm；流动相：CO2/IPA(+0.1％7.0mol/l NH3/MeOH)＝45/55；流速：120mL/min)，得到首先洗脱出来的异构体1为实施例110-1(19mg，相对保留时间较小)。手性分析方法110，Rt＝0.801，LCMS(m/z):651.2(M+H)；随后洗脱出来的异构体2为实施例110-2(27mg，相对保留时间交大)。手性分析方法110，Rt＝2.672，LCMS(m/z):651.2(M+H)。Example 110, (6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol (34 mg) was resolved by SFC (Waters SFC 150, separation column: 250*25mm 10μm; mobile phase: CO 2 /IPA (+0.1% 7.0mol/l NH 3 /MeOH) = 45/55; flow rate: 120mL/min), and the isomer 1 that eluted first is obtained as an example. 110-1 (19 mg, relatively small retention time). Chiral analysis method 110, Rt=0.801, LCMS (m/z): 651.2 (M+H); the isomer 2 that subsequently eluted was Example 110-2 (27 mg, relatively large retention time). Chiral analysis method 110, Rt=2.672, LCMS (m/z): 651.2 (M+H).
手性分析方法110：Waters UPCC(CA-352)，分析柱：100*3mm 3μm；流动相A：CO2，流动相B：IPA(+0.1％DEA)；流速：1.5mL/min；柱温：35℃；反压：1800psi；梯度：0-5.5min A/B＝60/40。


Chiral analysis method 110: Waters UPCC (CA-352), analytical column: 100*3mm 3μm; mobile phase A: CO 2 , mobile phase B: IPA (+0.1% DEA); flow rate: 1.5mL/min; column temperature: 35℃; back pressure: 1800psi; gradient: 0-5.5min A/ B=60/40.


实施例120
Example 120
(S)-4-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
(S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene )-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4 -oxazepan-6-ol
步骤A：(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step A: (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-methoxy-2 -(Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
室温条件下，依次将4-(7-氯-8-氟-5-甲氧基-2-(甲硫基)-1,3,6-三氮杂-4-萘基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(175mg,0.452mmol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(326mg,0.904mmol)、Pd(dtppf)2Cl(52mg,0.045mmol)、K3PO4(289mg,1.36mmol)加入到二氧六环(4mL)与水(1mL)的混合溶液中，N2置换三次后，升温至100℃搅拌2h。LCMS监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂和碱，浓缩有机液，得到的粗品经FCC(SiO2,EA/PE＝0-60％)纯化，得到黄色固体(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(200mg,收率75％)。LCMS(m/z):587.1(M+H)。At room temperature, 4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-1,3,6-triaza-4-naphthyl)-6-methyl 1,4-Oxaazepan-6-ol (175 mg, 0.452 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl) )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (326mg, 0.904mmol), Pd(dtppf) 2 Cl (52mg, 0.045mmol), K 3 PO 4 (289 mg, 1.36 mmol) was added to the mixed solution of dioxane (4 mL) and water (1 mL). After N 2 replacement three times, the temperature was raised to 100°C and stirred for 2 h. LCMS monitors the end of the reaction, returns the reaction solution to room temperature, filters through diatomaceous earth to remove the palladium catalyst and alkali, and concentrates the organic liquid. The obtained crude product is purified by FCC (SiO 2 , EA/PE=0-60%) to obtain a yellow solid ( S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-5-methoxy-2-(methylthio yl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (200 mg, yield 75%). LCMS(m/z):587.1(M+H).
步骤B：(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇 Step B: (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-5-methoxy-2 -(Methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
室温条件下，将m-CPBA(88mg,0.51mmol)加入到(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(200mg,0.341mol)和DCM(5mL)的溶液中并室温搅拌1h。TLC和LCMS监测反应结束，将反应液DCM(15mL)稀释，加入半饱和aq.NaHCO3(20mL)洗涤，DCM(20mL×2)萃取，收集的有机相用饱和NaCl(20mL)洗涤，无水Na2SO4干燥，过滤，有机液浓缩后，得到黄色固体(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(200mg,收率97％)。LCMS(m/z):603.1(M+H)。At room temperature, m-CPBA (88 mg, 0.51 mmol) was added to (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl) )-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol (200 mg, 0.341 mol) and DCM (5 mL) and stirred at room temperature for 1 h. TLC and LCMS monitored the end of the reaction. Dilute the reaction solution with DCM (15 mL), add half-saturated aq.NaHCO 3 (20 mL) for washing, and extract with DCM (20 mL × 2). The collected organic phase was washed with saturated NaCl (20 mL) and anhydrous. Dry over Na 2 SO 4 , filter, and concentrate the organic liquid to obtain a yellow solid (6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl) )-8-fluoro-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol (200 mg, yield 97%). LCMS(m/z):603.1(M+H).
步骤C：(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step C: (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((S, E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl )-6-methyl-1,4-oxazepan-6-ol
在-78℃干冰乙醇浴条件下，将t-BuONa(0.5mL,2M THF溶液,1mmol)滴加到(6S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(200mg,0.332mmol)、((S)-(E)-4-氟亚甲基-1-甲基-3-甲基哌啶-3-基)甲醇(86mg,0.50mmol)和THF(2mL)的混合溶液中并搅拌1h，LCMS监测反应结束，将反应液倒入半饱和NH4Cl水溶液(10mL)中，EA(20mL×2)萃取。收集有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，浓缩有机相，得到黄色固体(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(150mg,收率64％)。LCMS(m/z):712.2(M+1)。In a dry ice ethanol bath at -78°C, t-BuONa (0.5 mL, 2M THF solution, 1 mmol) was added dropwise to (6S)-4-(7-(8-ethyl-7-fluoro-3-(methane) Oxymethoxy)naphth-1-yl)-8-fluoro-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6- Methyl-1,4-oxazepan-6-ol (200mg, 0.332mmol), ((S)-(E)-4-fluoromethylene-1-methyl-3-methylpiper (ridin-3-yl)methanol (86 mg, 0.50 mmol) and THF (2 mL) and stirred for 1 h. LCMS monitored the end of the reaction. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (10 mL). EA (20 mL) ×2) Extraction. Collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate the organic phase to obtain yellow solid (S)-4-(7-(8-ethyl-7-fluoro-3-methoxy Methoxy)naphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methane Oxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, yield 64 %). LCMS(m/z):712.2(M+1).
步骤D：(S)-4-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step D: (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoro (Methylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl- 1,4-Oxaazepan-6-ol
室温条件下，将TFA(2mL)加入到(S)-4-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(150mg,0.211mol)和DCM(2mL)的混合溶液中并搅拌1h。LCMS和TLC监测反应结束,经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝40-60％)纯化，得到白色固体(S)-4-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(8.4mg,收率6％)。LCMS(m/z):668.3(M+H).1H NMR(400MHz,DMSO-d6)δ9.97–9.90(m,1H),7.79–7.54(m,1H),7.38–7.18(m,2H),7.11–6.96(m,1H),6.83–6.54(m,1H),4.69–4.59(m,1H),4.32–4.23(m,1H),4.01–3.86(m,6H),3.84–3.67(m,2H),3.53–3.38(m,2H),2.70–2.62(m,2H),2.46–2.35(m,1H),2.29–2.17(m,2H),2.17–2.08(m,3H),1.93–1.79(m,2H),1.31–1.19(m,2H),1.14–0.93(m,6H),0.88–0.69(m,3H).19F NMR(376MHz,DMSO-d6)δ-119.13–-120.20(m),-138.07–-139.06(m),-148.45–-149.26(m)。At room temperature, TFA (2 mL) was added to (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro -2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3 -d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (150 mg, 0.211 mol) and DCM (2 mL) mixed solution and stirred for 1 h. LCMS and TLC monitored the end of the reaction, and purified by pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 40-60%) to obtain a white solid (S)-4-(7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine- 3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol ( 8.4mg, yield 6%). LCMS(m/z):668.3(M+H). 1 H NMR(400MHz, DMSO-d 6 )δ9.97–9.90(m,1H),7.79–7.54(m,1H),7.38–7.18(m ,2H),7.11–6.96(m,1H),6.83–6.54(m,1H),4.69–4.59(m,1H),4.32–4.23(m,1H),4.01–3.86(m,6H),3.84 –3.67(m,2H),3.53–3.38(m,2H),2.70–2.62(m,2H),2.46–2.35(m,1H),2.29–2.17(m,2H),2.17–2.08(m, 3H),1.93–1.79(m,2H),1.31–1.19(m,2H),1.14–0.93(m,6H),0.88–0.69(m,3H). 19 F NMR (376MHz, DMSO-d 6 ) δ-119.13–-120.20(m),-138.07–-139.06(m),-148.45–-149.26(m).
实施例121
Example 121
(S)-4-(7-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧杂卓-6-醇
(S)-4-(7-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1 ,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepine -6-ol
步骤A：(S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step A: (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol
室温条件下，依次将4-(7-氯-8-氟-5-甲氧基-2-(甲硫基)-1,3,6-三氮杂萘-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(530mg,1.37mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(1.5g,2.8mmol)、Pd(dtppf)2Cl(100mg,0.0870mmol)、K3PO4(871mg,4.11mmol)加入到二氧六环(8mL)与水(2mL)的混合溶液中，N2置换三次后，升温至100℃搅拌2h。LCMS监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂和碱，浓缩有机液，得到的粗品经FCC(SiO2,EA/PE＝0-30％)纯化，得到黄色固体(S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(720mg,收率62％)。LCMS(m/z):851.2(M+H)。At room temperature, 4-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)-1,3,6-triazin-4-yl)-6-methyl Base-1,4-oxazepan-6-ol (530 mg, 1.37 mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)ethynyl) Propylsilyl)oxy)naphthalen-1-yl)boronic acid (1.5g, 2.8mmol), Pd(dtppf) 2 Cl (100mg, 0.0870mmol), K 3 PO 4 (871mg, 4.11mmol) were added to In the mixed solution of oxane (8 mL) and water (2 mL), after N2 replacement three times, the temperature was raised to 100°C and stirred for 2 h. LCMS monitors the end of the reaction, returns the reaction solution to room temperature, filters through diatomaceous earth to remove the palladium catalyst and alkali, and concentrates the organic liquid. The obtained crude product is purified by FCC (SiO 2 , EA/PE=0-30%) to obtain a yellow solid ( S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl )-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (720mg, yield 62%). LCMS(m/z):851.2(M+H).
步骤B：(6S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step B: (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacyclo Heptan-6-ol
室温条件下，将m-CPBA(259mg,1.50mmol)加入到(S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(720mg,0.847mol)和DCM(10mL)的溶液中并室温搅拌1h。TLC和LCMS监测反应结束，将反应液DCM(50mL)稀释，加入半饱和aq.NaHCO3(50mL)洗涤，DCM(50mL×2)萃取，收集的有机相用饱和NaCl(30mL)洗涤，无水Na2SO4干燥，过滤，有机液浓缩后，得到黄色固体(6S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(680mg,收率93％)。LCMS(m/z):866.5(M+H)。At room temperature, m-CPBA (259 mg, 1.50 mmol) was added to (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3- ((Triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6- into a solution of methyl-1,4-oxazepan-6-ol (720 mg, 0.847 mol) and DCM (10 mL) and stirred at room temperature for 1 h. TLC and LCMS monitored the end of the reaction. Dilute the reaction solution with DCM (50 mL), add half-saturated aq.NaHCO 3 (50 mL) for washing, and extract with DCM (50 mL × 2). The collected organic phase was washed with saturated NaCl (30 mL) and anhydrous. Dry over Na 2 SO 4 , filter, and concentrate the organic liquid to obtain a yellow solid (6S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)- 6-Methyl-1,4-oxazepan-6-ol (680 mg, yield 93%). LCMS(m/z):866.5(M+H).
步骤C：(S)-4-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step C: (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy) Naphthyl-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)-5-methoxy Pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
在-78℃干冰乙醇浴条件下，将t-BuONa(0.4mL,2M THF溶液,0.8mmol)滴加到(6S)-4-(8- 氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(220mg,0.254mmol)、((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲醇(53mg,0.31mmol)和THF(5mL)的混合溶液中并搅拌1h，LCMS监测反应结束后，将反应液倒入半饱和NH4Cl水溶液(10mL)中，EA(20mL×2)萃取。收集有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，浓缩有机相，得到黄色固体(S)-4-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(180mg,收率73％)。LCMS(m/z):488.8(M/2+1)。In a dry ice ethanol bath at -78°C, t-BuONa (0.4 mL, 2M THF solution, 0.8 mmol) was added dropwise to (6S)-4-(8- Fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)-5-methoxy- 2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (220 mg, 0.254 mmol) , ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methanol (53 mg, 0.31 mmol) and THF (5 mL) mixed solution After stirring for 1 hour and monitoring the reaction with LCMS, the reaction solution was poured into a semisaturated NH 4 Cl aqueous solution (10 mL), and extracted with EA (20 mL × 2). Collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate the organic phase to obtain yellow solid (S)-4-(8-fluoro-7-(7-fluoro-8-(triiso Propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)-2-(((S,E)-4-(fluoromethylene)-1 ,3-dimethylpiperidin-3-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxynitrogen Heterocycloheptan-6-ol (180 mg, yield 73%). LCMS(m/z):488.8(M/2+1).
步骤D：(S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step D: (S)-4-(8-fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene -1-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepane -6-ol
室温条件下，将CsF(180mg,1.18mmol)加入到(S)-4-(8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)-5-甲氧基吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(180mg,0.185mmol)和DMF(2mL)的混合溶液中，升温至50℃反应1h。LCMS和TLC监测反应结束,经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝40-70％)纯化，得到白色固体(S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(24mg,收率20％)。LCMS(m/z):664.3(M+H).1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.02–7.93(m,1H),7.51–7.43(m,1H),7.39(d,J＝2.6Hz,1H),7.27–7.20(m,1H),6.83–6.56(m,1H),5.09(d,J＝84.0Hz,1H),4.64–4.54(m,1H),4.32–4.25(m,1H),4.16–4.02(m,2H),4.00–3.81(m,6H),3.79–3.38(m,5H),2.70–2.64(m,2H),2.25–2.10(m,4H),1.95–1.78(m,2H),1.14–0.97(m,6H).19F NMR(376MHz,DMSO-d6)δ-110.27–-111.23(m),-138.17–-139.30(m),-149.09–-151.00(m)。

At room temperature, CsF (180 mg, 1.18 mmol) was added to (S)-4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-( (Triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl )methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (180 mg, 0.185 mmol) and DMF (2 mL), raise the temperature to 50°C and react for 1 hour. LCMS and TLC monitored the end of the reaction, and purified through pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 40-70%) to obtain a white solid (S)-4-(8-fluoro-7). -(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxy-2-( Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (24 mg, yield 20%). LCMS(m/z):664.3(M+H). 1 H NMR(400MHz, DMSO-d 6 )δ10.15(s,1H),8.02–7.93(m,1H),7.51–7.43(m,1H) ),7.39(d,J＝2.6Hz,1H),7.27–7.20(m,1H),6.83–6.56(m,1H),5.09(d,J＝84.0Hz,1H),4.64–4.54(m, 1H),4.32–4.25(m,1H),4.16–4.02(m,2H),4.00–3.81(m,6H),3.79–3.38(m,5H),2.70–2.64(m,2H),2.25– 2.10(m,4H),1.95–1.78(m,2H),1.14–0.97(m,6H). 19 F NMR (376MHz, DMSO-d 6 )δ-110.27–-111.23(m),-138.17–- 139.30(m),-149.09–-151.00(m).

实施例125
Example 125
(6S)-4-(6-氯-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-氟亚甲基-1，3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
(6S)-4-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-fluoro Methylene-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol
步骤D:(S)-4-(6-氯-2,8-二氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇Step D: (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris( Isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol
室温条件下，依次将(S)-4-(7-溴-6-氯-2,8-二氟-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(500mg,1.22mmol)、(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-((三异丙基甲硅烷基)氧基)萘-1-基)硼酸(996mg,1.84mmol)、Pd(OAc)2(27.5mg,0.122mmol)、BIDIME(80.8mg,0.245mmol)、K3PO4(779mg,3.67mmol)加入到无水甲苯(10mL)中，N2置换三次后，升温至110℃搅拌16h。LCMS监测反应结束，将反应液恢复至室温，硅藻土过滤除去钯催化剂，收集母液浓缩后，得到的粗品经FCC(SiO2，THF/PE＝0-30％)，得到黄色固体(S)-4-(6-氯-2,8-二氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(570mg,收率56％)。LCMS(m/z):826.2(M+H)。At room temperature, (S)-4-(7-bromo-6-chloro-2,8-difluoro-4-quinazolinyl)-6-methyl-1,4-oxane -6-ol (500mg, 1.22mmol), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1 -Boronic acid (996mg, 1.84mmol), Pd(OAc) 2 (27.5mg, 0.122mmol), BIDIME (80.8mg, 0.245mmol), K 3 PO 4 (779mg, 3.67mmol) were added to anhydrous toluene (10mL ), after N 2 replacement three times, the temperature was raised to 110°C and stirred for 16 hours. LCMS monitors the end of the reaction. Return the reaction solution to room temperature. Filter through diatomaceous earth to remove the palladium catalyst. After collecting the mother liquor and concentrating, the crude product obtained is subjected to FCC (SiO 2 , THF/PE = 0-30%) to obtain a yellow solid (S). -4-(6-chloro-2,8-difluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris(isopropyl)silane) (ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol (570 mg, yield 56%). LCMS(m/z):826.2(M+H).
步骤E：(S)-4-(2-(((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲氧基)-6-氯-8-氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环丙烷-6-醇Step E: (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)- 6-Chloro-8-fluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris(isopropyl)silyl)ethynyl)-1 -naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol
室温条件下，将NaH(18.9mg,60％,0.472mmol)加入到((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲醇(40.9mg,0.236mmol)和THF(5mL)的混合溶液中并搅拌20分钟，再将(S)-4-(6-氯-2,8-二氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环己烷-6-醇(130mg,0.157mmol)加入到上述反应液中,将反应液在室温下搅拌1h，TLC(EA/PE＝1/2)监测反应结束，将反应液倒入饱和的NH4Cl(30mL)溶液中，EA(30mL×3)萃取，收集有机相用饱和NaCl溶液(70mL)洗涤，无水Na2SO4干燥，过滤后浓缩，得到棕色固体(S)-4-(2-(((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲氧基)-6-氯-8-氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环丙烷-6-醇(150mg,收率97％)。LCMS(m/z):490.3(1/2M+H)。 At room temperature, NaH (18.9 mg, 60%, 0.472 mmol) was added to ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl) into a mixed solution of methanol (40.9mg, 0.236mmol) and THF (5mL) and stirred for 20 minutes, then (S)-4-(6-chloro-2,8-difluoro-7-(7-fluoro-3 -(Tris(isopropyl)methoxy)-8-(2-(Tris(isopropyl)silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl 1,4-Oxacyclohexane-6-ol (130 mg, 0.157 mmol) was added to the above reaction solution, and the reaction solution was stirred at room temperature for 1 h. TLC (EA/PE=1/2) monitored the completion of the reaction. , pour the reaction solution into saturated NH 4 Cl (30 mL) solution, extract with EA (30 mL × 3), collect the organic phase and wash with saturated NaCl solution (70 mL), dry over anhydrous Na 2 SO 4 , filter and concentrate to obtain Brown solid (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)-6 -Chloro-8-fluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris(isopropyl)silyl)ethynyl)-1- Naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxiran-6-ol (150 mg, yield 97%). LCMS(m/z):490.3(1/2M+H).
步骤F：(S)-4-(2-(((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲氧基)-6-氯-7-(8-乙炔基-7-氟-3-羟基-1-萘基)-8-氟-4-喹唑啉基)-6-甲基-1,4-氧杂环丙烷-6-醇Step F: (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)- 6-Chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxaheterocycle Propan-6-ol
室温条件下，将CsF(116mg,0.765mmol)加入到(S)-4-(2-(((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲氧基)-6-氯-8-氟-7-(7-氟-3-(三(异丙基)甲氧基)-8-(2-(三(异丙基)甲硅烷基)乙炔基)-1-萘基)-4-喹唑啉基)-6-甲基-1,4-氧杂环丙烷-6-醇(150mg,0.153mmol)和DMF(3mL)的混合溶液中，升温至50℃反应1h，LCMS监测反应结束，反应液过滤后经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝55-75％纯化，得到白色固体(S)-4-(2-(((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲氧基)-6-氯-7-(8-乙炔基-7-氟-3-羟基-1-萘基)-8-氟-4-喹唑啉基)-6-甲基-1,4-氧杂环丙烷-6-醇(14.7mg,收率14％)。LCMS(m/z):667.3(M+H).1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.52–8.27(m,1H),8.05–7.90(m,1H),7.52–7.43(m,1H),7.40(d,J＝2.6Hz,1H),7.14–6.99(m,1H),6.89–6.51(m,1H),5.37–5.20(m,1H),4.63–4.53(m,1H),4.33–4.19(m,3H),4.06–3.90(m,3H),3.89–3.64(m,2H),3.61–3.50(m,3H),2.73–2.64(m,2H),2.30–2.18(m,1H),2.14(s,3H),1.95–1.78(m,2H),1.22–1.14(m,3H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.36,-122.93,138.84。

At room temperature, CsF (116 mg, 0.765 mmol) was added to (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl- 3-piperidinyl)methoxy)-6-chloro-8-fluoro-7-(7-fluoro-3-(tris(isopropyl)methoxy)-8-(2-(tris(isopropyl) (silyl)ethynyl)-1-naphthyl)-4-quinazolinyl)-6-methyl-1,4-oxan-6-ol (150 mg, 0.153 mmol) and DMF ( 3mL) in the mixed solution, heated to 50°C and reacted for 1 hour. LCMS monitored the end of the reaction. The reaction solution was filtered and purified by pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 55-75%. A white solid (S)-4-(2-(((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidyl)methoxy)- was obtained 6-Chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-quinazolinyl)-6-methyl-1,4-oxaheterocycle Propan-6-ol (14.7 mg, yield 14%). LCMS (m/z): 667.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.52 –8.27(m,1H),8.05–7.90(m,1H),7.52–7.43(m,1H),7.40(d,J＝2.6Hz,1H),7.14–6.99(m,1H),6.89–6.51 (m,1H),5.37–5.20(m,1H),4.63–4.53(m,1H),4.33–4.19(m,3H),4.06–3.90(m,3H),3.89–3.64(m,2H) ,3.61–3.50(m,3H),2.73–2.64(m,2H),2.30–2.18(m,1H),2.14(s,3H),1.95–1.78(m,2H),1.22–1.14(m, 3H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.36,-122.93,138.84.

实施例132
Example 132
(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy -d 2 )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-5-methoxypyridin[4,3-d]pyrimidin-4-yl) -6-Methyl-1,4-oxazepan-6-ol
步骤A：(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene- 1-yl)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
在-78℃干冰乙醇浴条件下，将t-BuONa(0.78mL,2M THF溶液,1.56mmol)滴加到(6S)-4-(8-氟-7-(7-氟-8-(三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基-2-(甲基亚磺酰基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(450mg,0.520mmol)、((3S,4S)-4-(二氟甲基)-1-((2H)3)甲基)-3-甲基-3-哌啶基)(2H2)甲醇(124mg,0.626mmol)和THF(5mL)的混合溶液中并搅拌1h，LCMS监测反应结束，将反应液倒入半饱和NH4Cl水溶液(10mL)中，EA(20mL×2)萃取。收集有机相，饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，浓缩有机相，得到黄色固体(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(300mg,收率57％)。LCMS(m/z):501.3(M/2+1)。Under -78°C dry ice ethanol bath conditions, t-BuONa (0.78mL, 2M THF solution, 1.56mmol) was added dropwise to (6S)-4-(8-fluoro-7-(7-fluoro-8-(tri Isopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4 ,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol (450mg, 0.520mmol), ((3S,4S)-4-(difluoro Methyl)-1-(( 2 H) 3 )methyl)-3-methyl-3-piperidinyl)( 2 H 2 ) methanol (124 mg, 0.626 mmol) and THF (5 mL) were combined into a mixed solution. After stirring for 1 hour, LCMS monitored the reaction to completion. The reaction solution was poured into a semisaturated NH 4 Cl aqueous solution (10 mL), and extracted with EA (20 mL × 2). Collect the organic phase, wash with saturated NaCl solution, dry over anhydrous Na 2 SO 4 , filter, and concentrate the organic phase to obtain yellow solid (S)-4-(2-(((3S,4S)-4-(difluoromethyl) )-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-8-fluoro-7-(7-fluoro-8-((triisopropyl) Silyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6- Methyl-1,4-oxazepan-6-ol (300 mg, yield 57%). LCMS(m/z):501.3(M/2+1).
步骤B：(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step B: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidine-4 -yl)-6-methyl-1,4-oxazepan-6-ol
室温条件下，将CsF(300mg,1.93mmol)加入到(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(300mg,0.347mol)和DMF(3mL)的混合溶液中，升温至50℃反应1h。LCMS和TLC监测反应结束,经pre-HPLC(C18,ACN/(10mmol NH4HCO3/H2O)＝50-70％)纯化，得到白色固体(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(35mg,收率15％)。LCMS(m/z):689.3(M+H).1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.03–7.91(m,1H),7.52–7.43(m,1H),7.39(d,J＝2.6Hz,1H),7.29–7.22(m,1H),6.48–6.12(m,1H),5.25–4.98(m,1H),4.17–4.04(m,2H),3.97–3.83(m,5H),3.81–3.37(m,5H),2.90–2.76(m,2H),1.91–1.55(m,5H),1.14–0.99(m,6H).19F NMR(376MHz,DMSO-d6)δ-110.14–-110.90(m),-115.36–-119.56(m),-149.38–-150.27(m).At room temperature, CsF (300 mg, 1.93 mmol) was added to (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl -d 3 )piperidin-3-yl)methoxy-d 2 )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)ethynyl) Isopropylsilyl)oxy)naphthalen-1-yl)-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepine into a mixed solution of alkan-6-ol (300 mg, 0.347 mol) and DMF (3 mL), and the temperature was raised to 50°C for 1 h. LCMS and TLC monitored the end of the reaction, and purified through pre-HPLC (C18, ACN/(10mmol NH 4 HCO 3 /H 2 O) = 50-70%) to obtain a white solid (S)-4-(2-(((( 3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-7-(8-ethynyl -7-Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridin[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxynitrogen Heterocycloheptan-6-ol (35 mg, yield 15%). LCMS(m/z):689.3(M+H). 1 H NMR(400MHz, DMSO-d 6 )δ10.15(s,1H),8.03–7.91(m,1H),7.52–7.43(m,1H) ),7.39(d,J＝2.6Hz,1H),7.29–7.22(m,1H),6.48–6.12(m,1H),5.25–4.98(m,1H),4.17–4.04(m,2H), 3.97–3.83(m,5H),3.81–3.37(m,5H),2.90–2.76(m,2H),1.91–1.55(m,5H),1.14–0.99(m,6H). 19 F NMR (376MHz ,DMSO-d 6 )δ-110.14–-110.90(m),-115.36–-119.56(m),-149.38–-150.27(m).
实施例133
Example 133
(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇
(S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy -d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-5-methoxypyridin[4,3-d]pyrimidin-4-yl) -6-Methyl-1,4-oxazepan-6-ol
步骤A：(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇Step A: (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl) Methoxy-d 2 )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidine-4 -yl)-6-methyl-1,4-oxazepan-6-ol
室温下，将(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(25mg,37umol)溶于甲醇(10mL)，加入Pd/C(10mg,10％,9.0umol),H2气球置换两次并在室温搅拌2h。LCMS监测反应结束，反应液过滤得到澄清的有机相，浓缩完全后，加入乙腈(2mL),再加入去离子水(20mL)，冻干，得到白色固体(S)-4-(2-(((3S,4S)-4-(二氟甲基)-3-甲基-1-(甲基-d3)哌啶-3-基)甲氧基-d2)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-甲氧基吡啶[4,3-d]嘧啶-4-基)-6-甲基-1,4-氧氮杂环庚烷-6-醇(20mg,收率79％)。LCMS(m/z):693.4(M+H)。At room temperature, (S)-4-(2-(((3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl )methoxy-d 2 )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidine- 4-yl)-6-methyl-1,4-oxazepan-6-ol (25 mg, 37umol) was dissolved in methanol (10mL), and Pd/C (10mg, 10%, 9.0umol) was added. The H2 balloon was replaced twice and stirred at room temperature for 2 h. LCMS monitors the end of the reaction. The reaction solution is filtered to obtain a clear organic phase. After complete concentration, add acetonitrile (2mL), then add deionized water (20mL), and freeze-dry to obtain a white solid (S)-4-(2-(( (3S,4S)-4-(difluoromethyl)-3-methyl-1-(methyl-d 3 )piperidin-3-yl)methoxy-d 2 )-7-(8-ethyl (7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methoxypyridine[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxygen Azepan-6-ol (20 mg, yield 79%). LCMS(m/z):693.4(M+H).
实施例134
Example 134
(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸
(3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid
步骤A：(3R)-1-(6-氯-2,8-二氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇 Step A: (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl) Silyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(7-溴-6-氯-2,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(700mg,1.78mmol)、(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)硼酸(194mg,356μmol)、Pd(OAc)2(40mg,178μmol)、BIDIME(118mg,356μmol)、K3PO4(1.14g,5.35mmol)和1,4-二氧六环/H2O(V/V＝4/1，15mL)的混合溶液用N2置换三次，升温至110℃搅拌16h。LCMS监测反应完成，冷却后将反应液倒入水中(100mL)，EA(50mL×3)萃取，收集的有机相用饱和NaCl(20mL)洗涤，有机液浓缩，得到的粗品经FCC(SiO2,(EtOH:EA＝1:3)/PE＝0-20％)，得到黄色固体(3R)-1-(6-氯-2,8-二氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(790mg，收率55％)。LCMS(m/z):810.3(M+H)。At room temperature, (R)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (700 mg, 1.78 mmol ), (7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (194 mg, 356 μmol), Pd (OAc) 2 (40 mg, 178 μmol), BIDIME (118 mg, 356 μmol), K 3 PO 4 (1.14 g, 5.35 mmol) and 1,4-dioxane/H 2 O (V/V=4/1, 15 mL) of the mixed solution was replaced three times with N2 , and the temperature was raised to 110°C and stirred for 16 h. LCMS monitored the completion of the reaction. After cooling, the reaction solution was poured into water (100 mL), and extracted with EA (50 mL × 3). The collected organic phase was washed with saturated NaCl (20 mL), and the organic liquid was concentrated. The obtained crude product was subjected to FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-20%) to obtain a yellow solid (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-(( Triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (790mg, yield 55%). LCMS(m/z):810.3(M+H).
步骤B：(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazole lin-4-yl)-3-methylpiperidin-3-ol
在0℃条件下，将NaH(79mg,60wt％,1.97mmol)加入到(3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲醇(143mg,740μmol)和THF(3mL)的混合溶液中并搅拌30min，再将(3R)-1-(6-氯-2,8-二氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(400mg,493μmol)一次加入到上述反应液中并在25℃搅拌1h，LCMS监测反应完成，将反应液倒入半饱和的NH4Cl水溶液(50mL)中，EA(50mL×3)萃取，收集有机相，饱和NaCl水溶液(20mL)洗涤，无水Na2SO4干燥。过滤，浓缩有机相，经FCC(SiO2,(EtOH:EA＝1:3)/PE＝0-40％)，得到黄色固体(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(370mg，收率76％)。LCMS(m/z):492.2(M/2+H)。At 0°C, NaH (79 mg, 60 wt%, 1.97 mmol) was added to (3S, 4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methanol ( 143 mg, 740 μmol) and THF (3 mL) in a mixed solution and stirred for 30 min, then (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-(triiso Propylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg , 493 μmol) was added to the above reaction solution at once and stirred at 25°C for 1 hour. LCMS monitored the reaction to completion. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (50 mL), extract with EA (50 mL × 3), and collect the organic phase. , washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na 2 SO 4 . Filter, concentrate the organic phase, and pass through FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-40%) to obtain a yellow solid (3R)-1-(6-chloro-2-(((3S ,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropyl) Silyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (370 mg, Yield 76%). LCMS(m/z):492.2(M/2+H).
步骤C：(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸Step C: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid
室温条件下，将CsF(300mg,1.97mmol)加入到(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(370mg,376μmol)和DMF(3mL)的溶液中，升温至45℃反应1h，LCMS监测反应结束，反应液经Pre-HPLC(CAN/(0.1％TFA/H2O)＝35-45％)，制备得到淡黄色固体(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸(180mg，收率71％)。LCMS(m/z):671.0(M+H).1H NMR(400MHz,甲醇-d4)δ8.21–8.10(m,1H),7.86(dd,J＝9.2,5.7Hz,1H),7.38–7.27(m,2H),7.12–7.03(m,1H),6.43–6.11(m,1H),4.84–4.79(m,1H),4.69–4.55(m,1H),4.43–4.35(m,1H),4.34–4.22(m,1H),3.73–3.59(m,3H),3.48–3.32(m,2H),3.11–3.01(m,1H),3.01–2.94(m,1H),2.91–2.81(m,3H),2.36–1.99(m,4H),1.90–1.72(m,3H),1.32(s,3H),1.31–1.25(m,3H).19F NMR(376MHz,甲醇-d4)δ-77.29,-111.36,-120.83,-122.79,-126.34.At room temperature, CsF (300 mg, 1.97 mmol) was added to (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethyl) Piperidin-3-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) In a solution of oxy)naphthalen-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (370 mg, 376 μmol) and DMF (3 mL), the temperature was raised to 45°C and reacted for 1 hour, LCMS After monitoring the completion of the reaction, the reaction solution was subjected to Pre-HPLC (CAN/(0.1% TFA/H 2 O) = 35-45%) to prepare a light yellow solid (3R)-1-(6-chloro-2-(((( 3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid (180 mg, yield 71%). LCMS (m/z): 671.0 (M+H). 1 H NMR (400MHz, methanol-d 4 ) δ8.21–8.10 (m, 1H), 7.86 (dd, J = 9.2, 5.7Hz, 1H), 7.38–7.27(m,2H),7.12–7.03(m,1H),6.43–6.11(m,1H),4.84–4.79(m,1H),4.69–4.55(m,1H),4.43–4.35(m ,1H),4.34–4.22(m,1H),3.73–3.59(m,3H),3.48–3.32(m,2H),3.11–3.01(m,1H),3.01–2.94(m,1H),2.91 –2.81(m,3H),2.36–1.99(m,4H),1.90–1.72(m,3H),1.32(s,3H),1.31–1.25(m,3H). 19 F NMR (376MHz, methanol- d 4 )δ-77.29,-111.36,-120.83,-122.79,-126.34.
实施例135及136
Examples 135 and 136
(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸及(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸
(3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7 -(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid and (3R )-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8-ethyl -7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid
步骤A：(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸及(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸Step A: (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8 -Ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid
室温下，将(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸(60mg,89.4μmol),Pt/C(50mg,10wt％,24.15μmol)溶于甲醇(10mL),H2气球置换空气两次,并在H2气球条件下室温搅拌1h。LCMS监测反应完成,反应液过滤得到澄清的有机相,浓缩完全后经Pre-HPLC(CAN/(0.1％TFA/H2O)＝35％-45％)，制备得到淡黄色固体(3R)-1-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸(实施例135，15mg，收率25％)。LCMS(m/z):675.2(M+H)。1H NMR(400MHz,甲醇-d4)δ8.27–8.19(m,1H),7.68(dd,J＝9.0,5.8Hz,1H),7.30(d,J＝2.7Hz,1H),7.28–7.21(m,1H),6.93–6.85(m,1H),6.42–6.09(m,1H),4.53–4.42(m,1H),4.39–4.28(m,1H),4.27–4.18(m,1H),3.77–3.55(m,3H),3.51–3.39(m,1H),3.11–2.96(m,2H),2.91(s,3H),2.69–2.52(m,1H),2.38–2.11(m,5H),2.11–1.99(m,1H),1.91–1.71(m,3H),1.31–1.24(m,6H),0.81(q,J＝7.0Hz,3H).19F NMR(376MHz,甲醇-d4)δ-77.21,-120.69,-121.15,-123.12,-124.23。以及(3R)-1-(2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸(实施例136，7mg，收率12％)。LCMS(m/z):641.2(M+H)。1H NMR(400MHz,甲醇-d4)δ8.06(dd,J＝8.6,5.2Hz,1H),7.66(dd,J＝9.1,5.8Hz,1H),7.44–7.36(m,1H),7.31–7.20(m,2H),6.95(dd,J＝4.6,2.7Hz,1H),6.45–6.10(m,1H),4.56–4.46(m,1H),4.40–4.32(m,1H),4.31–4.26(m,1H),3.73–3.59(m,3H),3.53–3.44(m,1H),3.11–3.02(m,1H),3.02–2.97(m,1H),2.90(s,3H),2.49–2.40(m,1H),2.33–2.23(m,1H),2.20–2.15(m,2H),2.08–2.00(m,2H),1.89–1.75(m,3H),1.64–1.55(m,1H),1.30–1.24 (m,6H),0.79(q,J＝7.1Hz,3H).19F NMR(376MHz,甲醇-d4)δ-77.18,-121.06,-121.14,-122.96,-131.01.At room temperature, (3R)-1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoro Acetic acid (60 mg, 89.4 μmol), Pt/C (50 mg, 10 wt%, 24.15 μmol) were dissolved in methanol (10 mL), replaced with air twice by H 2 balloon, and stirred at room temperature for 1 h under H 2 balloon conditions. LCMS monitors the completion of the reaction. The reaction solution is filtered to obtain a clear organic phase. After complete concentration, Pre-HPLC (CAN/(0.1% TFA/H 2 O) = 35%-45%) is used to prepare a light yellow solid (3R)- 1-(6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8- Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetic acid (Example 135, 15 mg, Yield 25%). LCMS(m/z):675.2(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ8.27–8.19(m,1H),7.68(dd,J＝9.0,5.8Hz,1H),7.30(d,J＝2.7Hz,1H),7.28– 7.21(m,1H),6.93–6.85(m,1H),6.42–6.09(m,1H),4.53–4.42(m,1H),4.39–4.28(m,1H),4.27–4.18(m,1H ),3.77–3.55(m,3H),3.51–3.39(m,1H),3.11–2.96(m,2H),2.91(s,3H),2.69–2.52(m,1H),2.38–2.11(m ,5H),2.11–1.99(m,1H),1.91–1.71(m,3H),1.31–1.24(m,6H),0.81(q,J=7.0Hz,3H). 19 F NMR (376MHz, methanol -d 4 )δ-77.21,-120.69,-121.15,-123.12,-124.23. and (3R)-1-(2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-7-(8 -Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroacetic acid (Example 136, 7 mg , yield 12%). LCMS(m/z):641.2(M+H). 1 H NMR (400MHz, methanol-d 4 ) δ8.06 (dd, J＝8.6, 5.2Hz, 1H), 7.66 (dd, J＝9.1, 5.8Hz, 1H), 7.44–7.36 (m, 1H), 7.31–7.20(m,2H),6.95(dd,J＝4.6,2.7Hz,1H),6.45–6.10(m,1H),4.56–4.46(m,1H),4.40–4.32(m,1H), 4.31–4.26(m,1H),3.73–3.59(m,3H),3.53–3.44(m,1H),3.11–3.02(m,1H),3.02–2.97(m,1H),2.90(s,3H ),2.49–2.40(m,1H),2.33–2.23(m,1H),2.20–2.15(m,2H),2.08–2.00(m,2H),1.89–1.75(m,3H),1.64–1.55 (m,1H),1.30–1.24 (m, 6H), 0.79 (q, J = 7.1Hz, 3H). 19 F NMR (376MHz, methanol-d 4 ) δ -77.18, -121.06, -121.14, -122.96, -131.01.
实施例137
Example 137
(3R)-1-(6-氯-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐
(3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-( Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate
步骤A：(3R)-1-(6-氯-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) )oxy)naphth-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazole lin-4-yl)-3-methylpiperidin-3-ol
在0℃条件下，将NaH(40mg,60wt％,987μmol)加入到((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲醇(64mg,370μmol)和THF(5mL)的混合溶液中并搅拌30min，再将(3R)-1-(6-氯-2,8-二氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)喹唑啉-4-基)-3-甲基哌啶-3-醇(200mg,247μmol)一次性加入到上述反应液中并在25℃搅拌1h，LCMS监测反应完成，将反应液倒入半饱和的NH4Cl水溶液(20mL)中，EA(20mL×3)萃取，收集有机相后，饱和NaCl水溶液(20mL)洗涤，无水Na2SO4干燥。过滤，浓缩有机相经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-40％)，得到黄色固体(3R)-1-(6-氯-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(170mg，收率72％)。LCMS(m/z):474.8(M/2+H)。NaH (40 mg, 60 wt%, 987 μmol) was added to ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl) at 0°C. into a mixed solution of methanol (64 mg, 370 μmol) and THF (5 mL) and stirred for 30 min, then (3R)-1-(6-chloro-2,8-difluoro-7-(7-fluoro-8-(( Triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphth-1-yl)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 247 μmol) was added to the above reaction solution at one time and stirred at 25°C for 1 hour. LCMS monitored the reaction to completion. Pour the reaction solution into a semisaturated NH 4 Cl aqueous solution (20 mL), and extracted with EA (20 mL × 3). After collecting the organic phase, wash with saturated NaCl aqueous solution (20 mL) and dry over anhydrous Na 2 SO 4 . Filter, concentrate the organic phase and pass through FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-40%) to obtain yellow solid (3R)-1-(6-chloro-8-fluoro-7-( 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (170 mg, collected rate 72%). LCMS(m/z):474.8(M/2+H).
步骤B：(3R)-1-(6-氯-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐Step B: (3R)-1-(6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroethyl acid salt
室温条件下，将CsF(150mg,987μmol)加入到(3R)-1-(6-氯-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)-3-((三异丙基硅基)氧基)萘-1-基)-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(170mg,176μmol)和DMF(3mL)的溶液中，升温至45℃反应1h，LCMS监测反应完成，反应液经Pre-HPLC(CAN/(0.1％TFA/H2O)＝35-45％)，制备得到淡黄色固体(3R)-1-(6-氯-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐(80mg，收率70％)。LCMS(m/z):651.3(M+H).1H NMR(400MHz,甲醇-d4)δ8.12–8.04(m,1H),7.85(dd,J＝9.2,5.7Hz,1H), 7.37–7.27(m,2H),7.11–7.03(m,1H),7.02(s,0.5H),6.81(s,0.5H),4.76–4.59(m,1H),4.59–4.37(m,1H),4.35–4.16(m,1H),3.72–3.51(m,3H),3.51–3.32(m,2H),3.16–2.82(m,6H),2.71–2.48(m,1H),2.26–1.97(m,2H),1.91–1.69(m,3H),1.33–1.22(m,6H).19F NMR(376MHz,甲醇-d4)δ-77.22,-111.46,-126.88,-134.15。At room temperature, CsF (150 mg, 987 μmol) was added to (3R)-1-(6-chloro-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)- 3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine- In a solution of 3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (170 mg, 176 μmol) and DMF (3 mL), heat to 45°C and react for 1 hour, monitored by LCMS The reaction is completed, and the reaction solution is subjected to Pre-HPLC (CAN/(0.1% TFA/H 2 O) = 35-45%) to prepare a light yellow solid (3R)-1-(6-chloro-7-(8-acetylene) yl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidine-3 -(yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate (80 mg, yield 70%). LCMS (m/z): 651.3 (M+H). 1 H NMR (400MHz, methanol-d 4 ) δ8.12–8.04 (m, 1H), 7.85 (dd, J = 9.2, 5.7Hz, 1H), 7.37–7.27(m,2H),7.11–7.03(m,1H),7.02(s,0.5H),6.81(s,0.5H),4.76–4.59(m,1H),4.59–4.37(m,1H ),4.35–4.16(m,1H),3.72–3.51(m,3H),3.51–3.32(m,2H),3.16–2.82(m,6H),2.71–2.48(m,1H),2.26–1.97 (m,2H),1.91–1.69(m,3H),1.33–1.22(m,6H). 19 F NMR (376MHz, methanol-d 4 )δ-77.22,-111.46,-126.88,-134.15.
实施例138
Example 138
(3R)-1-(6-氯-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐
(3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-( Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate
步骤A：(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-2,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇Step A: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-difluoroquine Zozolin-4-yl)-3-methylpiperidin-3-ol
室温条件下，将(R)-1-(7-溴-6-氯-2,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(400mg,1.02mmol)，2-(8-乙基-7-氟-3-甲氧基甲氧基-1-萘基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(550mg,1.53mmol),Pd(PPh3)4(235mg,204μmol)、K3PO4(649mg,3.06mmol)和1,4-二氧六环/H2O(V/V＝4:1，15mL)的混合溶液N2置换三次后，升温至100℃搅拌8h。LCMS监测反应完成，将反应液倒入水中(50mL)，EA(50mL×3)萃取，收集的有机相用饱和NaCl水溶液(20mL)洗涤，有机液浓缩后得到的粗品经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-20％)，得到黄色固体(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-2,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg，收率11％)。LCMS(m/z):804.2(M+H)。At room temperature, (R)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 1.02 mmol ), 2-(8-ethyl-7-fluoro-3-methoxymethoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxa Borane (550mg, 1.53mmol), Pd(PPh 3 ) 4 (235mg, 204μmol), K 3 PO 4 (649mg, 3.06mmol) and 1,4-dioxane/H 2 O (V/V=4 :1, 15 mL), the mixed solution was replaced with N2 three times, then the temperature was raised to 100°C and stirred for 8 h. LCMS monitored the completion of the reaction. The reaction solution was poured into water (50 mL) and extracted with EA (50 mL × 3). The collected organic phase was washed with saturated NaCl aqueous solution (20 mL). The crude product obtained after the organic liquid was concentrated was subjected to FCC (SiO 2 , ( EtOH:EA=1:3)/PE=0-20%) to obtain yellow solid (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethyl) Oxy)naphth-1-yl)-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, yield 11%). LCMS(m/z):804.2(M+H).
步骤B：(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇Step B: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-( ((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine- 3-alcohol
在0℃条件下，将NaH(14mg,60wt％,330μmol)加入到((S)-(E)-4-氟亚甲基-1-甲基-3-甲基-3-哌啶基)甲醇(29mg,165μmol)和THF(3mL)的混合溶液中并搅拌30min，再将(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-2,8-二氟喹唑啉-4-基)-3-甲基哌啶-3-醇(60mg,110μmol)一次加入到上述反应液中并在25℃搅拌1h，LCMS监测反应完成，将反应液倒入半饱和的NH4Cl水溶液(20mL)中，EA(20mL×3)萃取，收集有机相后，饱和NaCl水溶液(20mL)洗涤，无水Na2SO4干燥。过滤，浓缩有机相经FCC(SiO2，(EtOH:EA＝1:3)/PE＝0-40％)，得到黄 色固体(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(50mg,收率65％)。LCMS(m/z):474.8(M/2+H)。NaH (14 mg, 60 wt%, 330 μmol) was added to ((S)-(E)-4-fluoromethylene-1-methyl-3-methyl-3-piperidinyl) at 0°C. into a mixed solution of methanol (29 mg, 165 μmol) and THF (3 mL) and stirred for 30 min, then (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxy) Methoxy)naphthyl-1-yl)-2,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (60 mg, 110 μmol) was added to the above reaction solution in one go. Stir for 1 hour at 25°C. LCMS monitors that the reaction is completed. Pour the reaction solution into a semi-saturated NH 4 Cl aqueous solution (20 mL), extract with EA (20 mL × 3), collect the organic phase, wash with a saturated NaCl aqueous solution (20 mL), and anhydrous Dry over Na2SO4 . Filter, concentrate the organic phase and pass through FCC (SiO 2 , (EtOH:EA=1:3)/PE=0-40%) to obtain yellow Color solid (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(( (S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3 -Alcohol (50 mg, yield 65%). LCMS(m/z):474.8(M/2+H).
步骤C：(3R)-1-(6-氯-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐Step C: (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)- 4-(Fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol·trifluoroethyl acid salt
室温条件下，将(3R)-1-(6-氯-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇(50mg,71.5μmol)溶于TFA(2mL)并将此溶液在室温搅拌30mins，LCMS监测反应完成，将反应液浓缩去除酸液。EA(10mL)稀释，加入半饱和的NaHCO3水溶液(15mL)溶液将pH调至弱碱性，EA(10mL×3)萃取。将有机相浓缩后经Pre-HPLC(CAN/(10mM NH4HCO3)＝50-80％)，制备得到淡黄色固体(3R)-1-(6-氯-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S,E)-4-(氟亚甲基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-4-基)-3-甲基哌啶-3-醇·三氟乙酸盐(15mg,收率32％)。LCMS(m/z):655.3(M+H).1H NMR(400MHz,甲醇-d4)δ8.10(dd,J＝15.8,1.6Hz,1H),7.65(dd,J＝9.1,5.9Hz,1H),7.27(d,J＝2.7Hz,1H),7.25–7.18(m,1H),6.89(d,J＝2.6Hz,1H),6.74(s,0.5H),6.52(s,0.5H),4.67–4.58(m,1H),4.44–4.36(m,1H),4.28–4.18(m,1H),4.09–4.02(m,1H),4.00–3.92(m,1H),3.58–3.40(m,2H),2.90–2.80(m,1H),2.80–2.70(m,1H),2.71–2.55(m,2H),2.39–2.27(m,1H),2.24(d,J＝2.0Hz,3H),2.21–2.10(m,1H),2.08–1.91(m,2H),1.88–1.72(m,2H),1.30–1.24(m,3H),1.20(s,3H),0.79(q,J＝7.7Hz,3H).19F NMR(376MHz,甲醇-d4)δ-121.32,-122.40,-139.60。At room temperature, (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2 -(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin Dissolve din-3-ol (50 mg, 71.5 μmol) in TFA (2 mL) and stir the solution at room temperature for 30 mins. LCMS monitors the completion of the reaction. The reaction solution is concentrated to remove the acid. Dilute with EA (10 mL), add half-saturated NaHCO 3 aqueous solution (15 mL) to adjust the pH to weak alkalinity, and extract with EA (10 mL × 3). The organic phase was concentrated and subjected to Pre-HPLC (CAN/(10mM NH 4 HCO 3 ) = 50-80%) to prepare a light yellow solid (3R)-1-(6-chloro-7-(8-ethyl- 7-Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,E)-4-(fluoromethylene)-1,3-dimethylpiperidin-3-yl )methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol trifluoroacetate (15 mg, yield 32%). LCMS (m/z): 655.3 (M+H). 1 H NMR (400MHz, methanol-d 4 ) δ8.10 (dd, J = 15.8, 1.6 Hz, 1H), 7.65 (dd, J = 9.1, 5.9 Hz,1H),7.27(d,J＝2.7Hz,1H),7.25–7.18(m,1H),6.89(d,J＝2.6Hz,1H),6.74(s,0.5H),6.52(s, 0.5H),4.67–4.58(m,1H),4.44–4.36(m,1H),4.28–4.18(m,1H),4.09–4.02(m,1H),4.00–3.92(m,1H),3.58 –3.40(m,2H),2.90–2.80(m,1H),2.80–2.70(m,1H),2.71–2.55(m,2H),2.39–2.27(m,1H),2.24(d,J＝ 2.0Hz,3H),2.21–2.10(m,1H),2.08–1.91(m,2H),1.88–1.72(m,2H),1.30–1.24(m,3H),1.20(s,3H),0.79 (q, J=7.7Hz, 3H). 19 F NMR (376MHz, methanol-d 4 ) δ -121.32, -122.40, -139.60.
参照上述实施例合成方案或适当变体，本发明还制备了下述化合物。









Referring to the synthetic schemes or appropriate variations of the above examples, the present invention also prepared the following compounds.









活性实施例Active examples
实施例1:本发明化合物对KRAS G12V突变的NCI-H727细胞的增殖抑制效果Example 1: The inhibitory effect of the compound of the present invention on the proliferation of NCI-H727 cells with KRAS G12V mutation
本实验评估并验证了本发明代表性化合物对KRAS G12V突变细胞NCI-H727细胞的增殖抑制活性。This experiment evaluates and verifies the proliferation inhibitory activity of the representative compounds of the present invention on KRAS G12V mutant cell NCI-H727 cells.
方法A：本实验使用如下细胞系：
Method A: This experiment uses the following cell lines:
将其置于37℃、5％CO2、95％湿度条件下培养。It was cultured at 37°C, 5% CO2, and 95% humidity.
本实验中使用如下材料、仪器和试剂：胎牛血清FBS(GIBCO,Cat#10091-148)；CellTiter-Luminescent Cell Viability Assay(Promega,Cat#G7573)；96孔透明平底黑壁板(Cat#3603)；Envision多功能能酶标仪，PE，2105；CO2培养箱，Thermo Scientific，Model 371；生物安全柜，Thermo Scientific，Model 1300 Series A2；倒置显微镜，Olympus，CKX53。NCI-H727细胞系购自ATCC，货号为CRL-5815。The following materials, instruments and reagents were used in this experiment: fetal bovine serum FBS (GIBCO, Cat#10091-148); CellTiter- Luminescent Cell Viability Assay (Promega, Cat#G7573); 96-well transparent flat bottom black wall plate ( Cat#3603); Envision multifunctional microplate reader, PE, 2105; CO 2 incubator, Thermo Scientific, Model 371; Biological safety cabinet, Thermo Scientific, Model 1300 Series A2; Inverted microscope, Olympus, CKX53. NCI-H727 cell line was purchased from ATCC with the catalog number CRL-5815.
该实验如下进行：The experiment proceeds as follows:
细胞培养和接种：收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整细胞浓度；分别添加90μL细胞悬液至96孔板中；将96孔板中的细胞置于37℃、5％CO2条件下培养。Cell culture and seeding: Harvest cells in logarithmic growth phase and count using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 μL of cell suspension to the 96-well plate; culture the cells in the 96-well plate at 37°C and 5% CO2 .
如下进行药物稀释和加药：单点抑制率测定药物配制：配制10倍药物溶液，在接种有细胞的96孔板中每孔加入10μL药物溶液，使得工作浓度为1μM，每个药物浓度设置三个复孔。IC50测定药物配制：配制10倍药物溶液，在接种有细胞的96孔板中每孔加入10μL药物溶液，使得工作浓度为最高10μM，3×稀释，9个浓度，每个药物浓度设置三个复孔。将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养3天，然后进行CTG检测。Carry out drug dilution and dosing as follows: Single-point inhibition rate determination Drug preparation: Prepare 10 times the drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is 1 μM, and set three times for each drug concentration. A compound hole. IC50 determination drug preparation: Prepare 10 times drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 μM, 3× dilution, 9 concentrations, and set three replicates for each drug concentration. hole. The cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 3 days, and then CTG detection was performed.
融化CTG试剂并平衡细胞板至室温30分钟，每孔加入等体积的CTG溶液，在定轨摇床上振动10分钟使细胞裂解。将细胞板放置于室温20分钟以稳定冷光信号，读取冷光值。Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 10 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal and read the luminescence value.
使用GraphPad Prism 8.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。Data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC50 value was calculated.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) × 100%.
方法B：将NCI-H727细胞(南京科佰生物科技有限公司，货号为CBP60182，贴壁，培养基RPMI-1640+10％FBS(GIBCO,Cat#10091-148))置于37℃、5％CO2、95％湿度条件下培养。Method B: Place NCI-H727 cells (Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60182, adherent, culture medium RPMI-1640+10% FBS (GIBCO, Cat#10091-148)) at 37°C, 5% Culture under CO 2 and 95% humidity conditions.
3D细胞活力检测：收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。配制含1％MC(甲基纤维素，Sigma,Cat#M0512)RPMI-1640培养基并加入10％FBS配制成3D细胞培养基，用3D培养基调整细 胞浓度约为14815个细胞/mL并使甲基纤维素(MC)的含量为0.65％；分别添加135μL细胞悬液至96孔透明平底黑壁板(Greiner,Cat#655096)中；将96孔板中的细胞置于37℃、5％CO2条件下过夜培养。3D cell viability assay: Harvest cells in logarithmic growth phase and count cells using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Prepare RPMI-1640 culture medium containing 1% MC (methylcellulose, Sigma, Cat#M0512) and add 10% FBS to prepare a 3D cell culture medium. Use the 3D culture medium to adjust the details. The cell concentration was approximately 14815 cells/mL and the content of methylcellulose (MC) was 0.65%; 135 μL of cell suspension was added to a 96-well transparent flat-bottomed black wall plate (Greiner, Cat#655096); The cells in the plate were cultured overnight at 37°C and 5% CO2 .
IC50测定药物配制：用培养基配制10倍药物溶液，在接种有细胞的96孔板中每孔加入10μL药物溶液，使得工作浓度为最高10μM，3×稀释，9个浓度，每个药物浓度设置2个复孔。将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养7天，然后进行CTG检测(Luminescent Cell Viability Assay(Promega,Cat#G7573))。IC 50 determination drug preparation: Use culture medium to prepare 10-fold drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, each drug concentration Set up 2 multiple holes. The cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 7 days, and then CTG detection was performed ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).
平衡细胞板至室温30分钟并融化CTG试剂，每孔加入75微升的CTG溶液检测，在定轨摇床上振动5分钟使细胞裂解。将细胞板放置于室温25分钟以稳定冷光信号，读取冷光值(多功能酶标仪，PerkinElmer#2105)。Equilibrate the cell plate to room temperature for 30 minutes and melt the CTG reagent. Add 75 μl of CTG solution to each well for detection, and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 25 minutes to stabilize the luminescence signal, and read the luminescence value ( Multifunctional microplate reader, PerkinElmer #2105).
使用GraphPad Prism软件分析数据，利用Dose-response-inhibition方程来拟合数据得出剂量-效应曲线，并由此计算IC50值。Use GraphPad Prism software to analyze the data, use the Dose-response-inhibition equation to fit the data to obtain a dose-response curve, and calculate the IC50 value from this.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) × 100%.
代表性本发明化合物对KRAS G12V突变的NCI-H727人肺癌细胞显示出令人满意的抗增殖活性，部分活性数据见下表：
Representative compounds of the present invention show satisfactory anti-proliferative activity against KRAS G12V mutated NCI-H727 human lung cancer cells. Part of the activity data is shown in the table below:
实施例2:本发明化合物对KRAS G12D突变的AGS细胞的增殖抑制效果Example 2: The inhibitory effect of the compound of the present invention on the proliferation of AGS cells with KRAS G12D mutation
本实验评估并验证了本发明代表性化合物对KRAS G12D突变细胞AGS细胞的增殖抑制活性。This experiment evaluates and verifies the proliferation inhibitory activity of the representative compounds of the present invention on KRAS G12D mutant AGS cells.
方法A：本实验使用如下细胞系：
Method A: This experiment uses the following cell lines:
将其置于37℃、5％CO2、95％湿度条件下培养。It was cultured at 37°C, 5% CO2, and 95% humidity.
本实验中使用如下材料、仪器和试剂：胎牛血清FBS(GIBCO,Cat#10099-141)；CellTiter-Luminescent Cell Viability Assay(Promega,Cat#G7572)；96孔透明平底黑壁板(Cat#3603)；Envision多功能能酶标仪，PE，2104；CO2培养箱，Thermo Scientific，Model 3100  Series；生物安全柜，苏净安泰，Model 1300 Series A2；倒置显微镜，重庆光电，XDS-1B。AGS细胞系购自ATCC，货号为CRL-1739。The following materials, instruments and reagents were used in this experiment: fetal bovine serum FBS (GIBCO, Cat#10099-141); CellTiter- Luminescent Cell Viability Assay (Promega, Cat#G7572); 96-well transparent flat bottom black wall plate ( Cat#3603); Envision Multi-Energy Microplate Reader, PE, 2104; CO2 Incubator, Thermo Scientific, Model 3100 Series; biological safety cabinet, Sujingantai, Model 1300 Series A2; inverted microscope, Chongqing Optoelectronics, XDS-1B. The AGS cell line was purchased from ATCC with the catalog number CRL-1739.
该实验如下进行：The experiment proceeds as follows:
细胞培养和接种：收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整细胞浓度；分别添加90μL细胞悬液至96孔板中；将96孔板中的细胞置于37℃、5％CO2条件下培养。Cell culture and seeding: Harvest cells in logarithmic growth phase and count using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentration; add 90 μL of cell suspension to the 96-well plate; culture the cells in the 96-well plate at 37°C and 5% CO2 .
如下进行药物稀释和加药：单点抑制率测定药物配制：配制10倍药物溶液，在接种有细胞的96孔板中每孔加入10μL药物溶液，使得工作浓度为1μM，每个药物浓度设置三个复孔。IC50测定药物配制：配制10倍药物溶液，在接种有细胞的96孔板中每孔加入10μL药物溶液，使得工作浓度为最高10μM，3.16×稀释，9个浓度，每个药物浓度设置三个复孔。将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养3天，然后进行CTG检测。Carry out drug dilution and dosing as follows: Single-point inhibition rate determination Drug preparation: Prepare 10 times the drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is 1 μM, and set three times for each drug concentration. A compound hole. IC50 determination drug preparation: Prepare 10 times drug solution, add 10 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 μM, 3.16× dilution, 9 concentrations, and set three replicates for each drug concentration. hole. The cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 3 days, and then CTG detection was performed.
融化CTG试剂并平衡细胞板至室温30分钟，每孔加入等体积的CTG溶液，在定轨摇床上振动5分钟使细胞裂解。将细胞板放置于室温20分钟以稳定冷光信号，读取冷光值。Melt the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well and shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal and read the luminescence value.
使用GraphPad Prism 8.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。Data were analyzed using GraphPad Prism 8.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC50 value was calculated.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) × 100%.
方法B：将AGS细胞(南京科佰生物科技有限公司，货号CBP60476，贴壁，培养基(F12K Nutrient Mixture+10％FBS(GIBCO,Cat#10091-148))在37℃、5％CO2、95％湿度条件下培养，1500/孔，收获处于对数生长期的细胞并采用基于经典台盼蓝染色法原理的Countstar自动细胞计数仪进行细胞计数及检测细胞活力，确保细胞活力在90％以上。调整细胞浓度；分别添加80μL细胞悬液至96孔透明平底黑壁板(Greiner,Cat#655090)中，将96孔板中的细胞置于37℃、5％CO2条件下培养。Method B: AGS cells (Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60476, adherent, culture medium (F12K Nutrient Mixture+10% FBS (GIBCO, Cat#10091-148)) were incubated at 37°C, 5% CO 2 , Culture under 95% humidity conditions, 1500/well, harvest cells in logarithmic growth phase, and use Countstar automatic cell counter based on the principle of classic trypan blue staining to count cells and detect cell viability to ensure that cell viability is above 90%. Adjust the cell concentration; add 80 μL of cell suspension to a 96-well transparent flat-bottomed black wall plate (Greiner, Cat#655090), and culture the cells in the 96-well plate at 37°C and 5% CO2 .
IC50测定药物配制：用培养基配制5倍药物溶液，在接种有细胞的96孔板中每孔加入20μL药物溶液，使得工作浓度为最高10μM，3×稀释，9个浓度，每个药物浓度设置2个复孔。将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养3天，然后进行CTG检测。IC 50 determination drug preparation: Use culture medium to prepare 5-fold drug solution, add 20 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, each drug concentration Set up 2 multiple holes. The cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 3 days, and then CTG detection was performed.
平衡细胞板至室温30分钟并融化CTG试剂(Luminescent Cell Viability Assay(Promega,Cat#G7573))，每孔加入50微升的CTG溶液，在定轨摇床上振动2分钟使细胞裂解。将细胞板放置于室温10分钟以稳定冷光信号，读取冷光值(多功能酶标仪，PerkinElmer#2105)。Equilibrate cell plate to room temperature for 30 minutes and melt CTG reagent ( Luminescent Cell Viability Assay (Promega, Cat#G7573)), add 50 μl of CTG solution to each well, and shake on an orbital shaker for 2 minutes to lyse the cells. Place the cell plate at room temperature for 10 minutes to stabilize the luminescence signal, and read the luminescence value ( Multifunctional microplate reader, PerkinElmer #2105).
使用GraphPad Prism软件分析数据，利用Dose-response-inhibition方程来拟合数据得出剂量-效应曲线，并由此计算IC50值。Use GraphPad Prism software to analyze the data, use the Dose-response-inhibition equation to fit the data to obtain a dose-response curve, and calculate the IC50 value from this.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。 Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) × 100%.
代表性本发明化合物对KRAS G12D突变的AGS人胃腺癌细胞显示出令人满意的抗增殖活性，部分活性数据见下表。
Representative compounds of the present invention show satisfactory anti-proliferative activity against KRAS G12D mutated AGS human gastric adenocarcinoma cells. Partial activity data are shown in the table below.
实施例3-1:本发明化合物的大鼠盒式给药(Cassette)药代动力学特性Example 3-1: Cassette pharmacokinetic properties of the compound of the present invention in rats
通过大鼠Cassette药代动力学实验(Nagilla R.等人,J.Pharm.Sci.2011,100,3862–3874.)评价了本发明部分化合物的药代动力学特征。The pharmacokinetic characteristics of some compounds of the present invention were evaluated through rat Cassette pharmacokinetic experiment (Nagilla R. et al., J. Pharm. Sci. 2011, 100, 3862-3874.).
该研究使用雄性SD大鼠，周龄：6-8周，体重220-250g,购自昭衍(苏州)新药研究中心有限公司；并使用以下试剂：甲苯磺丁脲(Tolbutamide)(阿拉丁，货号H1401054)；磺丁基β环糊精(Captisol，山东滨州智源生物,货号20191013)；丙二醇(15)硬脂酸酯(Solutol，美仑生物，货号S0206A)；DMSO(Vetec公司，货号WXBD0293V)；乙腈(Sigma-Aldrich，货号WXBD1744V)；甲醇(Sigma-Aldrich，货号WXBD2831V)。This study used male SD rats, age: 6-8 weeks, weight 220-250g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and the following reagents were used: Tolbutamide (Aladdin, Catalog No. H1401054); Sulfobutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biotechnology, Catalog No. 20191013); Propylene glycol (15) stearate (Solutol, Meilun Biotechnology, Catalog No. S0206A); DMSO (Vetec Company, Catalog No. WXBD0293V ); acetonitrile (Sigma-Aldrich, product number WXBD1744V); methanol (Sigma-Aldrich, product number WXBD2831V).
将化合物组合配制到5％DMSO/10％Solutol/85％(20％Captisol)的溶剂中，最终每个化合物的浓度为1mg/mL,将药物制剂按照1mL/kg的注射体积尾静脉注射给SD大鼠，分别在5min,15min,30min,1h,2h,4h,8h,24h从颈外静脉穿刺采血，低温离心20分钟，收集血浆，-20℃保存待测。The compound combination was formulated into a solvent of 5% DMSO/10% Solutol/85% (20% Captisol). The final concentration of each compound was 1 mg/mL. The pharmaceutical preparation was injected into the SD through the tail vein at an injection volume of 1 mL/kg. Rats were punctured and collected blood from the external jugular vein at 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h respectively, centrifuged at low temperature for 20 minutes, collected plasma, and stored it at -20°C for testing.
如下建立化合物LC-MS/MS分析方法：The compound LC-MS/MS analysis method is established as follows:
标准曲线配制：将每个化合物吸取20μL 1mg/mL DMSO储备液，转移至900μL 50％甲醇工作液中，逐级稀释，得到一条浓度为20000，10000，5000，1000，500，100，50，20，10ng/mL的标准曲线工作液，再吸取5μL标准曲线工作液与45μL大鼠空白血浆混合，得到一条浓度为2000，1000，500，100，50，10，5，2，1ng/mL的标准曲线，用于定量未知样品。Standard curve preparation: Take 20μL of 1mg/mL DMSO stock solution for each compound, transfer it to 900μL of 50% methanol working solution, and dilute it step by step to obtain a concentration curve of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, then take 5μL standard curve working solution and mix with 45μL rat blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL. Curve for quantifying unknown samples.
样品前处理：50μL未知血浆样品及标准曲线样品，加入250μL含有甲苯磺丁脲为内标的乙腈作为沉淀剂，沉淀血浆蛋白，萃取血浆中的待测化合物，低温离心20分钟，取上清液，将上清液与0.1％甲酸的水溶液混合，吸取5μL进样，采用LC-MS分析药物血药浓度。Sample pretreatment: 50 μL of unknown plasma samples and standard curve samples, add 250 μL of acetonitrile containing tolbutamide as the internal standard as a precipitating agent, precipitate plasma proteins, extract the compounds to be tested in the plasma, centrifuge at low temperature for 20 minutes, and take the supernatant. The supernatant was mixed with 0.1% formic acid aqueous solution, 5 μL was injected, and LC-MS was used to analyze the drug plasma concentration.
用质谱分析软件Analyst 1.6.1绘制标准曲线，定量未知样品，根据未知样品各时间点药物浓度用Winnonlin 8.2计算药物动力学参数。The mass spectrometry software Analyst 1.6.1 was used to draw a standard curve and the unknown samples were quantified. The pharmacokinetic parameters were calculated using Winnonlin 8.2 based on the drug concentration of the unknown samples at each time point.
实验结果显示,在盒式给药药代动力学评价中，本发明化合物、例如实施例化合物显示良 好的药代动力学性质。Experimental results show that in the pharmacokinetic evaluation of box-type administration, the compounds of the present invention, such as the compounds of the examples, show good Good pharmacokinetic properties.
实施例3-2：本发明化合物的小鼠药代动力学特性Example 3-2: Mouse pharmacokinetic properties of compounds of the present invention
通过小鼠药代动力学实验评价了本发明部分化合物的药代动力学特征。The pharmacokinetic characteristics of some compounds of the present invention were evaluated through mouse pharmacokinetic experiments.
【试验材料】雄性CD-1小鼠，周龄：6-8周，购自浙江浙江维通利华实验动物有限公司。[Test materials] Male CD-1 mice, age: 6-8 weeks, were purchased from Zhejiang Weitong Lihua Experimental Animal Co., Ltd.
【实验步骤】IV给药组将化合物配制到20％Captisol(磺丁基β环糊精)的醋酸钠缓冲液(10mM醋酸钠溶液，醋酸调pH至4.0)中，使得最终每个化合物的浓度为0.6mg/mL,将药物制剂按照5mL/kg的注射体积尾静脉注射给CD-1小鼠，给药后分别在5min,15min,30min,1h,2h,4h,6h,8h,24h从颌下静脉或其它合适方式采血，血液样品低温离心6分钟，收集血浆，-80℃保存待测。PO给药组将化合物配制到0.5％Tween80和99.5％(0.5％MC(400cp))的溶剂中，使得最终每个化合物的浓度为1mg/mL，将药物制剂按照10mL/kg的给药体积灌胃给药CD-1小鼠，给药后15min,30min,1h,2h,4h,6h,8h,24h从颌下静脉或其它合适方式采血，血液样品低温离心6分钟，收集血浆，-80℃保存待测。[Experimental Procedure] In the IV administration group, compounds were prepared into 20% Captisol (sulfobutyl β-cyclodextrin) sodium acetate buffer (10mM sodium acetate solution, acetic acid adjusted pH to 4.0), so that the final concentration of each compound The drug preparation is 0.6 mg/mL. The drug preparation is injected into the tail vein of CD-1 mice at an injection volume of 5 mL/kg. After administration, the drug preparation is injected from the jaw at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h respectively. Collect blood from the inferior vein or other appropriate methods, centrifuge the blood sample at low temperature for 6 minutes, collect the plasma, and store it at -80°C for testing. In the PO administration group, the compounds were formulated into a solvent of 0.5% Tween80 and 99.5% (0.5% MC (400cp)), so that the final concentration of each compound was 1 mg/mL, and the pharmaceutical preparation was poured into a dosage volume of 10 mL/kg. Gastrointestinal administration of CD-1 to mice. Collect blood from the submandibular vein or other appropriate methods at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration. Blood samples are centrifuged at low temperature for 6 minutes to collect plasma at -80°C. Save for testing.
【样品分析】取10μL血浆样品，加入200μL含有内标的甲醇作为沉淀剂，沉淀血浆蛋白，萃取血浆中的待测化合物，低温离心，取上清液10μL进样，采用LC-MS/MS分析药物血药浓度。[Sample analysis] Take 10 μL of plasma sample, add 200 μL of methanol containing internal standard as a precipitant, precipitate plasma proteins, extract the compounds to be tested in the plasma, centrifuge at low temperature, take 10 μL of supernatant and inject, and use LC-MS/MS to analyze the drug. Blood drug concentration.
【数据处理】通过不同时间点血药浓度数据，运用Winnonlin计算药代动力学参数。[Data processing] Use Winnonlin to calculate pharmacokinetic parameters through blood drug concentration data at different time points.
【实验结果】实验结果显示,在小鼠药代动力学评价中，本发明化合物、例如实施例化合物显示良好的药代动力学性质。[Experimental results] The experimental results show that in the pharmacokinetic evaluation in mice, the compounds of the present invention, such as the examples, showed good pharmacokinetic properties.
实施例4:本发明化合物对细胞色素P450抑制试验Example 4: Inhibition test of cytochrome P450 by the compounds of the present invention
本实验评价发明化合物对细胞色素P450的抑制作用。This experiment evaluates the inhibitory effect of the inventive compounds on cytochrome P450.
本实验使用如下试剂进行：人肝微粒体(Corning公司，货号452161)；还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH，MCE公司，货号HY-F0003/CS-4998)；非那西丁，双氯酚酸，α-萘黄酮，奥美拉唑和酮康唑均购自TCI公司；S-美芬妥英和睾酮购自CAYMAN公司；咪达唑仑购自Bioreclamation IVT；奎尼丁购自Damas-beta；磺胺苯吡唑购自MCE；丁呋洛尔购自TRC。This experiment was performed using the following reagents: human liver microsomes (Corning Company, Cat. No. 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE Company, Cat. No. HY-F0003/CS-4998); phenacetin , diclofenac, α-naphthoflavone, omeprazole and ketoconazole were purchased from TCI; S-mephenytoin and testosterone were purchased from CAYMAN; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from Bioreclamation IVT. From Damas-beta; sulfapyrazole was purchased from MCE; buturol was purchased from TRC.
配制0.1M磷酸钾缓冲液(K-buffer)：用磷酸二氢钾和磷酸氢二钾配制100mM磷酸钾缓冲液(K-buffer)，调节pH到7.4。Prepare 0.1M potassium phosphate buffer (K-buffer): Prepare 100mM potassium phosphate buffer (K-buffer) using potassium dihydrogen phosphate and dipotassium hydrogen phosphate, and adjust the pH to 7.4.
配制400×受试化合物及阳性对照抑制剂：Prepare 400× test compound and positive control inhibitor:
配制受试化合物溶液：将8μL的10mM受试化合物储备液溶于12μL乙腈中；配制CYP1A2,CYP2C9和CYP2D6抑制剂的混合溶液：将12μL 1mMα-萘黄酮，10μL 40mM磺胺苯吡唑，10μL 10mM奎尼丁和8μL DMSO溶液混合；配制CYP3A4的抑制剂溶液：将8μL 2.5mM的酮康唑DMSO溶液溶于12μL乙腈中；配制CYP2C19的抑制剂溶液：将8μL100mM的奥美 拉唑DMSO溶液溶于12μL乙腈中。Prepare test compound solution: Dissolve 8μL of 10mM test compound stock solution in 12μL acetonitrile; Prepare a mixed solution of CYP1A2, CYP2C9 and CYP2D6 inhibitors: Dissolve 12μL of 1mM α-naphthoflavone, 10μL of 40mM sulfapyrazole, 10μL of 10mM quinine Mix nitine and 8μL DMSO solution; prepare CYP3A4 inhibitor solution: dissolve 8μL 2.5mM ketoconazole DMSO solution in 12μL acetonitrile; prepare CYP2C19 inhibitor solution: dissolve 8μL 100mM Ogilvy Prazole DMSO solution was dissolved in 12 μL acetonitrile.
配制4×NADPH磷酸钾溶液：66.7mg NADPH加入到10mL 0.1M K-buffer,pH7.4。配制4×底物磷酸钾溶液：将各个底物按照浓度要求用10mL 0.1M K-buffer配制成4倍浓度测定所需溶液。Prepare 4×NADPH potassium phosphate solution: add 66.7mg NADPH to 10mL 0.1M K-buffer, pH7.4. Prepare 4× substrate potassium phosphate solution: Prepare each substrate according to the concentration requirements with 10mL 0.1M K-buffer to prepare a solution required for 4 times the concentration measurement.
配制0.2mg/mL人肝微粒体(HLM)溶液：将10μL 20mg/mL的人肝微粒体加入到990μL K-buffer中，冰浴保存待用。Preparation of 0.2 mg/mL human liver microsomes (HLM) solution: Add 10 μL of 20 mg/mL human liver microsomes into 990 μL K-buffer and store on ice for later use.
将600μL的0.2mg/mL HLM加入到96孔板中，加入3μL 400倍受试化合物溶液；将200μL的0.2mg/mL HLM加入到96孔板中，加入1μL稀释后的阳性对照抑制剂溶液。分装30μL化合物与人的肝微粒体的混合溶液到96孔板中，然后再加入15μL的底物溶液。将上述获得的溶液和配制好的NADPH溶液于37℃预热5min。将15μL预热的NADPH溶液加入反应板，混匀，开始反应。37℃孵育反应板。3A4反应5分钟；1A2，2C9，2D6反应10分钟；2C19反应45分钟。反应结束时，加入120μL含内标的乙腈终止反应。样品涡旋振荡10min，采用5594g离心15分钟，制备样品送至LC-MS/MS分析。Add 600 μL of 0.2 mg/mL HLM to the 96-well plate, and add 3 μL of the 400-fold test compound solution; add 200 μL of 0.2 mg/mL HLM to the 96-well plate, and add 1 μL of the diluted positive control inhibitor solution. Dispense 30 μL of the mixed solution of compound and human liver microsomes into a 96-well plate, and then add 15 μL of substrate solution. Preheat the solution obtained above and the prepared NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated NADPH solution to the reaction plate, mix well, and start the reaction. Incubate the reaction plate at 37°C. 3A4 reacts for 5 minutes; 1A2, 2C9, and 2D6 react for 10 minutes; 2C19 reacts for 45 minutes. At the end of the reaction, 120 μL of acetonitrile containing internal standard was added to terminate the reaction. The sample was vortexed for 10 minutes, centrifuged at 5594g for 15 minutes, and the sample was prepared and sent to LC-MS/MS for analysis.
【实验结果】【Experimental results】
实验结果显示，在测试浓度下，本发明化合物、例如实施例化合物对于药物代谢关键CYP亚型没有显著抑制作用，表现出更好的药物-药物相互作用安全性。Experimental results show that at the test concentration, the compounds of the present invention, such as the compounds of the examples, have no significant inhibitory effect on the key CYP subtypes of drug metabolism, and exhibit better drug-drug interaction safety.
实施例5：本发明化合物对KRAS G12C突变的NCI-H358细胞的增殖抑制效果Example 5: The inhibitory effect of the compound of the present invention on the proliferation of NCI-H358 cells with KRAS G12C mutation
本实验评估并验证了本发明代表性化合物对KRAS G12C突变细胞NCI-H358细胞的增殖抑制活性。This experiment evaluates and verifies the proliferation inhibitory activity of representative compounds of the present invention on KRAS G12C mutant cell NCI-H358 cells.
将NCI-H358细胞(南京科佰生物科技有限公司，货号为CBP60136，贴壁，培养基RPMI-1640+10％FBS(GIBCO,Cat#10091-148))置于37℃、5％CO2、95％湿度条件下培养。NCI-H358 cells (Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60136, adherent, culture medium RPMI-1640+10% FBS (GIBCO, Cat#10091-148)) were placed at 37°C, 5% CO 2 , Cultivated under 95% humidity conditions.
3D细胞活力检测：收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。配制含1％MC(Sigma,Cat#M0512)RPMI-1640培养基并加入10％FBS配制成3D细胞完全培养基，用3D培养基调整细胞浓度为12500个细胞/mL并使MC的含量为0.65％；分别添加80μL细胞悬液至96孔透明平底黑壁板(Greiner,Cat#655096)中；将96孔板中的细胞置于37℃、5％CO2条件下过夜培养。3D cell viability assay: Harvest cells in logarithmic growth phase and count cells using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Prepare RPMI-1640 medium containing 1% MC (Sigma, Cat#M0512) and add 10% FBS to prepare a complete 3D cell medium. Use the 3D medium to adjust the cell concentration to 12500 cells/mL and make the MC content 0.65 %; add 80 μL of cell suspension to a 96-well transparent flat-bottom black wall plate (Greiner, Cat#655096); place the cells in the 96-well plate at 37°C and 5% CO 2 to culture overnight.
IC50测定药物配制：用培养基配制5倍药物溶液，在接种有细胞的96孔板中每孔加入20μL药物溶液，使得工作浓度为最高10μM，3×稀释，9个浓度，每个药物浓度设置2个复孔；或者设置最终测试浓度分别为0.1uM及1.0uM，测试一些代表性化合物在两个浓度下的抑制率，据此推测化合物IC50范围。将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养5天，然后进行CTG检测(Luminescent Cell Viability Assay(Promega,Cat#G7573))。IC50 determination drug preparation: Use culture medium to prepare 5-fold drug solution, add 20 μL drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is up to 10 μM, 3× dilution, 9 concentrations, each drug concentration setting 2 duplicate wells; or set the final test concentrations to 0.1uM and 1.0uM respectively, test the inhibition rates of some representative compounds at two concentrations, and estimate the IC 50 range of the compound based on this. The cells in the 96-well plate that had been added with the drug were cultured at 37°C and 5% CO2 for 5 days, and then CTG detection was performed ( Luminescent Cell Viability Assay (Promega, Cat#G7573)).
平衡细胞板至室温30分钟并融化CTG试剂，每孔加入50微升的CTG溶液检测，在定 轨摇床上振动5分钟使细胞裂解。将细胞板放置于室温25分钟以稳定冷光信号，读取冷光值(多功能酶标仪，PerkinElmer#2105)。Balance the cell plate to room temperature for 30 minutes and melt the CTG reagent. Add 50 μl of CTG solution to each well for detection. Cells were lysed by shaking on an orbital shaker for 5 minutes. Place the cell plate at room temperature for 25 minutes to stabilize the luminescence signal, and read the luminescence value ( Multifunctional microplate reader, PerkinElmer #2105).
使用GraphPad Prism软件分析数据，利用Dose-response-inhibition方程来拟合数据得出剂量-效应曲线，并由此计算IC50值。Use GraphPad Prism software to analyze the data, use the Dose-response-inhibition equation to fit the data to obtain a dose-response curve, and calculate the IC50 value from this.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) × 100%.
代表性本发明化合物对KRAS G12C突变的NCI-H358人肺癌细胞显示出令人满意的抗增殖活性，IC50范围在<1uM，优选<0.1uM。Representative compounds of the present invention show satisfactory anti-proliferative activity against KRAS G12C mutated NCI-H358 human lung cancer cells, with IC50 ranging from <1uM, preferably <0.1uM.
实施例6：本发明化合物对7株肿瘤细胞的增殖抑制效果Example 6: Inhibitory effect of the compounds of the present invention on the proliferation of 7 tumor cell lines
本实验评估并验证了本发明代表性化合物对下列6株KRAS相关肿瘤细胞的增殖抑制活性。
This experiment evaluates and verifies the proliferation inhibitory activity of the representative compounds of the present invention on the following 6 strains of KRAS-related tumor cells.
本实验中使用如下材料、试剂和仪器：6株细胞均来自康源博创生物科技(北京)有限公司(NCI-H441，KC-0510；Capan-2，KC-0185；A549，KC-0284；HCT116，KC-0281；NCI-H460，KC-0512；EBC-1，KC-0195；A375，KC-0158)；RPMI-1640(Hyclone,SH30809.01)；胎牛血清FBS(GIBCO,10099-141)；甲基纤维素(methylcellulose，SIGMA，9004-67-5)；磷酸盐缓冲液PBS(Solarbio,P1020-500)；CellCounting-Lite 2.0 Luminescent Cell Viability Assay(南京诺唯赞，DD1101-04)；96孔透明平底黑壁板(Thermo,165305)；多功能酶标仪(BMG LABTECH，Plus)；CO2培养箱(Thermo Scientific，Model 3100 Series)。The following materials, reagents and instruments were used in this experiment: 6 cell lines were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. (NCI-H441, KC-0510; Capan-2, KC-0185; A549, KC-0284; HCT116, KC-0281; NCI-H460, KC-0512; EBC-1, KC-0195; A375, KC-0158); RPMI-1640 (Hyclone, SH30809.01); Fetal bovine serum FBS (GIBCO, 10099-141 ); Methylcellulose (methylcellulose, SIGMA, 9004-67-5); Phosphate buffer PBS (Solarbio, P1020-500); CellCounting-Lite 2.0 Luminescent Cell Viability Assay (Nanjing Novozymes, DD1101-04); 96-well transparent flat bottom black wall plate (Thermo, 165305); multifunctional microplate reader (BMG LABTECH, Plus); CO2 incubator (Thermo Scientific, Model 3100 Series).
实验方法：experimental method:
提前配置灭菌的1％methylcellulose 3D培养基。收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整NCI-H441，A549，HCT116，NCI-H460，EBC-1及A375等细胞浓度，使得甲基纤维素终浓度为0.65％，混匀静置；待细胞悬液中无可见气后分别添加180μL细胞悬液至96孔板中，共2500个细胞。使用完全培养基调整capan-2细胞浓度，分别添加180μL细胞悬液至96孔板中，共3000个细胞。将96孔板中的细胞置于37℃、5％CO2、95％湿度条件下培养过夜。 Prepare sterile 1% methylcellulose 3D medium in advance. Cells in logarithmic growth phase were harvested and counted using a platelet counter. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Adjust the cell concentrations of NCI-H441, A549, HCT116, NCI-H460, EBC-1 and A375 so that the final concentration of methylcellulose is 0.65%, mix and let stand; add 180 μL each after there is no visible gas in the cell suspension. The cell suspension was transferred to a 96-well plate for a total of 2500 cells. Use complete culture medium to adjust the capan-2 cell concentration, and add 180 μL of cell suspension to a 96-well plate, for a total of 3,000 cells. The cells in the 96-well plate were cultured overnight at 37°C, 5% CO2, and 95% humidity.
IC50测定药物配制：首先配制各化合物10mM DMSO储存液。第一次以DMSO为溶剂，3.16倍稀释，9个浓度，制备各化合物不同浓度DMSO溶液。第二次1：100稀释配制10倍各化合物稀释液，以完全培养基为溶剂。最后，在接种有细胞的96孔板中每孔加入20μL各化合物稀释液，最终药物最高浓度为10μM，9个浓度，3.16倍稀释，每个浓度设置三个复孔；或者设置最终测试浓度分别为0.1uM及1.0uM，测试一些代表性化合物在两个浓度下的抑制率，据此推测化合物IC50范围。Drug preparation for IC 50 determination: First prepare a 10mM DMSO stock solution of each compound. For the first time, DMSO was used as the solvent, diluted 3.16 times, and 9 concentrations to prepare DMSO solutions with different concentrations of each compound. For the second dilution of 1:100, prepare a 10-fold dilution of each compound, using complete culture medium as the solvent. Finally, add 20 μL of each compound dilution to each well of a 96-well plate seeded with cells. The final maximum drug concentration is 10 μM, 9 concentrations, 3.16-fold dilution, and three duplicate wells for each concentration; or set the final test concentration separately. 0.1uM and 1.0uM, test the inhibition rate of some representative compounds at two concentrations, and estimate the IC 50 range of the compound based on this.
将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养144小时，之后进行CTG分析。融化CTG试剂并平衡细胞板至室温30分钟。每孔加入等体积的CTG溶液。在定轨摇床上振动5分钟使细胞裂解。将细胞板放置于室温20分钟以稳定冷光信号。读取冷光值，收集数据。The cells in the drug-added 96-well plate were cultured at 37°C and 5% CO2 for 144 hours, and then CTG analysis was performed. Melt CTG reagent and equilibrate cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well. Cells were lysed by shaking on an orbital shaker for 5 minutes. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal. Read the luminescence value and collect data.
使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。Data were analyzed using GraphPad Prism 7.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC 50 value was calculated.
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum溶剂对照-Lum培养液对照)×100％Cell survival rate (%) = (Lum test drug-Lum culture medium control)/(Lum solvent control-Lum culture medium control) × 100%
细胞活性数据如下表所示，其中A表示IC50≤100nM；B表示100nM<IC50≤1000nM；C表示IC50>1000nM。

The cell activity data are shown in the table below, where A represents IC 50 ≤100nM; B represents 100nM <IC 50 ≤1000nM; C represents IC 50 >1000nM.

参比化合物1及参比化合物2参照文献WO2022132200A1中所述方法进行制备和表征。Reference compound 1 and reference compound 2 Preparation and characterization were performed with reference to the method described in document WO2022132200A1.
实施例7：本发明化合物在KRAS-G12D突变的人结肠癌细胞GP2d皮下异种移植BALB/c nude小鼠动物模型中的抗肿瘤作用Example 7: Anti-tumor effect of the compound of the present invention in the subcutaneous xenograft BALB/c nude mouse animal model of KRAS-G12D mutated human colon cancer cell GP2d
【实验材料】：GP2d细胞购自南京科佰生物科技有限公司.BALB/c nude小鼠，雌性，购自江苏集萃药康生物科技有限公司。[Experimental Materials]: GP2d cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. BALB/c nude mice, female, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
【实验步骤】：GP2d细胞在含DMEM和10％FBS的培养液中进行培养，收集对数生长期的细胞，PBS重悬至合适浓度以用于小鼠皮下肿瘤接种。实验小鼠于右后侧背部皮下接种，GP2d细胞接种量为：1×107/只，细胞重悬于1:1的PBS与基质胶中(接种体积为0.1mL)。当肿瘤平均体积生长至～150mm3时，根据肿瘤大小和小鼠体重随机分组给药。分组后随即开始给药，给药当天视为第0天。每天给药2次，灌胃给药，剂量为10mg/kg、30mg/kg或溶剂对照(0.5％Tween 80+99.5％的(0.5％MC(400cp))。实验期间，每周测量2次小鼠的体重和肿瘤的大小。肿瘤大小计算公式：肿瘤体积(mm3)＝0.5×(肿瘤长径×肿瘤短径2)。相对肿瘤抑制率TGI(％)：TGI％＝[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。[Experimental steps]: GP2d cells were cultured in a culture medium containing DMEM and 10% FBS. Cells in the logarithmic growth phase were collected and resuspended in PBS to an appropriate concentration for subcutaneous tumor inoculation in mice. Experimental mice were subcutaneously inoculated on the right rear back. The inoculation volume of GP2d cells was: 1×10 7 /mouse. The cells were resuspended in 1:1 PBS and Matrigel (the inoculation volume was 0.1 mL). When the average tumor volume grew to ∼150 mm3, the mice were randomly divided into groups for administration based on tumor size and body weight. Dosing began immediately after grouping, and the day of dosing was regarded as day 0. Administration was given twice a day by gavage at a dose of 10 mg/kg, 30 mg/kg or solvent control (0.5% Tween 80 + 99.5% (0.5% MC (400cp))). During the experiment, the microbiome was measured twice a week. The weight of the mouse and the size of the tumor. The calculation formula of tumor size: tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). Relative tumor inhibition rate TGI (%): TGI% = [1-(some The average tumor volume of the treatment group at the end of administration - the average tumor volume of the treatment group at the beginning of administration) / (the average tumor volume of the solvent control group at the end of treatment - the average tumor volume of the solvent control group at the beginning of treatment)] × 100%.
【实验结果】：10mg/kg实验结果由下表显示，代表性本发明化合物能够显著抑制GP2d肿瘤生长。
[Experimental results]: The experimental results at 10 mg/kg are shown in the table below. The representative compounds of the present invention can significantly inhibit the growth of GP2d tumors.
30mg/kg实验结果由下表显示，代表性本发明化合物能够显著抑制GP2d肿瘤生长。
The experimental results at 30 mg/kg are shown in the table below. The representative compounds of the present invention can significantly inhibit the growth of GP2d tumors.

Claims (21)

  1. 式(I)的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，
    Compounds of formula (I), their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates,
    其中：in:
    M选自N或C-R7；M is selected from N or CR 7 ;
    X选自C和S，p选自0和1，条件是p为0时X为S，p为1时X为C；X is selected from C and S, p is selected from 0 and 1, provided that when p is 0, X is S, and when p is 1, X is C;
    Y选自O、S和Se；Y is selected from O, S and Se;
    W选自OH和NH2；W is selected from OH and NH 2 ;
    B选自包含1至3个独立地选自N、O、P、Se和S的杂原子的5-7元单环杂环烷基，和包含1至4个独立地选自N、O、P、Se和S的杂原子的6-12元多环杂环烷基，条件是各自通过氮杂原子连接至分子的嘧啶环部分；B is selected from 5-7 membered monocyclic heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from N, O, P, Se, and S, and containing 1 to 4 heteroatoms independently selected from N, O, 6-12 membered polycyclic heterocycloalkyl groups of heteroatoms of P, Se and S, provided that each is connected to the pyrimidine ring portion of the molecule through a nitrogen heteroatom;
    Q选自其中Q is selected from in
    Z选自N、C、O、S和Se；Z is selected from N, C, O, S and Se;
    k选自0或1；k is selected from 0 or 1;
    m和n各自独立地选自0至2的整数；m and n are each independently selected from an integer from 0 to 2;
    R1选自-C1-6烷基和-(CH2)n-C3-6环烷基，各自独立地任选被卤素或C1-6烷氧基取代；R 1 is selected from -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, each independently optionally substituted by halogen or C 1-6 alkoxy;
    R2选自H、-C1-6烷基和-(CH2)n-C3-6环烷基，其中的C1-6烷基或C3-6环烷基各自独立地任选被卤素或C1-6烷氧基取代，R 2 is selected from H, -C 1-6 alkyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl or C 3-6 cycloalkyl is independently optional Substituted by halogen or C 1-6 alkoxy,
    或者连接于同一碳原子上的两个R2与它们所连接的碳原子一起形成C3-4环烷基；Or two R 2 connected to the same carbon atom together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
    R3选自H、卤素、-CN、-OH、-O-C1-6烷基、-O-C3-6环烷基、-C1-6烷基、-C2-6烯基、-C2- 6炔基和-(CH2)n-C3-6环烷基，其中每次出现的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各 自独立地任选被卤素、CN或C1-6烷氧基取代，R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 -6 alkynyl and - (CH 2 ) n -C 3-6 cycloalkyl, where each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3 -6 cycloalkyl each independently optionally substituted by halogen, CN or C 1-6 alkoxy,
    或者连接于同一个碳原子上的两个R3形成＝C(Rc)2、任选被卤素取代的螺C3-6环烷基或任选被卤素取代的螺4-7元杂环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，Or two R 3 connected to the same carbon atom form =C(R c ) 2 , spiro C 3-6 cycloalkyl optionally substituted by halogen or spiro 4-7 membered heterocycle optionally substituted by halogen Alkyl, wherein R c is each independently selected from H, halogen and -C 1-6 alkyl optionally substituted by halogen,
    或者连接于相邻环碳原子上的R1和R3或连接于相邻环碳原子上的两个R3与它们所连接的碳原子一起形成C3-4环烷基；Or R 1 and R 3 connected to adjacent ring carbon atoms or two R 3 connected to adjacent ring carbon atoms together with the carbon atoms to which they are connected form a C 3-4 cycloalkyl group;
    或者连接在非相邻环碳原子上的两个R3一起形成桥连亚甲基或亚乙基；Or two R 3 's connected to non-adjacent ring carbon atoms together form a bridged methylene or ethylene group;
    R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基和-(CH2)n-C3-6环烷基，其中的C1-6烷基、-C2-6烯基、-C2-6炔基或C3-6环烷基各自独立地任选被卤素、CN、-C1-6烷氧基或-O-CON(C1-6烷基)2取代；R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH 2 ) n -C 3-6 cycloalkyl, wherein C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally optionally replaced by halogen, CN, -C 1-6 alkoxy or -O-CON (C 1-6 alkyl) 2 substitution;
    R5选自H和卤素；R 5 is selected from H and halogen;
    R6选自H、卤素、-C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-Se-C1-6烷基和-C2-6炔基，各自独立地任选被卤素取代；R 6 is selected from H, halogen, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -Se-C 1-6 alkyl and -C 2-6 alkynyl, Each independently optionally substituted by halogen;
    R7选自H、卤素、CN和-C1-6烷基，其中-C1-6烷基任选被卤素或CN取代；R 7 is selected from H, halogen, CN and -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by halogen or CN;
    R8选自-OH、卤素、-CN、-B(OH)2、-C1-6烷基、-O-C1-6烷基、-CONH(C1-6烷基)、-CON(C1-6烷基)2、-CON(C1-6烷基)(C2-6烯基)、-CON(C1-6烷基)(C2- 6炔基)、-PO(C1-6烷基)2、-PO(C1-6烷基)(C2-6烯基)、-PO(C1-6烷基)(C2-6炔基)、-SO-N(C1-6烷基)2、-SO-N(C1-6烷基)(C2-6烯基)、-SO-N(C1-6烷基)(C2-6炔基)、-SO2-N(C1-6烷基)2、-SO2-N(C1-6烷基)(C2-6烯基)和-SO2-N(C1-6烷基)(C2-6炔基)，R 8 is selected from -OH, halogen, -CN, -B(OH) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -CONH(C 1-6 alkyl), -CON(C 1-6 alkyl) 2 , -CON(C 1-6 alkyl)(C 2-6 alkenyl), -CON(C 1-6 alkyl)(C 2- 6 alkynyl), -PO(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl)(C 2-6 alkenyl), -PO(C 1-6 alkyl)(C 2-6 alkynyl), -SO-N (C 1-6 alkyl) 2 , -SO-N(C 1-6 alkyl)(C 2-6 alkenyl), -SO-N(C 1-6 alkyl)(C 2-6 alkynyl ), -SO 2 -N(C 1-6 alkyl) 2 , -SO 2 -N(C 1-6 alkyl)(C 2-6 alkenyl) and -SO 2 -N(C 1-6 alkyl) base) (C 2-6 alkynyl),
    其中-C1-6烷基、-C2-6烯基或-C2-6炔基任选被卤素或CN取代；wherein -C 1-6 alkyl, -C 2-6 alkenyl or -C 2-6 alkynyl is optionally substituted by halogen or CN;
    R9和R10各自独立地选自H、卤素和任选被卤素取代的C1-6烷基；R 9 and R 10 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted by halogen;
    R11选自H、卤素、任选被卤素取代的-C1-6烷基、任选被卤素取代的-O-C1-6烷基和任选被卤素取代的-C2-6炔基；和R 11 is selected from H, halogen, -C 1-6 alkyl optionally substituted by halogen, -OC 1-6 alkyl optionally substituted by halogen, and -C 2-6 alkynyl optionally substituted by halogen; and
    t选自1至4的整数。t is selected as an integer from 1 to 4.
  2. 权利要求1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中X所在的稠合双环部分为其中R5为卤素，R6选自卤素、C1-6烷基或C2-6炔基，W为-OH，且R9和R10各 自独立地选自H或卤素，例如 The compound of formula (I) of claim 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the fused bicyclic portion where X is located is Wherein R 5 is halogen, R 6 is selected from halogen, C 1-6 alkyl or C 2-6 alkynyl, W is -OH, and R 9 and R 10 are each independently selected from H or halogen, e.g.
  3. 权利要求1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中X所在的稠合双环部分为其中R5为H或卤素，R6选自卤素、C1-6烷基或C2-6炔基，W为-OH，且R9和R10各自独立地选自H或卤素，例如 The compound of formula (I) of claim 1, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the fused bicyclic portion where X is located is Wherein R 5 is H or halogen, R 6 is selected from halogen, C 1-6 alkyl or C 2-6 alkynyl, W is -OH, and R 9 and R 10 are each independently selected from H or halogen, such as
  4. 权利要求1至3任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中B为被1-2个R8取代，优选 更优选其中R8之一为-OH且另一个为-C1-6烷基。The compound of formula (I) according to any one of claims 1 to 3, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein B is Replaced by 1-2 R 8 , preferably More preferably one of R 8 is -OH and the other is -C 1-6 alkyl.
  5. 权利要求1至4任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中：The compound of formula (I) according to any one of claims 1 to 4, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein:
    Q为其中R4为任选被-O-C1-6烷基或卤素取代的-C1-6烷基，优选-C1-3 烷基；R3选自卤素、CN、任选被卤素取代的-C1-6烷基、任选被卤素取代的-C2-6炔基和任选被卤素取代的-O-C1-6烷基，或者连接于同一个碳原子上的两个R3形成＝C(Rc)2或任选被卤素取代的螺C3-6环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基，且m选自1或2；Q is Wherein R 4 is -C 1-6 alkyl optionally substituted by -OC 1-6 alkyl or halogen, preferably -C 1-3 Alkyl; R 3 is selected from halogen, CN, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkynyl optionally substituted by halogen, and -OC 1-6 optionally substituted by halogen Alkyl, or two R 3 connected to the same carbon atom to form =C(R c ) 2 or spiro C 3-6 cycloalkyl optionally substituted by halogen, wherein each R c is independently selected from H, Halogen and -C 1-6 alkyl optionally substituted by halogen, and m is selected from 1 or 2;
    优选地，R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基，例如＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；Preferably, R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 connected to the same carbon atom form =C(R c ) 2 , wherein R c is each independently selected from H, Halogen and -C 1-3 alkyl optionally substituted by halogen, such as =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; R 4 Is -C 1-3 alkyl or -C 1-3 alkyl substituted by one or more deuteriums, such as methyl, -CD 3 ;
    其中与Y连接的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
  6. 权利要求5的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Q为 The compound of formula (I) of claim 5, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Q is
  7. 权利要求1至6任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中Y为O。The compound of formula (I) according to any one of claims 1 to 6, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein Y is O.
  8. 权利要求1至7任一项的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R7选自H、F、Cl、CN和-CF3。The compound of formula (I) according to any one of claims 1 to 7, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein R is selected from H , F, Cl, CN and -CF 3 .
  9. 权利要求1的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其具有以下子通式：

    The compound of formula (I) of claim 1, its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate, which has the following sub-general formula:

    其中各个取代基如前述任一权利要求所定义。wherein each substituent is as defined in any preceding claim.
  10. 权利要求9的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中The compound of formula (I) of claim 9, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein
    Y为O；Y is O;
    Z选自C、Se和O，优选O或C；Z is selected from C, Se and O, preferably O or C;
    R1为C1-6烷基，优选甲基；R 1 is C 1-6 alkyl, preferably methyl;
    R2为H，或连接在同一碳原子上的两个R2一起形成环丙基，R 2 is H, or two R 2 connected to the same carbon atom together form a cyclopropyl group,
    R3选自卤素、CN、任选被卤素取代的-C1-6烷基、任选被卤素取代的-C2-6炔基和任选被卤素取代的-O-C1-6烷基，或者连接于同一个碳原子上的两个R3形成＝C(Rc)2或任选被卤素取代的螺C3-6环烷基，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-6烷基；优选地，R3为 -C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基；R 3 is selected from halogen, CN, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkynyl optionally substituted by halogen, and -OC 1-6 alkyl optionally substituted by halogen, Or two R 3 connected to the same carbon atom form =C(R c ) 2 or spiro C 3-6 cycloalkyl optionally substituted by halogen, wherein R c is each independently selected from H, halogen and any Select -C 1-6 alkyl substituted by halogen; preferably, R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 attached to the same carbon atom form =C(R c ) 2 , where R c is each independently selected from H, halogen and optionally halogen Substituted -C 1-3 alkyl;
    R4选自H和C1-6烷基，优选C1-6烷基，例如甲基或乙基；更优选，R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；R 4 is selected from H and C 1-6 alkyl, preferably C 1-6 alkyl, such as methyl or ethyl; more preferably, R 4 is -C 1-3 alkyl or substituted by one or more deuterium -C 1-3 alkyl, such as methyl, -CD 3 ;
    R5选自H和卤素，优选卤素，例如F；R 5 is selected from H and halogen, preferably halogen, such as F;
    R6选自卤素、C1-6烷基和C2-6炔基，优选F、乙基或乙炔基；R 6 is selected from halogen, C 1-6 alkyl and C 2-6 alkynyl, preferably F, ethyl or ethynyl;
    R7选自H、卤素、CN和卤素取代的C1-6烷基，优选H、F、Cl、CN、CF3；R 7 is selected from H, halogen, CN and halogen-substituted C 1-6 alkyl, preferably H, F, Cl, CN, CF 3 ;
    R8选自OH和C1-6烷基，优选其中之一为-OH且另一个为C1-6烷基，优选甲基；R 8 is selected from OH and C 1-6 alkyl, preferably one of them is -OH and the other is C 1-6 alkyl, preferably methyl;
    R9为H或卤素，优选H；R 9 is H or halogen, preferably H;
    R11选自H、卤素、C1-6烷基、C1-6烷氧基和-C2-6炔基；R 11 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and -C 2-6 alkynyl;
    m选自1或2，k选自0；m is selected from 1 or 2, k is selected from 0;
    其中与Y连接的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group connected to Y are optionally replaced by deuterium.
  11. 权利要求10的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中对于式(I-A’-2)、(I-C’-2)、(I-A”’-2)或(I-C”’-2)，The compound of formula (I) of claim 10, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein for formula (I-A'-2) , (I-C'-2), (I-A”'-2) or (I-C”'-2),
    Z为C；Z is C;
    R1为C1-6烷基，优选甲基；R 1 is C 1-6 alkyl, preferably methyl;
    R3为-C1-3烷基，被卤素取代；或者连接于同一个碳原子上的两个R3形成＝C(Rc)2，其中Rc各自独立地选自H、卤素和任选被卤素取代的-C1-3烷基；R 3 is -C 1-3 alkyl, substituted by halogen; or two R 3 connected to the same carbon atom form =C(R c ) 2 , where R c is each independently selected from H, halogen and any Select -C 1-3 alkyl substituted by halogen;
    R4为-C1-3烷基或被一个或多个氘取代的-C1-3烷基，例如甲基、-CD3；R 4 is -C 1-3 alkyl or -C 1-3 alkyl substituted by one or more deuteriums, such as methyl, -CD 3 ;
    R5选自H和卤素，优选卤素，例如F；R 5 is selected from H and halogen, preferably halogen, such as F;
    R6选自卤素、C1-6烷基和C2-6炔基，优选乙基或乙炔基；R 6 is selected from halogen, C 1-6 alkyl and C 2-6 alkynyl, preferably ethyl or ethynyl;
    R7选自H、卤素、CN和卤素取代的C1-6烷基，优选H、F、Cl、CN、CF3；R 7 is selected from H, halogen, CN and halogen-substituted C 1-6 alkyl, preferably H, F, Cl, CN, CF 3 ;
    R8选自OH和C1-6烷基，优选其中之一为-OH且另一个为C1-6烷基，优选甲基；R 8 is selected from OH and C 1-6 alkyl, preferably one of them is -OH and the other is C 1-6 alkyl, preferably methyl;
    R9为H；R 9 is H;
    R11选自H、卤素、C1-6烷基和C1-6烷氧基；R 11 is selected from H, halogen, C 1-6 alkyl and C 1-6 alkoxy;
    其中与Y连接的Q的亚甲基的两个氢原子任选被氘代替。The two hydrogen atoms of the methylene group of Q connected to Y are optionally replaced by deuterium.
  12. 权利要求9至11任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中分别为 The compound of any one of claims 9 to 11, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein respectively
  13. 权利要求9至12任一项的化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中结构片段为 The compound of any one of claims 9 to 12, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, wherein the structural fragment for
  14. 化合物或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其为实施例1-185的化合物。A compound, or a stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate thereof, which is a compound of Examples 1-185.
  15. 药物组合物，包含根据权利要求1-14任一项的化合物其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，以及药学上可接受的赋形剂。Pharmaceutical compositions comprising a compound according to any one of claims 1 to 14, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable of excipients.
  16. 权利要求1-14任一项的化合物或其药学上可接受的盐或溶剂合物或权利要求15的药物组合物，用作药物，用于治疗和/或预防由KRas突变及KRAS扩增介导的疾病。The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition of claim 15 for use as a medicament for the treatment and/or prevention of KRAS mutations and KRAS amplification. induced diseases.
  17. 权利要求1-14任一项的化合物或其药学上可接受的盐或溶剂合物或根据权利要求15的药物组合物在制备用于预防或治疗由KRas突变及KRAS扩增介导的疾病的用药物中的用途。A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 15 for use in the prevention or treatment of diseases mediated by KRas mutations and KRAS amplifications. Use in medicines.
  18. 权利要求17的用途，其中由KRas突变及KRAS扩增介导的疾病选自：胰腺癌、肺癌、肺腺癌、骨癌、皮肤癌、头颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤(CNS)、原发性CNS淋巴瘤、脊柱肿瘤、脑干神经胶质瘤或垂体腺瘤。The use of claim 17, wherein the disease mediated by KRAS mutation and KRAS amplification is selected from: pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, Ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer , Thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethra cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, Central nervous system tumors (CNS), primary CNS lymphoma, spinal tumors, brainstem gliomas, or pituitary adenomas.
  19. 权利要求18的用途，其中由KRas突变及KRAS扩增介导的疾病选自胰腺癌、结肠癌、直肠癌、肺腺癌、肺癌、胆管癌、子宫内膜癌、卵巢癌、白血病；最优选选自胰腺癌、结肠癌、直肠癌、肺腺癌、胆管癌。The use of claim 18, wherein the disease mediated by KRas mutation and KRAS amplification is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, and leukemia; most preferably Selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.
  20. 治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白及KRAS扩增介导的疾病的方法，包括向有需要的对象施用治疗有效量的根据权利要求1-14任一项的化合物或其药学上可接受的盐或溶剂合物或根据权利要求15的药物组合物。A method for treating and/or preventing diseases mediated by Ras mutant proteins, especially KRas mutant proteins and KRAS amplification, comprising administering to a subject in need a therapeutically effective amount of a compound according to any one of claims 1-14 or its Pharmaceutically acceptable salts or solvates or pharmaceutical compositions according to claim 15.
  21. 权利要求20的方法，其中由KRas突变及KRAS扩增介导的疾病选自胰腺癌、结肠癌、直肠癌、肺腺癌、肺癌、胆管癌、子宫内膜癌、卵巢癌、白血病；最优选选自胰腺癌、结肠癌、直肠癌、肺腺癌、胆管癌。 The method of claim 20, wherein the disease mediated by KRas mutation and KRAS amplification is selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, and leukemia; most preferably Selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, and bile duct cancer.
PCT/CN2023/114683 2022-08-24 2023-08-24 Compound with anti-kras mutant tumor activity WO2024041606A1 (en)

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