WO2023151621A1 - Compound having anti-kras mutant tumor activity - Google Patents

Compound having anti-kras mutant tumor activity Download PDF

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Publication number
WO2023151621A1
WO2023151621A1 PCT/CN2023/075209 CN2023075209W WO2023151621A1 WO 2023151621 A1 WO2023151621 A1 WO 2023151621A1 CN 2023075209 W CN2023075209 W CN 2023075209W WO 2023151621 A1 WO2023151621 A1 WO 2023151621A1
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cancer
alkyl
compound
pharmaceutically acceptable
solvate
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PCT/CN2023/075209
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French (fr)
Chinese (zh)
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尚尔昌
仲伯禹
张彦涛
宋光琳
王龙飞
陈国猛
侯福良
汪瑞祥
胡旭波
郑爱军
杨安江
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泰励生物科技（上海）有限公司
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Publication of WO2023151621A1 publication Critical patent/WO2023151621A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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

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 that can be used 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 homologue
  • Ras represents a group of closely related monomeric globular proteins belonging to the GTPase protein family.
  • Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, and differentiation.
  • These regulatory functions of Ras are carried out by switching 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, in a dormant or off state, when 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 transformed into the active form of Ras, which recruits and activates various downstream effectors for signal transmission, and can transmit the signal on the cell surface to the cytoplasm, thereby Controls numerous key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).
  • GEF guanine nucleotide exchange factor
  • Ras has GTPase activity, which can cleave the terminal phosphate of GTP to 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 be activated for a long time, thereby continuously transmitting signals of growth and division to cells, stimulating cell proliferation, and eventually leading to tumor formation And development.
  • Ras genes H-RAS, K-RAS and N-RAS which encode highly homologous HRas, NRas and KRas proteins of about 21 KDa, respectively.
  • H-RAS ubiquitously expressed Ras genes
  • K-RAS ubiquitously expressed Ras genes
  • N-RAS which encode highly homologous HRas, NRas and KRas proteins of about 21 KDa, respectively.
  • researchers first discovered the mutational activation of Ras 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%) highest mutation rate.
  • Ras tumor protein a well-accepted and very attractive anticancer drug target in the field of pharmacy.
  • Ras mutations are most commonly found in KRas, and KRas mutations can be observed in about 85% of Ras mutation-driven cancers; most Ras mutations occur at codons G12, G13, and Q61, and about 80% of KRas mutations are hair Born at the glycine of codon 12, such as G12C mutation, G12D mutation, G12V mutation, G13D mutation, etc.
  • KRas mutations are common in pancreatic, lung adenocarcinoma, colorectal, gallbladder, thyroid, and cholangiocarcinomas, and can also be found in 25% of patients with non-small cell lung cancer (McCormick, F.
  • KRas mutant protein has become the most important branch in the research of Ras drug targets, and the development of its inhibitors is also regarded as a very promising research and development direction in the development of anticancer/tumor drugs.
  • Ras due to the smooth surface of Ras protein, it lacks obvious groove-like or pocket structures for binding small molecule inhibitors, and its affinity for guanine substrates is very high (skin Mole level), making the development of its small molecule inhibitors into an insoluble dilemma, so 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 having KRas mutein inhibitory activity. These compounds of the present invention have improved structural patterns, compared with existing KRas mutant protein inhibitors in the prior art, have enhanced KRas mutant protein inhibitory activity and related tumor suppression activity, and have good pharmacokinetic properties. Therefore, it has good druggability, such as being able to be easily absorbed in the body after administration in a convenient manner, and has reduced toxic and side effects, improved drug resistance and safety, and reduced drug interaction risks.
  • the present invention provides a compound of formula (A) as defined herein below, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient or carrier.
  • the present invention also provides the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use as a medicine.
  • the present invention also provides the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, which is used as an inhibitor of Ras mutein, especially KRas mutein, preferably KRas G12D.
  • the present invention also provides the compound of the present invention or its pharmaceutically acceptable salt or solvate or comprising its pharmaceutical composition.
  • the present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising it for the treatment and/or prevention of Ras mutein, especially KRas mutein, preferably KRas G12D mutein mediated disease use.
  • the present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition containing it for the treatment and/or prevention of Ras mutein, especially KRas mutein, preferably KRas G12D Use in medicine for mutant protein-mediated diseases.
  • the present invention also provides a method for treating and/or preventing a disease mediated by a Ras mutein, especially a KRas mutein, preferably a KRas G12D mutein, comprising administering a therapeutically effective amount of a compound of the present invention or its pharmaceutical preparation to a subject in need thereof.
  • a Ras mutein especially a KRas mutein, preferably a KRas G12D mutein
  • An acceptable salt or solvate or a pharmaceutical composition comprising it.
  • the present invention also provides a method for treating tumor or cancer, which comprises administering the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising the same to a patient in need.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D.
  • the invention also provides pharmaceutical combinations comprising a compound of the invention and one or more other pharmaceutically active agents.
  • 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 Ras codon, A Ras protein with a mutation to glycine at codon 13 or glutamine at codon 61, such as mutant HRas, NRas or KRas. Mutations of these residues in the active site of Ras 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” against 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 aspartic acid at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12 Mutation of glycine to valine at G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); especially KRas mutein, more particularly KRas-G12C mutein, KRas- G12D mutein, KRas-G12V mutein, KRas-G13D mutein, most particularly
  • treating refers to administering one or more of the compounds of the present invention described herein or their pharmaceutical preparations 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 for curing, alleviating, alleviating or affecting the disease or the symptoms of the disease.
  • treatment is curative or ameliorative.
  • prophylaxis as used herein is well known in the art and refers to giving a person suspected of having or being susceptible to A subject, such as a mammal, such as a human, of a Ras mutation-mediated disease, especially cancer or tumor, is administered one or more compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, such that To reduce the risk of developing a defined disease, or to prevent the onset of a disease.
  • prevention encompasses the use of the compounds of the invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
  • inhibitor and “reduce” or any variation of these terms, as used herein, 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 refer to Any measurable reduction or complete inhibition of the activity of a target of interest.
  • the activity can be reduced by about, at most about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.
  • the term "selective inhibition” refers to the ability of a biologically active agent to preferentially reduce signaling activity of a target of interest over off-target signaling activity by interacting directly or indirectly with the target.
  • the compound of the present invention has the ability to selectively inhibit the G12 or G13 mutation of the KRas, HRas or NRas protein, such as G12C mutation, G12D mutation, The G12V mutation and the G13D mutation, preferably the ability of the G12D mutation to selectively inhibit the KRas protein.
  • the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% for a specific Ras mutation compared to another specific Ras mutation , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range of better activity derivable therein, or with At least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100- , 250- or 500-fold better activity.
  • Ras mutation-mediated disease refers to a disease in which Ras mutation promotes the occurrence and development of the disease, or inhibiting Ras mutation will reduce the incidence of the disease, reduce or eliminate the disease symptoms.
  • Ras mutation-mediated disease preferably refers to KRas mutation-mediated disease, most preferably KRas-G12D-mediated disease, and more preferably cancer or tumor.
  • cancer refers to abnormal cell growth and proliferation, whether malignant or benign, and to all precancerous and cancerous cells and tissues.
  • the cancer or tumor includes, but is 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 cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine 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,
  • the cancer or tumor is associated with a Ras mutation, especially a KRas mutation, preferably a KRas G12D mutation, including but not limited to the above tumor types and their preferred ranges.
  • a KRas mutation especially a KRas G12D mutation, including but not limited to the above tumor types and their preferred ranges.
  • Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, leukemia and ovarian cancer.
  • the term "subject”, “individual” or “patient” as used herein refers to a vertebrate animal.
  • the spine The animal is a mammal.
  • Mammals include, but are not limited to, farm animals (such as cows), sport 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 the amount or dose that is generally sufficient to produce a beneficial therapeutic effect on the "Ras mutation-mediated disease” such as cancer or tumor patients in need of treatment.
  • Those skilled in the art can determine the effective amount or dosage of the active ingredients in the present invention by conventional methods and in combination with conventional influencing factors.
  • the term "pharmaceutical combination" as used herein means that the compounds of the present invention may be combined with other active agents for the purposes of the present 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 which is compatible with the compounds of the invention, i.e. does not adversely affect each other, or has complementary activities. ) 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 amounts effective to achieve the intended purpose.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, either simultaneously or sequentially when administered separately. The sequential administration 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 salt refers to those salts which retain the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable, including acid addition salts and base addition salts.
  • “Pharmaceutically acceptable acid addition salts” may be formed from compounds having a basic group with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids may be selected from Aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids such as formic, acetic, propionic, glycolic, gluconic, lactic, pyruvic, oxalic, 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,
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc., and those derived from pharmaceutically acceptable Salts of organic non-toxic bases are accepted, 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, Histamine acid, caffeine, procaine, hybamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, the
  • isomers refers to any stereoisomers, enantiomeric mixtures, including racemates, diastereomeric mixtures, geometric isomers, atropic isomers, which may exist in the structure of a compound isomers and/or tautomers.
  • Methods for determination and separation of the stereochemistry of the isomers are well known to those skilled in the art (SP 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, so the present invention covers all possible isomeric forms of the compounds defined herein, and pharmaceutically acceptable salts or solvates thereof , unless otherwise indicated.
  • the structure fragments used in this article The bond indicated to cross it is the bond by which the structural fragment connects to the rest of the molecule.
  • the compounds of the invention include unlabeled forms of the compounds of the invention as well as 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 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 are useful, for example, as probes in biological assays, analytical tools or as therapeutic agents.
  • compounds of the invention are provided in unlabeled form.
  • solvate refers to a solvent addition form of a compound containing stoichiometric or non-stoichiometric solvent, including any solvated form of the compounds of the invention, including for example solvates with water, such as hydrated , or a solvate with an organic solvent, such as methanol, ethanol, or acetonitrile, ie as methanolate, ethanolate, or acetonitrile, respectively; or in any polymorphic form. It should be understood that such solvates of the compounds of the invention also include solvates of the pharmaceutically acceptable salts of the compounds of the invention.
  • metabolite as used herein means a product produced by the metabolism of a compound in vivo. 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.
  • the term "pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances, 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 carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), Calcium Sulfate, Vegetable Oil, Polyols (such as Propylene Glycol, Glycerin, Mannitol, Sorbitol, etc.), Milk Chemical agents (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, cellulose acetate, etc.
  • gelatin talc
  • solid lubricants such as magnesium stearate
  • Calcium Sulfate such as magnesium
  • halogen or "halo” as used herein means F, Cl, Br or I.
  • halogen-substituted as used herein when defining a radical is intended to include monohalogenated or polyhalogenated radicals in which one or more identical or different halogens replace one or more of the corresponding radicals. hydrogen.
  • alkyl as used herein means a linear or branched monovalent saturated hydrocarbon group composed of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, eg 1-8, 1-6, 1-5, 1-4, 1-3 or 1-2 carbon atoms.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl (including normal propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2 - Methylpentyl etc.
  • C 1-6 alkyl optionally substituted by halogen refers to the above-mentioned C 1-6 alkyl, wherein one or more (eg 1, 2, 3, 4 or 5 ) hydrogen atoms are optionally replaced by halogen.
  • 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 and the like.
  • alkenyl refers to a straight or branched chain unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one double bond.
  • alkenyl groups have 2-8, eg 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms.
  • C 2-6 alkenyl refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, Pentenyl, etc., the carbon atom connected to the rest of the molecule in the alkenyl group can be either saturated or ethylenically bonded.
  • alkynyl refers to a straight or branched chain unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one triple bond.
  • alkynyl groups have 2-8, eg 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms.
  • C2-6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms , such as ethynyl, propynyl, propargyl, butynyl etc., the carbon atom in the alkynyl group that is 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 spiro non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring carbon atoms.
  • the cycloalkyl group may have 3 to 12 carbon atoms (ie, C 3-12 cycloalkyl group), 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 (e.g., 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 as used herein means a monocyclic, fused Polycyclic, spiro or bridged polycyclic non-aromatic saturated ring structures, or N-oxide, or its S-oxide or S-dioxide.
  • a heterocycloalkyl group may have 3 to 12 ring members (may be referred to as a 3-12 membered heterocycloalkyl group), 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 6 ring members.
  • Heterocycloalkyl groups generally contain up to 4 (eg 1, 2, 3 or 4) heteroatoms, for example 4-7 membered heterocycloalkanes containing 1 to 3 heteroatoms selected from N, O, S base.
  • suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, and 3 -pyrrolidinyl), tetrahydrofuryl (such as 1-tetrahydrofuryl, 2-tetrahydrofuryl and 3-tetrahydrofuryl), tetrahydrothiophenyl (such as 1-tetrahydrothiophenyl, 2-tetrahydrofuryl and 3-tetrahydrofuryl Thienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-pipe
  • Cycloheptyl is for example 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 that is bonded to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.
  • heterocycloalkyl groups such as It should be understood that structures with asymmetric centers encompass their racemic and/or single enantiomeric forms, e.g. Representable
  • heteroaryl as used herein means a monocyclic or fused ring comprising one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and the specified number of ring atoms Polycyclic aromatic ring structures, or N-oxides thereof, or S-oxides or S-dioxides thereof. Specifically, the aromatic ring structure may have 5 to 10 ring members.
  • Heteroaryl can be, for example, a 5-6 membered monocyclic ring, or consist of fused two 6-membered rings, fused two 5-membered rings, fused 6-membered and 5-membered rings, or fused 5-membered A fused bicyclic structure formed by a ring and a 4-membered ring.
  • the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom.
  • the heteroaryl group can be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O or S.
  • suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl;
  • suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazine base.
  • heteroaryl can also be a fused ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, such as benzofuran, benzothiophene, indole, benzimidazole, Indazole, Benzotriazole, Pyrrolo[2,3-b]pyridine, Pyrrolo[2,3-c]pyridine, Pyrrolo[3,2-c]pyridine, Pyrrolo[3,2-b] Pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazole A[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, Purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyrida
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents that are the same or different.
  • an optionally substituted group has 3 substituents which are the same or different.
  • an optionally substituted group has 4 substituents which are the same or different.
  • an optionally substituted group has 5 same or different substituents.
  • Cn -n+m or Cn - Cm in the definition of the compounds 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 , including 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.
  • n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is from 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 including 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 and 6- 10-membered rings, etc.
  • the word “comprises” and variations of the word such as “comprises” and “comprising”, means “including but not limited to” and is not intended to exclude other additives such as , ingredient, integer, or step.
  • an element is described as comprising a plurality of ingredients, steps or conditions, it should be understood that the element may also be described as comprising any combination of the plurality of ingredients, steps or conditions, or as “comprising a plurality or combination of ingredients, steps or conditions” or “consists essentially of a plurality or combination of ingredients, steps or conditions”.
  • compositions comprising the same, pharmaceutical combinations, kits, and related uses and methods
  • the dosages referred to are based on the weight of the free form, excluding any salts, hydrates or Solvates, unless the specification states that the dosage is based on the weight of the salt, hydrate or solvate.
  • Ras inhibitors As described above, compounds capable of inhibiting Ras muteins, especially KRas muteins, more especially KRas-G12D muteins, can be used to treat or prevent diseases (such as cancer or tumors) mediated by said muteins. Therefore, in this field, various structural types of Ras inhibitors have been developed (Duan Ni et al., Pharmacology & Therapeutics, Volume 202, October 2019, p1-17; US2019/0144444A1, WO2019/110751A1, WO2017/172979A1, WO2021/041671A1 , WO2021/107160A1 and WO2021/081212A1).
  • KRas inhibitors still have problems to be solved, including, for example, many inhibitors have unsatisfactory antitumor activity, or have toxic side effects leading to poor drug resistance, or pharmacokinetic properties are not enough to allow Administration in a convenient way means poor "druggability", and so on.
  • inhibitors with good antitumor activity it is still expected to further improve its inhibitory activity on target proteins in vivo, further improve its drug resistance (less toxic side effects or better safety) ) and further improve its pharmacokinetic properties in order to provide more and better treatment options for the clinic.
  • the present inventors have developed a group of compounds with obvious inhibitory activity on Ras mutein, especially KRas mutein, more especially KRas-G12D mutein.
  • specific stereochemical substituent modification was carried out at the specific position of the pyrimidine ring of the KRas inhibitor structure to obtain
  • the inhibitory activity to the KRas-G12D mutant protein is further improved, and the compound obtained by such modification has good safety, has reduced drug interaction risk, and has good or even further improved pharmacokinetic properties, Allows for administration in a convenient manner.
  • the present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors, more specifically KRas-G12D inhibitor compounds; pharmaceutical compositions containing such compounds as active ingredients; as medicines, for the treatment or prevention of Ras, in particular KRas, more in particular KRas-G12D mediated or benefiting from said compounds of Ras, in particular KRas, more in particular KRas-G12D inhibited tumors or cancers; use of said compounds for the treatment or prevention of Ras, specifically KRas, more specifically KRas-G12D mediates or benefits from Ras, specifically KRas, more specifically KRas-G12D inhibited diseases such as tumors or cancer methods; and the compound is prepared for the treatment or Use in a medicament for the prevention of diseases such as tumors or cancers mediated by or benefiting from the inhibition of Ras, specifically KRas, more specifically KRas-G12D.
  • Ras inhibitors specifically KRas inhibitors, more specifically KRas-G12D inhibitor compounds
  • the present invention thus provides the following technical solutions.
  • compound of the invention and “compound of the invention” and the like used throughout this application, unless otherwise defined, include Compounds as defined in the various embodiments and preferred embodiments thereof herein or in each embodiment thereof, including isomers thereof, including atropisomers, enantiomeric mixtures, especially racemates, diastereoisomers Mixtures of isomers, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopic variations, and salts (eg, pharmaceutically acceptable salts).
  • the present invention also encompasses N-oxides of the compounds of the present invention as long as these compounds contain a basic nitrogen atom such as is present in nitrogen-containing heterocycles and are chemically and biologically feasible.
  • Certain compounds of the present invention may exist in polymorphic or amorphous forms, and thus they also fall within the scope of the present invention.
  • Embodiment 1 the compound of formula (A) or their pharmaceutically acceptable salt or solvate,
  • X is selected from N, CH, CF, C-Cl and C- CF3 ;
  • Y is selected from O, S and NR b ;
  • R is selected from halogen, C 1-6 alkyl or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by halogen;
  • R at each occurrence is independently selected from H and C 1-6 alkyl optionally substituted by halogen;
  • R 1 is selected from H, CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p -C 3-6 cycloalkyl and -(CH 2 ) p -4-7 membered heterocycloalkyl, wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and 4- Each 7-membered heterocycloalkyl group is independently optionally substituted by halogen, CN, -C 1-6 alkyl, -OR b or -N(R b ) 2 ; or
  • R 1 and R 3 connected to the adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group with the ring carbon atoms to which they are connected;
  • R 2 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally replaced by halogen, -C 1 -6 alkyl, -OR b or -N(R b ) 2 substituted; or when n is 2, two R 2 together with the carbon atoms they are connected to form a C 3-6 cycloalkyl;
  • R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O-(CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4- 7-membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered heteroaryl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -( CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 and -OC(O)-N(R b ) 2 , Wherein -C 1-6
  • R3s connected to adjacent ring carbon atoms form a fused C3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected;
  • R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -C(O)-OR b and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl independently optionally halogen, -CN, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b
  • R and R are each independently selected from H or halogen
  • R 6 and R 8 are each independently selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl;
  • n and p are each independently selected from an integer of 0-3;
  • n is an integer selected from 0-2.
  • Embodiment 1-1 The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from N, CH, C-F and C-Cl.
  • Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O- (CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4-7 membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered heteroaryl, - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered hetero Cycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 and
  • R 3 connected to adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected.
  • R3s attached to the same carbon atom form a spiro C 3-6 cycloalkyl or a spiro 4-7 membered heterocycloalkyl; or
  • R 3 connected to adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected.
  • X is selected from N, CH, C-F and C-Cl;
  • Y is selected from O, S and NR b ;
  • R a is selected from F and Cl;
  • R at each occurrence is independently selected from H and C 1-6 alkyl optionally substituted by halogen;
  • R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, - OR b or -N(R b ) 2 substitution;
  • R 2 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -N(R b ) 2 substitution;
  • R 3 is selected from H, halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O) -N(R b ) 2 and -C 1- 6 alkyl, wherein -C 1-6 alkyl is optionally replaced by halogen, -CN, -OR b , -N(R b ) 2 , -C(O) -OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitutions;
  • R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C(O)-OR b and -C (O)-N(R b ) 2 , wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally By halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 replaces;
  • R and R are each independently selected from H or halogen
  • R is selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl;
  • R 8 is selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl.
  • R a is C 1-6 alkyl or -OC 1-6 alkyl, optionally substituted by halogen,
  • R a is C 1-6 alkyl or -OC 1-6 alkyl, optionally substituted by halogen,
  • R a is C 1-6 alkyl or -OC 1-6 alkyl, optionally substituted by halogen,
  • halogen for example 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 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
  • R 1 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not Limited to vinyl and ethynyl.
  • R 1 is selected from -C 1- 6 alkyl, -(CH 2 ) p -C 3-6 ring Alkyl and -(CH 2 ) p -4-7 membered heterocycloalkyl, in which -C 1-6 alkyl, -C 3-6 cycloalkyl and 4-7 membered
  • Each heterocycloalkyl is independently optionally substituted by halogen, CN, -C 1-6 alkyl, -OR b or -N(R b ) 2 .
  • R 1 is -C 1-6 alkyl, optionally substituted by halogen or -OR b , 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 -OH, -CH 2 -CN, -CH 2 CH 2 -OH, -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, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH
  • R 1 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but not limited to ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • R is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl, 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 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • R 2 is -C 1-6 alkyl, optionally substituted by halogen or -OR b , 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 -OH, -CH 2 CH 2 -OH, -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, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2
  • R 2 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but Not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • R 3 is -OH or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally Substituted by -OH, halogen or -OC 1-6 alkyl, such as but not limited to -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 , -O-CH 2 F, -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F, -O -CH2CHF2 , -O - CH2CF3 , -O - CH2CH2CF3 .
  • R 3 is selected from -O-(CH 2 ) p -C 3-6 cycloalkyl, - O-(CH 2 ) p -4-7 membered heterocycloalkyl and -O-(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to -O -oxa or azetidine, -O-CH 2 -oxa or azetidine, -O-oxa or azetidine, -O-CH 2 -oxa or azetidine Alkane, wherein -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl , -OR
  • R 3 is selected from -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl and -(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, Cyclopentyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, oxa or azetidinyl, oxa or azetidinyl, oxazacycline Pentyl, -CH 2 -oxa or azetidine, -CH 2 -oxa or azetidine, in which -C 3-6 cycloalkyl
  • R 3 is -N(R b ) 2 , such as but not limited to -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NH-CH 2 F, -NH-CHF 2 , -N(CH 3 )-CF 3 , -NH- CH2CH2F , -NH - CH2CHF2 , -NH- CH2CF3 , -NH- CH2CH2CF3 .
  • R 3 is -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 , such as but not limited to -C(O)-OH, -C(O)-NH 2 or -OC(O)-NH 2 , -C(O)- OCH 3 , -C(O)-N(CH 3 ) 2 , -OC(O)-N(CH 3 ) 2 .
  • R 3 is -C 1-6 alkyl, optionally replaced by halogen, -CN, -OR b , - N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 , preferably optionally substituted by -OR b Or -OC(O)-N(R b ) 2 substitution, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH( CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CF 3 , -CH 2 CH 2 F, -
  • R3s attached to adjacent ring carbon atoms form a fused 4-7 membered heterocycloalkyl together with the ring carbon atoms to which they are attached, such as but not limited to fused azepine or oxetane, Aza or oxolane.
  • R 3 is -C 1-6 alkyl, substituted by -OC(O)-N(R b ) 2 , such as but not Limited to -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC (O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC (O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , - CH2 -OC(O)-N( CH2CH3 ) ( CH3 ), -CH2CH2 - OC(O)-N( CH2CH3 ) ( CH3 ).
  • R is selected from H, halogen, -OR b or -OC(O)-N(R b ) 2- substituted -C 1-6 alkyl, such as but not limited to H, F, -OH, -O-CH 3 , -O- CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 )(CH 3 ), -O-CH 2 F, -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 , -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 - OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 3 )
  • R 4 is -C(O)-OR b and -C(O)-N(R b ) 2 , such as but not limited to -C(O)-OCH 3 , -C(O)-OCH 2 CH 3 , -C(O)-NH 2 , -C(O)-NH-CH 3 , -C(O)-N(CH 3 ) 2 , -C(O)-N(CH 2 CH 3 ) 2 , -C(O)-N(CH 2 CH 3 )(CH 3 ).
  • R 4 is selected from -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl and -(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, oxa or azetidinyl, oxa or azetidinyl, oxazacyclopentyl , oxa or azepine, -CH 2 -oxa or azetidine, -CH 2 -oxa or azetidine, pyrazolyl
  • R 4 is -C 3-6 cycloalkyl, optionally replaced by halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitutions, such as but not limited to Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl each independently substituted by a substituent selected from the group consisting of F, Cl, Br, I , -CN, -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -NH 2 , -
  • R 4 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but not limited to ring Propyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclobutyl or cyclopentyl substituted by F, cyclopropyl, cyclobutyl or cyclopentyl substituted by -O- CH3 .
  • R 4 is selected from -C 1- 6 alkyl, -C 2-6 alkenyl, -C 2- 6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, -C 2-6 alkenyl, -C 2- 6 alkyne and -C 3-6 cycloalkyl are each independently optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 F,
  • Y is O
  • R is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, as exemplified in embodiments 11 and 15;
  • R2 is H
  • R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , as exemplified in embodiment 36.
  • Y is O
  • R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, as exemplified in embodiment 15;
  • R2 is H
  • R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , as exemplified in embodiment 36.
  • the compound of the present invention covers each of the above independent embodiments or each specific embodiment, and also covers any combination or sub-combination of the above-mentioned embodiments or specific embodiments, and also covers any of the above preferred or exemplary embodiments. Any combination of the given embodiments constitutes an embodiment.
  • Ras muteins are known to play a role in tumorigenesis as well as a variety of other diseases.
  • the compounds of the present invention having the above-mentioned structural features can potently inhibit cell proliferation in cell lines carrying KRas mutant proteins, especially KRas-G12D mutant proteins, thereby being useful in preventing, suppressing and/or treating It has potential value as anti-proliferation, pro-apoptosis and/or anti-invasion drugs in related tumor diseases.
  • the compounds of the invention are expected to be useful in the prophylaxis or treatment of those diseases or conditions which are mediated by or benefit from inhibition of a Ras mutein, especially a KRas-G12D mutein, such as defined herein cancer or tumor.
  • High mutein inhibitory activity the compounds of the present invention, especially the compounds specifically exemplified in the context herein, show proliferation inhibitory activity on Ras mutant cells, especially KRas G12D mutant cells, in the KRAS G12D mutant cell AGS cell proliferation inhibition assay,
  • the IC50 value is lower than 10 ⁇ M, such as lower than 5 ⁇ M, such as 0.001-5 ⁇ M, 0.01-5 ⁇ M; preferably lower than 1 ⁇ M, such as 0.001-1 ⁇ M, 0.01-1 ⁇ M; more preferably lower than 0.5 ⁇ M, such as 0.001-0.5 ⁇ M, 0.01-0.5 ⁇ M, 0.01 ⁇ 0.2 ⁇ M, 0.01 ⁇ 0.1 ⁇ M, 0.01 ⁇ 0.05 ⁇ M, for example, determined according to the method described in Activity Example 1; and
  • AGS (3D) cell proliferation inhibition assay of KRAS G12D mutation shows proliferation inhibitory activity against Ras mutation, especially KRas G12D mutant cells, with an IC50 value of 0.001-5 ⁇ M, such as 0.01-5 ⁇ M, such as 0.001-0.5 ⁇ M, preferably 0.01-0.2 ⁇ M, more preferably 0.01-0.1 ⁇ M, most preferably 0.01-0.05 ⁇ M, as exemplified in Activity Example 4;
  • the present invention also provides the following technical solutions in various aspects.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a KRas mutein inhibitor, more specifically a KRAS G12D inhibitor.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, for treating and/or preventing Ras mutein, specifically KRas mutein, more specifically KRAS G12D mutein-mediated Or a disease or condition benefiting from inhibition of a Ras mutation, specifically a KRas mutein, more specifically a KRAS G12D mutein.
  • the present invention provides a method for treating and/or preventing Ras mutant protein, specifically KRas mutant protein, more specifically KRAS G12D mutant protein, which promotes the occurrence and development of the disease or inhibits Ras mutation Proteins, specifically KRas mutant proteins, more specifically KRAS G12D mutant proteins will reduce the incidence of disease, reduce or eliminate the compounds of the present invention for diseases such as tumors or cancers, including but not limited to: lung cancer, pulmonary Adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma,
  • diseases such as tumor
  • the present invention provides for the treatment of patients with pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, Compounds of formula (I) or their isomers, pharmaceutically acceptable salts or solvates thereof for patients with lung adenocarcinoma and cholangiocarcinoma.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (A) as defined above or 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 or KRas G13D mutations, especially KRas G12D mutations, such as tumors or cancers .
  • compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th edition.
  • it can be formulated as tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like.
  • the composition may contain conventional components in pharmaceutical formulations, such as diluents (such as glucose, lactose or mannitol), carriers, pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, Wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, coloring agents, perfuming agents, flavoring agents, other known additives and other active agents.
  • diluents such as glucose, lactose or mannitol
  • carriers pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, Wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, coloring agents, perfuming agents, flavoring agents, other known additives and other active agents.
  • diluents such as glucose, lactose or
  • the dosing 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 particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors well known to medical practitioners.
  • Optimal dosage levels and frequency of administration of a compound or pharmaceutical composition of this invention can be determined by those skilled in the art by standard experiments in the field of pharmaceutical research.
  • compositions of the present invention may be administered by any suitable means, 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 can also be taken.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
  • the pharmaceutical compositions of the invention are administered orally.
  • suitable dosage ranges of the compounds of the present invention can be routinely determined by those skilled in the art, and may be, for example, 1-1000 mg/day.
  • the compounds of the invention and the compounds of various specific embodiments thereof, 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 Or the inhibitory effect of KRas G13D mutation, especially KRas G12D.
  • KRas mutations such as KRas G12C, KRas G12D, KRas G12V
  • the inhibitory effect of KRas G13D mutation especially KRas G12D.
  • the present invention provides a method for inhibiting Ras mutations in cells, especially KRas mutations, preferably KRas G12D mutations, comprising allowing the cells to react with a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof contact to inhibit the activity of Ras mutations, especially KRas mutations, preferably KRas G12D mutations, in cells.
  • 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 the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof , or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method for treating and/or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations, comprising administering a therapeutically effective amount of the present invention's formula ( A) a compound or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of formula (A) of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof,
  • KRas mutation preferably KRas G12D mutation
  • KRas G12V preferably KRas G12D mutation mediated disease.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the preparation of Use in medicines for treating and/or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations.
  • the abnormal cell growth may be mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, most preferably KRas G12D mutation Disease especially refers to cancer or tumors.
  • KRas mutation especially KRas G12C, KRas G12D, KRas G12V or KRas G13D, most preferably KRas G12D mutation Disease especially refers 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, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer , gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal gland 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 tumor (CNS), original Primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma.
  • the abnormal cell growth or the disease mediated by Ras mutation is preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, Cancer, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, bile duct cancer.
  • the present invention provides the above-mentioned methods and application technical solutions for treating or preventing cancer or tumors by inhibiting KRas-G12D mutation.
  • the present invention provides the above-mentioned methods and application technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and cholangiocarcinoma by inhibiting KRas-G12D mutation.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D. Therefore, the present invention relates to the in vitro use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor, especially a KRas G12D inhibitor, in particular to the compound of the present invention or a pharmaceutically acceptable salt or In vitro use of the solvate as a research tool compound for KRas inhibitors, especially KRas G12D inhibitors.
  • the present invention also relates to a method, especially an in vitro method, of inhibiting KRas, especially KRas G12D, which method comprises administering a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof to a sample (eg, a biological sample).
  • a sample eg, a biological sample.
  • in vitro is used in this particular context in the sense of "in vitro of a living human or animal", which specifically includes experiments with cells, cellular or subcellular extracts and/or biomolecules in artificial environments, For example, aqueous solutions or media may be provided in flasks, test tubes, petri dishes, microtiter plates, and the like.
  • the compounds of the invention may be administered as the sole active ingredient or in combination with another drug or therapy.
  • the present invention provides a pharmaceutical combination comprising or consisting of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and a further active agent.
  • the drug combination is used to inhibit abnormal cell growth in mammals Long, or for the treatment and/or prevention of diseases mediated by Ras mutations, preferably KRas mutations, most preferably KRas-G12D mutations.
  • 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 which is compatible with the compounds of the invention, i.e. does not adversely affect each other, or has complementary activities. ) compounds, for example, these active agents may be compounds known to modulate other biologically active pathways, or may 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 that may be used in combination with the compounds of the invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiation therapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, Topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents.
  • the other active agents used in combination with the present invention may be administered simultaneously, separately or sequentially with the compound of the present 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 administered separately in different discrete units with the compound of the present invention, such as a combination product, preferably in the form of a kit, which may be administered simultaneously or simultaneously when administered separately.
  • the sequential 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 invention and other active agents may be obtained (i) (i) before sending the combination product to a physician (for example, in the case of a kit comprising the compound of the invention and the additional drug); (ii) immediately before administration. Added by the physician himself (or under the direction of the physician); (iii) by the patient himself, for example during the sequential administration of the compound of the invention and the other active agent together in the combination therapy.
  • the compounds of the present invention may also be combined with antineoplastic therapies including, but not limited to, surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • antineoplastic therapies including, but not limited to, surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and
  • the means for separately containing the compositions such as containers, dispenser bottles or discrete foil packs, eg blister packs for packaging tablets, capsules and the like, also includes instructions for use.
  • the kits of the invention are 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 mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, most Preferably the KRas G12D mutation mediated disease is as defined above for the methods and uses of the invention.
  • the present invention also provides a process for the preparation of the compounds defined in the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can be prepared by various 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 as being suitable for the particular type of reaction involved, such as 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.
  • Starting materials and intermediates in the synthetic reaction schemes can be isolated and purified, if necessary, by conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. If 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 admixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography.
  • the mixture of isomers formed can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as 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).
  • 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, Using well-known methods, such as formation of diastereomeric pairs, by salification with an optically active acid, 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 of protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd Edition), John Wiley & Sons, NY (1999).
  • X and Y are as defined above for the compounds of the invention, wherein PG represents a suitable protecting group which can be determined by a person skilled in the art based on knowledge of organic chemistry.
  • 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 was introduced into Boc-protected 3,8-diazacyclo[3.2.1]octane 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 and the like.
  • step B compound 2 is reacted with corresponding alcohols, amines or thiols in, for example, DIEA/dioxane, NaH/THF, etc., to obtain compound 3.
  • the corresponding alcohols, amines or thiols are commercially available, or can be obtained according to the methods used in the examples herein or methods similar thereto, or can be obtained according to the methods in related literatures in the field of organic chemistry.
  • the latter introduces phenolic compounds via Suzuki-Miyaura coupling reaction in Step C to give compounds 4 or 5.
  • step D the protective group of compound 4 or 5 is removed to obtain the compound of general formula I or II.
  • Typical Suzuki palladium coupling conditions are well known in the art and those skilled in the art know of a variety of conditions to facilitate such cross-coupling reactions , for example Pd(dtbpf) Cl2 / K3PO4 /dioxane /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 , tetraphenylphosphinepalladium, and palladium(II) acetate, etc.
  • suitable ligands may include Tricyclohexylphosphine, triphenylphosphine, etc.
  • suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide,
  • 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.
  • the compound carrying a protecting group PG is an acid-sensitive protecting group such as MOM
  • the final compound can be obtained by removing PG and Boc in one step at the same time under conditions such as trifluoroacetic acid or hydrochloric acid;
  • compound 4 or 5 needs to be deprotected through a multi-step reaction, such as removing TIPS protection by a reagent such as CsF, and then removing Boc by trifluoroacetic acid or hydrochloric acid to obtain the final compound.
  • step A compound 2 is commercially available or can be obtained according to standard methods well known in the field of organic chemistry, or the method steps described in Synthetic Scheme A.
  • Compound 2 is fluorinated by halogen exchange reaction under conditions such as KF/DMSO to obtain compound 6.
  • Compound 6 then undergoes the Suzuki-Miyaura coupling reaction in Step B, the aromatic nucleophilic substitution reaction in Step C, and the deprotecting group removal reaction in Step D to obtain the final compound I or II.
  • the typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and deprotection 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 C compound 7 is resolved by SFC to obtain axichiral pure intermediate compounds 9 and 10.
  • the final compound was prepared via steps D and E using intermediate 9 in the subsequent synthesis.
  • the nucleophilic substitution reaction and protecting group removal reaction involved in steps D and E are carried out by referring to the method described in Synthesis Scheme A.
  • ACN acetonitrile
  • Boc tert-butoxycarbonyl
  • CDCl 3 deuterochloroform
  • DCM diichloromethane
  • DIEA or DIPEA N,N-diisopropylethylamine
  • DMF N,N -dimethylformamide
  • DMSO dimethylsulfoxide
  • DMSO- d6 hexadeuteriodimethylsulfoxide
  • EA ethyl acetate
  • EDTA-K2 dipotassium ethylenediaminetetraacetic acid
  • EtOH ethanol
  • FCC flash column chromatography
  • g gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl/MeOH (hydrogen chloride methanol solution); HLM (human liver microsome); H 2 O (water); H 2 SO 4 (sulfuric acid); IV (intravenous administration); K 2 CO 3 (potassium carbonate);
  • Step B 7-Bromo-2,4-dichloro-8-fluoroquinazoline
  • Step C (1R,5S)-3-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8- tert-butyl carboxylate
  • 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 D (1R,5S)-3-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane -8-tert-butyl carboxylate
  • Step A (1R,5S)-3-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-tert-butyl carboxylate
  • Step A (1R,5S)-3-(2,6,8-Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl Base) oxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step A 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-ol
  • Step B 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl triflate
  • trifluoromethanesulfonic anhydride (326g, 1.16mol) was added dropwise to 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((tri Isopropylsilyl)oxy)naphthalen-1-ol (397g, 0.77mol) and DIPEA (298g, 2.31mol) in DCM (4L). After the dropwise addition, keep the temperature and continue to stir for 0.5h, and TLC monitors the completion of the reaction. The system was added to water (800 mL), the layers were separated, and the aqueous phase was extracted with DCM (1.2 L).
  • Step C (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid
  • Step A 2-Fluoroethyl 4-toluenesulfonate
  • Step B 1-(tert-butyl)-2-methyl(R)-2-methylpyrrolidine-1,2-dicarboxylate
  • Step D (R)-1-(2-Fluoroethyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester
  • Step E (R)-(1-(2-Fluoroethyl)-2-methylpyrrolidin-2-yl)methanol
  • intermediate b is carried out with reference to the synthesis scheme of intermediate a, in step A, 2,2-difluoroethane-1-ol is used instead of 2- Fluoroethane-1-ol, use 2,2-difluoroethyl 4-methylbenzenesulfonate in Step D instead of 2-fluoroethyl 4-toluenesulfonate.
  • LC-MS (ESI, m/z): 180.1 (M+H).
  • Step B (R)-methyl 1-ethyl-2-methylpyrrolidine-2-carboxylate
  • step B The synthesis method of step B is carried out with reference to the step E of intermediate a, using (R)-1-ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester instead of (R)-1-(2-fluoroethyl base)-2-methylpyrrolidine-2-carboxylic acid methyl ester.
  • LCMS (ESI, m/z): 143.2 (M+H).
  • Step A (R)-1-Cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester
  • bromocyclobutane (1.13g, 8.3mmol) was added to (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), potassium carbonate (2.30 g, 16.7mmol), cuprous iodide (311mg, 1.1mmol), N 1 -benzyl-N 2 -(5-methyl-[1,1'-biphenyl]-2-yl) oxalamide (574mg , 1.7 mmol) and DMSO (20 mL), the temperature was raised to 100° C. and the reaction was stirred overnight after nitrogen replacement for one minute.
  • Step B (R)-(1-Cyclobutyl-2-methylpyrrolidin-2-yl)methanol
  • Step B (3S,7aS)-3-(tert-butyl)-7a-cyclopropyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one
  • Step D (S)-2-Cyclopropyl-1-methylpyrrolidine-2-carboxylic acid
  • Step B ((2R)-1-(1-methoxypropan-2-yl)-2-methylpyrrolidin-2-yl)methanol
  • intermediate h1 The synthesis of intermediate h1 is carried out with reference to the synthesis method of intermediate h, and in step A, oxetanone is used instead of 1-methoxypropan-2-one.
  • Step A 2-Methyl-3-oxopyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
  • Step B (R)-2-Methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step B (2R,3R)-3-Methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (k1-2a) and (2R ,3S)-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester (k1-2b)
  • Step C ((2S,3R)-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (k1a) and ((2S,3S)-3-methoxy-1, 2-Dimethylpyrrolidin-2-yl)methanol (k1b)
  • k1-2b (285mg, 0.99mmol) was prepared from (2R,3S)-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2- Ethyl ester (k1-2b) After the above steps, the crude product k1b (130 mg, yield 88%) was obtained as a colorless transparent oil.
  • Step A (R)-2-Methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step B (2R,3S)-2,3-Dimethylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
  • Step B Ethyl (2R,3S)-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylate
  • Step C ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol
  • Step B ((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol
  • Step A (S)-3-Fluoro-2-methyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step B (2S)-3-Fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step C (2S,3R)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylate and 1-(tert-butyl)2-ethyl(2S,3S)-3-fluoro- 2-Methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester
  • Step D ((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (k3b)
  • Step A (2R,3R)-3-(Hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • reaction solution was poured into ice water (100 mL) to quench, and extracted with ethyl acetate (80 mL ⁇ 3).
  • Step B (2R,3R)-3-Formyl-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
  • Step C (2R)-3-Cyano-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step E Ethyl (2R,3S)-3-cyano-1,2-dimethylpyrrolidine-2-carboxylate and (2R,3S)-3-cyano-1,2-dimethylpyrrole Ethyl alkane-2-carboxylate
  • Step F (2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile and (2R,3R)-2-(hydroxymethyl)-1,2-bis Methylpyrrolidine-3-carbonitrile
  • Step A (2R,3R)-3-(Difluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
  • Step B ((2R,3R)-3-(Difluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
  • Step A (2R,3R)-3-(Fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
  • Step B ((2R,3R)-3-(Fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
  • LiAlH 4 -THF (1M, 1.24mmol, 1.24mL) was added dropwise into (2R,3R)-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-( tert-butyl) ester 2-ethyl ester (90mg, 0.31mmol) in THF (3mL) solution, the resulting system was heated to 70°C and stirred for 3h. 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.
  • Step A (R)-3-(fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step B (2R,3S)-3-(Fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
  • Step D Ethyl (2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylate
  • Step E ((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
  • Step A (1R,5S)-3-(7-Bromo-8-fluoro-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy Base) quinazoline-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step B (1R,5S)-3-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene- 1-yl)-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8- tert-butyl diazacyclo[3.2.1]octane-8-carboxylate
  • Step C 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-( 2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -2-ol
  • Step D 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-( 2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 2 The synthesis of Example 2 was carried out with reference to the synthesis scheme of Example 1, using (R)-(1-(2,2-difluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate Enzyme b) instead of (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a).
  • Example 3 The synthesis of Example 3 was carried out with reference to the synthesis scheme of Example 1.
  • step A (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (intermediate c) was used instead of (R)-(1 -(2-Fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a).
  • Step B 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl Silyl)oxy)naphthalen-1-yl)quinazoline
  • Step C 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Example 37 The synthesis of Example 37 was carried out with reference to the synthesis method of Example 36.
  • Step A (R)-(1-ethyl-2-methylpyrrolidin-2-yl)methanol was used instead of (R)-(1-cyclopropane yl-2-methylpyrrolidin-2-yl)methanol.
  • Example 61 was synthesized with reference to the synthesis scheme of Example 1, using (1R,5S)-3-(7-bromo-2-chloro-8-fluoropyridino[4,3-d]pyrimidine-4- Base)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-butyl ester (intermediate CI) instead of (1R,5S)-3-(7-bromo-2-chloro-8 -Fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate AI), and using (R)-(1,2 -Dimethylpyrrolidin-2-yl)methanol (intermediate c) instead of (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a) .
  • Step A (R)-methyl 1-(2-hydroxy-2-methylpropyl)-2-methylpyrrolidine-2-carboxylate
  • Step B (R)-1-(2-(Hydroxymethyl)-2-methylpyrrolidin-1-yl)-2-methylpropan-2-ol
  • Example 154-1 The synthesis of Example 154-1 was carried out with reference to the synthesis method of Example 36.
  • step A intermediate B-III-2 was used instead of intermediate B-III ((1R,5S)-3-(2,6,8-three Fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1-yl)quinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl); and intermediate k1b (((2S,3S)-3-methoxy-1,2- Dimethylpyrrolidin-2-yl)methanol) instead of intermediate d4 ((R)-(1-allyl-2-methylpyrrolidin-2-yl)methanol).
  • Step A (Ra)-(1R,5S)-3-(6,8-Difluoro-2-(((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl )Methoxy)-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazolin-4-yl)-3,8 - tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate
  • reaction solution was poured into saturated NH 4 Cl aqueous solution (20 mL), extracted with EA (30 mL ⁇ 3), and the combined organic phases were washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step B (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(( (2S,3S)-3-fluoro-1,2-dimethyl Pyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol
  • Step C (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(( (2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Step A (1R,5S)-3-(6,8-Difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl )-2-(((2R,3S)- 1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- tert-butyl carboxylate
  • Step B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl) Ethynyl)naphth-2-ol
  • Step C 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2R,3S)-1 -Ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ⁇ dicarboxylate
  • Example 166 was synthesized with reference to Example 165, using ((2R,3R)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol in step A (intermediate k6a ) instead of ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • Example 167 was synthesized with reference to Example 165, using ((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol in step A (intermediate k6b ) instead of ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • Example 168 The synthesis of Example 168 was carried out with reference to Example 165, using ((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2c) in step A instead of ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • LCMS (m/z): 314.7 (M/2+H).
  • Example 169 The synthesis of Example 169 was carried out with reference to Example 165, using ((2R,3S)-1-cyclopropyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2d) in step A instead of ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • LCMS (m/z): 628.3 (M+H).
  • Example 170 The synthesis of Example 170 was carried out with reference to Example 165, using ((2R,3S)-1,2,3-trimethylpyrrolidin-2-yl)methanol (intermediate k2a) in step A instead of ((2R, 3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • LCMS (m/z): 602.3 (M+H).
  • Example 171 The synthesis of Example 171 was carried out with reference to Example 165, using (2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4a) in step A instead of ( (2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • LCMS (m/z): 613.3 (M+H).
  • Example 172 was carried out with reference to Example 165, using (2R,3R)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4b) in step A instead of ( (2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b).
  • LCMS m/z: 613.3 (M+H).
  • the present invention synthesizes following compound:
  • Embodiment 1 the compound of the present invention is to the proliferation inhibitory effect of the AGS cell of KRAS G12D mutation
  • This experiment evaluates and verifies the proliferation inhibitory activity of representative compounds of the present invention on KRAS G12D mutant AGS cells.
  • fetal bovine serum FBS (GIBCO, Cat#10099-141); CellTiter- Luminescent Cell Viability Assay (Promega, Cat#G7572); 96-well clear flat-bottom black wall plate ( Cat#3603); Envision multifunctional microplate reader, PE, 2104; CO 2 incubator, Thermo Scientific, Model 3100 Series; biological safety cabinet, Sujing Antai, Model 1300 Series A2; inverted microscope, Chongqing Optoelectronics, XDS- 1B.
  • AGS cell line was purchased from ATCC, catalog number is CRL-1739.
  • Cells in logarithmic growth phase were harvested and counted using a platelet counter. The cell viability was detected by the trypan blue exclusion method to ensure that the cell viability was 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% CO 2 .
  • Drug dilution and dosing were carried out as follows: single-point inhibition rate determination drug preparation: prepare 10-fold drug solution, add 10 ⁇ L of 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. multiple holes.
  • Drug preparation for IC50 determination prepare a 10-fold drug solution, add 10 ⁇ L of drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 ⁇ M, 3.16 ⁇ dilution, 9 concentrations, and set three replicates for each drug concentration. hole.
  • the cells in the 96-well plate that had been dosed were placed at 37° C. and 5% CO 2 to continue culturing for 3 days, and then CTG detection was performed.
  • GraphPad Prism 8.0 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated accordingly.
  • Cell survival rate (%) (Lum test drug -Lum culture solution control )/(Lum cell control -Lum culture solution control ) ⁇ 100%.
  • Representative compounds of the present invention exhibit satisfactory anti-proliferation activity on AGS human gastric adenocarcinoma cells with KRAS G12D mutation, and some activity data are shown in the table below.
  • Embodiment 2 the rat box type administration (Cassette) pharmacokinetic characteristic of compound of the present invention
  • the compound combination is formulated into the solvent of 5%DMSO/10%Solutol/85% (20%Captisol), and finally each compound
  • concentration of the drug was 1mg/mL
  • the drug preparation was injected into the tail vein of SD rats according to the injection volume of 1mL/kg, and blood was collected from the external jugular vein at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h respectively. After centrifugation for 20 minutes, the plasma was collected and stored at -20°C until testing.
  • Standard curve preparation draw 20 ⁇ L of 1mg/mL DMSO stock solution for each compound, transfer to 900 ⁇ L of 50% methanol working solution, and serially dilute to obtain a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, then draw 5 ⁇ L standard curve working solution and mix with 45 ⁇ L rat blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL Curve for quantification of unknown samples.
  • Sample pretreatment 50 ⁇ L unknown plasma sample and standard curve sample, add 250 ⁇ L acetonitrile containing tolbutamide as internal standard as precipitant, precipitate plasma protein, extract the compound to be tested in plasma, centrifuge at low temperature for 20 minutes, take supernatant, The supernatant was mixed with an aqueous solution of 0.1% formic acid, 5 ⁇ L was drawn and injected, and the blood drug concentration of the drug was analyzed by LC-MS.
  • the standard curve was drawn with the mass spectrometry software Analyst 1.6.1, the unknown samples were quantified, and the pharmacokinetic parameters were calculated with Winnonlin 8.2 according to the drug concentration at each time point of the unknown samples.
  • Embodiment 3 the compounds of the present invention inhibit test of cytochrome P450
  • human liver microsomes (Corning Company, product number 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE Company, product number HY-F0003/CS-4998); phenacetin , diclofenac, ⁇ -naphthoflavone, omeprazole and ketoconazole were purchased from TCI Company; S-Mephenytoin and testosterone were purchased from CAYMAN Company; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from from Damas-beta; sulfabenzopyrazole was purchased from MCE; bufurolol was purchased from TRC.
  • K-buffer prepare 0.1M potassium phosphate buffer (K-buffer): prepare 100mM potassium phosphate buffer (K-buffer) with potassium dihydrogen phosphate and dipotassium hydrogen phosphate, and adjust the pH to 7.4.
  • test compound solution dissolve 8 ⁇ L of 10 mM test compound stock solution in 12 ⁇ L acetonitrile; prepare the mixed solution of CYP1A2, CYP2C9 and CYP2D6 inhibitors: mix 12 ⁇ L 1mM ⁇ -naphthoflavone, 10 ⁇ L 40mM sulfabenzopyrazole, 10 ⁇ L 10mM quinolone Mix nicotine and 8 ⁇ L DMSO solution; prepare CYP3A4 inhibitor solution: dissolve 8 ⁇ L 2.5 mM ketoconazole DMSO solution in 12 ⁇ L acetonitrile; prepare CYP2C19 inhibitor solution: dissolve 8 ⁇ L 100 mM omeprazole DMSO solution in 12 ⁇ l of acetonitrile.
  • HMM human liver microsome
  • 3A4 reacts for 5 minutes; 1A2, 2C9, 2D6 reacts for 10 minutes; 2C19 reacts for 45 minutes.
  • 120 ⁇ L of acetonitrile containing internal standard was added to terminate the reaction. Samples were vortexed for 10 minutes, centrifuged at 5594g for 15 minutes, and samples were prepared for LC-MS/MS analysis.
  • Embodiment 4 the compound of the present invention is to the proliferation inhibitory effect of the AGS (3D) cell of KRAS G12D mutation
  • culture medium RPMI1640 HyClone, Cat#SH30809.01
  • fetal bovine serum FBS GBICO, Cat#10099-141
  • Luminescent Cell Viability Assay Najing Novizyme, Cat#DD1101-04
  • 96-well polystyrene microplate black wall
  • SIGMA methylcellulose
  • AGS cells KC-0405, Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • multi-functional microplate reader BMG LABTECH, Plus
  • CO incubator Thermo Scientific, Model 3100 Series).
  • Cells in logarithmic growth phase were harvested and counted using a platelet counter. The cell viability was detected by the trypan blue exclusion method to ensure that the cell viability was above 90%. Adjust the cell concentration, add 180 ⁇ L of the cell suspension to the 96-well plate after there is no visible gas in the cell suspension, so that the final concentration of methylcellulose is 0.65%, and the number of cells is 2400/well. The cells in the 96-well plate were cultured overnight at 37° C., 5% CO 2 , and 95% humidity.
  • Drug dilution and dosing were carried out as follows: prepare a 10-fold drug solution with the culture medium, add 20 ⁇ L of the drug solution to each well of a 96-well plate seeded with cells, so that the working concentration is the highest 10 ⁇ M, 3.16 ⁇ dilution, a total of 9 concentrations, Three replicate wells were set up for each drug concentration, and the DMSO content was 0.1%. The cells in the 96-well plate that had been dosed were placed at 37°C, 5% CO 2 , and 95% humidity for 120 hours, and then CTG analysis was performed. .
  • GraphPad Prism 7.0 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated accordingly.
  • Cell survival rate (%) (Lum test drug -Lum culture solution control )/(Lum cell control -Lum culture solution control ) ⁇ 100%.
  • the compounds of the present invention exhibit satisfactory inhibitory activity on the proliferation of KRas G12D mutant cells on 3D cultured AGS cell lines, with IC50 values of 0.01-0.5 ⁇ M, such as 0.01-0.1 ⁇ M, 0.01-0.05 ⁇ M.
  • Embodiment 5 the mouse box type administration (Cassette) pharmacokinetic characteristic of compound of the present invention
  • the compound combination was formulated into a solvent of 5% DMSO+95% (0.5% MC), and the final concentration of each compound was 1 mg/mL, and the drug preparation was intragastrically administered to CD-1 mice at a volume of 10 mL/kg, Blood was collected from the saphenous vein of the hindlimb at 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h, and centrifuged at low temperature for 20 minutes to collect plasma, which was stored at -20°C for testing.
  • Preparation of standard curve draw 20 ⁇ L of 1mg/mL DMSO stock solution for each compound, transfer to 900 ⁇ L of 50% methanol working solution, and serially dilute to obtain a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, and then draw 2 ⁇ L standard curve working solution and mix with 18 ⁇ L mouse blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL Curve for quantification of unknown samples.
  • Sample pretreatment 20 ⁇ L unknown plasma sample and standard curve sample, add 250 ⁇ L acetonitrile containing tolbutamide as internal standard as precipitant, precipitate plasma protein, extract the compound to be tested in plasma, centrifuge at low temperature for 20 minutes, take supernatant, The supernatant was mixed with 0.1% formic acid aqueous solution 1:1, 10 ⁇ L was drawn and injected, and the blood drug concentration of the drug was analyzed by LC-MS.
  • the standard curve was drawn with the mass spectrometry software Analyst 1.6.1, the unknown samples were quantified, and the pharmacokinetic parameters were calculated with Winnonlin 8.2 according to the drug concentration at each time point of the unknown samples.

Abstract

The present invention provides compounds capable of being used as KRAS inhibitors and having a structure of formula (A), a pharmaceutical composition comprising such compounds, a method for preparing such compounds, and a use of the compounds in treatment of cancers.

Description

具有抗KRAS突变肿瘤活性的化合物Compounds with anti-KRAS mutant tumor activity 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 that can be used 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 homologue, 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, and differentiation. These regulatory functions of Ras are carried out by switching 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, in a dormant or off state, when 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 transformed into the active form of Ras, which recruits and activates various downstream effectors for signal transmission, and can transmit the signal on the cell surface to the cytoplasm, thereby 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 to 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 be activated for a long time, thereby continuously transmitting signals of growth and division to cells, stimulating cell proliferation, and eventually 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 encode highly homologous HRas, NRas and KRas proteins of about 21 KDa, respectively. In 1982, researchers first discovered the mutational activation of Ras 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%) highest mutation rate. Transgenic and genetically engineered mouse models have also revealed that mutated Ras proteins are sufficient to drive and initiate various types of cancer, and that Ras oncogenes are also critical for the maintenance and progression of tumors in various cancer types, such as mutations in Ras In cancer cell lines and animal models of cancer, RNA intervention has been shown to slow tumor growth. These studies have made the Ras tumor protein a well-accepted and very attractive anticancer drug target in the field of pharmacy.
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、G13D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。Studies have shown that Ras mutations are most commonly found in KRas, and KRas mutations can be observed in about 85% of Ras mutation-driven cancers; most Ras mutations occur at codons G12, G13, and Q61, and about 80% of KRas mutations are hair Born at the glycine of codon 12, such as G12C mutation, G12D mutation, G12V mutation, G13D mutation, etc. KRas mutations are common in pancreatic, lung adenocarcinoma, colorectal, gallbladder, thyroid, and cholangiocarcinomas, and can also be 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 in the research of Ras drug targets, and the development of its inhibitors is also regarded as a very promising research and development direction in the development of anticancer/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, the research and development of drugs targeting Ras in the past decades has shown that due to the smooth surface of Ras protein, it lacks obvious groove-like or pocket structures for binding small molecule inhibitors, and its affinity for guanine substrates is very high (skin Mole level), making the development of its small molecule inhibitors into an insoluble dilemma, so 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 having KRas mutein inhibitory activity. These compounds of the present invention have improved structural patterns, compared with existing KRas mutant protein inhibitors in the prior art, have enhanced KRas mutant protein inhibitory activity and related tumor suppression activity, and have good pharmacokinetic properties. Therefore, it has good druggability, such as being able to be easily absorbed in the body after administration in a convenient manner, and has reduced toxic and side effects, improved drug resistance and safety, and reduced drug interaction risks.
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(A)的化合物或其药学上可接受的盐或溶剂合物。The present invention provides a compound of formula (A) as defined herein below, or a pharmaceutically acceptable salt or solvate thereof.
本发明还提供了包含本发明化合物或其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 present invention also provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient or carrier.
本发明还提供了用作药物的本发明化合物或其药学上可接受的盐或溶剂合物。The present invention also provides the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use as a medicine.
本发明还提供了本发明化合物或其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、优选KRas G12D的抑制剂。The present invention also provides the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, which is used as an inhibitor of Ras mutein, especially KRas mutein, preferably KRas G12D.
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、优选KRas G12D突变蛋白介导的疾病的本发明化合物或其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 the compound of the present invention or its pharmaceutically acceptable salt or solvate or comprising its pharmaceutical composition.
本发明还提供了本发明化合物或其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、优选KRas G12D突变蛋白介导的疾病的用途。The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising it for the treatment and/or prevention of Ras mutein, especially KRas mutein, preferably KRas G12D mutein mediated disease use.
本发明还提供了本发明化合物或其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、优选KRas G12D突变蛋白介导的疾病的药物中的用途。 The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition containing it for the treatment and/or prevention of Ras mutein, especially KRas mutein, preferably KRas G12D Use in medicine for mutant protein-mediated diseases.
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、优选KRas G12D突变蛋白介导的疾病的方法，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 and/or preventing a disease mediated by a Ras mutein, especially a KRas mutein, preferably a KRas G12D mutein, comprising administering a therapeutically effective amount of a compound of the present invention or its pharmaceutical preparation to a subject in need thereof. An acceptable salt or solvate or a pharmaceutical composition comprising it.
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 tumor or cancer, which comprises administering the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising the same to a patient in need.
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 G12D的研究工具化合物的用途。The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D.
本发明还提供了药物组合，其包含本发明化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 and one or more other pharmaceutically active agents.
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. In the case that a specific term or phrase is not specifically defined, it should be understood according to the ordinary meaning in the art. In case of conflict, the present specification, including definitions, will control.
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 case of conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.
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 mutein" as 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 Ras codon, A Ras protein with a mutation to glycine at codon 13 or glutamine at codon 61, such as mutant HRas, NRas or KRas. Mutations of these residues in the active site of Ras 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-G13D突变蛋白，最特别地是指KRas-G12D突变蛋白。For the purposes of the present invention, "Ras mutant" or "Ras mutein" and "Ras" against 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 aspartic acid at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (mutation of codon G12 Mutation of glycine to valine at G12), KRas-G13D (mutation of glycine to aspartic acid at codon G13); especially KRas mutein, more particularly KRas-G12C mutein, KRas- G12D mutein, KRas-G12V mutein, KRas-G13D mutein, most particularly KRas-G12D mutein.
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 "treating" as used herein refers to administering one or more of the compounds of the present invention described herein or their pharmaceutical preparations 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 for curing, alleviating, alleviating or affecting the disease or the symptoms of the disease. Preferably, 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 "prophylaxis" as used herein is well known in the art and refers to giving a person suspected of having or being susceptible to A subject, such as a mammal, such as a human, of a Ras mutation-mediated disease, especially cancer or tumor, is administered one or more compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, such that To reduce the risk of developing a defined disease, or to prevent the onset of a disease. The term "prevention" encompasses the use of the compounds of the invention prior to the 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。The terms "inhibit" and "reduce" or any variation of these terms, as used herein, 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 refer to Any measurable reduction or complete inhibition of the activity of a target of interest. For example, compared to normal conditions, the activity (such as KRas activity) can be reduced by about, at most about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% %, 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“选择性抑制”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，相比脱靶的信号活性，优先降低目标靶点的信号传导活性。就本发明化合物而言，相对于Ras蛋白的一个或多个密码子发生的各类突变，其具有选择性抑制KRas、HRas或NRas蛋白的G12或G13突变的能力，例如G12C突变、G12D突变、G12V突变和G13D突变，优选选择性抑制KRas蛋白的G12D突变的能力。例如，与对另一种特定Ras突变相比，本发明对特定Ras突变具有至少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的更好活性的抑制，或与对另一种特定Ras突变的活性相比，对特定Ras突变(例如KRas-G12D)具有至少1-、2-、3-、4-、5-、10-、25-、50-、100-、250-或500-倍的更好活性。As used herein, the term "selective inhibition" refers to the ability of a biologically active agent to preferentially reduce signaling activity of a target of interest over off-target signaling activity by interacting directly or indirectly with the target. As far as the compound of the present invention is concerned, relative to various mutations that occur in one or more codons of the Ras protein, it has the ability to selectively inhibit the G12 or G13 mutation of the KRas, HRas or NRas protein, such as G12C mutation, G12D mutation, The G12V mutation and the G13D mutation, preferably the ability of the G12D mutation to selectively inhibit the KRas protein. For example, the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% for a specific Ras mutation compared to another specific Ras mutation , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range of better activity derivable therein, or with At least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100- , 250- or 500-fold better activity.
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，最优选KRas-G12D介导的疾病，更进一步优选癌症或肿瘤。The term "Ras mutation-mediated disease" as used herein refers to a disease in which Ras mutation promotes the occurrence and development of the disease, or inhibiting Ras mutation will reduce the incidence of the disease, reduce or eliminate the disease symptoms. For the present invention, "Ras mutation-mediated disease" preferably refers to KRas mutation-mediated disease, most preferably KRas-G12D-mediated disease, and more preferably cancer or tumor.
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 to all precancerous and cancerous cells and tissues. For each aspect of the invention, the cancer or tumor includes, but is 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 cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine 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 tumor (CNS), primary CNS lymphoma, spinal tumor, 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、优选KRas G12D突变相关，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 each aspect of the present invention, preferably, the cancer or tumor is associated with a Ras mutation, especially a KRas mutation, preferably a KRas G12D mutation, including but not limited to the above tumor types and their preferred ranges. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, 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。The term "subject", "individual" or "patient" as used herein refers to a vertebrate animal. In some embodiments, the spine The animal is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport 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 the amount or dose that is generally sufficient to produce a beneficial therapeutic effect on the "Ras mutation-mediated disease" such as cancer or tumor patients in need of treatment. Those skilled in the art can determine the effective amount or dosage of the active ingredients in the present invention by conventional methods and in combination 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 present invention may be combined with other active agents for the purposes of the present 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 which is compatible with the compounds of the invention, i.e. does not adversely affect each other, or has complementary activities. ) 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 amounts effective to achieve the intended purpose. The other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, either simultaneously or sequentially when administered separately. The sequential administration 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。As used herein, the term "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.
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 salt" as used herein refers to those salts which retain the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable, including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" may be formed from compounds having a basic group with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids may be selected from Aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids such as formic, acetic, propionic, glycolic, gluconic, lactic, pyruvic, oxalic, 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, pahydronaphthalene 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 sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc., and those derived from pharmaceutically acceptable Salts of organic non-toxic bases are accepted, 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, Histamine acid, caffeine, procaine, hybamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine, N- Ethyl piperidine, 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 stereoisomers, enantiomeric mixtures, including racemates, diastereomeric mixtures, geometric isomers, atropic isomers, which may exist in the structure of a compound isomers and/or tautomers. Methods for determination and separation of the stereochemistry of the isomers are well known to those skilled in the art (SP 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, so the present invention covers all possible isomeric forms of the compounds defined herein, and pharmaceutically acceptable salts or solvates thereof , unless otherwise indicated.
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 herein Indicates the absolute configuration of the stereocenter, that is, the chiral center, and correspondingly uses R or S to represent the absolute configuration of the chiral center in the names of the compounds or intermediates provided by the present invention; in some definitions of the compounds of the present invention, it is also Axial chirality can be used to represent compound configurations, and the determination of these configurations uses the Cahn-Ingold-Prelog rules well known to those skilled in the art. The absolute configurations of axial chirality in the two example structures shown in the following figures are described as follows:
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。The structure fragments used in this article The bond indicated to cross it is the bond by which the structural fragment connects to the rest of the molecule.
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。The compounds of the invention include unlabeled forms of the compounds of the invention as well as 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 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 are useful, for example, as probes in biological assays, analytical tools or as therapeutic agents. In certain embodiments, 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。As used herein, the term "solvate" refers to a solvent addition form of a compound containing stoichiometric or non-stoichiometric solvent, including any solvated form of the compounds of the invention, including for example solvates with water, such as hydrated , or a solvate with an organic solvent, such as methanol, ethanol, or acetonitrile, ie as methanolate, ethanolate, or acetonitrile, respectively; or in any polymorphic form. It should be understood that such solvates of the compounds of the invention also include solvates of the 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 a product produced by the metabolism of a compound in vivo. 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。As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances, 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 carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), Calcium Sulfate, Vegetable Oil, Polyols (such as Propylene Glycol, Glycerin, Mannitol, Sorbitol, etc.), Milk Chemical agents (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, 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" as used herein when defining a radical is intended to include monohalogenated or polyhalogenated radicals in which one or more identical or different halogens replace one or more of the corresponding radicals. 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 composed of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, eg 1-8, 1-6, 1-5, 1-4, 1-3 or 1-2 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl (including normal propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2 - Methylpentyl 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。As used herein, the term "C 1-6 alkyl optionally substituted by halogen" refers to the above-mentioned C 1-6 alkyl, wherein one or more (eg 1, 2, 3, 4 or 5 ) hydrogen atoms are optionally replaced by halogen. Those skilled in the art should 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 and the like.
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 chain unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one double bond. In particular, alkenyl groups have 2-8, eg 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 linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, butenyl, Pentenyl, etc., the carbon atom connected to the rest of the molecule in the alkenyl group can be either saturated or ethylenically bonded.
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 chain unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and containing at least one triple bond. In particular, alkynyl groups have 2-8, eg 2 to 6, 2 to 5, 2 to 4 or 2 to 3 carbon atoms. For example, as used herein, the term " C2-6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms , such as ethynyl, propynyl, propargyl, butynyl etc., the carbon atom in the alkynyl group that is 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 spiro non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring carbon atoms. The cycloalkyl group may have 3 to 12 carbon atoms (ie, C 3-12 cycloalkyl group), 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 (e.g., 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环结构，或其 N-氧化物，或其S-氧化物或S-二氧化物。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6个环成员。杂环烷基通常含有至多4个(例如1个、2个、3个或4个)杂原子，例如含有1至3个选自N、O、S的杂原子的4-7元杂环烷基。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。The term "heterocycloalkyl" as used herein means a monocyclic, fused Polycyclic, spiro or bridged polycyclic non-aromatic saturated ring structures, or N-oxide, or its S-oxide or S-dioxide. A heterocycloalkyl group may have 3 to 12 ring members (may be referred to as a 3-12 membered heterocycloalkyl group), 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 6 ring members. Heterocycloalkyl groups generally contain up to 4 (eg 1, 2, 3 or 4) heteroatoms, for example 4-7 membered heterocycloalkanes containing 1 to 3 heteroatoms selected from N, O, S base. Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, and 3 -pyrrolidinyl), tetrahydrofuryl (such as 1-tetrahydrofuryl, 2-tetrahydrofuryl and 3-tetrahydrofuryl), tetrahydrothiophenyl (such as 1-tetrahydrothiophenyl, 2-tetrahydrofuryl and 3-tetrahydrofuryl Thienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4-tetrahydropyranyl), Tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl (e.g. morpholino), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepine Cycloheptyl is for example 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 that is bonded to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.
优选的杂环烷基例如 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 Preferred heterocycloalkyl groups such as It should be understood that structures with asymmetric centers encompass their racemic and/or single enantiomeric forms, e.g. Representable
本文所用的术语“杂芳基”意指包括一或多个(例如1、2、3或4个)独立地选自O、N及S的杂原子及指定环原子数的单环或稠合多环芳族环结构，或其N-氧化物，或其S-氧化物或S-二氧化物。具体地，该芳族环结构可具有5至10个环成员。杂芳基可为例如5-6元单环、或由稠合的两个6元环、稠合的两个5元环、稠合的6元环和5元环、或稠合的5元环和4元环形成的稠合双环结构。杂芳基环通常将含有至多4个杂原子、更通常至多3个杂原子、更通常至多2个、例如单个独立地选自O、N及S的杂原子，其中N和S可以是氧化状态如N氧化物、S＝O或S(O)2。在一个实施方案中，杂芳基环含有至少一个环氮原子、至少一个环硫原子或至少一个环氧原子。例如，杂芳基可以是包含1或2个独立地选自N、O或S的杂原子的5-6元杂芳基。适合的5元单环杂芳基的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基及四唑基；适合的6元单环杂芳基的实例包括但不限于吡啶基、吡嗪基、哒嗪基、嘧啶基及三嗪基。例如，杂芳基也可以是包含1、2、3或4个独立地选自N、O或S的杂原子的稠合环，例如苯并呋喃、苯并噻吩、吲哚、苯并咪唑、吲唑、苯并三唑、吡咯并[2,3-b]吡啶、吡咯并[2,3-c]吡啶、吡咯并[3,2-c]吡啶、吡咯并[3,2-b]吡啶、咪唑并[4,5-b]吡啶、咪唑并[4,5-c]吡啶、吡唑并[4,3-d]吡啶、吡唑并[4,3-c]吡啶、吡唑并[3,4-c]吡啶、吡唑并[3,4-b]吡啶、异吲哚、 嘌呤、中氮茚、咪唑并[1,2-a]吡啶、咪唑并[1,5-a]吡啶、吡唑并[1,5-a]哒嗪、吡咯并[1,2-b]嘧啶、咪唑并[1,2-c]嘧啶、5H-吡咯并[3,2-b]吡嗪、1H-吡唑并[4,3-b]吡嗪、1H-吡唑并[3,4-d]嘧啶、7H-吡咯并[2,3-d]嘧啶、喹啉、异喹啉、噌啉、喹唑啉、喹喔啉、酞嗪、1,6-萘啶、1,7-萘啶、1,8-萘啶、1,5-萘啶、2,6-萘啶、2,7-萘啶、吡啶并[3,2-d]嘧啶、吡啶并[4,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[2,3-b]吡嗪、吡啶并[3,4-b]吡嗪、嘧啶并[5,4-d]嘧啶、吡嗪并[2,3-b]吡嗪和嘧啶并[4,5-d]嘧啶。杂芳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。The term "heteroaryl" as used herein means a monocyclic or fused ring comprising one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and the specified number of ring atoms Polycyclic aromatic ring structures, or N-oxides thereof, or S-oxides or S-dioxides thereof. Specifically, the aromatic ring structure may have 5 to 10 ring members. Heteroaryl can be, for example, a 5-6 membered monocyclic ring, or consist of fused two 6-membered rings, fused two 5-membered rings, fused 6-membered and 5-membered rings, or fused 5-membered A fused bicyclic structure formed by a ring and a 4-membered ring. The heteroaryl ring will generally contain up to 4 heteroatoms, more usually up to 3 heteroatoms, more usually up to 2, for example a single heteroatom independently selected from O, N and S, where N and S may be in the oxidation state Such as N oxide, S=O or S(O) 2 . In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom. For example, the heteroaryl group can be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O or S. Examples of suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, Thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl; examples of suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazine base. For example, heteroaryl can also be a fused ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, such as benzofuran, benzothiophene, indole, benzimidazole, Indazole, Benzotriazole, Pyrrolo[2,3-b]pyridine, Pyrrolo[2,3-c]pyridine, Pyrrolo[3,2-c]pyridine, Pyrrolo[3,2-b] Pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazole A[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, Purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b] Pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3, 4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7 -Naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3- d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimido[4,5-d]pyrimidine. The atom in the heteroaryl group that is bonded to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.
本文所用的术语“羟基”是指-OH基团。As used herein, the term "hydroxyl" refers to a -OH group.
本文所用的术语“氰基”是指-CN基团。As used herein, the term "cyano" refers to a -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。The term "optionally substituted" as used herein, unless otherwise indicated, means that a group may be unsubstituted or replaced by one or more (eg 1, 2, 3, 4 or 5 or more, or any derivable therein) range) is substituted with the substituents listed for the group, wherein the substituents may be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents that are the same or different. In another embodiment, an optionally substituted group has 3 substituents which are the same or different. In another embodiment, an optionally substituted group has 4 substituents which are the same or different. In another embodiment, an optionally substituted group has 5 same or different substituents.
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元环和6-10元环等。Unless otherwise specified, Cn -n+m or Cn - Cm in the definition of the compounds 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 , including 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. Similarly, n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is from 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 including 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 and 6- 10-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 it is 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 valence 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 following claims, the word "comprises" and variations of the word such as "comprises" and "comprising", means "including but not limited to" and is not intended to exclude other additives such as , ingredient, integer, or step. When an element is described as comprising a plurality of ingredients, steps or conditions, it should be understood that the element may also be described as comprising any combination of the plurality of ingredients, steps or conditions, or as "comprising a plurality or combination of ingredients, steps or conditions" or "consists 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 should be understood that when describing herein the compounds of the present invention, pharmaceutical compositions comprising the same, pharmaceutical combinations, kits, and related uses and methods, the dosages referred to are based on the weight of the free form, excluding any salts, hydrates or Solvates, unless the specification states 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 present invention
如上所述，能够抑制Ras突变蛋白、尤其KRas突变蛋白、更尤其KRas-G12D突变蛋白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(Duan Ni等人，Pharmacology&Therapeutics,Volume 202,October 2019,p1-17；US2019/0144444A1、WO2019/110751A1、WO2017/172979A1、WO2021/041671A1、WO2021/107160A1和WO2021/081212A1)。As described above, compounds capable of inhibiting Ras muteins, especially KRas muteins, more especially KRas-G12D muteins, can be used to treat or prevent diseases (such as cancer or tumors) mediated by said muteins. Therefore, in this field, various structural types of Ras inhibitors have been developed (Duan Ni et al., Pharmacology & Therapeutics, Volume 202, October 2019, p1-17; US2019/0144444A1, WO2019/110751A1, WO2017/172979A1, WO2021/041671A1 , WO2021/107160A1 and WO2021/081212A1).
但是，一方面，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，等等。进一方面，即便是对于具有良好抗肿瘤活性的抑制剂，人们仍期望能够进一步提高其在体内对靶蛋白的抑制活性、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。However, on the one hand, existing KRas inhibitors still have problems to be solved, including, for example, many inhibitors have unsatisfactory antitumor activity, or have toxic side effects leading to poor drug resistance, or pharmacokinetic properties are not enough to allow Administration in a convenient way means poor "druggability", and so on. On the other hand, even for inhibitors with good antitumor activity, it is still expected to further improve its inhibitory activity on target proteins in vivo, further improve its drug resistance (less toxic side effects or better safety) ) and further improve its pharmacokinetic properties in order to provide more and better treatment options for the clinic.
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、更尤其KRas-G12D突变蛋白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抑制剂结构的嘧啶环的特定位点进行特定立体化学的取代基修饰，获得相比相应的外消旋化合物或对映异构体而言进一步提高的对KRas-G12D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 present inventors have developed a group of compounds with obvious inhibitory activity on Ras mutein, especially KRas mutein, more especially KRas-G12D mutein. Through structural modification and activity verification, the inventors found that specific stereochemical substituent modification was carried out at the specific position of the pyrimidine ring of the KRas inhibitor structure to obtain The inhibitory activity to the KRas-G12D mutant protein is further improved, and the compound obtained by such modification has good safety, has reduced drug interaction risk, and has good or even further improved pharmacokinetic properties, Allows for administration in a convenient manner.
由此，本发明主要提供有效的Ras抑制剂、具体地KRas抑制剂、更具体地KRas-G12D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、更具体地KRas-G12D介导或得益于Ras、具体地KRas、更具体地KRas-G12D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、更具体地KRas-G12D介导或得益于Ras、具体地KRas、更具体地KRas-G12D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、更具体地KRas-G12D介导或得益于Ras、具体地KRas、更具体地KRas-G12D抑制的疾病如肿瘤或癌症的药物中的用途。Thus, the present invention mainly provides effective Ras inhibitors, specifically KRas inhibitors, more specifically KRas-G12D inhibitor compounds; pharmaceutical compositions containing such compounds as active ingredients; as medicines, for the treatment or prevention of Ras, in particular KRas, more in particular KRas-G12D mediated or benefiting from said compounds of Ras, in particular KRas, more in particular KRas-G12D inhibited tumors or cancers; use of said compounds for the treatment or prevention of Ras, specifically KRas, more specifically KRas-G12D mediates or benefits from Ras, specifically KRas, more specifically KRas-G12D inhibited diseases such as tumors or cancer methods; and the compound is prepared for the treatment or Use in a medicament for the prevention of diseases such as tumors or cancers mediated by or benefiting from the inhibition of Ras, specifically KRas, more specifically KRas-G12D.
本发明由此提供以下技术方案。The present invention thus provides the following technical solutions.
本发明化合物Compounds of the 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 "compound of the invention" and "compound of the invention" and the like used throughout this application, unless otherwise defined, include Compounds as defined in the various embodiments and preferred embodiments thereof herein or in each embodiment thereof, including isomers thereof, including atropisomers, enantiomeric mixtures, especially racemates, diastereoisomers Mixtures of isomers, geometric isomers, tautomers, solvates, metabolites, prodrugs, isotopic variations, and salts (eg, 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 thus covered 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, preferred are compounds of the present 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 present invention also encompasses N-oxides of the compounds of the present invention as long as these compounds contain a basic nitrogen atom such as is present in nitrogen-containing heterocycles and are chemically and biologically feasible. Certain compounds of the present invention may exist in polymorphic or amorphous forms, and thus they also fall within the scope of the present invention.
本发明提供如下化合物实施方案：The present invention provides the following compound embodiments:
1.实施方案1：式(A)的化合物或它们药学上可接受的盐或溶剂合物，
1. Embodiment 1: the compound of formula (A) or their pharmaceutically acceptable salt or solvate,
其中：in:
X选自N、CH、C-F、C-Cl和C-CF3；X is selected from N, CH, CF, C-Cl and C- CF3 ;
Y选自O、S和NRb；Y is selected from O, S and NR b ;
Ra选自卤素、C1-6烷基或-O-C1-6烷基，其中C1-6烷基任选被卤素取代；R is selected from halogen, C 1-6 alkyl or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by halogen;
Rb在每次出现时独立地选自H和任选被卤素取代的C1-6烷基； R at each occurrence is independently selected from H and C 1-6 alkyl optionally substituted by halogen;
R1选自H、CN、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基和-(CH2)p-4-7元杂环烷基，其中的-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和4-7元杂环烷基各自独立地任选被卤素、CN、-C1-6烷基、-ORb或-N(Rb)2取代；或R 1 is selected from H, CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p -C 3-6 cycloalkyl and -(CH 2 ) p -4-7 membered heterocycloalkyl, wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and 4- Each 7-membered heterocycloalkyl group is independently optionally substituted by halogen, CN, -C 1-6 alkyl, -OR b or -N(R b ) 2 ; or
R1和连接于邻位环碳原子上的R3与它们所连接的环碳原子一起形成稠合的C3-6环烷基；R 1 and R 3 connected to the adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group with the ring carbon atoms to which they are connected;
R2选自H、-C1-6烷基和-C3-6环烷基，其中的C1-6烷基和C3-6环烷基各自独立地任选被卤素、-C1-6烷基、-ORb或-N(Rb)2取代；或当n为2时，两个R2与它们所连接的碳原子一起形成C3-6环烷基；R 2 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally replaced by halogen, -C 1 -6 alkyl, -OR b or -N(R b ) 2 substituted; or when n is 2, two R 2 together with the carbon atoms they are connected to form a C 3-6 cycloalkyl;
R3选自H、卤素、-CN、-OH、-OC1-6烷基、-O-(CH2)p-C3-6环烷基、-O-(CH2)p-4-7元杂环烷基、-O-(CH2)p-5-10元杂芳基、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基、-(CH2)p-5-10元杂芳基、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2和-O-C(O)-N(Rb)2， 其中的-C1-6烷基、C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代；或R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O-(CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4- 7-membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered heteroaryl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -( CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 and -OC(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O)-N(R b ) 2 instead; or
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；或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 each R c is independently selected from H, Halogen and -C 1-6 alkyl optionally substituted by halogen; or
连接于相邻环碳原子上的两个R3与它们所连接的环碳原子一起形成稠合C3-6环烷基或稠合4-7元杂环烷基；Two R3s connected to adjacent ring carbon atoms form a fused C3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected;
R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基、-(CH2)p-5-10元杂芳基、-C(O)-ORb和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代；R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -C(O)-OR b and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl independently optionally halogen, -CN, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitution;
Z选自其中Z from in
R5和R7各自独立地选自H或卤素；R and R are each independently selected from H or halogen;
R6和R8各自独立地选自H、卤素、-C1-6烷基和-C2-6炔基；R 6 and R 8 are each independently selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl;
m和p各自独立地选自0-3的整数；m and p are each independently selected from an integer of 0-3;
n是选自0-2的整数。n is an integer selected from 0-2.
1-1.实施方案1的化合物或其药学上可接受的盐或溶剂合物，其中X选自N、CH、C-F和C-Cl。1-1. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from N, CH, C-F and C-Cl.
1-1-1.实施方案1的化合物或其药学上可接受的盐或溶剂合物，其中R3选自H、卤素、-CN、-OH、-OC1-6烷基、-O-(CH2)p-C3-6环烷基、-O-(CH2)p-4-7元杂环烷基、-O-(CH2)p-5-10元杂芳基、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基、-(CH2)p-5-10元杂芳基、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2和-O-C(O)-N(Rb)2，其中的-C1-6烷基、C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代；或1-1-1. The compound of Embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O- (CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4-7 membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered heteroaryl, - C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered hetero Cycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 and - OC(O)-N(R b ) 2 , wherein -C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently any Selected from halogen, -CN, oxo, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O)-N(R b ) 2 substitution; or
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各自独立地选自卤素和任选被卤素取代的-C1-6烷基；或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 each R c is independently selected from halogen and -C 1-6 alkyl optionally substituted by halogen; or
连接于相邻环碳原子上的两个R3与它们所连接的环碳原子一起形成稠合C3-6环烷基或稠合4-7元杂环烷基。Two R 3 connected to adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected.
1-2.实施方案1-1的化合物或其药学上可接受的盐或溶剂合物，其中R3选自H、卤素、-CN、-OH、-OC1-6烷基、-O-(CH2)p-C3-6环烷基、-O-(CH2)p-4-7元杂环烷基、-O-(CH2)p-5-10元 杂芳基、-C1-6烷基、-C2-6烯基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基、-(CH2)p-5-10元杂芳基、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2和-O-C(O)-N(Rb)2，其中的-C1-6烷基、C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代；或1-2. The compound of embodiment 1-1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O- (CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4-7 membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered Heteroaryl, -C 1-6 alkyl, -C 2-6 alkenyl, -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl , -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 and -OC(O )-N(R b ) 2 , wherein -C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen , -CN, oxo, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , - OC(O)-N(R b ) 2 substitution; or
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；或Two R3s attached to the same carbon atom form a spiro C 3-6 cycloalkyl or a spiro 4-7 membered heterocycloalkyl; or
连接于相邻环碳原子上的两个R3与它们所连接的环碳原子一起形成稠合C3-6环烷基或稠合4-7元杂环烷基。Two R 3 connected to adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected.
1-3.实施方案1至1-2的化合物或其药学上可接受的盐或溶剂合物，其为式(A-1)化合物，
1-3. The compound of Embodiment 1 to 1-2, or a pharmaceutically acceptable salt or solvate thereof, which is a compound of formula (A-1),
其中：in:
X选自N、CH、C-F和C-Cl；X is selected from N, CH, C-F and C-Cl;
Y选自O、S和NRb；Y is selected from O, S and NR b ;
Ra选自F和Cl；R a is selected from F and Cl;
Rb在每次出现时独立地选自H和任选被卤素取代的C1-6烷基； R at each occurrence is independently selected from H and C 1-6 alkyl optionally substituted by halogen;
R1选自H、-C1-6烷基和-C3-6环烷基，其中的-C1-6烷基和-C3-6环烷基各自独立地任选被卤素、-ORb或-N(Rb)2取代；R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, - OR b or -N(R b ) 2 substitution;
R2选自H、-C1-6烷基和-C3-6环烷基，其中的C1-6烷基和C3-6环烷基各自独立地任选被卤素、-ORb或-N(Rb)2取代；R 2 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -N(R b ) 2 substitution;
R3选自H、卤素、-CN、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2和-C1- 6烷基，其中的-C1-6烷基任选被卤素、-CN、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代；R 3 is selected from H, halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O) -N(R b ) 2 and -C 1- 6 alkyl, wherein -C 1-6 alkyl is optionally replaced by halogen, -CN, -OR b , -N(R b ) 2 , -C(O) -OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitutions;
R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基、-C(O)-ORb和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2-6烯基、-C2-6炔基和-C3-6环烷基各自独立地任选被卤素、-CN、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代； R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C(O)-OR b and -C (O)-N(R b ) 2 , wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally By halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 replaces;
Z选自其中Z from in
R5和R7各自独立地选自H或卤素；R and R are each independently selected from H or halogen;
R6选自H、卤素、-C1-6烷基和-C2-6炔基；R is selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl;
R8选自H、卤素、-C1-6烷基和-C2-6炔基。R 8 is selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl.
2.实施方案1至1-3的化合物或其药学上可接受的盐或溶剂合物，其中X为N。2. The compound according to embodiments 1 to 1-3, wherein X is N, or a pharmaceutically acceptable salt or solvate thereof.
3.实施方案1至1-3的化合物或其药学上可接受的盐或溶剂合物，其中X为CH。3. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is CH.
4.实施方案1至1-3的化合物或其药学上可接受的盐或溶剂合物，其中X为C-F。4. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.
5.实施方案1至1-3的化合物或其药学上可接受的盐或溶剂合物，其中X为C-Cl。5. The compound of embodiments 1 to 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-Cl.
5-1.实施方案1的化合物或其药学上可接受的盐或溶剂合物，其中X为C-CF3。5-1. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-CF 3 .
6.实施方案1至5-1任一项的化合物或其药学上可接受的盐或溶剂合物，其中Y为O。6. The compound according to any one of Embodiments 1 to 5-1, wherein Y is O, or a pharmaceutically acceptable salt or solvate thereof.
7.实施方案1至5.1任一项的化合物或其药学上可接受的盐或溶剂合物，其中Y为S。7. The compound according to any one of Embodiments 1 to 5.1, wherein Y is S, or a pharmaceutically acceptable salt or solvate thereof.
8.实施方案1至5.1任一项的化合物或其药学上可接受的盐或溶剂合物，其中Y为NRb，例如但不限于-NH-、-N(CH3)-、-N(CH2CH3)-。8. The compound of any one of embodiments 1 to 5.1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is NR b , such as but not limited to -NH-, -N(CH 3 )-, -N( CH2CH3 )- .
9.实施方案1-8任一项的化合物或其药学上可接受的盐或溶剂合物，其中Ra为卤素，例如F或Cl。9. The compound according to any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein Ra is halogen, eg F or Cl.
10.实施方案1-8任一项的化合物或其药学上可接受的盐或溶剂合物，其中Ra为C1-6烷基或-O-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、-CH2F、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CH2Cl、-O-CH2CH3、-O-CH2CH2CH3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3、-O-CH2F、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3。10. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R a is C 1-6 alkyl or -OC 1-6 alkyl, optionally substituted by halogen, For example 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 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 , -CH 2 Cl, -O-CH 2 CH 3 , -O -CH 2 CH 2 CH 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 , -O-CH 2 F, -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 .
11.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1为H。11. The compound of any one of embodiments 1-10, wherein R1 is H, or a pharmaceutically acceptable salt or solvate thereof.
11-1.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1为CN。11-1. The compound according to any one of Embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is CN.
11-2.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1为-C2-6烯基或-C2-6炔基，例如但不限于乙烯基、乙炔基。11-2. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not Limited to vinyl and ethynyl.
12.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1选自-C1- 6烷基、-(CH2)p-C3-6环烷基和-(CH2)p-4-7元杂环烷基，其中的-C1-6烷基、-C3-6环烷基和4-7元 杂环烷基各自独立地任选被卤素、CN、-C1-6烷基、-ORb或-N(Rb)2取代。12. The compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from -C 1- 6 alkyl, -(CH 2 ) p -C 3-6 ring Alkyl and -(CH 2 ) p -4-7 membered heterocycloalkyl, in which -C 1-6 alkyl, -C 3-6 cycloalkyl and 4-7 membered Each heterocycloalkyl is independently optionally substituted by halogen, CN, -C 1-6 alkyl, -OR b or -N(R b ) 2 .
12-1.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1和连接于邻位环碳院子上的R3与它们所连接的环碳原子一起形成稠合的C3-6环烷基，例如但不限于稠合环丙基或稠合环丁基。12-1. The compound according to any one of Embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 3 connected to the ortho-ring carbon yard and the ring carbon atom to which they are connected Together to form a fused C3-6 cycloalkyl, such as but not limited to fused cyclopropyl or fused cyclobutyl.
12-2.实施方案1-10任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1选自-C1-6烷基和-C3-6环烷基，各自独立地任选被卤素、CN或-ORb取代。12-2. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl, each independently optionally substituted by halogen, CN or -ORb .
13.实施方案12-2的化合物或其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-ORb取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OH、-CH2-CN、-CH2CH2-OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CH2Cl、-CF(CF3)2。13. The compound of embodiment 12-2 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C 1-6 alkyl, optionally substituted by halogen or -OR b , 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 -OH, -CH 2 -CN, -CH 2 CH 2 -OH, -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, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , -C2F5 , -C2Cl5 , -CH2Cl , -CF( CF3 ) 2 .
14.实施方案12-2的化合物或其药学上可接受的盐或溶剂合物，其中R1为-C3-6环烷基，任选被卤素或-ORb取代，例如但不限于环丙基、环丁基、环戊基、环己基、 14. The compound of embodiment 12-2 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but not limited to ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl,
15.实施方案12-2的化合物或其药学上可接受的盐或溶剂合物，其中R1选自-C1-6烷基和-C3-6环烷基，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、环丙基、环丁基、环戊基、环己基。15. The compound of embodiment 12-2 or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl, 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 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
16.实施方案1-15任一项的化合物或其药学上可接受的盐或溶剂合物，其中R2为H。16. The compound of any one of embodiments 1-15, wherein R2 is H, or a pharmaceutically acceptable salt or solvate thereof.
17.实施方案1-15任一项的化合物或其药学上可接受的盐或溶剂合物，其中R2选自-C1- 6烷基和-C3-6环烷基，各自独立地任选被卤素或-ORb取代。17. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl, each independently Optionally substituted by halo or -ORb .
18.实施方案1-15任一项的化合物或其药学上可接受的盐或溶剂合物，其中R2为-C1-6烷基，任选被卤素或-ORb取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH2CH2CH3、-CH2CH(CH3)CH3、-C(CH3)3、-CH2-OH、-CH2CH2-OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH2CH2-O-CH2CH3、-CH2F、-CHF2、-CF3、-CCl3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-C2Cl5、-CH2Cl、-CF(CF3)2。18. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -C 1-6 alkyl, optionally substituted by halogen or -OR b , 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 -OH, -CH 2 CH 2 -OH, -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, -CHF 2 , -CF 3 , -CCl 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2F , -CH2CH2CHF2 , -CH2CH2CF3 , -C2F5 , -C2Cl5 , -CH2Cl , -CF( CF3 ) 2 .
18-1.实施方案1-15任一项的化合物或其药学上可接受的盐或溶剂合物，其中当n为2时，两个R2与它们所连接的碳原子一起形成C3-6环烷基，例如环丙基、环丁基。 18-1. The compound according to any one of embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein when n is 2, two R 2 together with the carbon atoms to which they are attached form C 3- 6Cycloalkyl , such as cyclopropyl, cyclobutyl.
19.实施方案1-15任一项的化合物或其药学上可接受的盐或溶剂合物，其中R2为-C3-6环烷基，任选被卤素或-ORb取代，例如但不限于环丙基、环丁基、环戊基、环己基、 19. The compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but Not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
20.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为H。20. The compound of any one of embodiments 1-19, wherein R3 is H, or a pharmaceutically acceptable salt or solvate thereof.
21.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为卤素，例如F、Cl、Br或I。21. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen, such as F, Cl, Br or I.
22.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为-CN。22. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CN.
23.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为-OH或-OC1-6烷基，其中的C1-6烷基任选被-OH、卤素或-OC1-6烷基取代，例如但不限于-OH、-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-O-CH2-O-CH3、-O-CH2CH2-O-CH3、-O-CH2F、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3。23. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OH or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally Substituted by -OH, halogen or -OC 1-6 alkyl, such as but not limited to -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH 2 -O-CH 3 , -O-CH 2 CH 2 -O-CH 3 , -O-CH 2 F, -O-CHF 2 , -O-CF 3 , -O-CH 2 CH 2 F, -O -CH2CHF2 , -O - CH2CF3 , -O - CH2CH2CF3 .
23-1.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3选自-O-(CH2)p-C3-6环烷基、-O-(CH2)p-4-7元杂环烷基和-O-(CH2)p-5-10元杂芳基，其中p选自0、1或2，例如但不限于-O-氧杂或氮杂环丁烷、-O-CH2-氧杂或氮杂环丁烷、-O-氧杂或氮杂环戊烷、-O-CH2-氧杂或氮杂环戊烷，其中的-C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代。23-1. The compound according to any one of embodiments 1-19 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from -O-(CH 2 ) p -C 3-6 cycloalkyl, - O-(CH 2 ) p -4-7 membered heterocycloalkyl and -O-(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to -O -oxa or azetidine, -O-CH 2 -oxa or azetidine, -O-oxa or azetidine, -O-CH 2 -oxa or azetidine Alkane, wherein -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl , -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O)-N(R b ) 2 substitution.
23-2.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3选自-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基和-(CH2)p-5-10元杂芳基，其中p选自0、1或2，例如但不限于环丙基、环丁基、环戊基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、氧杂或氮杂环丁基、氧杂或氮杂环戊基、氧氮杂环戊基、-CH2-氧杂或氮杂环丁烷、-CH2-氧杂或氮杂环戊烷，其中的-C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代。23-2. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl and -(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, Cyclopentyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, oxa or azetidinyl, oxa or azetidinyl, oxazacycline Pentyl, -CH 2 -oxa or azetidine, -CH 2 -oxa or azetidine, in which -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5 The -10-membered heteroaryl groups are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , - Substituted by C(O)-N(R b ) 2 , -OC(O)-N(R b ) 2 .
24.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为-N(Rb)2，例如但不限于-NH2、-NH-CH3、-NH-CH2CH3、-N(CH3)2、-N(CH2CH3)2、-NH-CH2F、-NH-CHF2、-N(CH3)-CF3、-NH-CH2CH2F、-NH-CH2CHF2、-NH-CH2CF3、-NH-CH2CH2CF3。24. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -N(R b ) 2 , such as but not limited to -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NH-CH 2 F, -NH-CHF 2 , -N(CH 3 )-CF 3 , -NH- CH2CH2F , -NH - CH2CHF2 , -NH- CH2CF3 , -NH- CH2CH2CF3 .
25.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2，例如但不限于-C(O)-OH、-C(O)-NH2或-O-C(O)-NH2、-C(O)-OCH3、-C(O)-N(CH3)2、-O-C(O)-N(CH3)2。 25. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 , such as but not limited to -C(O)-OH, -C(O)-NH 2 or -OC(O)-NH 2 , -C(O)- OCH 3 , -C(O)-N(CH 3 ) 2 , -OC(O)-N(CH 3 ) 2 .
26.实施方案1-19任一项的化合物或其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、-CN、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代，优选任选被-ORb或-O-C(O)-N(Rb)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH(CH3)CH3、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CHFCH3、-CH2CHF2、-CH(CH3)(CH2F)、-CH2CHFCH3、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-CH2CN、-CH2CH2CN、-CH2-OH、-CH2CH2-OH、-CH2-C(CH3)2(OH)、-CH2-CH(CH3)(OH)、-CH(CH3)CH2OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH(CH3)CH2OCH3、-CH2-CH(CH3)(OCH3)、-CH2CH2-O-CH2CH3、-CH2-NH2、-CH2-NH(CH3)、-CH2-N(CH3)2、-CH2CH2-NH2、-CH2CH2-NH(CH3)、-CH2CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH2CH2-NH-CH3、-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)。26. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C 1-6 alkyl, optionally replaced by halogen, -CN, -OR b , - N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 , preferably optionally substituted by -OR b Or -OC(O)-N(R b ) 2 substitution, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH( CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CHFCH 3 , -CH 2 CHF 2 , -CH(CH 3 )(CH 2 F), -CH 2 CHFCH 3 , -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 , -CH 2 CN, -CH 2 CH 2 CN, -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -C(CH 3 ) 2 (OH ), -CH 2 -CH(CH 3 )(OH), -CH(CH 3 )CH 2 OH, -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH( CH 3 )CH 2 OCH 3 , -CH 2 -CH(CH 3 )(OCH 3 ), -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 -NH 2 , -CH 2 CH 2 -NH(CH 3 ), -CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -NH-CH 3 , -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC (O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ), -CH 2 CH 2 -OC(O)-N ( CH2CH3 ) ( CH3 ).
26-1-1.实施方案1-19任一项的化合物或其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，例如但不限于螺环丙基、螺环丁基。26-1-1. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein two R3s connected to the same carbon atom form a spiroC3-6 cycloalkane groups, such as but not limited to spirocyclopropyl, spirocyclobutyl.
26-1-2.实施方案1-19任一项的化合物或其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4-7元杂环烷基，例如但不限于氮杂或氧杂环丁基、氮杂或氧杂环戊基。26-1-2. The compound according to any one of Embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein two R3s connected to the same carbon atom form a spiro 4-7 membered heterocyclic ring Alkyl such as, but not limited to, aza or oxetanyl, aza or oxolyl.
26-1-3.实施方案1-19任一项的化合物或其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,优选＝CHF；更优选地，形成＝C(Rc)2的两个R3所连接的环碳原子与R1所连接的环碳原子相邻。26-1-3. The compound according to any one of Embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, 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 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 =CHF; more preferably, the ring carbon atoms to which R 3 is connected to form =C(R c ) 2 are connected to R 1 The ring carbon atoms are adjacent.
26-2.实施方案1-19任一项的化合物或其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与它们所连接的环碳原子一起形成稠合C3-6环烷基，例如但不限于稠合环丙基；或者26-2. The compound according to any one of Embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein two R3s attached to adjacent ring carbon atoms are together with the ring carbon atoms to which they are attached Forming a fused C 3-6 cycloalkyl group, such as but not limited to a fused cyclopropyl group; or
连接于相邻环碳原子上的两个R3与它们所连接的环碳原子一起形成稠合4-7元杂环烷基，例如但不限于稠合的氮杂或氧杂环丁烷、氮杂或氧杂环戊烷。Two R3s attached to adjacent ring carbon atoms form a fused 4-7 membered heterocycloalkyl together with the ring carbon atoms to which they are attached, such as but not limited to fused azepine or oxetane, Aza or oxolane.
26-3.实施方案1-19任一项的化合物或其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，例如但不限于乙烯基、乙炔基。26-3. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not Limited to vinyl and ethynyl.
27.实施方案26的化合物或其药学上可接受的盐或溶剂合物，其中R3为-C1-6烷基，被-O-C(O)-N(Rb)2取代，例如但不限于-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)。27. The compound of embodiment 26 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C 1-6 alkyl, substituted by -OC(O)-N(R b ) 2 , such as but not Limited to -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC (O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , - CH2 -OC(O)-N( CH2CH3 ) ( CH3 ), -CH2CH2 - OC(O)-N( CH2CH3 ) ( CH3 ).
28.实施方案1-19任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3选自H、卤素、-ORb或被-O-C(O)-N(Rb)2取代的-C1-6烷基，例如但不限于H、F、-OH、-O-CH3、-O- CH2CH3、-O-CH2CH2CH3、-O-CH(CH3)(CH3)、-O-CH2F、-O-CHF2、-O-CF3、-O-CH2CH2F、-O-CH2CHF2、-O-CH2CF3、-O-CH2CH2CF3、-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)，优选被卤素取代的-C1-6烷基，例如但不限于-CH2F、-CHF2；或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,优选＝CHF，更优选形成＝C(Rc)2的两个R3所连接的环碳原子与R1所连接的环碳原子相邻。28. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from H, halogen, -OR b or -OC(O)-N(R b ) 2- substituted -C 1-6 alkyl, such as but not limited to H, F, -OH, -O-CH 3 , -O- CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -O-CH(CH 3 )(CH 3 ), -O-CH 2 F, -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 , -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 - OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 -OC(O) -N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ) , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ), preferably -C 1-6 alkyl substituted by halogen, such as but not limited to -CH 2 F, -CHF 2 ; Or two R 3 connected to the same carbon atom form =C(R c ) 2 , wherein each R c is independently selected from H, F, Cl, Br, I, -C 1- optionally substituted by halogen 6 alkyl, such as but not limited to =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 , preferably =CHF, more preferably =C(R c ) The ring carbon atoms connected by the two R 3 of 2 are adjacent to the ring carbon atoms connected by R 1 .
29.实施方案1-28任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4为H。29. The compound of any one of embodiments 1-28, wherein R4 is H, or a pharmaceutically acceptable salt or solvate thereof.
30.实施方案1-28任一项的化合物或其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、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH(CH3)CH3、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CHFCH3、-CH2CHF2、-CH(CH3)(CH2F)、-CH2CHFCH3、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-CH2CN、-CH2CH2CN、-CH2-OH、-CH2CH2-OH、-CH2-C(CH3)2(OH)、-CH2-CH(CH3)(OH)、-CH(CH3)CH2OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH(CH3)CH2OCH3、-CH2-CH(CH3)(OCH3)、-CH2CH2-O-CH2CH3、-CH2-NH2、-CH2-NH(CH3)、-CH2-N(CH3)2、-CH2CH2-NH2、-CH2CH2-NH(CH3)、-CH2CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH2CH2-NH-CH3、-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)。30. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 1-6 alkyl, optionally replaced by halogen, -CN, -OR b , - N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitution, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C( CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CHFCH 3 , -CH 2 CHF 2 , -CH(CH 3 )(CH 2 F), -CH 2 CHFCH 3 , -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 , -CH 2 CN, -CH 2 CH 2 CN, -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -C(CH 3 ) 2 (OH), -CH 2 -CH(CH 3 )(OH), -CH(CH 3 )CH 2 OH, -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH(CH 3 )CH 2 OCH 3 , -CH 2 -CH(CH 3 )(OCH 3 ), -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -N(CH 3 ) 2 , -CH 2 CH 2 -NH 2 , -CH 2 CH 2 -NH(CH 3 ), -CH 2 CH 2 -N(CH 3 ) 2 , -CH 2 -NH-CH 2 CH 3 , -CH 2 CH 2 -NH-CH 3 , -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC(O)- N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 -OC (O)-N ( CH2CH3 )( CH3 ), -CH2CH2 - OC (O)-N( CH2CH3 )( CH3 ).
31.实施方案30的化合物或其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、-ORb或-O-C(O)-N(Rb)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH(CH3)CH3、-C(CH3)3、-CH2F、-CHF2、-CH2CH2F、-CHFCH3、-CH2CHF2、-CH(CH3)(CH2F)、-CH2CHFCH3、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-CH2-OH、-CH2CH2-OH、-CH2-C(CH3)2(OH)、-CH2-CH(CH3)(OH)、-CH(CH3)CH2OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH(CH3)CH2OCH3、-CH2-CH(CH3)(OCH3)、-CH2CH2-O-CH2CH3、-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)。31. The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 1-6 alkyl, optionally replaced by halogen, -OR b or -OC(O)-N(R b ) 2 substitutions, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CH 2 CH 2 F, -CHFCH 3 , -CH 2 CHF 2 , -CH(CH 3 )( CH2F ) , -CH2CHFCH3 , -CH2CF3 , -CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , -C2F5 , -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -C(CH 3 ) 2 (OH), -CH 2 -CH(CH 3 )(OH), -CH(CH 3 )CH 2 OH, - CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3 , -CH(CH 3 )CH 2 OCH 3 , -CH 2 -CH(CH 3 )(OCH 3 ), -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -OC(O)-NH 2 , -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N( CH 2 CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ), -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ) .
32.实施方案1-28任一项的化合物或其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 32. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 2-6 alkenyl or -C 2-6 alkynyl, such as but not limited to
33.实施方案1-28任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4为-C(O)-ORb和-C(O)-N(Rb)2，例如但不限于-C(O)-OCH3、-C(O)-OCH2CH3、-C(O)-NH2、-C(O)-NH-CH3、 -C(O)-N(CH3)2、-C(O)-N(CH2CH3)2、-C(O)-N(CH2CH3)(CH3)。33. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C(O)-OR b and -C(O)-N(R b ) 2 , such as but not limited to -C(O)-OCH 3 , -C(O)-OCH 2 CH 3 , -C(O)-NH 2 , -C(O)-NH-CH 3 , -C(O)-N(CH 3 ) 2 , -C(O)-N(CH 2 CH 3 ) 2 , -C(O)-N(CH 2 CH 3 )(CH 3 ).
34.实施方案1-28任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4选自-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基和-(CH2)p-5-10元杂芳基，其中p选自0、1或2，例如但不限于环丙基、环丁基、环戊基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、氧杂或氮杂环丁基、氧杂或氮杂环戊基、氧氮杂环戊基、氧杂或氮杂环己烷、-CH2-氧杂或氮杂环丁烷、-CH2-氧杂或氮杂环戊烷、吡唑基、-CH2-吡唑基，其中的-C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代。34. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl and -(CH 2 ) p -5-10 membered heteroaryl, wherein p is selected from 0, 1 or 2, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, oxa or azetidinyl, oxa or azetidinyl, oxazacyclopentyl , oxa or azepine, -CH 2 -oxa or azetidine, -CH 2 -oxa or azetidine, pyrazolyl, -CH 2 -pyrazolyl, wherein -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitution.
34-1.实施方案1-28任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4为-C3-6环烷基，任选被卤素、-CN、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代，例如但不限于环丙基、环丁基、环戊基、环己基，或各自独立地被选自以下的取代基取代的环丙基、环丁基、环戊基或环己基：F、Cl、Br、I、-CN、-OH、-O-CH3、-O-CH2CH3、-O-CH2CH2CH3、-NH2、-NH(CH3)、-N(CH3)2、-NH-CH2CH3、-N(CH2CH3)2、-N(CH3)(CH2CH3)。34-1. The compound of any one of embodiments 1-28 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 3-6 cycloalkyl, optionally replaced by halogen, -CN, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N(R b ) 2 substitutions, such as but not limited to Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl each independently substituted by a substituent selected from the group consisting of F, Cl, Br, I , -CN, -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH 2 CH 2 CH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ).
35.实施方案34-1的化合物或其药学上可接受的盐或溶剂合物，其中R4为-C3-6环烷基，任选被卤素或-ORb取代，例如但不限于环丙基、环丁基、环戊基、被F取代的环丙基、环丁基或环戊基、被-O-CH3取代的环丙基、环丁基或环戊基。35. The compound of embodiment 34-1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 3-6 cycloalkyl, optionally substituted by halogen or -OR b , such as but not limited to ring Propyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclobutyl or cyclopentyl substituted by F, cyclopropyl, cyclobutyl or cyclopentyl substituted by -O- CH3 .
36.实施方案1-28任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4选自-C1- 6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2-6烯基、-C2- 6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH(CH3)(CH3)、-CH2CH(CH3)CH3、-C(CH3)3、-CH2F、-CHF2、-CH2CH2F、-CHFCH3、-CH2CHF2、-CH(CH3)(CH2F)、-CH2CHFCH3、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-C2F5、-CH2-OH、-CH2CH2-OH、-CH2-C(CH3)2(OH)、-CH2-CH(CH3)(OH)、-CH(CH3)CH2OH、-CH2-O-CH2CH3、-CH2CH2-O-CH3、-CH(CH3)CH2OCH3、-CH2-CH(CH3)(OCH3)、-CH2CH2-O-CH2CH3、-CH2-O-C(O)-NH2、-CH2CH2-O-C(O)-NH2、-CH2-O-C(O)-N(CH3)2、-CH2CH2-O-C(O)-N(CH3)2、-CH2-O-C(O)-N(CH2CH3)2、-CH2CH2-O-C(O)-N(CH2CH3)2、-CH2-O-C(O)-N(CH2CH3)(CH3)、-CH2CH2-O-C(O)-N(CH2CH3)(CH3)、 -C(O)-NH2、-C(O)-NH-CH3、-C(O)-N(CH3)2、-C(O)-N(CH2CH3)2、-C(O)-N(CH2CH3)(CH3)、环丙基、环丁基、环戊基、环己基，或各自独立地被选自以下的取代基取代的环丙基、环丁基、环戊基或环己基：F、Cl、Br、I、-CN、-OH、-O-CH3、-O-CH2CH3和-O-CH2CH2CH3。36. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is selected from -C 1- 6 alkyl, -C 2-6 alkenyl, -C 2- 6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, -C 2-6 alkenyl, -C 2- 6 alkyne and -C 3-6 cycloalkyl are each independently optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )(CH 3 ), -CH 2 CH(CH 3 )CH 3 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CH 2 CH 2 F, -CHFCH 3 , -CH 2 CHF 2 , -CH(CH 3 )(CH 2 F), -CH 2 CHFCH 3 , -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 , -CH 2 -OH, -CH 2 CH 2 -OH, -CH 2 -C(CH 3 ) 2 (OH), -CH 2 -CH(CH 3 )(OH), -CH(CH 3 )CH 2 OH, -CH 2 -O-CH 2 CH 3 , -CH 2 CH 2 -O-CH 3. -CH(CH 3 )CH 2 OCH 3 , -CH 2 -CH(CH 3 )(OCH 3 ), -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -OC(O)-NH 2. -CH 2 CH 2 -OC(O)-NH 2 , -CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 ) 2 , -CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ), -CH 2 CH 2 -OC(O)-N(CH 2 CH 3 )(CH 3 ), -C(O)-NH 2 , -C(O)-NH-CH 3 , -C(O)-N(CH 3 ) 2 , -C(O)-N(CH 2 CH 3 ) 2 , -C (O)-N(CH 2 CH 3 )(CH 3 ), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropyl, cyclobutyl each independently substituted by a substituent selected from the following radical, cyclopentyl or cyclohexyl: F, Cl, Br, I, -CN, -OH, -O-CH 3 , -O-CH 2 CH 3 and -O-CH 2 CH 2 CH 3 .
37.实施方案36的化合物或其药学上可接受的盐或溶剂合物，其中R4为-C1-6烷基，任选被卤素或-ORb、优选任选被F取代。 37. The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 1-6 alkyl optionally substituted by halogen or -OR b , preferably optionally substituted by F.
38.实施方案1的化合物或其药学上可接受的盐或溶剂合物，其中Z为Ra为F，由此式A具有式I：例如其中X、Y、R1、R2、R3、R4、R5、R6、n和m如以上实施方案1-37相应所定义。38. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Ra is F , whereby formula A has formula I: For example wherein X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and m are as defined for embodiments 1-37 above, respectively.
39.实施方案38的化合物或其药学上可接受的盐或溶剂合物，其为式I-1：39. The compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, which is of formula I-1:
例如 For example
40.实施方案38的化合物或其药学上可接受的盐或溶剂合物，其为式I-2：40. The compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, which is of formula I-2:
例如 For example
41.实施方案38的化合物或其药学上可接受的盐或溶剂合物，其为式I-3：41. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, which is of formula I-3:
例如 For example
42.实施方案38的化合物或其药学上可接受的盐或溶剂合物，其为式I-4：42. The compound of embodiment 38, or a pharmaceutically acceptable salt or solvate thereof, which is of formula I-4:
例如 For example
42-1.实施方案38的化合物或其药学上可接受的盐或溶剂合物，其为式I-5：42-1. The compound of embodiment 38 or a pharmaceutically acceptable salt or solvate thereof, which is formula I-5:
例如 For example
43.实施方案38至42-1任一项的化合物或其药学上可接受的盐或溶剂合物，其中43. The compound of any one of embodiments 38 to 42-1, or a pharmaceutically acceptable salt or solvate thereof, wherein
Y为O；Y is O;
R1选自H、-C1-6烷基和-C3-6环烷基，如实施方案11和15所示例；R is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, as exemplified in embodiments 11 and 15;
R2为H； R2 is H;
R3选自H、卤素、-ORb或被-O-C(O)-N(Rb)2取代的-C1-6烷基；或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＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；优选R3为F、-CH2F、-CHF2、＝CHF，如实施方案21、23、26-1-3和27所示例；R 3 is selected from H, halogen, -OR b or -C 1-6 alkyl substituted by -OC(O)-N(R b ) 2 ; or two R 3 connected to the same carbon atom form = C(R c ) 2 , wherein each R c is independently selected from H, F, Cl, Br, I, -C 1-6 alkyl optionally substituted by halogen, such as =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; preferably R 3 is F, -CH 2 F, -CHF 2 , =CHF, as in embodiments 21, 23, 26-1- Examples in 3 and 27;
R4选自-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2- 6烯基、-C2-6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代，优选任选被卤素、-ORb或-O-C(O)-N(Rb)2取代的-C1-6烷基，如实施方案36所示例。R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , as exemplified in embodiment 36.
44.实施方案38-43任一项的化合物或其药学上可接受的盐或溶剂合物，其中R5选自H或卤素，优选为F。44. The compound according to any one of embodiments 38-43, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from H or halogen, preferably F.
45.实施方案38-44的化合物或其药学上可接受的盐或溶剂合物，其中R6为卤素，例如F、Cl、Br、I。45. The compound of embodiment 38-44, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is halogen, eg F, Cl, Br, I.
46.实施方案38-44的化合物或其药学上可接受的盐或溶剂合物，其中R6为-C1-6烷基，例如但不限于-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3。46. The compound of embodiment 38-44 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -C 1-6 alkyl, such as but not limited to -CH 3 , -CH 2 CH 3 , -CH 2CH2CH3 , -CH2CH2CH2CH3 . _ _ _
47.实施方案38-44的化合物或其药学上可接受的盐或溶剂合物，其中R6为-C2-6炔基， 例如但不限于优选 47. The compound of embodiment 38-44, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is -C 2-6 alkynyl, For example but not limited to preferred
48.实施方案1的化合物或其药学上可接受的盐或溶剂合物，其中Z为Ra为F，由此式A具有式II：例如其中X、Y、R1、R2、R3、R4、R7、R8、n和m各自如以上实施方案1-37相应所定义。48. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Ra is F , whereby formula A has formula II: For example wherein X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , n and m are each as defined in Embodiments 1-37 above respectively.
49.实施方案48的化合物或其药学上可接受的盐或溶剂合物，其为式II-1：49. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, which is of formula II-1:
例如 For example
50.实施方案48的化合物或其药学上可接受的盐或溶剂合物，其为式II-2：50. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, which is of formula II-2:
例如 For example
51.实施方案48的化合物或其药学上可接受的盐或溶剂合物，其为式II-3： 51. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, which is of formula II-3:
例如 For example
52.实施方案48的化合物或其药学上可接受的盐或溶剂合物，其为式II-4：52. The compound of embodiment 48, or a pharmaceutically acceptable salt or solvate thereof, which is of formula II-4:
例如 For example
52-1.实施方案48的化合物或其药学上可接受的盐或溶剂合物，其为式II-5：52-1. The compound of embodiment 48 or a pharmaceutically acceptable salt or solvate thereof, which is of formula II-5:
例如 For example
53.实施方案48至52-1任一项的化合物或其药学上可接受的盐或溶剂合物，其中53. The compound of any one of embodiments 48 to 52-1, or a pharmaceutically acceptable salt or solvate thereof, wherein
Y为O；Y is O;
R1选自H、-C1-6烷基和-C3-6环烷基，如实施方案15所示例；R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, as exemplified in embodiment 15;
R2为H； R2 is H;
R3选自H、卤素、-ORb或被-O-C(O)-N(Rb)2取代的-C1-6烷基；或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＝CH2、＝CHF、＝CF2、＝CCl2、＝C(CH3)2、＝C(CF3)2；优选R3为F、-CH2F、-CHF2、＝CHF如实施方案21、23、26-1-3和27所示例；R 3 is selected from H, halogen, -OR b or -C 1-6 alkyl substituted by -OC(O)-N(R b ) 2 ; or two R 3 connected to the same carbon atom form = C(R c ) 2 , wherein each R c is independently selected from H, F, Cl, Br, I, -C 1-6 alkyl optionally substituted by halogen, such as =CH 2 , =CHF, =CF 2 , =CCl 2 , =C(CH 3 ) 2 , =C(CF 3 ) 2 ; preferably R 3 is F, -CH 2 F, -CHF 2 , =CHF as in embodiments 21, 23, 26-1-3 and 27 example;
R4选自-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2- 6烯基、-C2-6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代，优选任选被卤素、-ORb或-O-C(O)-N(Rb)2取代的-C1-6烷基，如实施方案36所示例。R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 , as exemplified in embodiment 36.
54.实施方案48-53任一项的化合物或其药学上可接受的盐或溶剂合物，其中R7为H。 54. The compound of any one of embodiments 48-53, wherein R7 is H, or a pharmaceutically acceptable salt or solvate thereof.
55.实施方案48-53任一项的化合物或其药学上可接受的盐或溶剂合物，其中R7为卤素，优选为F。55. The compound according to any one of embodiments 48-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is halogen, preferably F.
56.实施方案48-55任一项的化合物或其药学上可接受的盐或溶剂合物，其中R8为卤素，例如F、Cl、Br和I。56. The compound according to any one of embodiments 48-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 is halogen such as F, Cl, Br and I.
57.化合物，选自下文实施例1-232的化合物或其药学上可接受的盐或溶剂合物。57. A compound selected from the compounds of Examples 1-232 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 compound of the present invention covers each of the above independent embodiments or each specific embodiment, and also covers any combination or sub-combination of the above-mentioned embodiments or specific embodiments, and also covers any of the above preferred or exemplary embodiments. Any combination of the given 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、尤其是KRas-G12D突变蛋白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、尤其KRas-G12D突变蛋白介导的或得益于Ras突变、尤其KRas-G12D突变蛋白抑制的疾病或病症，例如本文所定义的癌症或肿瘤。As mentioned above, Ras muteins, especially KRas muteins, are known to play a role in tumorigenesis as well as a variety of other diseases. Surprisingly, we have found that the compounds of the present invention having the above-mentioned structural features can potently inhibit cell proliferation in cell lines carrying KRas mutant proteins, especially KRas-G12D mutant proteins, thereby being useful in preventing, suppressing and/or treating It has potential value as anti-proliferation, pro-apoptosis and/or anti-invasion drugs in related tumor diseases. In particular, the compounds of the invention are expected to be useful in the prophylaxis or treatment of those diseases or conditions which are mediated by or benefit from inhibition of a Ras mutein, especially a KRas-G12D mutein, such as defined herein cancer or tumor.
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 G12D突变细胞AGS细胞增殖抑制测定法中显示对Ras突变、尤其是KRas G12D突变细胞具有增殖抑制活性，IC50值低于10μM，例如低于5μM，例如0.001～5μM、0.01～5μM；优选低于1μM，例如0.001～1μM、0.01～1μM；更优选低于0.5μM，例如0.001～0.5μM、0.01～0.5μM、0.01～0.2μM、0.01～0.1μM、0.01～0.05μM，例如按照活性实施例1所述方法测定；以及High mutein inhibitory activity: the compounds of the present invention, especially the compounds specifically exemplified in the context herein, show proliferation inhibitory activity on Ras mutant cells, especially KRas G12D mutant cells, in the KRAS G12D mutant cell AGS cell proliferation inhibition assay, The IC50 value is lower than 10 μM, such as lower than 5 μM, such as 0.001-5 μM, 0.01-5 μM; preferably lower than 1 μM, such as 0.001-1 μM, 0.01-1 μM; more preferably lower than 0.5 μM, such as 0.001-0.5 μM, 0.01-0.5 μM, 0.01～0.2μM, 0.01～0.1μM, 0.01～0.05μM, for example, determined according to the method described in Activity Example 1; and
在KRAS G12D突变的AGS(3D)细胞增殖抑制测定法中显示对Ras突变、尤其是KRas G12D突变细胞具有增殖抑制活性，IC50值为0.001～5μM，例如0.01～5μM，例如0.001～0.5μM，优选0.01～0.2μM，更优选0.01～0.1μM，最优选0.01～0.05μM，如活性实施例4所示例；In the AGS (3D) cell proliferation inhibition assay of KRAS G12D mutation, it shows proliferation inhibitory activity against Ras mutation, especially KRas G12D mutant cells, with an IC50 value of 0.001-5 μM, such as 0.01-5 μM, such as 0.001-0.5 μM, preferably 0.01-0.2 μM, more preferably 0.01-0.1 μM, most preferably 0.01-0.05 μM, as exemplified in Activity Example 4;
●明显令人满意的安全性，药物相互作用的风险降低，毒性和/或副作用明显减少，如活性实施例3所验证；●Apparently satisfactory safety, reduced risk of drug interaction, significantly reduced toxicity and/or side effects, as verified in Activity Example 3;
●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，如活性实施例2所验证；和/或●Good pharmacokinetic properties, such as longer t 1/2 , so that, for example, the dosing interval can be increased, and the half-life can be longer, so that patients have better compliance, as verified in Example 2 ;and / or
●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，如下文活性实施例2所验证。●AUC 0-t data with the best comprehensive effect of safety/activity, better druggability and higher bioavailability, as verified by Activity Example 2 below.
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 the following technical solutions in various 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 a medicament
一方面，本发明提供了本发明化合物或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, or 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或其药学上可接受的盐或溶剂合物，用作KRas突变蛋白抑制剂、更具体地KRAS G12D抑制剂。In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use as a KRas mutein inhibitor, more specifically a KRAS G12D inhibitor.
另一方面，本发明提供本发明化合物或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、更具体地KRAS G12D突变蛋白介导的或得益于Ras突变、具体地KRas突变蛋白、更具体地KRAS G12D突变蛋白抑制的疾病或病症。In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, for treating and/or preventing Ras mutein, specifically KRas mutein, more specifically KRAS G12D mutein-mediated Or a disease or condition benefiting from inhibition of a Ras mutation, specifically a KRas mutein, more specifically a KRAS G12D mutein.
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、更具体地KRAS G12D突变蛋白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、更具体地KRAS G12D突变蛋白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 a specific embodiment, the present invention provides a method for treating and/or preventing Ras mutant protein, specifically KRas mutant protein, more specifically KRAS G12D mutant protein, which promotes the occurrence and development of the disease or inhibits Ras mutation Proteins, specifically KRas mutant proteins, more specifically KRAS G12D mutant proteins will reduce the incidence of disease, reduce or eliminate the compounds of the present invention for diseases such as tumors or cancers, including but not limited to: lung cancer, pulmonary Adenocarcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine 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 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 for the treatment of patients with pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, cholangiocarcinoma, endometrial cancer, ovarian cancer, leukemia; most preferably selected from the group consisting of pancreatic cancer, colon cancer, rectal cancer, Compounds of formula (I) or their isomers, pharmaceutically acceptable salts or solvates thereof 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(A)化合物或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或KRas G13D突变、尤其KRas G12D突变介导的疾病，例如肿瘤或癌症。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (A) as defined above or 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 or KRas G13D mutations, especially KRas G12D mutations, 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 above-mentioned pharmaceutical compositions of the present invention 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 as tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. The composition may contain conventional components in pharmaceutical formulations, such as diluents (such as glucose, lactose or mannitol), carriers, pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, Wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, coloring agents, perfuming 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, in 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 dosing 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 particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors well known to medical practitioners. Optimal dosage levels and frequency of administration of a compound or pharmaceutical composition of this invention can be determined by those skilled in the art by 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 by any suitable means, 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 can also be taken. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, the 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, suitable dosage ranges of the compounds of the present invention can be routinely determined by those skilled in the art, and may be, for example, 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 understood that the dosage is based on the weight of the free base, excluding any hydrate or solvate thereof, unless the instructions state that the dosage is based on the salt, hydrate or solvent compound weight.
治疗方法和用途Treatments 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或KRas G13D突变、尤其是KRas G12D的抑制作用。As mentioned above, the compounds of the invention and the compounds of various specific embodiments thereof, 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 Or the inhibitory effect of KRas G13D mutation, especially KRas G12D.
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或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、优选KRas G12D突变的活性。Therefore, in another aspect, the present invention provides a method for inhibiting Ras mutations in cells, especially KRas mutations, preferably KRas G12D mutations, comprising allowing the cells to react with a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof contact to inhibit the activity of Ras mutations, especially KRas mutations, preferably KRas G12D mutations, 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或其药学上可接受的盐或溶剂合物、或包含本发明的化合物或其药学上可接受的盐或溶剂合物的药物组合物。Based on the same nature, 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 the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof , or a pharmaceutical composition comprising a compound of the present invention or 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、优选KRas G12D突变介导的疾病的方法，包括向有需要的对象施用治疗有效量的本发明式(A)化合物或其药学上可接受的盐或溶剂合物、或包含本发明的式(A)化合物或其药学上可接受的盐或溶剂合物的药物组合物。In another aspect, the present invention provides a method for treating and/or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations, comprising administering a therapeutically effective amount of the present invention's formula ( A) a compound or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of formula (A) of the present invention or a pharmaceutically acceptable salt or solvate thereof.
另一方面，本发明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、或包含本发明的化合物或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 G12D突变，或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、尤其KRas突变、优选KRas G12C、KRas G12D、KRas G12V或KRas G13D、最优选KRas G12D突变介导的疾病。 In another aspect, the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, For suppressing Ras mutation in cells, especially KRas mutation, preferably KRas G12D mutation, or for suppressing abnormal cell growth in mammals, or for treating and/or preventing Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, most preferably KRas G12D mutation mediated disease.
另一方面，本发明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、或包含本发明的化合物或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、优选KRas G12D突变介导的疾病的药物中的用途。In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the preparation of Use in medicines for treating and/or preventing diseases mediated by Ras mutations, especially KRas mutations, preferably KRas G12D mutations.
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或KRas G13D、最优选KRas G12D突变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 of the above-mentioned methods and technical solutions provided by the present invention, the abnormal cell growth may be mediated by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, most preferably KRas G12D mutation Disease especially refers 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, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer , gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, Adrenal gland 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 tumor (CNS), original Primary CNS lymphoma, spinal tumor, 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、优选KRas G12D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 application technical scheme provided by the present invention above, the abnormal cell growth or the disease mediated by Ras mutation, especially KRas mutation, preferably KRas G12D is preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, Cancer, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, 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-G12D突变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-G12D突变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 the above-mentioned methods and application technical solutions for treating or preventing cancer or tumors by inhibiting KRas-G12D mutation. In a further preferred embodiment, the present invention provides the above-mentioned methods and application technical solutions for treating or preventing pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma and cholangiocarcinoma by inhibiting KRas-G12D mutation.
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 G12D的研究工具化合物的用途。因此，本发明涉及本发明化合物或其药学上可接受的盐或溶剂合物作为KRas抑制剂、特别是KRas G12D抑制剂的体外用途，特别地涉及本发明化合物或其药学上可接受的盐或溶剂合物作为KRas抑制剂、特别是KRas G12D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、特别是KRas G12D的方法，特别是体外方法，该方法包括将本发明的化合物或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 present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor in research, especially as a research tool compound for inhibiting KRas G12D. Therefore, the present invention relates to the in vitro use of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof as a KRas inhibitor, especially a KRas G12D inhibitor, in particular to the compound of the present invention or a pharmaceutically acceptable salt or In vitro use of the solvate as a research tool compound for KRas inhibitors, especially KRas G12D inhibitors. The present invention also relates to a method, especially an in vitro method, of inhibiting KRas, especially KRas G12D, which method comprises administering a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof to a sample (eg, a biological sample). It is to be understood that the term "in vitro" is used in this particular context in the sense of "in vitro of a living human or animal", which specifically includes experiments with cells, cellular or subcellular extracts and/or biomolecules in artificial environments, For example, aqueous solutions or media may be provided in flasks, test tubes, petri dishes, microtiter plates, and the like.
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 invention may be administered as the sole active ingredient or in combination with another drug or therapy.
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或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、最优选KRas-G12D突变介导的疾病。Thus, in another aspect, the present invention provides a pharmaceutical combination comprising or consisting of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and a further active agent. The drug combination is used to inhibit abnormal cell growth in mammals Long, or for the treatment and/or prevention of diseases mediated by Ras mutations, preferably KRas mutations, most preferably KRas-G12D mutations.
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 which is compatible with the compounds of the invention, i.e. does not adversely affect each other, or has complementary activities. ) compounds, for example, these active agents may be compounds known to modulate other biologically active pathways, or may 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 invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiation therapy, 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。The other active agents used in combination with the present invention may be administered simultaneously, separately or sequentially with the compound of the present 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 administered separately in different discrete units with the compound of the present invention, such as a combination product, preferably in the form of a kit, which may be administered simultaneously or simultaneously when administered separately. Performed sequentially, the sequential 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 invention and other active agents may be obtained (i) (i) before sending the combination product to a physician (for example, in the case of a kit comprising the compound of the invention and the additional drug); (ii) immediately before administration. Added by the physician himself (or under the direction of the physician); (iii) by the patient himself, for example during the sequential administration of the compound of the invention and the other active agent 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 may also be combined with antineoplastic 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。Therefore, in another aspect, the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, and The means for separately containing the compositions, such as containers, dispenser bottles or discrete foil packs, eg blister packs for packaging tablets, capsules and the like, also includes instructions for use. The kits of the invention are 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或KRas G13D、最优选KRas G12D突变介导的疾病如上文对于本发明方法和用途所定义。For the above-mentioned technical scheme of the pharmaceutical composition, pharmaceutical combination or kit of the present invention, the abnormal cell growth involved may be caused by Ras mutation, especially KRas mutation, preferably KRas G12C, KRas G12D, KRas G12V or KRas G13D, most Preferably the KRas G12D mutation mediated disease is 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 present invention described above, the compounds of the examples herein are preferred.
本发明化合物的制备方法The preparation method of the compound 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。In another aspect, the present invention also provides a process for the preparation of the compounds defined in the present invention.
本发明的化合物或其药学上可接受的盐或溶剂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 compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can be prepared by various 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, for example Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", page 7 Edition, Wiley, 2013). For the individual reaction steps of the respective general synthetic schemes, suitable reaction conditions 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 can 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, for example, inert to the reagents used). and solvents or diluents that 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 nature of the reactants. , -20 to 40° C. or reflux temperature), at atmospheric pressure or in a closed vessel, 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 starting materials and reagents used in the preparation of compounds are commercially available, or compounds known in the literature, or can be obtained by the following methods, 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 as being suitable for the particular type of reaction involved, such as 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。Starting materials and intermediates in the synthetic reaction schemes can be isolated and purified, if necessary, by conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. If 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 admixing 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)。Those skilled in the art will recognize the presence or absence of stereogenic centers in the compounds of the invention. At all stages of the reaction, the mixture of isomers formed can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as 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。Where a mixture of stereoisomers is produced during the preparation of a compound of the invention, 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, Using well-known methods, such as formation of diastereomeric pairs, by salification with an optically active acid, 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 a specific reactive group with an appropriate protecting group to avoid interference with the reaction of other reactive groups. Suitable protecting groups and methods of protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd Edition), 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 illustrate general synthetic schemes for the synthesis of compounds of the invention. Other routes and other reactants and intermediates known to those of ordinary skill in the art may also be used to obtain 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、X和Y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 8. X and Y are as defined above for the compounds of the invention, wherein PG represents a suitable protecting group which can be determined by a person skilled in the art based on knowledge of organic chemistry.
合成方案ASynthetic Scheme A
本发明通式I及II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 general formulas I and II of the present invention can be prepared according to the following schemes or suitable variants 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Boc保护的3,8-二氮杂环[3.2.1]辛烷，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 was introduced into Boc-protected 3,8-diazacyclo[3.2.1]octane 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 and the like.
在步骤B中，使化合物2与相应的醇类、胺类或者硫醇类化合物、在例如DIEA/二氧六环中、在NaH/THF等条件下反应，得到化合物3。其中相应的醇类、胺类或者硫醇类化合物商购可得，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偶联反应引入酚类化合物，得到化合物4或者5。在步骤D中，将化合物4或者5脱除所带保护基，得到通式I或II的化合物。In step B, compound 2 is reacted with corresponding alcohols, amines or thiols in, for example, DIEA/dioxane, NaH/THF, etc., to obtain compound 3. Wherein the corresponding alcohols, amines or thiols are commercially available, or can be obtained according to the methods used in the examples herein or methods similar thereto, or can be obtained according to the methods in related literatures in the field of organic chemistry. The latter introduces phenolic compounds via Suzuki-Miyaura coupling reaction in Step C to give compounds 4 or 5. In step D, the protective group of compound 4 or 5 is removed to obtain the compound of general formula I or II.
典型的Suzuki钯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，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 palladium coupling conditions are well known in the art and those skilled in the art know of a variety of conditions to facilitate such cross-coupling reactions , for example Pd(dtbpf) Cl2 / K3PO4 /dioxane /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 , tetraphenylphosphinepalladium, and palladium(II) acetate, etc.; if desired, suitable ligands may include Tricyclohexylphosphine, triphenylphosphine, etc.; suitable bases also include potassium fluoride, cesium carbonate, sodium carbonate, potassium tert-butoxide, potassium phosphate monohydrate, and the like.
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，当化合物携带保护基PG为MOM等酸敏感性保护基时，可以在例如三氟乙酸或者盐酸等条件下同时一步脱除PG及Boc得到最终化合物；当化合物携带保护基PG为TIPS等非酸性敏感保护基时，化合物4或者5需要通过多步反应脱除保护基，例如通过CsF等试剂脱除TIPS保护，再通过三氟乙酸或者盐酸等条件脱除Boc，得到最终化合物。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 the compound carrying a protecting group PG is an acid-sensitive protecting group such as MOM, the final compound can be obtained by removing PG and Boc in one step at the same time under conditions such as trifluoroacetic acid or hydrochloric acid; In the case of an acid-sensitive protecting group, compound 4 or 5 needs to be deprotected through a multi-step reaction, such as removing TIPS protection by a reagent such as CsF, and then removing Boc by trifluoroacetic acid or hydrochloric acid to obtain the final compound.
合成方案BSynthesis Scheme B
本发明的通式I及II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 I and II of the present invention can also be prepared according to the following schemes or suitable variants thereof.
在步骤A中，化合物2商购可得或可以按照有机化学领域众所周知的标准方法、或合成方案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等条件下进行氟代，得到化合物6。化合物6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或者II。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 is commercially available or can be obtained according to standard methods well known in the field of organic chemistry, or the method steps described in Synthetic Scheme A. Compound 2 is fluorinated by halogen exchange reaction under conditions such as KF/DMSO to obtain compound 6. Compound 6 then undergoes the Suzuki-Miyaura coupling reaction in Step B, the aromatic nucleophilic substitution reaction in Step C, and the deprotecting group removal reaction in Step D to obtain the final compound I or II. The typical conditions of the Suzuki-Miyaura coupling reaction, nucleophilic substitution reaction and deprotection 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.
合成方案CSynthesis Scheme C
本发明通式I及II化合物的合成还可以根据以下方案或其适当变体制备。
The synthesis of compounds of general formulas I and II of the present invention can also be prepared according to the following schemes or appropriate variants thereof.
本方案合成从化合物6开始，依次经过步骤A的芳香亲核取代、步骤B的Suzuki-Miyaura偶联反应及步骤C的保护基脱除反应，得到通式I或者II的化合物。此方案中涉及偶联反应、亲核取代反应及保护基脱除反应的典型条件与合成方案A中所述相关反应条件类似，可以参照实施。The synthesis of this scheme starts from compound 6, and sequentially undergoes the aromatic nucleophilic substitution in step A, the Suzuki-Miyaura coupling reaction in step B, and the deprotection reaction in step C to obtain the compound of general formula I or II. The typical conditions involved in the coupling reaction, nucleophilic substitution reaction and deprotection reaction in this scheme are similar to the relevant reaction conditions described in Synthesis Scheme A, and can be referred to for implementation.
以上合成方案中所涉及的Suzuki-Miyaura偶联、芳香亲核取代以及保护剂脱除等反应的典型反应条件及所用试剂均是本领域熟知的，属于本领域技术人员的常规经验范围，或者可以由本领域技术人员基于本领域此类反应的典型条件、基于所用原料和目标产物的特征而做出适当改变而确定。The typical reaction conditions and the reagents used in the Suzuki-Miyaura coupling involved in the above synthesis scheme, aromatic nucleophilic substitution, and protective agent removal are well known in the art, and belong to the routine experience of those skilled in the art, or can It is determined by those skilled in the art with appropriate changes based on the typical conditions for this type of reaction in the art, based on the characteristics of the starting materials used and the target product.
合成方案DSynthetic Scheme D
本发明中涉及轴手性的通式I及II化合物的合成还可以根据以下方案或其适当变体制备。

The synthesis of compounds of general formulas I and II involving axial chirality in the present invention can also be prepared according to the following schemes or appropriate variants thereof.

本方案中化合物7的合成参照方案B中所述，在步骤C中化合物7经SFC拆分得到轴手性纯中间体化合物9和10。在后续合成中使用中间体9通过步骤D及E制备最终化合物。步骤D和E所涉及亲核取代反应及保护基脱出反应参照合成方案A中所述方法进行。The synthesis of compound 7 in this scheme refers to that described in scheme B. In step C, compound 7 is resolved by SFC to obtain axichiral pure intermediate compounds 9 and 10. The final compound was prepared via steps D and E using intermediate 9 in the subsequent synthesis. The nucleophilic substitution reaction and protecting group removal reaction involved in steps D and E are carried out by referring to the method described in Synthesis Scheme A.
合成实施例Synthetic 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 embodiment. It should be noted that the following examples are illustrative and should not be considered as limiting the protection 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)；CDCl3(氘代氯仿)；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(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)；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(口服给药)；POCl3(三氯氧磷)；r.t.(室温)；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); CDCl 3 (deuterochloroform); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMF (N,N -dimethylformamide); DMSO (dimethylsulfoxide); DMSO- d6 (hexadeuteriodimethylsulfoxide); EA (ethyl acetate); EDTA-K2 (dipotassium ethylenediaminetetraacetic acid) ; EtOH (ethanol); FCC (flash column chromatography); g (gram); h (hour); HCl (hydrogen chloride); HCl-MeOH or HCl/MeOH (hydrogen chloride methanol solution); HLM (human liver microsome); H 2 O (water); H 2 SO 4 (sulfuric acid); IV (intravenous administration); K 2 CO 3 (potassium carbonate); LCMS (liquid mass spectrometry); Online); MeOH (methanol); Methanol-d 4 (tetradeuteriomethanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters); mmol (millimole); MOM (methoxy 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-butylphosphino)ferrocenepalladium dichloride); PdCl 2 (dppf) or Pd(dppf)Cl 2 (1,1'-bisbis Pd(OAc) (palladium acetate); Pd(PPh 3 ) 4 (tetraphenylphosphine palladium); PE (petroleum ether); PO (oral administration); POCl 3 (phosphorus oxychloride); rt (room temperature); 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 (micromole).
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。名称或结构出现任何偏差并非有意，在这种情况下，结合上下文合理确定化合物的结构。In the following examples, the names and structures of the synthesized target compounds are given. Any deviation in name or structure is not intentional, in which case the structure of the compound is reasonably determined from the context.
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。The experimental methods for which specific conditions are not indicated in the following examples are usually in accordance with the conventional conditions of this type of reaction, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise stated, 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。The experimental materials and reagents used in the following examples can be obtained from commercially available channels if there is no special instructions, according to the prior art prepared by the method or according to the method disclosed in the present 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 Bruker (400MHz), and chemical shifts were expressed relative to deuterated solvent peaks (CDCl 3 : δ=7.26ppm; CD 3 OD: δ=3.31ppm; DMSO-d 6 δ (ppm): δ=2.50ppm) represents; liquid mass spectrometry is recorded with Aglient 1260 liquid chromatography+Aglient G6125B mass spectrometer LCMS liquid mass spectrometry instrument. Gas chromatography-mass spectrometry was performed using Shimadzu GCMS-QP2010SE.
手性分析方法：Chiral analysis method:
SFC-1：Waters UPCC,分析柱：Daicel100*3mm 3μm；流动相A：CO2，流动相B：EtOH(0.1％DEA)；流速：1.5mL/min；柱温：35℃；反压：1800psi；梯度：0-0.5min A/B＝95/5,0.5-5.5min A/B＝95/5-60/40,5.5-8.0min A/B＝60/40.SFC-1: Waters UPCC, analytical column: Daicel 100*3mm 3μm; mobile phase A: CO 2 , mobile phase B: EtOH (0.1% DEA); flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-0.5min A/B ＝95/5,0.5-5.5min A/B＝95/5-60/40,5.5-8.0min A/B＝60/40.
SFC-2：Waters UPCC,分析柱：Daicel100*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：0-8.0min A/B＝60/40.SFC-2: Waters UPCC, analytical column: Daicel 100*3mm 3μm; mobile phase A: CO 2 , mobile phase B: IPA (0.1% DEA); flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A/B =60/40.
SFC-3：Waters UPCC,分析柱：Daicel100*3mm 3μm；流动相A：CO2，流动相B：EtOH(0.1％DEA)；流速：1.5mL/min；柱温：35℃；反压：1800psi；梯度：0-8.0min A/B＝60/40.SFC-3: Waters UPCC, analytical column: Daicel 100*3mm 3μm; mobile phase A: CO 2 , mobile phase B: EtOH (0.1% DEA); flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A/B =60/40.
SFC-4：Waters UPCC,分析柱：Daicel100*3mm 3μm；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：0-0.5min A/B＝95/5,0.5-5.0min A/B＝95/5-60/40,5.0-8.0min A/B＝60/40.SFC-4: Waters UPCC, analytical column: Daicel 100*3mm 3μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.1% DEA); flow rate: 1.5mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-0.5min A/B ＝95/5,0.5-5.0min A/B＝95/5-60/40,5.0-8.0min A/B＝60/40.
SFC-5：Waters UPCC,分析柱：Daicel100*4.6mm 5μm；流动相A：CO2，流动相B：MeOH(0.1％DEA)；流速：2.0mL/min；柱温：35℃；反压：1800psi；梯度：0-8.0min A/B＝90/10.SFC-5: Waters UPCC, analytical column: Daicel 100*4.6mm 5μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.1% DEA); flow rate: 2.0mL/min; column temperature: 35°C; back pressure: 1800psi; gradient: 0-8.0min A/ B=90/10.
SFC-6：Waters UPCC,分析柱：Daicel100*4.6mm 5μm；流动相A：CO2，流动相B：MeOH；流速：1.5mL/min；柱温：40℃；反压：1800psi；梯度：0-8.0min A/B＝95/5.SFC-6: Waters UPCC, analytical column: Daicel 100*4.6mm 5μm; mobile phase A: CO 2 , mobile phase B: MeOH; flow rate: 1.5mL/min; column temperature: 40°C; back pressure: 1800psi; gradient: 0-8.0min A/B＝95/5 .
中间体A-I
Intermediate AI
(1R,5S)-3-(7-溴-2-氯-8-氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯
(1R,5S)-3-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert Butyl ester
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 2h. The reaction gradually changed from solid to liquid, and then continued to change to solid. After the LCMS monitoring reaction ended, it was washed with hot water (250mL), and the solid was collected by filtration to obtain 7-bromo-8-fluoroquinazoline-2,4(1H ,3H)-diketone (12 g, crude). 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。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)。At room temperature, DIPEA (13.5mL, 77.2mmol) was added to 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.0g, 15.4mmol) and POCl 3 (35.9 mL, 386.0mmol) of the mixture, heated to 100°C and stirred for 5h. After monitoring the completion of the reaction, it was concentrated to remove most of the solvent and base, and added ACN (10 mL) for dilution. Under stirring at room temperature, the resulting diluted solution was slowly added dropwise to water, and the solid was precipitated, 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).
步骤C：(1R,5S)-3-(7-溴-2-氯-8-氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯Step C: (1R,5S)-3-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8- tert-butyl carboxylate
在室温条件下，将(1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(5.2g,24.7mmol)加入至7-溴-2,4-二氯-8-氟喹唑啉(7.3g,24.7mmol)、DIPEA(9.6g,74.0mmol)和THF(30mL)的混合液中，并在室温条件下搅拌30min。监测反应结束后，加入EA(100mL)稀释，再加入水(50mL)，然后用EA(100mL×3)萃取，收集萃取液，食盐水(30mL)洗涤，无水Na2SO4干燥。过滤，减压浓缩，得到黄色固体(1R,5S)-3-(7-溴-2-氯-8-氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(11.1g,收率95％)。LCMS(ESI,m/z):473.0(M+H)。At room temperature, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.2g, 24.7mmol) was added to 7-bromo-2 , in a mixture of 4-dichloro-8-fluoroquinazoline (7.3g, 24.7mmol), DIPEA (9.6g, 74.0mmol) and THF (30mL), and stirred at room temperature for 30min. After monitoring the reaction, add EA (100 mL) for dilution, then add water (50 mL), then extract with EA (100 mL×3), collect the extract, wash with brine (30 mL), and dry over anhydrous Na 2 SO 4 . Filtration and concentration under reduced pressure gave yellow solid (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1 ] tert-butyl octane-8-carboxylate (11.1 g, yield 95%). LCMS (ESI, m/z): 473.0 (M+H).
中间体B-I
Intermediate BI
(1R,5S)-3-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯
(1R,5S)-3-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8- tert-butyl carboxylate
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2h，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)。Into a round bottom flask equipped with a stir bar was added methyl 2-amino-4-bromo-3,5-difluorobenzoate (10 g, 37.6 mmol) and THF (100 mL) at room temperature. 2,2,2-Trichloroacetyl isocyanate (8.5 g, 45.1 mmol) was added dropwise to the system with stirring at room temperature. The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to obtain methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate as a brown solid (crude ), 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2h，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 methyl 4-bromo-3,5-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate obtained in the previous step into a round bottom with a stirring bar The flask was charged, and NH 3 (100 mL, 7M MeOH solution) was added. The resulting mixture was stirred at room temperature for 2 h, and the reaction was complete as monitored by LCMS. Concentrated under reduced pressure, the resulting solid was slurried with methyl tert-butyl ether, filtered to obtain a light yellow solid 7-bromo-6,8-difluoroquinazoline-2,4-diol (14g, crude product), without further 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)。In a round bottom flask equipped with a stirrer bar was added 7-bromo-6,8-difluoroquinazoline-2,4-diol (14 g, crude), POCl 3 (112 mL). With stirring at room temperature, DIEA (28 mL) was added dropwise to the system. After the dropwise addition was completed, the temperature of the system was raised 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 precipitate was collected by filtration and dried to obtain a yellow solid 7-bromo-2,4-dichloro-6,8-difluoroquinazoline ( 11g, crude product), directly used in subsequent reactions. LCMS (ESI, m/z): 312.9 (M+H).
步骤D：(1R,5S)-3-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯Step D: (1R,5S)-3-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane -8-tert-butyl carboxylate
在置有搅拌子的圆底烧瓶中加入7-溴-2,4-二氯-6,8-二氟喹唑啉(11g，粗品)、DIEA(10mL)、THF(100mL)。室温搅拌下，缓慢加入(1R,5S)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(7.4g，35mmol)，所得混合物搅拌反应1h，将反应液浓缩，倒入至水中，过滤，干燥，得到产品黄色固体(1R,5S)-3-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(15g，四步总收率65％)。LCMS(ESI,m/z):499.0(M+H)。7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (11 g, crude product), DIEA (10 mL), THF (100 mL) were added to a round bottom flask equipped with a stirring bar. Under stirring at room temperature, (1R,5S)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (7.4g, 35mmol) was slowly added, and the resulting mixture was stirred and reacted for 1h, and the reaction The solution was concentrated, poured into water, filtered, and dried to obtain the product yellow solid (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3, tert-butyl 8-diazacyclo[3.2.1]octane-8-carboxylate (15 g, 65% overall yield over four steps). LCMS (ESI, m/z): 499.0 (M+H).
中间体B-II
Intermediate B-II
(1R,5S)-3-(7-溴-2,6,8-三氟喹唑啉-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯
(1R,5S)-3-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl acid
步骤A：(1R,5S)-3-(7-溴-2,6,8-三氟喹唑啉-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯Step A: (1R,5S)-3-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-tert-butyl carboxylate
将(1R,5S)-3-(7-溴-2-氯-6,8-二氟喹唑啉-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(18g,36.75mmol)、KF(42.7g,735mmol)和DMSO(200mL)在100℃条件下搅拌过夜。检测反应结束后，将反应液恢复至室温，然后慢慢倒入到在搅拌状态下的H2O(2L)水中，黄色固体析出，过滤，滤饼用水(200mL)洗涤后，收集滤饼，干燥后得到黄色的产物(1R,5S)-3-(7-溴-2,6,8-三氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(15.3g,收率88％)。LCMS(m/z):473.4(M+H)。(1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- tert-Butyl 8-carboxylate (18g, 36.75mmol), KF (42.7g, 735mmol) and DMSO (200mL) were stirred overnight at 100°C. After the detection reaction was completed, the reaction solution was returned to room temperature, and then slowly poured into H 2 O (2L) water under stirring, a yellow solid precipitated, filtered, and the filter cake was washed with water (200mL), and the filter cake was collected. After drying, the yellow product (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane was obtained tert-butyl alkane-8-carboxylate (15.3 g, yield 88%). LCMS (m/z): 473.4 (M+H).
中间体B-III
Intermediate B-III
(1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯
(1R,5S)-3-(2,6,8-Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy Base)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
步骤A：(1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯Step A: (1R,5S)-3-(2,6,8-Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl Base) oxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
室温条件下，将(1R,5S)-3-(7-溴-2,6,8-三氟喹唑啉-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(5g,10.56mmol)、(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(6.88g,12.68mmol)、Pd(OAc)2(237mg,1.06mmol)、BIDIME(698mg,2.11mmol)、K3PO4(6.73g,31.69mmol)溶于叔戊醇(60mL)，N2置换三次，加热至110℃搅拌过夜。检测反应结束后，过硅藻土，EA(50mL)洗涤，得到的有机相浓缩经FCC(SiO2,EA/PE＝0～50％)纯化，得到黄色固体(1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(4.3g,收率46％)。1H NMR(400MHz,CDCl3)δ7.74(dd,J＝9.1,5.6Hz,1H),7.39(dd,J＝9.8,1.7Hz,1H),7.34(d,J＝2.6Hz,1H),7.29(d,J＝8.7Hz,1H),7.10(d,J＝2.6Hz,1H),4.72(s,1H),4.40(s,2H),4.25–4.01(m,1H),3.77(d,J＝16.4Hz,1H),3.43(s,1H),2.04(d,J＝7.2Hz,3H),1.68(s,1H),1.57(s,4H),1.29(ddt,J＝14.1,9.8,7.3Hz,4H),1.11(dd,J＝7.5,1.3Hz,19H),1.05(s,2H),0.89(d,J＝7.4Hz,10H),0.84(d,J＝7.5Hz,9H),0.54(s,J＝7.4Hz,3H).LCMS(m/z):891.4(M+H)。At room temperature, (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane tert-butyl alkane-8-carboxylate (5g, 10.56mmol), (7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene- 1-yl)boronic acid (6.88g, 12.68mmol), Pd(OAc) 2 (237mg, 1.06mmol), BIDIME (698mg, 2.11mmol), K 3 PO 4 (6.73g, 31.69mmol) were dissolved in tert-amyl alcohol ( 60 mL), N 2 was replaced three times, heated to 110°C and stirred overnight. After the detection reaction was completed, it was washed with diatomaceous earth and EA (50 mL), and the obtained organic phase was concentrated and purified by FCC (SiO 2 , EA/PE=0-50%) to obtain a yellow solid (1R,5S)-3-( 2,6,8-Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalen-1-yl)quinoline Azolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.3 g, yield 46%). 1 H NMR (400MHz, CDCl 3 ) δ7.74(dd, J=9.1,5.6Hz,1H),7.39(dd,J=9.8,1.7Hz,1H),7.34(d,J=2.6Hz,1H) ,7.29(d,J=8.7Hz,1H),7.10(d,J=2.6Hz,1H),4.72(s,1H),4.40(s,2H),4.25–4.01(m,1H),3.77( d,J=16.4Hz,1H),3.43(s,1H),2.04(d,J=7.2Hz,3H),1.68(s,1H),1.57(s,4H),1.29(ddt,J=14.1 ,9.8,7.3Hz,4H),1.11(dd,J=7.5,1.3Hz,19H),1.05(s,2H),0.89(d,J=7.4Hz,10H),0.84(d,J=7.5Hz , 9H), 0.54 (s, J=7.4Hz, 3H). LCMS (m/z): 891.4 (M+H).
中间体B-III-1和中间体B-III-2
Intermediate B-III-1 and Intermediate B-III-2
化合物(1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(中间体B-III,40g)经SFC(SFC350,Waters)拆分(分离柱：DAICEL250*50mm,10μm；流动相：CO2/MeOH＝75/25；流速：140mL/min),得到首先洗脱出来的异构体1，为中间体B-III-1(24g,相对保留时间较短)。手性分析方法SFC-4，Rt＝3.768min。LCMS(m/z):891.4(M+H)。随后洗脱出来的异构体2为中间体B-III-2(17g,相对保留时间较长)。手性分析方法SFC-4，Rt＝4.115min。1H NMR(400MHz,Chloroform-d)δ7.74(dd,J＝9.1,5.7Hz,1H),7.40(dd,J＝9.7,1.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.29(d,J＝8.7Hz,1H),7.10(d,J＝2.6Hz,1H),4.81–4.64(m,1H),4.51–4.32(m,2H),4.18–4.03(m,1H),3.91–3.69(m,1H),3.52–3.32(m,1H),2.30–1.93(m,3H),1.53(s,9H),1.37–1.21(m,4H),1.16–1.05(m,18H),0.94–0.80(m,18H),0.62–0.47(m,3H).19F NMR(376MHz,Chloroform-d)δ-47.14,-105.65,-112.24,-120.80.LCMS(m/z):891.4(M+H)。Compound (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl) Oxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate B-III, 40g ) was resolved by SFC (SFC350, Waters) (separation column: DAICEL 250*50mm, 10μm; mobile phase: CO 2 /MeOH=75/25; flow rate: 140mL/min), the first eluted isomer 1 was obtained, which was intermediate B-III-1 (24g, relative retention time shorter). Chiral analysis method SFC-4, Rt=3.768min. LCMS (m/z): 891.4 (M+H). The subsequently eluted isomer 2 was intermediate B-III-2 (17 g, relatively longer retention time). Chiral analysis method SFC-4, Rt=4.115min. 1 H NMR (400MHz, Chloroform-d) δ7.74(dd, J=9.1,5.7Hz,1H),7.40(dd,J=9.7,1.7Hz,1H),7.34(d,J=2.5Hz,1H ),7.29(d,J=8.7Hz,1H),7.10(d,J=2.6Hz,1H),4.81–4.64(m,1H),4.51–4.32(m,2H),4.18–4.03(m, 1H),3.91–3.69(m,1H),3.52–3.32(m,1H),2.30–1.93(m,3H),1.53(s,9H),1.37–1.21(m,4H),1.16–1.05( m,18H),0.94–0.80(m,18H),0.62–0.47(m,3H) .19F NMR(376MHz,Chloroform-d)δ-47.14,-105.65,-112.24,-120.80.LCMS(m/ z): 891.4 (M+H).
中间体C-I
Intermediate CI
(1R,5S)-3-(7-溴-2-氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯中间体C-I参照文献WO2021041671A1进行制备和表征。(1R,5S)-3-(7-Bromo-2-chloro-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane - tert-butyl 8-carboxylate intermediate C-I was prepared and characterized with reference to document WO2021041671A1.
中间体1Intermediate 1
(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
(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid
步骤A：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-醇Step A: 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-ol
冰浴搅拌下，将TIPSCl(177g,920mmol)滴加到7-氟-8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二醇(300g,837mmol)和咪唑(119g,1.76mol)的DCM(3L)溶液中。滴加完成后将体系缓慢升至室温并搅拌6h。TLC监测反应完成，加入水(900mL)，搅拌30min，分液。水相用DCM(900mL)萃取，合并有机相，无水硫酸钠干燥。过滤，浓缩至干，经硅胶Plug(PE/EA＝50:1)纯化，得到化合物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-醇(397g,收率92％)。Under stirring in an ice bath, TIPSCl (177g, 920mmol) was added dropwise to 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (300g, 837mmol) and imidazole ( 119g, 1.76mol) in DCM (3L) solution. After the dropwise addition, the system was slowly raised to room temperature and stirred for 6 h. The completion of the reaction was monitored by TLC, and water (900 mL) was added, stirred for 30 min, and separated. The aqueous phase was extracted with DCM (900 mL), and the combined organic phases were dried over anhydrous sodium sulfate. Filtration, concentration to dryness, and purification by silica gel Plug (PE/EA=50:1) gave compound 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) Silyl)oxy)naphthalen-1-ol (397 g, yield 92%).
步骤B：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-基三氟甲磺酸酯Step B: 7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl triflate
在-45～-35℃条件下，将三氟甲磺酸酐(326g,1.16mol)滴加到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-醇(397g,0.77mol)和DIPEA(298g,2.31mol)的DCM(4L)溶液中。滴加完成后，保持温度继续搅拌0.5h，TLC监测反应完成。将体系加入至水(800mL)中，分液，水相用DCM(1.2L)萃取。合并有机相，无水硫酸钠干燥，过滤，浓缩至干。经硅胶Plug(PE/EA＝50:1)纯化，得到化合物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-基三氟甲磺酸酯(469g,收率94％)。At -45～-35°C, trifluoromethanesulfonic anhydride (326g, 1.16mol) was added dropwise to 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((tri Isopropylsilyl)oxy)naphthalen-1-ol (397g, 0.77mol) and DIPEA (298g, 2.31mol) in DCM (4L). After the dropwise addition, keep the temperature and continue to stir for 0.5h, and TLC monitors the completion of the reaction. The system was added to water (800 mL), the layers were separated, and the aqueous phase was extracted with DCM (1.2 L). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Purified by silica gel Plug (PE/EA=50:1), the compound 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy ) naphthalen-1-yl triflate (469 g, yield 94%).
步骤C：(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Step C: (7-Fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid
氮气保护下，将Pd(dppf)Cl2(13.2g,18.2mmol)加入到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-基三氟甲磺酸酯(235g,0.36mol)、5,5,5',5'-四甲基-2,2'-二(1,3,2-二氧硼烷)(164g,0.73mol)和醋酸钾(107g,1.1mol)的二氧六环(2.4L)溶液中。体系升至85℃搅拌反应20h。TLC监测反应完成，冷至室温，硅藻土过滤，EA冲洗，浓缩后经硅胶柱(EA/PE＝0-5％)纯化，得到粗品化合物。Under nitrogen protection, Pd(dppf)Cl 2 (13.2g, 18.2mmol) was added to 7-fluoro-8-((triisopropylsilyl)ethynyl)- 3-((triisopropylsilyl)oxy)naphthalen-1-yl triflate (235g, 0.36mol), 5,5,5',5'-tetramethyl-2,2 '-bis(1,3,2-dioxaborane) (164g, 0.73mol) and potassium acetate (107g, 1.1mol) in dioxane (2.4L) solution. The system was raised to 85°C and stirred for 20h. The completion of the reaction was monitored by TLC, cooled to room temperature, filtered with celite, washed with EA, concentrated and purified by silica gel column (EA/PE=0-5%) to obtain the crude compound.
将上述粗品化合物溶于甲醇(1.2L)，加入1N HCl(2.4L)，所得混合物室温搅拌30min。加入EA(2.4L)，继续搅拌2h。静置分液，有机相依次用水(2.4L)和饱和食盐水(2.4L×2)洗涤，浓缩后，得到(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(183g,收率92％)。1H NMR(400MHz,Chloroform-d)δ7.66–7.60(m,1H),7.34(d,J＝2.5Hz,1H),7.24–7.19(m,1H),7.18(d,J＝2.5Hz,1H),4.52(s,2H),1.35–1.29(m,3H),1.24–1.21(m,3H),1.20–1.17(m,18H),1.12(d,J＝7.3Hz,18H).LCMS(m/z):543.3(M+H)。The above crude compound was dissolved in methanol (1.2 L), 1N HCl (2.4 L) was added, and the resulting mixture was stirred at room temperature for 30 min. EA (2.4 L) was added and stirring was continued for 2 h. Stand for liquid separation, the organic phase was washed with water (2.4L) and saturated brine (2.4L×2) successively, and after concentration, (7-fluoro-8-((triisopropylsilyl)ethynyl)- 3-((triisopropylsilyl)oxy)naphthalen-1-yl)boronic acid (183 g, yield 92%). 1 H NMR (400MHz, Chloroform-d) δ7.66–7.60(m,1H),7.34(d,J=2.5Hz,1H),7.24–7.19(m,1H),7.18(d,J=2.5Hz ,1H),4.52(s,2H),1.35–1.29(m,3H),1.24–1.21(m,3H),1.20–1.17(m,18H),1.12(d,J＝7.3Hz,18H). LCMS (m/z): 543.3 (M+H).
中间体a
intermediate a
(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇
(R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol
步骤A：2-氟乙基4-甲苯磺酸酯Step A: 2-Fluoroethyl 4-toluenesulfonate
在冰浴条件下，将4-甲苯磺酰氯(6.1g,32mmol)加入到2-氟乙烷-1-醇(2.0g,31mmol)，三乙胺(6.5mL,47mmol)和DCM(20mL)的混合溶液中，添加结束后恢复到室温搅拌过夜。TLC监测反应完成，加入水(50mL)，DCM(150mL×2)萃取。合并有机相，饱和食盐水洗涤，减压浓缩后经FCC(SiO2，EA/PE＝0-20％)纯化得到无色油状物2-氟乙基4-甲苯磺酸酯(6.2g,收率91％)。GC-MS(EI,m/z):218。4-Toluenesulfonyl chloride (6.1 g, 32 mmol) was added to 2-fluoroethane-1-ol (2.0 g, 31 mmol), triethylamine (6.5 mL, 47 mmol) and DCM (20 mL) under ice bath condition After the addition, return to room temperature and stir overnight. TLC monitored the completion of the reaction, added water (50 mL), and extracted with DCM (150 mL×2). The organic phases were combined, washed with saturated brine, concentrated under reduced pressure and purified by FCC (SiO 2 , EA/PE=0-20%) to obtain a colorless oily substance 2-fluoroethyl 4-toluenesulfonate (6.2 g, harvested rate 91%). GC-MS (EI, m/z): 218.
步骤B：1-(叔丁基)-2-甲基(R)-2-甲基吡咯烷-1,2-二羧酸酯Step B: 1-(tert-butyl)-2-methyl(R)-2-methylpyrrolidine-1,2-dicarboxylate
冰浴、氮气保护下，将CH3I(6.4g,45.4mmol)的DMF(10mL)溶液缓慢滴入(R)-1-(叔丁氧羰基)-2-甲基吡咯烷-2-羧酸(CAS：166170-15-6，购自毕得医药，货号：BD246964)(8.0g,34.9mmol)、K2CO3(14.5g,104.7mmol)和DMF(40mL)混合液中。滴加完毕后，反应液恢复至室温并搅拌过夜。TLC监测反应结束，把反应液加入到水(300mL)中，EA(200mL×3)萃取。合并有机相用饱和食盐水洗涤，减压浓缩后经FCC(SiO2，EA/PE＝0-20％)纯化，得到无色油状 物1-(叔丁基)-2-甲基(R)-2-甲基吡咯烷-1,2-二羧酸酯(8.2g,收率98％)。LCMS(ESI,m/z):266.30(M+Na)。Under ice bath and nitrogen protection, a solution of CH 3 I (6.4g, 45.4mmol) in DMF (10mL) was slowly dropped into (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylate Acid (CAS: 166170-15-6, purchased from Bi De Pharmaceutical, product number: BD246964) (8.0g, 34.9mmol), K 2 CO 3 (14.5g, 104.7mmol) and DMF (40mL) mixed solution. After the dropwise addition, the reaction solution was returned to room temperature and stirred overnight. The completion of the reaction was monitored by TLC, and the reaction solution was added into water (300 mL), and extracted with EA (200 mL×3). The combined organic phases were washed with saturated brine, concentrated under reduced pressure and purified by FCC (SiO 2 , EA/PE=0-20%) to obtain a colorless oil Product 1-(tert-butyl)-2-methyl(R)-2-methylpyrrolidine-1,2-dicarboxylate (8.2 g, yield 98%). LCMS (ESI, m/z): 266.30 (M+Na).
步骤C：(R)-2-甲基吡咯烷-2-羧酸甲酯·盐酸盐Step C: (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride
室温条件下，将4M HCl-dioxane(30mL)加入到1-(叔丁基)-2-甲基(R)-2-甲基吡咯烷-1,2-二羧酸酯(7.2g,29.6mmol)并在室温搅拌1h。LCMS监测反应结束后，将反应液直接浓缩，得到白色固体(R)-2-甲基吡咯烷-2-羧酸甲酯·盐酸盐(5.1g,收率96％)。LCMS(ESI,m/z):144.1(M+H)。At room temperature, 4M HCl-dioxane (30mL) was added to 1-(tert-butyl)-2-methyl(R)-2-methylpyrrolidine-1,2-dicarboxylate (7.2g, 29.6 mmol) and stirred at room temperature for 1 h. After the reaction was monitored by LCMS, the reaction solution was directly concentrated to obtain (R)-methyl 2-methylpyrrolidine-2-carboxylate·hydrochloride (5.1 g, yield 96%) as a white solid. LCMS (ESI, m/z): 144.1 (M+H).
步骤D：(R)-1-(2-氟乙基)-2-甲基吡咯烷-2-羧酸甲酯Step D: (R)-1-(2-Fluoroethyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester
室温条件下，将(R)-2-甲基吡咯烷-2-羧酸甲酯·盐酸盐(1.0g,5.6mmol)、2-氟乙基4-甲苯磺酸酯(1.5g,6.68mmol)、K2CO3(3.1g,22.3mmol)依次加入到无水乙腈(10mL)中。所得混合物升温至90℃搅拌过夜，硅藻土过滤，收集滤液。减压浓缩得粗品，经FCC(SiO2，EA/PE＝0-15％)纯化，得无色液体(R)-1-(2-氟乙基)-2-甲基吡咯烷-2-羧酸甲酯(860mg,收率82％)。LCMS(ESI,m/z):190.1(M+H)。At room temperature, (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), 2-fluoroethyl 4-toluenesulfonate (1.5g, 6.68 mmol), K 2 CO 3 (3.1 g, 22.3 mmol) were sequentially added to anhydrous acetonitrile (10 mL). The resulting mixture was warmed to 90°C and stirred overnight, filtered through celite, and the filtrate was collected. Concentrate under reduced pressure to obtain a crude product, which is purified by FCC (SiO 2 , EA/PE=0-15%) to obtain a colorless liquid (R)-1-(2-fluoroethyl)-2-methylpyrrolidine-2- Methyl carboxylate (860 mg, yield 82%). LCMS (ESI, m/z): 190.1 (M+H).
步骤E：(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇Step E: (R)-(1-(2-Fluoroethyl)-2-methylpyrrolidin-2-yl)methanol
冰浴条件下，将LiAlH4(4.2mL，4.2mmol，1M THF溶液)滴入(R)-1-(2-氟乙基)-2-甲基吡咯烷-2-羧酸甲酯(800mg,4.2mmol)的THF(20mL)溶液中。所得混合物在0℃下搅拌反应20分钟，缓慢加入Na2SO4·10H2O至没有气体产生以淬灭反应。反应液经硅藻土过滤，滤液减压浓缩得产物(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇(780mg,crude)，直接用于后续反应。LCMS(ESI,m/z):162.1(M+H)。LiAlH 4 (4.2mL, 4.2mmol, 1M THF solution) was dropped into (R)-1-(2-fluoroethyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (800mg , 4.2mmol) in THF (20mL) solution. The resulting mixture was stirred at 0°C for 20 minutes, and Na 2 SO 4 ·10H 2 O was slowly added until no gas was generated to quench the reaction. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the product (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (780 mg, crude), which was directly used in follow-up response. LCMS (ESI, m/z): 162.1 (M+H).
下列中间体参照中间体a的合成方法进行制备：
The following intermediates are prepared with reference to the synthetic method of intermediate a:
中间体b
intermediate b
(R)-(1-(2,2-二氟乙基)-2-甲基吡咯烷-2-基)甲醇(R)-(1-(2,2-difluoroethyl)-2-methylpyrrolidin-2-yl)methanol
中间体b的合成参照中间体a合成方案进行，在步骤A中使用2,2-二氟乙烷-1-醇代替2- 氟乙烷-1-醇，在步骤D中使用2,2-二氟乙基4-甲基苯磺酸酯代替2-氟乙基4-甲苯磺酸酯。LC-MS(ESI,m/z):180.1(M+H)。The synthesis of intermediate b is carried out with reference to the synthesis scheme of intermediate a, in step A, 2,2-difluoroethane-1-ol is used instead of 2- Fluoroethane-1-ol, use 2,2-difluoroethyl 4-methylbenzenesulfonate in Step D instead of 2-fluoroethyl 4-toluenesulfonate. LC-MS (ESI, m/z): 180.1 (M+H).
中间体c
intermediate c
(R)-(1,2-二甲基吡咯烷-2-基)甲醇
(R)-(1,2-Dimethylpyrrolidin-2-yl)methanol
步骤A：(R)-(1,2-二甲基吡咯烷-2-基)甲醇Step A: (R)-(1,2-Dimethylpyrrolidin-2-yl)methanol
冰浴条件下，LiAlH4(21.8mL,21.8mmol,1M THF溶液)滴加到(R)-1-(叔丁氧羰基)-2-甲基吡咯烷-2-羧酸(1.0g,4.4mmol)的THF(15mL)溶液中，加完后升温至70℃搅拌过夜。TLC监测反应结束，缓慢加入Na2SO4·10H2O至没有气体产生以淬灭反应。反应液经硅藻土过滤，得到的滤液减压浓缩得产物(R)-(1,2-二甲基吡咯烷-2-基)甲醇(700mg,crude)，直接用于后续反应。Under ice-bath conditions, LiAlH 4 (21.8mL, 21.8mmol, 1M THF solution) was added dropwise to (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0g, 4.4 mmol) in THF (15 mL), after the addition was complete, the temperature was raised to 70°C and stirred overnight. The end of the reaction was monitored by TLC, and Na 2 SO 4 ·10H 2 O was slowly added until no gas was generated to quench the reaction. The reaction solution was filtered through celite, and the obtained filtrate was concentrated under reduced pressure to obtain the product (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (700 mg, crude), which was directly used in subsequent reactions.
中间体d
intermediate d
(R)-(1-乙基-2-甲基吡咯烷-2-基)甲醇
(R)-(1-Ethyl-2-methylpyrrolidin-2-yl)methanol
步骤A：(R)-1-乙基-2-甲基吡咯烷-2-羧酸甲酯Step A: (R)-methyl 1-ethyl-2-methylpyrrolidine-2-carboxylate
室温下，将碘乙烷(1.74g,11.1mmol)加入到(R)-2-甲基吡咯烷-2-羧酸甲酯·盐酸盐(1.0g,5.6mmol)，碳酸钾(3.07g,22.2mmol)和CAN(20mL)的混合溶液中，加完后升温至90℃搅拌过夜。TLC(EA:PE＝1:5,碘为显色剂)监测反应结束后，硅藻土过滤，收集滤液并浓缩，所得粗品经通过FCC(EA/PE＝0-15％)，得到无色液体(R)-1-乙基-2-甲基吡咯烷-2-羧酸甲酯(600mg,收率63％)。LCMS(ESI,m/z):172.2(M+H)。At room temperature, iodoethane (1.74g, 11.1mmol) was added to (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), potassium carbonate (3.07g , 22.2mmol) and CAN (20mL), after the addition, the temperature was raised to 90°C and stirred overnight. TLC (EA:PE=1:5, iodine is the chromogenic agent) monitors the end of the reaction, filters through diatomaceous earth, collects the filtrate and concentrates, and the obtained crude product is passed through FCC (EA/PE=0-15%) to obtain a colorless Liquid (R)-methyl 1-ethyl-2-methylpyrrolidine-2-carboxylate (600 mg, yield 63%). LCMS (ESI, m/z): 172.2 (M+H).
步骤B：(R)-1-乙基-2-甲基吡咯烷-2-羧酸甲酯 Step B: (R)-methyl 1-ethyl-2-methylpyrrolidine-2-carboxylate
步骤B的合成方法参照中间体a步骤E所述进行，使用(R)-1-乙基-2-甲基吡咯烷-2-羧酸甲酯代替(R)-1-(2-氟乙基)-2-甲基吡咯烷-2-羧酸甲酯。LCMS(ESI,m/z):143.2(M+H)。The synthesis method of step B is carried out with reference to the step E of intermediate a, using (R)-1-ethyl-2-methylpyrrolidine-2-carboxylic acid methyl ester instead of (R)-1-(2-fluoroethyl base)-2-methylpyrrolidine-2-carboxylic acid methyl ester. LCMS (ESI, m/z): 143.2 (M+H).
下列中间体参照中间体d的合成方法进行制备：

The following intermediates are prepared with reference to the synthetic method of intermediate d:

中间体e
intermediate e
(R)-(1-环丁基-2-甲基吡咯烷-2-基)甲醇
(R)-(1-Cyclobutyl-2-methylpyrrolidin-2-yl)methanol
步骤A：(R)-1-环丁基-2-甲基吡咯烷-2-羧酸甲酯Step A: (R)-1-Cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester
室温下，将溴代环丁烷(1.13g,8.3mmol)加入到(R)-2-甲基吡咯烷-2-羧酸甲酯盐酸盐(1.0g,5.6mmol)，碳酸钾(2.30g,16.7mmol)，碘化亚铜(311mg,1.1mmol),N1-苄基-N2-(5-甲基-[1,1'-联苯]-2-基)草酰胺(574mg,1.7mmol)和DMSO(20mL)的混合溶液中，氮气置换一分钟后升温至100℃反应搅拌过夜。TLC(EA:PE＝1:5,碘为显色剂)检测反应结束后，加入水(100mL)，EA(50mL×3)萃取。合并有机相用饱和食盐水洗涤,无水硫酸钠干燥。过滤，减压浓缩后经FCC(EA/PE＝0-15％)，得到无色液体(R)-1-环丁基-2-甲基吡咯烷-2-羧酸甲酯(900mg,收率82％)。LCMS(ESI,m/z):198.1(M+H)。At room temperature, bromocyclobutane (1.13g, 8.3mmol) was added to (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), potassium carbonate (2.30 g, 16.7mmol), cuprous iodide (311mg, 1.1mmol), N 1 -benzyl-N 2 -(5-methyl-[1,1'-biphenyl]-2-yl) oxalamide (574mg , 1.7 mmol) and DMSO (20 mL), the temperature was raised to 100° C. and the reaction was stirred overnight after nitrogen replacement for one minute. TLC (EA:PE=1:5, iodine as color reagent) detected that after the reaction was completed, water (100 mL) was added, and EA (50 mL×3) was extracted. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, FCC (EA/PE=0-15%) gave colorless liquid (R)-methyl 1-cyclobutyl-2-methylpyrrolidine-2-carboxylate (900 mg, yield rate of 82%). LCMS (ESI, m/z): 198.1 (M+H).
步骤B：(R)-(1-环丁基-2-甲基吡咯烷-2-基)甲醇Step B: (R)-(1-Cyclobutyl-2-methylpyrrolidin-2-yl)methanol
冰浴条件下，将LiAlH4(4.56mmol,4.56mL,1M THF溶液)滴入(R)-1-环丁基-2-甲基吡咯烷-2-羧酸甲酯(900mg,4.56mmol)和THF(20mL)的混合溶液中，并在0℃条件下反应20分钟，TLC(EA:PE＝1:5,碘为显色剂)检测反应结束后，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，收率滤液，减压浓缩后经FCC(EA/PE＝0-15％,MeOH/DCM＝0-10％)纯化，得到无色液体(R)-(1-环丁基-2-甲基吡咯烷-2-基)甲醇(300mg,收率39％)。LCMS(ESI,m/z):170.1(M+H)。Under ice-bath conditions, LiAlH 4 (4.56mmol, 4.56mL, 1M THF solution) was dropped into (R)-1-cyclobutyl-2-methylpyrrolidine-2-carboxylic acid methyl ester (900mg, 4.56mmol) and THF (20mL) in a mixed solution, and reacted at 0°C for 20 minutes, TLC (EA:PE=1:5, iodine as the color reagent) detected after the reaction was completed, and Na 2 SO 4 ·10H 2 O The reaction was quenched until no gas was produced, the reaction solution was filtered through diatomaceous earth, the yield filtrate was concentrated under reduced pressure and purified by FCC (EA/PE=0-15%, MeOH/DCM=0-10%) to obtain Colored liquid (R)-(1-cyclobutyl-2-methylpyrrolidin-2-yl)methanol (300 mg, yield 39%). LCMS (ESI, m/z): 170.1 (M+H).
中间体g
intermediate g
(S)-(2-环丙基-1-甲基吡咯烷-2-基)甲醇
(S)-(2-Cyclopropyl-1-methylpyrrolidin-2-yl)methanol
步骤A：(3S,7aR)-3-(叔丁基)四氢-1H,3H吡咯[1,2-c]噁唑-1-酮Step A: (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3Hpyrrole[1,2-c]oxazol-1-one
室温搅拌下，将三氟乙酸(891mg,7.82mmol)滴加到D-脯氨酸(10g,86.9mmol)、硅胶粉(10g)和THF(150mL)的溶液中。再依次滴加新戊醛(33.6g,391mmol)和三甲氧基甲烷(11.1g,104mmol)到上述反应液中，滴加完毕后，继续在室温条件下搅拌过夜。过滤除去硅胶粉，收集母液，浓缩得到黄色油状液体(3S,7aR)-3-(叔丁基)四氢-1H,3H吡咯[1,2-c]噁唑-1-酮(12.5g，收率78.5％)。1H NMR(400MHz,CDCl3)δ4.53(s,1H),3.80(dd,J＝8.9,4.4Hz,1H),3.21(dt,J＝10.5,6.5Hz,1H),2.83(dt,J＝10.5,6.3Hz,1H),2.25–2.10(m,1H),2.10–1.96(m,1H),1.88–1.76(m,1H),1.75–1.62(m,1H),0.93(s,9H).With stirring at room temperature, trifluoroacetic acid (891 mg, 7.82 mmol) was added dropwise to a solution of D-proline (10 g, 86.9 mmol), silica gel powder (10 g) and THF (150 mL). Pivalaldehyde (33.6g, 391mmol) and trimethoxymethane (11.1g, 104mmol) were added dropwise to the above reaction solution in turn, and after the dropwise addition was completed, stirring was continued at room temperature overnight. The silica gel powder was removed by filtration, the mother liquor was collected and concentrated to obtain (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3H pyrrole[1,2-c]oxazol-1-one (12.5g, Yield 78.5%). 1 H NMR (400MHz, CDCl 3 ) δ4.53(s, 1H), 3.80(dd, J=8.9, 4.4Hz, 1H), 3.21(dt, J=10.5, 6.5Hz, 1H), 2.83(dt, J＝10.5,6.3Hz,1H),2.25–2.10(m,1H),2.10–1.96(m,1H),1.88–1.76(m,1H),1.75–1.62(m,1H),0.93(s, 9H).
步骤B：(3S,7aS)-3-(叔丁基)-7a-环丙基四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮Step B: (3S,7aS)-3-(tert-butyl)-7a-cyclopropyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one
氮气保护下，在干冰-乙醇浴中，将LDA(20.46mL，2.0M in THF)滴加到(3S,7aR)-3-(叔丁基)四氢-1H,3H吡咯[1,2-c]噁唑-1-酮(5.0g,27.28mmol)的无水THF(50mL)的溶液中。保持冷浴温度搅拌0.5h后，将溴代环丙烷(9.9g,81.85mmol)滴加到上述反应液中并继续保温搅拌1h。将反应液倒入饱和NH4Cl水溶液(100mL)中，加入EA(100mL×3)萃取。合并有机相，用饱和NaCl(50mL)洗涤，浓缩后经FCC(SiO2，EA/PE＝0～15％)纯化，得到黄色油状液体(3S,7aS)-3-(叔丁基)-7a-环丙基四氢-1H,3H-吡咯并[1,2-c]恶唑-1-酮(450mg,收率7.4％)。LCMS(m/z):224.1(M+H)。Under nitrogen protection, LDA (20.46mL, 2.0M in THF) was added dropwise to (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3Hpyrrole[1,2- c] A solution of oxazol-1-one (5.0 g, 27.28 mmol) in anhydrous THF (50 mL). After stirring for 0.5 h at the cold bath temperature, bromocyclopropane (9.9 g, 81.85 mmol) was added dropwise to the above reaction solution and continued to keep stirring for 1 h. The reaction solution was poured into saturated NH4Cl aqueous solution (100 mL), and EA (100 mL×3) was added for extraction. The organic phases were combined, washed with saturated NaCl (50 mL), concentrated and purified by FCC (SiO 2 , EA/PE=0-15%) to obtain (3S,7aS)-3-(tert-butyl)-7a as a yellow oily liquid -Cyclopropyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one (450 mg, yield 7.4%). LCMS (m/z): 224.1 (M+H).
步骤C：(S)-2-环丙基吡咯烷-2-羧酸盐酸盐Step C: (S)-2-Cyclopropylpyrrolidine-2-carboxylate hydrochloride
将4M HCl-二噁烷(10mL)与(3S,7aS)-3-(叔丁基)-7a-环丙基四氢-1H,3H-吡咯并[1,2-c]噁唑-1-酮(400mg，1.79mmol)的混合物升温至80℃搅拌过夜。将体系减压浓缩，得到棕色固体(S)-2-环丙基吡咯烷-2-羧酸盐酸盐(350mg，收率88％)。LCMS(m/z):156.1(M+H)。Mix 4M HCl-dioxane (10mL) with (3S,7aS)-3-(tert-butyl)-7a-cyclopropyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1 - A mixture of ketones (400mg, 1.79mmol) was warmed to 80°C and stirred overnight. The system was concentrated under reduced pressure to obtain (S)-2-cyclopropylpyrrolidine-2-carboxylic acid hydrochloride (350 mg, yield 88%) as a brown solid. LCMS (m/z): 156.1 (M+H).
步骤D：(S)-2-环丙基-1-甲基吡咯烷-2-羧酸Step D: (S)-2-Cyclopropyl-1-methylpyrrolidine-2-carboxylic acid
将NaBH3CN(185mg，2.90mmol)加入到(S)-2-环丙基吡咯烷-2-羧酸盐酸盐(300mg, 1.93mmol)、甲醛(1.57g,19.3mmol,33％in water)和MeOH(10mL)的混合物中，所得体系在室温搅拌1h。减压浓缩除去大量甲醇，加入EA(30mL)稀释，硅藻土过滤。收集有机相，减压浓缩后经FCC(SiO2，MeOH/DCM＝0～30％)纯化，得到无色液体(S)-2-环丙基-1-甲基吡咯烷-2-羧酸(280mg,收率86％)。LCMS(m/z):170.1(M+H)。NaBH 3 CN (185 mg, 2.90 mmol) was added to (S)-2-cyclopropylpyrrolidine-2-carboxylate hydrochloride (300 mg, 1.93 mmol), formaldehyde (1.57 g, 19.3 mmol, 33% in water) and MeOH (10 mL), the resulting system was stirred at room temperature for 1 h. Concentrate under reduced pressure to remove a large amount of methanol, add EA (30 mL) to dilute, and filter through celite. The organic phase was collected, concentrated under reduced pressure and purified by FCC (SiO 2 , MeOH/DCM=0-30%) to obtain (S)-2-cyclopropyl-1-methylpyrrolidine-2-carboxylic acid as a colorless liquid (280mg, yield 86%). LCMS (m/z): 170.1 (M+H).
步骤E：(S)-(2-环丙基-1-甲基吡咯烷-2-基)甲醇Step E: (S)-(2-Cyclopropyl-1-methylpyrrolidin-2-yl)methanol
室温条件下，将硼烷(1M in THF，17.73mL)加入到(S)-2-环丙基-1-甲基吡咯烷-2-羧酸(300mg，1.77mmol)的无水THF(5mL)溶液中。体系升温至65℃搅拌过夜。检测反应结束后，用冰浴冷却，搅拌下，缓慢滴入甲醇至无气体放出。体系经硅藻土过滤，EA(50mL)洗涤滤饼。合并滤液减压浓缩后，经FCC(SiO2，MeOH/DCM＝0～30％)纯化，得到无色油状液体(S)-(2-环丙基-1-甲基吡咯烷-2-基)甲醇(200mg,收率73％)。LCMS(m/z):156.1(M+H)。Add borane (1M in THF, 17.73mL) to (S)-2-cyclopropyl-1-methylpyrrolidine-2-carboxylic acid (300mg, 1.77mmol) in anhydrous THF (5mL) at room temperature ) solution. The system was warmed up to 65°C and stirred overnight. After the detection reaction is finished, cool with an ice bath, and slowly add methanol dropwise under stirring until no gas is released. The system was filtered through celite, and the filter cake was washed with EA (50 mL). After the combined filtrates were concentrated under reduced pressure, they were purified by FCC (SiO 2 , MeOH/DCM=0-30%) to obtain (S)-(2-cyclopropyl-1-methylpyrrolidin-2-yl) as a colorless oily liquid ) methanol (200mg, yield 73%). LCMS (m/z): 156.1 (M+H).
中间体g1
intermediate g1
(R)-(2-乙基-1-甲基吡咯烷-2-基)甲醇(R)-(2-Ethyl-1-methylpyrrolidin-2-yl)methanol
中间体g1的合成参照中间体g的合成方法进行，在步骤B中使用碘乙烷代替溴代环丙烷。LCMS(m/z):144.1(M+H)。The synthesis of intermediate g1 is carried out with reference to the synthesis method of intermediate g, and iodoethane is used in step B instead of bromocyclopropane. LCMS (m/z): 144.1 (M+H).
中间体h
intermediate h
((2R)-1-(1-甲氧基丙-2-基)-2-甲基吡咯烷-2-基)甲醇
((2R)-1-(1-methoxyprop-2-yl)-2-methylpyrrolidin-2-yl)methanol
步骤A：甲基(2R)-1-(1-甲氧基丙烷-2-基)-2-甲基吡咯烷-2-羧酸盐Step A: Methyl (2R)-1-(1-methoxypropan-2-yl)-2-methylpyrrolidine-2-carboxylate
室温条件下，将(R)-2-甲基吡咯烷-2-羧酸甲酯盐酸盐(1.0g,5.57mmol)、1-甲氧基丙烷-2-酮(980mg,11.13mmol)、NaOH(222.6mg,5.57mmol)、HCO2H(512mg,11.13mmol)加入甲醇(15mL)溶液中并搅拌30分钟，然后将NaBH3CN(525mg,8.35mmol)加入到上述反应液中，在室温条件下，搅拌过夜。检测反应结束后，加入EA(50mL)稀释，H2O(20mL),EA(50mL×2)萃取，收集有机相浓缩经FCC(SiO2,EA/PE＝0～20％)，得到(2R)-1-(1-甲氧基丙烷-2-基)-2-甲基吡咯烷-2-羧酸甲酯(300mg,收率25％)的无色液体。LCMS(m/z):216.1(M+H)。 At room temperature, (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.57mmol), 1-methoxypropan-2-one (980mg, 11.13mmol), NaOH (222.6mg, 5.57mmol), HCO 2 H (512mg, 11.13mmol) were added to methanol (15mL) solution and stirred for 30 minutes, then NaBH 3 CN (525mg, 8.35mmol) was added to the above reaction solution, at room temperature Stirring overnight. After the detection reaction, add EA (50mL) to dilute, H 2 O (20mL), EA (50mL×2) to extract, collect the organic phase and concentrate it by FCC (SiO 2 , EA/PE=0～20%) to obtain (2R )-1-(1-methoxypropan-2-yl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (300 mg, yield 25%) was a colorless liquid. LCMS (m/z): 216.1 (M+H).
步骤B：((2R)-1-(1-甲氧基丙-2-基)-2-甲基吡咯烷-2-基)甲醇Step B: ((2R)-1-(1-methoxypropan-2-yl)-2-methylpyrrolidin-2-yl)methanol
冰浴条件下，将LiAH4(1.86mL,1.86mmol,1M in THF)滴加到(2R)-1-(1-甲氧基丙烷-2-基)-2-甲基吡咯烷-2-羧酸甲酯(400mg,1.86mmol)和THF(8mL)的溶液中并搅拌10分钟。TLC监测反应结束后，在冰浴条件下，缓慢将Na2SO4·10H2O加入反应液中直至不再有气体生成。加入无水硫酸钠干燥溶液，过滤，收集母液浓缩，得到无色液体((2R)-1-(1-甲氧基丙烷-2-基)-2-甲基吡咯烷-2-基)甲醇(300mg,收率86％)，直接用于后续反应，无需进一步纯化。Under ice-bath conditions, LiAH 4 (1.86mL, 1.86mmol, 1M in THF) was added dropwise to (2R)-1-(1-methoxypropan-2-yl)-2-methylpyrrolidin-2- methyl carboxylate (400mg, 1.86mmol) and THF (8mL) and stirred for 10 minutes. After the reaction was monitored by TLC, Na 2 SO 4 ·10H 2 O was slowly added to the reaction solution under ice bath conditions until no more gas was generated. Add anhydrous sodium sulfate to dry the solution, filter, collect the mother liquor and concentrate to obtain a colorless liquid ((2R)-1-(1-methoxypropan-2-yl)-2-methylpyrrolidin-2-yl)methanol (300mg, yield 86%), used directly in subsequent reactions without further purification.
中间体h1
intermediate h1
(R)-(2-甲基-1-(氧杂环丁烷-3-基)吡咯烷-2-基)甲醇(R)-(2-Methyl-1-(oxetan-3-yl)pyrrolidin-2-yl)methanol
中间体h1的合成参照中间体h的合成方法进行，在步骤A中使用氧杂环丁酮代替1-甲氧基丙-2-酮。LCMS(m/z):172.1(M+H)。The synthesis of intermediate h1 is carried out with reference to the synthesis method of intermediate h, and in step A, oxetanone is used instead of 1-methoxypropan-2-one. LCMS (m/z): 172.1 (M+H).
中间体k
intermediate k
(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯
(R)-2-Methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester
步骤A：2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: 2-Methyl-3-oxopyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
冰浴条件下，将CH3I(81.4g,573mmol)滴加到3-氧吡咯烷-1,2-二甲酸1-(叔丁基)酯2-乙基酯(59.0g,229mmol)、K2CO3(79.2g,573mmol)和无水乙腈(600mL)的混合溶液中，滴加完成后，将反应液升温至45℃并搅拌过夜。TLC检测反应结束后，浓缩除去溶剂，加入饱和NH4Cl水溶液(500mL)淬灭。所得体系用EA(600mL×2)萃取，合并的有机相用饱和NaCl水溶液(500mL)洗涤，收集有机相，浓缩后经FCC(SiO2，EA/PE＝0-15％)纯化，得到无色油状液体2-甲基-3-氧吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(42.0g,收率68％)。LCMS(m/z):294.0(M+Na)。1H NMR(400MHz,Chloroform-d)δ4.21–4.10(m,2H),3.91–3.81(m,1H),3.75–3.68(m,1H),2.80–2.72(m,1H),2.69–2.60(m,1H),1.63–1.58(m,3H),1.49–1.44(m,9H),1.27–1.24(m,3H).CH 3 I (81.4g, 573mmol) was added dropwise to 1-(tert-butyl) 2-ethyl 3-oxopyrrolidine-1,2-dicarboxylate (59.0g, 229mmol), In a mixed solution of K 2 CO 3 (79.2 g, 573 mmol) and anhydrous acetonitrile (600 mL), after the dropwise addition was completed, the reaction solution was heated to 45° C. and stirred overnight. After the reaction was detected by TLC, the solvent was removed by concentration and quenched by adding saturated NH 4 Cl aqueous solution (500 mL). The resulting system was extracted with EA (600mL×2), the combined organic phase was washed with saturated aqueous NaCl (500mL), the organic phase was collected, concentrated and purified by FCC (SiO 2 , EA/PE=0-15%) to give a colorless Oily liquid 2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (42.0 g, yield 68%). LCMS (m/z): 294.0 (M+Na). 1 H NMR (400MHz, Chloroform-d) δ4.21–4.10(m,2H),3.91–3.81(m,1H),3.75–3.68(m,1H),2.80–2.72(m,1H),2.69– 2.60(m,1H),1.63–1.58(m,3H),1.49–1.44(m,9H),1.27–1.24(m,3H).
步骤B：(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯 Step B: (R)-2-Methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
将2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(31g)经SFC(SFC150,Waters)拆分(分离柱：DAICEL250*25mm,10μm；流动相：CO2/MeOH＝85/15；流速：70mL/min),得到首先洗脱出来的异构体1，为中间体k(11.8g,相对保留时间较短)，手性分析方法SFC-5，Rt＝1.135min。LCMS(m/z):891.4(M+H)。随后洗脱出来的异构体2为化合物k-a(8.7g,相对保留时间较长)，手性分析方法SFC-5，Rt＝1.502min。2-Methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (31g) was resolved by SFC (SFC150, Waters) (separation column: DAICEL 250*25mm, 10μm; mobile phase: CO 2 /MeOH＝85/15; flow rate: 70mL/min), the first eluted isomer 1 was obtained as intermediate k (11.8g, relatively short retention time) , chiral analysis method SFC-5, Rt=1.135min. LCMS (m/z): 891.4 (M+H). The subsequently eluted isomer 2 is compound ka (8.7g, relatively longer retention time), chiral analysis method SFC-5, Rt=1.502min.
中间体k1a及中间体k1b
Intermediate k1a and intermediate k1b
((2S,3R)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(k1a)及((2S,3S)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(k1b)
((2S,3R)-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (k1a) and ((2S,3S)-3-methoxy-1,2-di Methylpyrrolidin-2-yl)methanol (k1b)
步骤A：(2R)-3-羟基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (2R)-3-Hydroxy-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
在冰浴条件下，向(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(300mg,1.11mmol)的甲醇(5mL)溶液中加入硼氢化钠(62mg,1.66mmol)。所得反应液在0℃下反应20min，TLC检测反应完成后，向反应液中加入10mL饱和氯化铵溶液和30mL水，混合反应液经乙酸乙酯萃取，有机相经无水硫酸钠干燥、过滤、浓缩，得到无色透明油状粗产物(2R)-3-羟基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(300mg,收率99％)。1H NMR(400MHz,DMSO-d6)δ5.61–5.47(m,1H),4.17–3.90(m,3H),3.62–3.45(m,1H),3.26–3.14(m,1H),1.97–1.75(m,2H),1.47(s,3H),1.39–1.30(m,9H),1.21–1.10(m,3H).Under ice bath conditions, to (R)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (300mg, 1.11mmol) Sodium borohydride (62 mg, 1.66 mmol) was added to the methanol (5 mL) solution. The resulting reaction solution was reacted at 0°C for 20 minutes. After the reaction was detected by TLC, 10 mL of saturated ammonium chloride solution and 30 mL of water were added to the reaction solution. The mixed reaction solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. , concentrated to obtain a colorless transparent oily crude product (2R)-3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (300mg, yield 99%). 1 H NMR (400MHz,DMSO-d 6 )δ5.61–5.47(m,1H),4.17–3.90(m,3H),3.62–3.45(m,1H),3.26–3.14(m,1H),1.97 –1.75(m,2H),1.47(s,3H),1.39–1.30(m,9H),1.21–1.10(m,3H).
步骤B：(2R,3R)-3-甲氧基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k1-2a)及(2R,3S)-3-甲氧基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k1-2b)Step B: (2R,3R)-3-Methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (k1-2a) and (2R ,3S)-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester (k1-2b)
在冰浴条件下，向(2R)-3-羟基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(300mg,1.1mmol)的DMF(5mL)溶液中加入氢化钠(88mg,2.2mmol)，反应液在0℃下反应20min。然后加入碘甲烷(311mg,2.2mmol)，所得反应液在室温条件下继续反应12h。TLC监测反应完成后，向反应液中加入水(30mL)，乙酸乙酯萃取，有机相经无水硫酸钠干燥、过滤、浓缩，所得粗产物经FCC(SiO2,EA/PE＝5％-10％)纯化，得到黄色油状产物k1-2a(90mg,收率18％)，1H NMR (400MHz,DMSO-d6)δ4.21–3.98(m,2H),3.95–3.82(m,1H),3.42–3.34(m,1H),3.28–3.14(m,4H),2.21–2.08(m,1H),1.85–1.65(m,1H),1.38–1.36(m,3H),1.34–1.26(m,9H),1.23–1.15(m,3H)；和黄色油状产物k1-2b(285mg,收率54％)，1H NMR(400MHz,DMSO-d6)δ4.14–3.93(m,2H),3.84–3.69(m,1H),3.60–3.47(m,1H),3.30–3.19(m,4H),2.11–1.99(m,1H),1.89–1.76(m,1H),1.53(s,3H),1.40–1.29(m,9H),1.21–1.08(m,3H).Under ice-bath conditions, to (2R)-3-hydroxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (300mg, 1.1mmol) in DMF Sodium hydride (88mg, 2.2mmol) was added to the solution (5mL), and the reaction solution was reacted at 0°C for 20min. Then iodomethane (311mg, 2.2mmol) was added, and the resulting reaction solution was continued to react at room temperature for 12h. After the completion of the reaction monitored by TLC, water (30 mL) was added to the reaction solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained crude product was subjected to FCC (SiO 2 , EA/PE=5%- 10%) was purified to obtain yellow oily product k1-2a (90mg, yield 18%), 1 H NMR (400MHz,DMSO-d 6 )δ4.21–3.98(m,2H),3.95–3.82(m,1H),3.42–3.34(m,1H),3.28–3.14(m,4H),2.21–2.08( m,1H), 1.85–1.65(m,1H), 1.38–1.36(m,3H), 1.34–1.26(m,9H), 1.23–1.15(m,3H); and yellow oily product k1-2b (285mg , yield 54%), 1 H NMR (400MHz, DMSO-d 6 ) δ4.14–3.93 (m, 2H), 3.84–3.69 (m, 1H), 3.60–3.47 (m, 1H), 3.30–3.19 (m,4H),2.11–1.99(m,1H),1.89–1.76(m,1H),1.53(s,3H),1.40–1.29(m,9H),1.21–1.08(m,3H).
步骤C：((2S,3R)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(k1a)及((2S,3S)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇(k1b)Step C: ((2S,3R)-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methanol (k1a) and ((2S,3S)-3-methoxy-1, 2-Dimethylpyrrolidin-2-yl)methanol (k1b)
在冰水浴条件下，向(2R,3R)-3-甲氧基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k1-2a)(90mg,0.31mmol)中加入1N的四氢铝锂THF溶液(1.3mL，1.3mmol)。所得溶液在70℃下搅拌反应12h。LCMS检测反应完成后，向反应液中依次加入水(1mL),EtOAc(30mL)。所得反应混合物经硅藻土过滤，浓缩滤液，得到无色透明油状粗产物k1a(50mg,收率99％)，直接用于后续步骤。LCMS(m/z):160.1(M+H)。Under ice-water bath conditions, to (2R,3R)-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (k1-2a ) (90mg, 0.31mmol) was added 1N THF solution (1.3mL, 1.3mmol) of lithium aluminum hydride. The resulting solution was stirred and reacted at 70 °C for 12 h. After the reaction was detected by LCMS, water (1 mL) and EtOAc (30 mL) were successively added to the reaction solution. The obtained reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the crude product k1a (50 mg, yield 99%) as a colorless transparent oil, which was directly used in subsequent steps. LCMS (m/z): 160.1 (M+H).
k1-2b(285mg,0.99mmol)经过相同方法，由(2R,3S)-3-甲氧基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k1-2b)经上述步骤，得到无色透明油状粗产物k1b(130mg,收率88％)。k1-2b (285mg, 0.99mmol) was prepared from (2R,3S)-3-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2- Ethyl ester (k1-2b) After the above steps, the crude product k1b (130 mg, yield 88%) was obtained as a colorless transparent oil.
中间体k2a
intermediate k2a
((2R,3S)-1,2,3-三甲基吡咯烷-2-基)甲醇
((2R,3S)-1,2,3-trimethylpyrrolidin-2-yl)methanol
步骤A：(R)-2-甲基-3-亚甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (R)-2-Methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
冰浴搅拌下，将叔丁醇钾的THF溶液(22.1mL,1M,22.1mmol)滴加到甲基三苯基溴化膦(7.94g,22.1mmol)的甲苯(50mL)溶液中，使所得混合物在冰浴下反应0.5h。将(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(4.0g,14.7mmol)的甲苯(10mL)溶液滴加到上述反应体系中，自然升温到室温搅拌反应1h，后升温至110℃搅拌反应过夜。TLC监测反应完成，冷却至室温，浓缩至干，得到粗产品，经FCC(SiO2，EA/PE＝0-100％)纯化，得到无色油状产物(R)-2-甲基-3-亚甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(2.8g,收率71％)。LCMS(m/z):170.1(M-Boc+H)。Under stirring in an ice bath, a THF solution of potassium tert-butoxide (22.1 mL, 1M, 22.1 mmol) was added dropwise to a solution of methyltriphenylphosphine bromide (7.94 g, 22.1 mmol) in toluene (50 mL), and the resulting The mixture was reacted under ice bath for 0.5h. A solution of (R)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (4.0g, 14.7mmol) in toluene (10mL) Add it dropwise to the above reaction system, naturally warm up to room temperature and stir for 1 hour, then raise the temperature to 110°C and stir overnight. The completion of the reaction was monitored by TLC, cooled to room temperature, and concentrated to dryness to obtain a crude product, which was purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a colorless oily product (R)-2-methyl-3- Methylenepyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (2.8 g, yield 71%). LCMS (m/z): 170.1 (M-Boc+H).
步骤B：(2R,3S)-2,3-二甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step B: (2R,3S)-2,3-Dimethylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
室温下，将(R)-2-甲基-3-亚甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(590mg,2.19mmol)溶解到乙醇(20mL)中。随后在氮气保护下，加入干钯碳(500mg,10％wt，0.47mmol)。用 氢气球置换体系三次，后在氢气氛围下搅拌反应过夜。TLC监测反应结束后，经硅藻土过滤，滤液浓缩至干，得到无色油状产物(2R,3S)-2,3-二甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(450mg,收率76％)。LCMS(m/z):172.1(M-Boc+H)。1H NMR(400MHz,CDCl3)δ4.27–4.03(m,2H),3.84–3.64(m,1H),3.37–3.24(m,1H),2.21–2.02(m,1H),1.88–1.78(m,1H),1.78–1.67(m,1H),1.60–1.50(m,3H),1.49–1.37(m,9H),1.32–1.21(m,3H),0.95(d,J＝7.0Hz,3H).Dissolve (R)-2-methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (590mg, 2.19mmol) in ethanol (20mL). Then dry palladium on carbon (500 mg, 10% wt, 0.47 mmol) was added under nitrogen protection. use The hydrogen balloon replaced the system three times, and then stirred and reacted overnight under a hydrogen atmosphere. After the reaction was monitored by TLC, it was filtered through celite, and the filtrate was concentrated to dryness to obtain a colorless oily product (2R,3S)-2,3-dimethylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl base) ester 2-ethyl ester (450 mg, yield 76%). LCMS (m/z): 172.1 (M-Boc+H). 1 H NMR (400MHz, CDCl 3 ) δ4.27–4.03(m,2H),3.84–3.64(m,1H),3.37–3.24(m,1H),2.21–2.02(m,1H),1.88–1.78 (m,1H),1.78–1.67(m,1H),1.60–1.50(m,3H),1.49–1.37(m,9H),1.32–1.21(m,3H),0.95(d,J＝7.0Hz ,3H).
步骤C：((2R,3S)-1,2,3-三甲基吡咯烷-2-基)甲醇Step C: ((2R,3S)-1,2,3-Trimethylpyrrolidin-2-yl)methanol
在室温搅拌下，将LiAlH4(2.21mL,1M THF溶液,2.21mmol)缓慢滴加到(2R,3S)-2,3-二甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(200mg,0.74mmol)的无水THF(2mL)溶液中，所得混合物升温至70℃搅拌反应3h。TLC监测反应结束后,将体系用冰浴冷却，加入十水硫酸钠淬灭反应直至无气泡产生。加入适量乙酸乙酯，所得体系经无水硫酸钠干燥，过滤浓缩至干，得到无色油状粗产物((2R,3S)-1,2,3-三甲基吡咯烷-2-基)甲醇(100mg,收率95％)，直接用于后续反应。LCMS(m/z):144.1(M+H)。Under stirring at room temperature, LiAlH 4 (2.21mL, 1M THF solution, 2.21mmol) was slowly added dropwise to (2R,3S)-2,3-dimethylpyrrolidine-1,2-dicarboxylic acid 1-(tert Butyl) ester 2-ethyl ester (200mg, 0.74mmol) in anhydrous THF (2mL) solution, the resulting mixture was heated to 70°C and stirred for 3h. After the reaction was monitored by TLC, the system was cooled with an ice bath, and sodium sulfate decahydrate was added to quench the reaction until no bubbles were generated. An appropriate amount of ethyl acetate was added, the resulting system was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a colorless oily crude product ((2R,3S)-1,2,3-trimethylpyrrolidin-2-yl)methanol (100mg, yield 95%), directly used in subsequent reactions. LCMS (m/z): 144.1 (M+H).
中间体k2b
intermediate k2b
((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇
((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol
步骤A：(2R,3S)-2,3-二甲基吡咯烷-2-羧酸乙酯Step A: Ethyl (2R,3S)-2,3-dimethylpyrrolidine-2-carboxylate
将(2R,3S)-1-叔丁氧羰基-2,3-二甲基吡咯烷-2-羧酸乙酯(400mg,1.47mmol)溶于二氯甲烷(2mL),再加入三氟乙酸(2mL)。所得溶液在室温下反应1h。TLC检测反应完成后，将反应液浓缩，得到黄色油状粗产物(2R,3S)-2,3-二甲基吡咯烷-2-羧酸乙酯(250mg,收率99％)。1H NMR(400MHz,Chloroform-d)δ4.36–4.18(m,2H),3.61–3.32(m,2H),2.43–2.16(m,2H),1.77–1.64(m,1H),1.64(s,3H),1.31(t,J＝7.1Hz,3H),1.04(d,J＝6.9Hz,3H).Dissolve ethyl (2R,3S)-1-tert-butoxycarbonyl-2,3-dimethylpyrrolidine-2-carboxylate (400 mg, 1.47 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (2 mL). The resulting solution was reacted at room temperature for 1 h. After the completion of the reaction as detected by TLC, the reaction solution was concentrated to obtain the crude (2R,3S)-2,3-dimethylpyrrolidine-2-carboxylic acid ethyl ester (250 mg, yield 99%) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ4.36–4.18(m,2H),3.61–3.32(m,2H),2.43–2.16(m,2H),1.77–1.64(m,1H),1.64( s,3H),1.31(t,J=7.1Hz,3H),1.04(d,J=6.9Hz,3H).
步骤B：(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-羧酸乙酯Step B: Ethyl (2R,3S)-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylate
将(2R,3S)-2,3-二甲基吡咯烷-2-羧酸乙酯(250mg,1.46mmol)溶于乙腈(5mL)中,再加入碳酸钾(1.01g,7.30mmol)和碘乙烷(455mg,2.92mmol)。所得溶液在80℃下反应12h。TLC检测反应完成后，将反应液经硅藻土过滤，浓缩滤液，所得粗产品经FCC(SiO2，EA/PE＝50％～100％)纯化，得到无色油状产物(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-羧酸乙酯(190mg,收率65％)。1H NMR(400MHz,Chloroform-d)δ4.13(q,J＝7.1Hz,2H),3.27–3.16(m,1H),2.80–2.61(m,2H),2.36–2.18(m,1H),2.12–1.94(m,2H),1.72–1.58(m,1H),1.31–1.22(m,6H),1.07(t,J＝7.2Hz,3H),0.92(d,J＝6.7Hz,3H). Dissolve ethyl (2R,3S)-2,3-dimethylpyrrolidine-2-carboxylate (250 mg, 1.46 mmol) in acetonitrile (5 mL), and add potassium carbonate (1.01 g, 7.30 mmol) and iodine Ethane (455 mg, 2.92 mmol). The resulting solution was reacted at 80°C for 12h. After the reaction was detected by TLC, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the obtained crude product was purified by FCC (SiO 2 , EA/PE=50%-100%) to obtain a colorless oily product (2R,3S)- Ethyl 1-ethyl-2,3-dimethylpyrrolidine-2-carboxylate (190 mg, yield 65%). 1 H NMR (400MHz, Chloroform-d) δ4.13 (q, J = 7.1Hz, 2H), 3.27–3.16 (m, 1H), 2.80–2.61 (m, 2H), 2.36–2.18 (m, 1H) ,2.12–1.94(m,2H),1.72–1.58(m,1H),1.31–1.22(m,6H),1.07(t,J＝7.2Hz,3H),0.92(d,J＝6.7Hz,3H ).
步骤C：((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇Step C: ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol
将(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-羧酸乙酯(190mg,0.95mmol)溶于THF(2mL)中,在冰浴条件下缓慢加入LiAlH4-THF溶液(1.9mL,1M,1.9mmol)。所得溶液在0℃下搅拌反应20min。TLC检测反应完成后，向反应液中依次加入水(1mL)、EA(30mL)。所得反应液经硅藻土过滤，浓缩滤液，得到无色透明针状固体产物((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(110mg,收率73％)。1H NMR(400MHz,Chloroform-d)δ3.33(d,J＝10.6Hz,1H),3.16(dd,J＝8.7,6.7Hz,1H),3.10(d,J＝10.6Hz,1H),2.69–2.56(m,1H),2.46–2.31(m,2H),1.88–1.74(m,2H),1.48–1.30(m,1H),1.11(t,J＝7.2Hz,3H),1.07(d,J＝6.6Hz,3H),0.87(s,3H).Dissolve ethyl (2R,3S)-1-ethyl-2,3-dimethylpyrrolidine-2-carboxylate (190mg, 0.95mmol) in THF (2mL), and slowly add LiAlH in ice bath 4- THF solution (1.9 mL, 1 M, 1.9 mmol). The resulting solution was stirred and reacted at 0 °C for 20 min. After the reaction was detected by TLC, water (1 mL) and EA (30 mL) were sequentially added to the reaction solution. The resulting reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the product ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (110 mg, Yield 73%). 1 H NMR (400MHz, Chloroform-d) δ 3.33 (d, J = 10.6Hz, 1H), 3.16 (dd, J = 8.7, 6.7Hz, 1H), 3.10 (d, J = 10.6Hz, 1H), 2.69–2.56(m,1H),2.46–2.31(m,2H),1.88–1.74(m,2H),1.48–1.30(m,1H),1.11(t,J＝7.2Hz,3H),1.07( d,J=6.6Hz,3H),0.87(s,3H).
中间体k2c
intermediate k2c
((2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-基)甲醇
((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol
步骤A：(2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-羧酸乙酯Step A: Ethyl (2R,3S)-1-allyl-2,3-dimethylpyrrolidine-2-carboxylate
将(2R,3S)-2,3-二甲基吡咯烷-2-羧酸乙酯(250mg,1.46mmol)溶于乙腈(5mL)中,再加入碳酸钾(1.01g,7.30mmol)和烯丙基溴(353mg,2.92mmol)。所得溶液在80℃下反应6h。TLC检测反应完成后，将反应液经硅藻土过滤，浓缩滤液，所得粗产品经FCC(SiO2，EA/PE＝20％～50％)纯化，得到无色油状产物(2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-羧酸乙酯(160mg,收率52％)。1H NMR(400MHz,DMSO-d6)δ5.85–5.67(m,1H),5.21–4.92(m,2H),4.08(q,J＝7.1Hz,2H),3.31–3.23(m,1H),3.06–2.96(m,1H),2.87–2.76(m,1H),2.73–2.60(m,1H),2.02–1.85(m,2H),1.60–1.46(m,1H),1.25–1.14(m,6H),0.86(d,J＝6.6Hz,3H).Dissolve ethyl (2R,3S)-2,3-dimethylpyrrolidine-2-carboxylate (250mg, 1.46mmol) in acetonitrile (5mL), and add potassium carbonate (1.01g, 7.30mmol) and alkene Propyl bromide (353 mg, 2.92 mmol). The resulting solution was reacted at 80°C for 6h. After the reaction was detected by TLC, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the obtained crude product was purified by FCC (SiO 2 , EA/PE=20%-50%) to obtain a colorless oily product (2R,3S)- Ethyl 1-allyl-2,3-dimethylpyrrolidine-2-carboxylate (160 mg, yield 52%). 1 H NMR (400MHz, DMSO-d 6 ) δ5.85–5.67(m,1H),5.21–4.92(m,2H),4.08(q,J=7.1Hz,2H),3.31–3.23(m,1H ),3.06–2.96(m,1H),2.87–2.76(m,1H),2.73–2.60(m,1H),2.02–1.85(m,2H),1.60–1.46(m,1H),1.25–1.14 (m,6H),0.86(d,J=6.6Hz,3H).
步骤B：((2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-基)甲醇Step B: ((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol
将(2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-羧酸乙酯(160mg,0.75mmol)溶于THF(2mL)中,在冰水浴条件下缓慢加入1N的四氢铝锂THF溶液(1.5mL,1.5mmol)。所得溶液在0℃下反应20min。TLC检测反应完成后，向反应液中依次加入水(1mL)、EA(30mL)。所得反应液经硅藻土过滤，浓缩滤液，得到无色透明油状产物((2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-基)甲醇(90mg,收率70％)。1H NMR(400MHz,DMSO-d6)δ5.87–5.69(m,1H),5.22–4.90(m,2H),3.50–3.25(m,2H),3.23–3.04(m,2H),2.85–2.74(m,1H),2.64–2.52(m,1H),1.85–1.68(m,2H),1.47–1.33(m,1H),0.98(d,J＝6.7Hz,3H),0.86(s,3H).Dissolve ethyl (2R,3S)-1-allyl-2,3-dimethylpyrrolidine-2-carboxylate (160mg, 0.75mmol) in THF (2mL), and slowly add 1N solution of lithium aluminum hydride in THF (1.5 mL, 1.5 mmol). The resulting solution was reacted at 0°C for 20 min. After the reaction was detected by TLC, water (1 mL) and EA (30 mL) were sequentially added to the reaction solution. The resulting reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a colorless and transparent oily product ((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol (90mg, harvested rate of 70%). 1 H NMR (400MHz,DMSO-d 6 )δ5.87–5.69(m,1H),5.22–4.90(m,2H),3.50–3.25(m,2H),3.23–3.04(m,2H),2.85 –2.74(m,1H),2.64–2.52(m,1H),1.85–1.68(m,2H),1.47–1.33(m,1H),0.98(d,J＝6.7Hz,3H),0.86(s ,3H).
中间体k3a及k3b
Intermediate k3a and k3b
((2S,3R)-3-氟-1,2-二甲基吡咯烷-2-基)甲醇(中间体k3a)及((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲醇(中间体k3b)
((2S,3R)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (intermediate k3a) and ((2S,3S)-3-fluoro-1,2-dimethyl pyrrolidin-2-yl)methanol (intermediate k3b)
步骤A：(S)-3-氟-2-甲基-2,5-二氢-1H-吡咯-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (S)-3-Fluoro-2-methyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
室温条件下，将DAST(8.0mL,9.8g,60.8mmol)加入到(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(1.0g,3.69mmol)和DCM(10mL)的混合溶液中，并升温到50℃搅拌反应48h。LCMS监测反应结束，将反应液恢复到室温，慢慢加入到半饱和NaHCO3水溶液(30mL)中，用DCM(50mL×3)萃取。合并的有机相用饱和NaCl水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩后得到的粗品经FCC(SiO2,EA/PE＝0～10％)纯化，得到无色油状液体(S)-3-氟-2-甲基-2,5-二氢-1H-吡咯-1,2-二羧酸1-(叔丁基)酯2-乙基酯(350mg,收率35％)。1H NMR(400MHz,Chloroform-d)δ5.34–5.12(m,1H),4.22–4.15(m,2H),3.85–3.45(m,1H),2.57–2.19(m,1H),1.48–1.45(m,3H),1.45–1.41(m,9H),1.31–1.27(m,3H).LCMS(m/z):218.1(M+H-56)。At room temperature, DAST (8.0mL, 9.8g, 60.8mmol) was added to (R)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2 - in a mixed solution of ethyl ester (1.0g, 3.69mmol) and DCM (10mL), and heated to 50°C and stirred for 48h. The completion of the reaction was monitored by LCMS, and the reaction solution was returned to room temperature, slowly added to a half-saturated NaHCO 3 aqueous solution (30 mL), and extracted with DCM (50 mL×3). The combined organic phases were washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by FCC (SiO 2 , EA/PE=0-10%) to obtain a colorless oily liquid (S)-3-fluoro-2-methyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (350mg, yield 35 %). 1 H NMR (400MHz, Chloroform-d) δ5.34–5.12(m,1H),4.22–4.15(m,2H),3.85–3.45(m,1H),2.57–2.19(m,1H),1.48– 1.45 (m, 3H), 1.45–1.41 (m, 9H), 1.31–1.27 (m, 3H). LCMS (m/z): 218.1 (M+H-56).
步骤B：(2S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step B: (2S)-3-Fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
室温条件下，将Pd/C(5％wt,1.09g,0.51mmol)加入到(S)-3-氟-2-甲基-2,5-二氢-1H-吡咯-1,2-二羧酸1-(叔丁基)酯2-乙基酯(350mg,1.28mmol)、EA(10mL)及CH3COOH(10mL)的混合溶液中，使所得混合物在60psi H2压力下室温反应过夜。LCMS监测反应结束，硅藻土过滤，EA(50ml)洗涤，滤液浓缩，得到无色油状液体产物(2S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(350mg,收率99％)。1H NMR(400MHz,Chloroform-d)δ5.04–4.78(m,1H),4.37–4.07(m,2H),3.79–3.58(m,2H),2.22–2.05(m,2H),1.67–1.54(m,3H),1.51–1.39(m,9H),1.34–1.23(m,3H).LCMS(m/z):220.0(M+H-56)。At room temperature, Pd/C (5%wt, 1.09g, 0.51mmol) was added to (S)-3-fluoro-2-methyl-2,5-dihydro-1H-pyrrole-1,2-di In a mixed solution of 1-(tert-butyl)carboxylate 2-ethylester (350mg, 1.28mmol), EA (10mL) and CH3COOH (10mL), the resulting mixture was reacted overnight at room temperature under 60 psi H2 pressure . LCMS monitored the end of the reaction, filtered with celite, washed with EA (50ml), and concentrated the filtrate to obtain a colorless oily liquid product (2S)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-( tert-butyl) ester 2-ethyl ester (350 mg, yield 99%). 1 H NMR (400MHz, Chloroform-d) δ5.04–4.78(m,1H),4.37–4.07(m,2H),3.79–3.58(m,2H),2.22–2.05(m,2H),1.67– 1.54 (m, 3H), 1.51–1.39 (m, 9H), 1.34–1.23 (m, 3H). LCMS (m/z): 220.0 (M+H-56).
步骤C：(2S,3R)-3-氟-2-甲基吡咯烷-1,2-二羧酸酯及1-(叔丁基)2-乙基(2S,3S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step C: (2S,3R)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylate and 1-(tert-butyl)2-ethyl(2S,3S)-3-fluoro- 2-Methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester
将(2S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(350mg,1.27mmol)经SFC(SFC-150,Waters)拆分(分离柱：DAICEL250*25mm,10um；动相： CO2/MeOH＝98/2；流速：60mL/min)，得到首先洗脱出来的异构体1为化合物(2S,3R)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k3-2a,10mg,保留时间相对较短)，手性分析方法SFC-6，Rt＝1.192。LCMS(m/z):220.0(M+H-56)。后洗脱出来的异构体2为化合物(2S,3S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k3-2b,180mg,保留时间相对较长)，手性分析方法SFC-6，Rt＝1.377。1H NMR(400MHz,Chloroform-d3)δ5.03–4.79(m,1H),4.35–4.07(m,2H),3.80–3.59(m,2H),2.24–1.98(m,1H),1.65–1.56(m,3H),1.49–1.39(m,9H),1.32–1.22(m,3H).19F NMR(376MHz,Chloroform-d3)δ-180.50。(2S)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (350mg, 1.27mmol) was subjected to SFC (SFC-150, Waters ) split (separation column: DAICEL 250*25mm, 10um; moving phase: CO 2 /MeOH=98/2; flow rate: 60mL/min), the first eluted isomer 1 was obtained as compound (2S,3R)-3-fluoro-2-methylpyrrolidine-1,2-di Carboxylic acid 1-(tert-butyl) ester 2-ethyl ester (k3-2a, 10 mg, relatively short retention time), chiral analysis method SFC-6, Rt=1.192. LCMS (m/z): 220.0 (M+H-56). Isomer 2 eluting later is the compound (2S,3S)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester (k3 -2b, 180mg, relatively long retention time), chiral analysis method SFC-6, Rt=1.377. 1 H NMR (400MHz, Chloroform-d 3 ) δ5.03–4.79(m,1H),4.35–4.07(m,2H),3.80–3.59(m,2H),2.24–1.98(m,1H),1.65 -1.56 (m, 3H), 1.49 - 1.39 (m, 9H), 1.32 - 1.22 (m, 3H). 19 F NMR (376 MHz, Chloroform-d 3 ) δ-180.50.
步骤D：((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲醇(k3b)Step D: ((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (k3b)
室温条件下，将LiAH4(3.27mL,3.27mmol,1M THF溶液)加入到(2S,3S)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k3-2b,180mg,0.65mmol)中并升温至70℃搅拌3h。LCMS监测反应结束后，在冰浴条件下，缓慢将Na2SO4·10H2O加入反应液中直到不再生成气体为止，加入适量EA，无水硫酸钠干燥，过滤，滤液减压浓缩，得到无色液体(4-甲氧基-1,3-二甲基哌啶-3-基)甲醇(95mg,收率99％)。LCMS(m/z):148.1(M+H)。At room temperature, LiAH 4 (3.27mL, 3.27mmol, 1M THF solution) was added to (2S,3S)-3-fluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl ) ester 2-ethyl ester (k3-2b, 180mg, 0.65mmol) and heated to 70°C and stirred for 3h. After the reaction was monitored by LCMS, Na 2 SO 4 10H 2 O was slowly added to the reaction solution under ice bath conditions until no more gas was generated, an appropriate amount of EA was added, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (4-Methoxy-1,3-dimethylpiperidin-3-yl)methanol (95 mg, yield 99%) was obtained as a colorless liquid. LCMS (m/z): 148.1 (M+H).
((2S,3R)-3-氟-1,2-二甲基吡咯烷-2-基)甲醇(k3a)经过相同方法，由(2S,3R)-3-氟-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(k3-2a)经上述步骤得到。((2S,3R)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (k3a) was converted from (2S,3R)-3-fluoro-2-methylpyrrolidinium by the same method -1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (k3-2a) was obtained through the above steps.
中间体k4a及k4b
Intermediate k4a and k4b
(2R,3S)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈及(2R,3R)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈
(2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile and (2R,3R)-2-(hydroxymethyl)-1,2-dimethylpyrrole Alkane-3-carbonitrile
步骤A：(2R,3R)-3-(羟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (2R,3R)-3-(Hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
在冰浴条件下，将1M BH3/THF(11.4mL,11.4mmol)缓慢滴加到(R)-2-甲基-3-亚甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(2.80g,10.4mmol)的无水THF(60mL)溶液中。所得混合物 升至室温搅拌反应3h后，冰浴冷却，将3N氢氧化钠水溶液(3.8mL,11.4mmol)和30％的双氧水(9.0mL,88.1mmol)依次滴加到反应体系中。滴加完成后，将体系恢复至室温，搅拌反应过夜。TLC监测反应结束后，将反应液倒入冰水(100mL)中淬灭，乙酸乙酯萃取(80mL×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，得到的粗产品经FCC(SiO2，EA/PE＝0-25％)纯化，得到无色油状物(2R,3R)-3-(羟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(1.2g,收率30％)。LCMS(m/z):187.9(M-Boc+H)。1H NMR(400MHz,CDCl3)δ7.86(brs,1H),4.29–4.12(m,1H),4.12–4.00(m,1H),3.80–3.62(m,1H),3.61–3.44(m,2H),3.42–3.25(m,1H),2.64–2.21(m,1H),2.01–1.88(m,1H),1.88–1.47(m,4H),1.46–1.30(m,9H),1.27–1.14(m,3H)。Under ice-bath conditions, 1M BH 3 /THF (11.4 mL, 11.4 mmol) was slowly added dropwise to (R)-2-methyl-3-methylenepyrrolidine-1,2-dicarboxylic acid 1-( tert-butyl) ester 2-ethyl ester (2.80 g, 10.4 mmol) in anhydrous THF (60 mL). The resulting mixture After rising to room temperature and stirring for 3 h, cooling in an ice bath, 3N aqueous sodium hydroxide solution (3.8 mL, 11.4 mmol) and 30% hydrogen peroxide (9.0 mL, 88.1 mmol) were sequentially added dropwise to the reaction system. After the dropwise addition was completed, the system was returned to room temperature, and the reaction was stirred overnight. After the reaction was monitored by TLC, the reaction solution was poured into ice water (100 mL) to quench, and extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and the obtained crude product was purified by FCC (SiO 2 , EA/PE=0-25%) to obtain a colorless oil (2R, 3R) -3-(Hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (1.2 g, yield 30%). LCMS (m/z): 187.9 (M-Boc+H). 1 H NMR (400MHz, CDCl 3 )δ7.86(brs,1H),4.29–4.12(m,1H),4.12–4.00(m,1H),3.80–3.62(m,1H),3.61–3.44(m ,2H),3.42–3.25(m,1H),2.64–2.21(m,1H),2.01–1.88(m,1H),1.88–1.47(m,4H),1.46–1.30(m,9H),1.27 –1.14(m,3H).
步骤B：(2R,3R)-3-甲酰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step B: (2R,3R)-3-Formyl-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
室温条件下，把戴斯马丁氧化剂(7.40g,17.4mmol)分批加入到(2R,3R)-3-(羟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(1.00g,3.48mmol)的二氯甲烷(200mL)溶液中，所的混合物室温搅拌反应过夜。大量白色固体产生，LCMS监测反应结束。反应液用硅藻土过滤，滤饼用二氯甲烷洗涤两遍。收集滤液，减压浓缩，所得粗产物通过FCC(SiO2，EA/PE＝0-50％)纯化，得到无色油状产物(2R,3R)-3-甲酰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(660mg,收率66％)。LCMS(m/z):186.1(M-Boc+H)。At room temperature, add Dess Martin oxidant (7.40g, 17.4mmol) to (2R,3R)-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1- (tert-butyl)ester 2-Ethyl ester (1.00g, 3.48mmol) in dichloromethane (200mL) solution, the resulting mixture was stirred at room temperature overnight. A large amount of white solid was produced, and the reaction was completed by LCMS monitoring. The reaction solution was filtered with celite, and the filter cake was washed twice with dichloromethane. The filtrate was collected and concentrated under reduced pressure, and the obtained crude product was purified by FCC (SiO 2 , EA/PE=0-50%) to obtain the colorless oily product (2R,3R)-3-formyl-2-methylpyrrolidine- 1-(tert-butyl) 1,2-dicarboxylate 2-ethyl ester (660 mg, yield 66%). LCMS (m/z): 186.1 (M-Boc+H).
步骤C：(2R)-3-氰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step C: (2R)-3-Cyano-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
室温下，将(2R,3R)-3-甲酰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(400mg,1.40mmol)和二苯基膦酰羟胺(DPPH,392mg,1.68mmol)溶于甲苯(10mL)溶液中，所得混合物加热到85℃，搅拌反应过夜。LCMS检测反应结束，冷却到室温，浓缩至干，得到粗产品，通过FCC(SiO2，EA/PE＝0-50％)纯化，得到无色油状产物(2R)-3-氰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(240mg,收率61％)。LCMS(m/z):183.1(M-Boc+H)。1H NMR(400MHz,CDCl3)δ4.30–4.08(m,2H),3.91–3.70(m,0.5H),3.68–3.54(m,0.5H),3.54–3.42(m,0.5H),3.41–3.32(m,0.5H),3.31–3.20(m,0.5H),3.03–2.87(m,0.5H),2.35–2.22(m,1H),2.21–2.04(m,1H),1.71–1.57(m,3H),1.43–1.32(m,9H),1.29–1.13(m,3H)。At room temperature, (2R,3R)-3-formyl-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (400mg, 1.40mmol) and di Phenylphosphonohydroxylamine (DPPH, 392mg, 1.68mmol) was dissolved in toluene (10mL) solution, the resulting mixture was heated to 85°C and stirred overnight. LCMS detected the completion of the reaction, cooled to room temperature, and concentrated to dryness to obtain a crude product, which was purified by FCC (SiO 2 , EA/PE=0-50%) to obtain a colorless oily product (2R)-3-cyano-2- Methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (240 mg, yield 61%). LCMS (m/z): 183.1 (M-Boc+H). 1 H NMR (400MHz, CDCl 3 ) δ4.30–4.08(m,2H),3.91–3.70(m,0.5H),3.68–3.54(m,0.5H),3.54–3.42(m,0.5H), 3.41–3.32(m,0.5H),3.31–3.20(m,0.5H),3.03–2.87(m,0.5H),2.35–2.22(m,1H),2.21–2.04(m,1H),1.71– 1.57(m,3H), 1.43–1.32(m,9H), 1.29–1.13(m,3H).
步骤D：(2R)-3-氰基-2-甲基吡咯烷-2-羧酸乙酯盐酸盐Step D: Ethyl (2R)-3-cyano-2-methylpyrrolidine-2-carboxylate hydrochloride
室温下，将4M盐酸-二氧六环(5mL,20mmol)滴加到(2R)-3-氰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(220mg,0.78mmol)的EA(5mL)溶液中。所的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(2R)-3-氰基-2-甲基吡咯烷-2-羧酸乙酯盐酸盐(170mg,收率100％)。LCMS(m/z):183.1(M+H)。1H NMR(400MHz,D2O)δ4.41–4.24(m,2H),3.93(t,J＝7.9Hz,0.5H),3.71(t,J＝7.9,6.4Hz,0.5H),3.67–3.41(m,2H),2.70–2.35(m,2H),1.79(s,1.5H),1.71(s,1.5H),1.31–1.17(m,3H)。Add 4M hydrochloric acid-dioxane (5mL, 20mmol) dropwise to (2R)-3-cyano-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester at room temperature 2-Ethyl ester (220mg, 0.78mmol) in EA (5mL) solution. The resulting mixture was stirred at room temperature for 1 h. LCMS monitored the completion of the reaction, and concentrated under reduced pressure to obtain (2R)-3-cyano-2-methylpyrrolidine-2-carboxylic acid ethyl ester hydrochloride (170 mg, yield 100%) as a white solid. LCMS (m/z): 183.1 (M+H). 1 H NMR (400MHz, D 2 O) δ4.41–4.24 (m, 2H), 3.93 (t, J = 7.9Hz, 0.5H), 3.71 (t, J = 7.9, 6.4Hz, 0.5H), 3.67 –3.41 (m, 2H), 2.70 – 2.35 (m, 2H), 1.79 (s, 1.5H), 1.71 (s, 1.5H), 1.31 – 1.17 (m, 3H).
步骤E：(2R,3S)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯及(2R,3S)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯 Step E: Ethyl (2R,3S)-3-cyano-1,2-dimethylpyrrolidine-2-carboxylate and (2R,3S)-3-cyano-1,2-dimethylpyrrole Ethyl alkane-2-carboxylate
室温下，将甲醛水溶液(5mL,35～40％wt，～60mmol)加入到(2R)-3-氰基-2-甲基吡咯烷-2-羧酸乙酯盐酸盐(170mg,0.78mmol)的甲醇(10mL)溶液中，所的混合物在室温搅拌0.5h。分批加入氰基硼氢化钠(244mg,3.89mmol)，所得体系在室温继续搅拌反应1h。LCMS监测反应完成。将反应液浓缩得到粗产品，通过FCC(SiO2，EA/PE＝0-100％)纯化，得到无色油状产物(2R,3S)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯(59mg,收率39％)，LCMS(m/z):197.1(M+H)。1H NMR(400MHz,CDCl3)δ4.20(q,J＝7.2Hz,2H),3.51(dd,J＝9.4,5.9Hz,1H),3.04–2.95(m,1H),2.85–2.76(m,1H),2.38(s,3H),2.36–2.27(m,1H),2.18–2.08(m,1H),1.49(s,3H),1.30(t,J＝7.2Hz,3H)；以及无色油状产物(2R,3R)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯(50mg,收率33％)，LCMS(m/z):197.1(M+H)。1H NMR(400MHz,CDCl3)δ4.28(q,J＝7.1Hz,2H),3.19–3.11(m,1H),2.96–2.86(m,2H),2.35–2.25(m,5H),1.47(s,3H),1.35(t,J＝7.1Hz,3H)。Add aqueous formaldehyde (5mL, 35~40%wt,~60mmol) to ethyl (2R)-3-cyano-2-methylpyrrolidine-2-carboxylate hydrochloride (170mg, 0.78mmol ) in methanol (10 mL), and the resulting mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (244 mg, 3.89 mmol) was added in batches, and the resulting system was stirred and reacted at room temperature for 1 h. LCMS monitored the completion of the reaction. The reaction solution was concentrated to obtain a crude product, which was purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a colorless oily product (2R,3S)-3-cyano-1,2-dimethylpyrrolidine -2-Carboxylic acid ethyl ester (59 mg, yield 39%), LCMS (m/z): 197.1 (M+H). 1 H NMR (400MHz, CDCl 3 ) δ4.20 (q, J=7.2Hz, 2H), 3.51 (dd, J=9.4, 5.9Hz, 1H), 3.04–2.95 (m, 1H), 2.85–2.76 ( m,1H), 2.38(s,3H), 2.36–2.27(m,1H), 2.18–2.08(m,1H), 1.49(s,3H), 1.30(t,J=7.2Hz,3H); and Colorless oily product (2R,3R)-3-cyano-1,2-dimethylpyrrolidine-2-carboxylic acid ethyl ester (50 mg, yield 33%), LCMS (m/z): 197.1 (M +H). 1 H NMR (400MHz, CDCl3) δ4.28 (q, J = 7.1Hz, 2H), 3.19–3.11 (m, 1H), 2.96–2.86 (m, 2H), 2.35–2.25 (m, 5H), 1.47 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).
步骤F：(2R,3S)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈及(2R,3R)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈Step F: (2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile and (2R,3R)-2-(hydroxymethyl)-1,2-bis Methylpyrrolidine-3-carbonitrile
在室温条件下，将LiAlH4-THF(0.4mL,0.4mmol,1M THF溶液)缓慢滴加到(2R,3S)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯(50mg,0.25mmol)的无水THF(1mL)溶液中，所得混合物室温搅拌反应0.5h。TLC监测反应完成，冰浴冷却，缓慢加入十水硫酸钠淬灭反应直至无气泡产生。补加适量乙酸乙酯，无水硫酸钠干燥，过滤浓缩至干，得到无色油状粗产物(2R,3S)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈(中间体k4a，30mg,收率76％)。LCMS(m/z):155.1(M+H)。At room temperature, LiAlH 4 -THF (0.4mL, 0.4mmol, 1M THF solution) was slowly added dropwise to (2R,3S)-3-cyano-1,2-dimethylpyrrolidine-2-carboxylic acid Ethyl ester (50 mg, 0.25 mmol) was dissolved in anhydrous THF (1 mL), and the resulting mixture was stirred at room temperature for 0.5 h. The completion of the reaction was monitored by TLC, cooled in an ice bath, and sodium sulfate decahydrate was slowly added 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 (2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3- Nitrile (intermediate k4a, 30 mg, yield 76%). LCMS (m/z): 155.1 (M+H).
(2R,3R)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈(中间体k4b)经相同方法，由(2R,3R)-3-氰基-1,2-二甲基吡咯烷-2-羧酸乙酯(化合物k4-6b)通过上述步骤，得到中间体k4b(30mg，收率76％)。LCMS(m/z):155.1(M+H)。(2R,3R)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4b) was prepared from (2R,3R)-3-cyano-1, 2-Dimethylpyrrolidine-2-carboxylic acid ethyl ester (compound k4-6b) Through the above steps, intermediate k4b (30 mg, yield 76%) was obtained. LCMS (m/z): 155.1 (M+H).
中间体k5a
intermediate k5a
((2R,3R)-3-(二氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇
((2R,3R)-3-(Difluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
步骤A：(2R,3R)-3-(二氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (2R,3R)-3-(Difluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
室温条件下，将DAST(440mg,2.7mmol)滴加到(2R,3R)-3-甲酰基-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(260mg,0.91mmol)的二氯甲烷(10mL)溶液中，所得混合物室温搅拌过夜。LCMS监测反应完成，加入饱和NaHCO3水溶液(10mL)，搅拌5分钟后，分液，水层 用二氯甲烷萃取两遍。合并有机相，浓缩至干，得到粗产品，通过FCC(SiO2，EA/PE＝0-50％)纯化，得到无色油状产物(2R,3R)-3-(二氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(130mg,收率46％)。LCMS(m/z):208.0(M-Boc+H)。1H NMR(400MHz,CDCl3)δ5.97–5.61(m,1H),4.33–4.10(m,2H),3.73–3.55(m,1H),3.54–3.40(m,1H),2.95–2.74(m,1H),2.13–2.03(m,1H),2.03–1.85(m,1H),1.54–1.45(m,3H),1.45–1.37(m,9H),1.33–1.21(m,3H)。At room temperature, DAST (440mg, 2.7mmol) was added dropwise to (2R,3R)-3-formyl-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2- Ethyl ester (260 mg, 0.91 mmol) was dissolved in dichloromethane (10 mL), and the resulting mixture was stirred at room temperature overnight. LCMS monitors that the reaction is complete, adding saturated NaHCO aqueous solution (10mL), stirring for 5 minutes, separating the layers, and the aqueous layer Extract twice with dichloromethane. The combined organic phases were concentrated to dryness to give the crude product, which was purified by FCC ( SiO2 , EA/PE = 0-50%) to give the product (2R,3R)-3-(difluoromethyl)-2 as a colorless oil -Methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester (130 mg, yield 46%). LCMS (m/z): 208.0 (M-Boc+H). 1 H NMR (400MHz, CDCl 3 ) δ5.97–5.61(m,1H),4.33–4.10(m,2H),3.73–3.55(m,1H),3.54–3.40(m,1H),2.95–2.74 (m,1H),2.13–2.03(m,1H),2.03–1.85(m,1H),1.54–1.45(m,3H),1.45–1.37(m,9H),1.33–1.21(m,3H) .
步骤B：((2R,3R)-3-(二氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇Step B: ((2R,3R)-3-(Difluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
在室温条件下，(2R,3R)-3-(二氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(130mg,0.423mmol)溶解到无水THF(1.5mL)中，缓慢滴加1M LiAlH4-THF(1.27mL,1.27mmol)到体系中，所得混合物升温至70℃搅拌反应3h。TLC监测反应完成，冰浴冷却，缓慢加入十水硫酸钠淬灭反应直至无气泡产生。补加适量乙酸乙酯，无水硫酸钠干燥，过滤浓缩至干，得到无色油状粗产物((2R,3R)-3-(二氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇(60mg,收率79％)。LCMS(m/z):180.0(M+H)。At room temperature, (2R,3R)-3-(difluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (130mg, 0.423mmol) was dissolved in anhydrous THF (1.5mL), and 1M LiAlH 4 -THF (1.27mL, 1.27mmol) was slowly added dropwise to the system, and the resulting mixture was heated to 70°C and stirred for 3h. The completion of the reaction was monitored by TLC, cooled in an ice bath, and sodium sulfate decahydrate was slowly added to quench the reaction until no bubbles were generated. An appropriate amount of ethyl acetate was added, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a colorless oily crude product ((2R,3R)-3-(difluoromethyl)-1,2-dimethylpyrrolidine- 2-yl)methanol (60mg, yield 79%). LCMS (m/z): 180.0 (M+H).
中间体k6a
intermediate k6a
((2R,3R)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇
((2R,3R)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
步骤A：(2R,3R)-3-(氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (2R,3R)-3-(Fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl)ester 2-ethylester
冰浴下，将DAST(247mg,1.53mmol)加入到(2R,3R)-3-(羟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(220mg,0.76mmol)和DCM(5mL)的混合溶液中，所得混合物升至室温搅拌2h。LCMS监测反应结束后，加入饱和碳酸氢钠(30mL)，DCM(30mL×2)萃取。有机相用饱和食盐水(70mL)洗涤,收集有机相浓缩并进一步经FCC(SiO2，EA/PE＝0-30％)纯化，得到无色液体(2R,3R)-3-(氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(90mg,收率41％)。LC-MS(m/z):234.0(M-56+H)。Add DAST (247mg, 1.53mmol) to (2R,3R)-3-(hydroxymethyl)-2-methylpyrrolidine-1,2-dicarboxylate 1-(tert-butyl) under ice bath In a mixed solution of 2-ethyl ester (220 mg, 0.76 mmol) and DCM (5 mL), the resulting mixture was warmed to room temperature and stirred for 2 h. After the reaction was monitored by LCMS, saturated sodium bicarbonate (30 mL) was added and extracted with DCM (30 mL×2). The organic phase was washed with saturated brine (70 mL), the collected organic phase was concentrated and further purified by FCC (SiO 2 , EA/PE=0-30%) to obtain a colorless liquid (2R,3R)-3-(fluoromethyl )-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester (90mg, yield 41%). LC-MS (m/z): 234.0 (M-56+H).
步骤B：((2R,3R)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇Step B: ((2R,3R)-3-(Fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
室温下，将LiAlH4-THF(1M,1.24mmol,1.24mL)滴加入(2R,3R)-3-(氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(90mg,0.31mmol)的THF(3mL)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℃)浓缩，得到无色液体((2R,3R)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇(50mg,收率99％)。LC-MS(m/z):162.1(M+H)。At room temperature, LiAlH 4 -THF (1M, 1.24mmol, 1.24mL) was added dropwise into (2R,3R)-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-( tert-butyl) ester 2-ethyl ester (90mg, 0.31mmol) in THF (3mL) solution, the resulting system was heated to 70°C and stirred for 3h. 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 celite, and the obtained filtrate was concentrated at low temperature (35°C) to obtain a colorless liquid ((2R,3R)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl ) methanol (50mg, yield 99%). LC-MS (m/z): 162.1 (M+H).
中间体k6b
intermediate k6b
((2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇
((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
步骤A：(R)-3-(氟亚甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step A: (R)-3-(fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
冰浴条件下，将叔丁醇钾的THF溶液(7.74mL,1M,7.74mmol)滴加到(氟甲基)四氟硼酯三苯基磷(2.96g,7.74mmol)的甲苯(30mL)溶液中，所得体系在冰浴下搅拌1h。将(R)-2-甲基-3-氧代吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(1.40g,5.16mmol)的甲苯(5mL)溶液滴加到上述体系中，保持温度反应0.5h，自然升温到室温搅拌反应0.5h，后升至110℃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(R)-3-(氟亚甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(700mg,收率47％)。LCMS(m/z):188.0(M-Boc+H)。Under ice-bath conditions, a THF solution of potassium tert-butoxide (7.74mL, 1M, 7.74mmol) was added dropwise to (fluoromethyl)tetrafluoroborate triphenylphosphine (2.96g, 7.74mmol) in toluene (30mL) solution, the resulting system was stirred for 1 h under an ice bath. A solution of (R)-2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethyl ester (1.40g, 5.16mmol) in toluene (5mL) Add it dropwise to the above system, keep the temperature for reaction for 0.5h, naturally raise the temperature to room temperature and stir for 0.5h, then rise to 110°C and stir overnight. The completion of the reaction was monitored by TLC, cooled to room temperature, and concentrated to dryness under reduced pressure to obtain a crude product, which was purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a colorless oily product (R)-3-(fluoromethoxy Methyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (700 mg, yield 47%). LCMS (m/z): 188.0 (M-Boc+H).
步骤B：(2R,3S)-3-(氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯Step B: (2R,3S)-3-(Fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)ester 2-ethylester
室温氮气保护下，将Pd/C(500mg,10％w/w,0.470mmol)加入到(R)-3-(氟亚甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(700mg,2.44mmol)的甲醇(25mL)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，得到无色油状产物(2R,3S)-3-(氟甲基)-2-甲基吡咯烷-1,2-二羧酸1-(叔丁基)酯2-乙基酯(400mg,收率57％)。LCMS(m/z):190.0(M-Boc+H)。1H NMR(400MHz,CDCl3)δ4.55–4.46(m,0.5H),4.46–4.34(m,1H),4.34–4.26(m,0.5H),4.24–4.06(m,2H),3.87–3.69(m,1H),3.46–3.34(m,1H),2.52–2.33(m,1H),1.98–1.85(m,2H),1.70–1.59(m,3H),1.49–1.39(m,9H),1.33–1.20(m,3H)。Under nitrogen protection at room temperature, Pd/C (500mg, 10%w/w, 0.470mmol) was added to (R)-3-(fluoromethylene)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (700 mg, 2.44 mmol) in methanol (25 mL). The system was replaced with a hydrogen balloon, and the reaction was stirred overnight in a hydrogen atmosphere. After the reaction was monitored by TLC, it was filtered with diatomaceous earth, and the filtrate was concentrated to dryness to obtain a colorless oily product (2R,3S)-3-(fluoromethyl)-2-methylpyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-ethyl ester (400 mg, yield 57%). LCMS (m/z): 190.0 (M-Boc+H). 1 H NMR (400MHz, CDCl 3 ) δ4.55–4.46(m,0.5H),4.46–4.34(m,1H),4.34–4.26(m,0.5H),4.24–4.06(m,2H),3.87 –3.69(m,1H),3.46–3.34(m,1H),2.52–2.33(m,1H),1.98–1.85(m,2H),1.70–1.59(m,3H),1.49–1.39(m, 9H), 1.33–1.20 (m, 3H).
步骤C：(2R,3S)-3-(氟甲基)-2-甲基吡咯烷-2-羧酸乙酯盐酸盐Step C: Ethyl (2R,3S)-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylate hydrochloride
室温下，将4M盐酸-二氧六环(10mL,20mmol)滴加到(2R,3S)-3-(氟甲基)-2-甲基吡咯烷- 1,2-二羧酸1-(叔丁基)酯2-乙基酯(200mg,0.69mmol)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(2R,3S)-3-(氟甲基)-2-甲基吡咯烷-2-羧酸乙酯盐酸盐(200mg,粗品)。LCMS(m/z):190.2(M+H)。At room temperature, 4M hydrochloric acid-dioxane (10mL, 20mmol) was added dropwise to (2R,3S)-3-(fluoromethyl)-2-methylpyrrolidine- In ethyl acetate (10 mL) solution of 1-(tert-butyl) 1,2-dicarboxylic acid 2-ethyl ester (200 mg, 0.69 mmol), the resulting mixture was stirred at room temperature for 1 h. The completion of the reaction was monitored by LCMS, and the mixture was concentrated under reduced pressure to obtain ethyl (2R,3S)-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylate hydrochloride (200 mg, crude product) as a white solid. LCMS (m/z): 190.2 (M+H).
步骤D：(2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-羧酸乙酯Step D: Ethyl (2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidine-2-carboxylate
室温下，将(2R,3S)-3-(氟甲基)-2-甲基吡咯烷-2-羧酸乙酯盐酸盐(200mg,上步粗品)溶于甲醇(5mL)，加入甲醛水溶液(2mL,35～40％w/w,～24mmol)，室温搅拌0.5h。分批加入氰基硼氢化钠(244mg,3.89mmol)，所得混合物室温搅拌反应0.5h。LCMS监测反应结束，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(2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-羧酸乙酯(100mg)。LCMS(m/z):204.1(M+H)。At room temperature, dissolve ethyl (2R,3S)-3-(fluoromethyl)-2-methylpyrrolidine-2-carboxylate hydrochloride (200 mg, crude product from the previous step) in methanol (5 mL), add formaldehyde Aqueous solution (2mL, 35~40%w/w,~24mmol), stirred at room temperature for 0.5h. Sodium cyanoborohydride (244mg, 3.89mmol) was added in batches, and the resulting mixture was stirred at room temperature for 0.5h. The completion of the reaction was monitored by LCMS, and the crude product was obtained by concentration, which was purified by FCC (SiO 2 , EA/PE=0-100%) to obtain a colorless oily product (2R,3S)-3-(fluoromethyl)-1,2- Ethyl dimethylpyrrolidine-2-carboxylate (100 mg). LCMS (m/z): 204.1 (M+H).
步骤E：((2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇Step E: ((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol
在室温条件下，将LiAlH4-THF(0.59mL,1M,0.59mmol)慢慢滴加到(2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-羧酸乙酯(100mg,0.49mmol)的无水THF(1mL)溶液中，所得混合物室温搅拌反应1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((2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇(50.0mg,收率63％)。LCMS(m/z):162.1(M+H)。At room temperature, LiAlH 4 -THF (0.59mL, 1M, 0.59mmol) was slowly added dropwise to (2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidine-2- Ethyl carboxylate (100 mg, 0.49 mmol) was dissolved in anhydrous THF (1 mL), and the resulting mixture was stirred at room temperature for 1 hour. TLC monitored the completion of the reaction, cooled in an ice bath, and added sodium sulfate decahydrate to quench the reaction until no bubbles were generated. An appropriate amount of ethyl acetate was added, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a colorless oily crude product ((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidine- 2-yl)methanol (50.0 mg, yield 63%). LCMS (m/z): 162.1 (M+H).
根据上述合成方案或者适当变体，制备如下中间体：



According to the above synthetic scheme or appropriate variants, the following intermediates are prepared:



实施例1
Example 1
4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-(2-fluoro Ethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
步骤A：(1R,5S)-3-(7-溴-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯Step A: (1R,5S)-3-(7-Bromo-8-fluoro-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy Base) quinazoline-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
室温条件下，将NaH(176mg,4.4mmol,60％-矿物油)加入到(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇(425mg,2.6mmol)的THF(15mL)溶液中，保持室温搅拌20分钟，然后将(1R,5S)-3-(7-溴-2,8-二氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(400mg,0.88mmol)加入到上述混合溶液中继续搅拌0.5h。LCMS监测反应完成，加入水(50mL)，EA(50mL×2)萃取。合并有机相，饱和食盐水洗涤，减压浓缩，所得粗品经FCC(SiO2，EA/PE＝0-40％)纯化，得到黄色固体(1R,5S)-3-(7-溴-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(480mg,收率92％)。LCMS(ESI,m/z):618.3(M+Na)。At room temperature, NaH (176mg, 4.4mmol, 60%-mineral oil) was added to (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (425mg, 2.6mmol) in THF (15mL) solution, kept stirring at room temperature for 20 minutes, then (1R,5S)-3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8 - tert-butyl diazacyclo[3.2.1]octane-8-carboxylate (400mg, 0.88mmol) was added to the above mixed solution and continued stirring for 0.5h. The completion of the reaction was monitored by LCMS, water (50 mL) was added, and EA (50 mL×2) was extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The resulting crude product was purified by FCC (SiO 2 , EA/PE=0-40%) to obtain (1R,5S)-3-(7-bromo-8- Fluoro-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazepine Cyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (480mg, yield 92%). LCMS (ESI, m/z): 618.3 (M+Na).
步骤B：(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯 Step B: (1R,5S)-3-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene- 1-yl)-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8- tert-butyl diazacyclo[3.2.1]octane-8-carboxylate
氮气保护下，将(1R,5S)-3-(7-溴-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(200mg,0.33mmol)、三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环-2-基)萘-1-基)乙炔基)硅烷(206mg,0.40mmol)、Pd(dtbpf)Cl2(22mg,0.033mmol)、K3PO4(285mg,1.3mmol)和二氧六环/H2O(V/V＝4:1,8mL)的混合溶液加热至100℃搅拌反应2h。LCMS监测反应结束后，体系冷却至室温，加入水(30mL)，EA(50mL×2)萃取。合并有机相用饱和食盐水洗涤，减压浓缩，得到的粗品经FCC(SiO2，EA/PE＝0-60％)纯化，得到黄色油状物(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(140mg,收率46％)。LCMS(ESI,m/z):902.3(M+H)。Under nitrogen protection, (1R,5S)-3-(7-bromo-8-fluoro-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl) Methoxy)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200mg, 0.33mmol), triisopropyl ((6 -(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)naphthalene-1-yl)ethynyl) Silane (206 mg, 0.40 mmol), Pd(dtbpf)Cl 2 (22 mg, 0.033 mmol), K 3 PO 4 (285 mg, 1.3 mmol) and dioxane/H 2 O (V/V=4:1,8 mL ) mixed solution was heated to 100°C and stirred for 2h. After the reaction was monitored by LCMS, the system was cooled to room temperature, water (30 mL) was added, and EA (50 mL×2) was extracted. The combined organic phases were washed with saturated brine and concentrated under reduced pressure. The obtained crude product was purified by FCC (SiO 2 , EA/PE=0-60%) to obtain (1R,5S)-3-(8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((R)-1-(2 -fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid Tert-butyl ester (140mg, yield 46%). LCMS (ESI, m/z): 902.3 (M+H).
步骤C：4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇Step C: 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-( 2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -2-ol
室温条件下，将TFA(10mL)加入到(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(140mg,0.16mmol)中，所得体系搅拌反应1h。LCMS监测反应结束，加入EA(30mL)稀释，饱和NaHCO3水溶液调pH到8，EA(50mL×3)萃取。合并有机相用饱和食盐水洗涤，减压浓缩得到黄色固体4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(100mg,收率85％)。LCMS(ESI,m/z):758.3(M+H)。At room temperature, TFA (10 mL) was added to (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Silyl)ethynyl)naphthalen-1-yl)-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazoline-4 -yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (140mg, 0.16mmol), the resulting system was stirred and reacted for 1h. LCMS monitored the completion of the reaction, added EA (30 mL) to dilute, adjusted the pH to 8 with saturated NaHCO 3 aqueous solution, and extracted with EA (50 mL×3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to obtain a yellow solid 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8- Fluoro-2-((R)-1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-( (Triisopropylsilyl)ethynyl)naphthalen-2-ol (100 mg, yield 85%). LCMS (ESI, m/z): 758.3 (M+H).
步骤D：4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇Step D: 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-( 2-fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(100mg,0.13mmol)，CsF(100mg,0.66mmol)和DMF(3mL)的混合溶液加热至50℃搅拌反应1h。LCMS监测反应结束，将体系降至室温，过滤，所得滤液经Pre-HPLC(C18E,ACN/(0.1％NH4CO3/H2O)＝50-70％)纯化，得到白色固体4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-8-氟-2-((R)-1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(40mg,收率51％)。1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝9.2,6.0Hz,1H),7.72(d,J＝8.6Hz,1H),7.50–7.42(m,1H),7.36(d,J＝2.5Hz,1H),7.17(dd,J＝8.6,6.8Hz,1H),7.07(d,J＝2.5Hz,1H),4.52–4.42(m,1H),4.41–4.26(m,2H),4.24–4.11(m,3H),3.84(s,1H),3.51(s,2H),3.49–3.40(m,3H),3.08–2.90(m,2H),2.82–2.63(m,2H),1.96–1.85(m,1H),1.79–1.63(m,6H),1.61–1.51(m,1H),1.06(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.55,-128.39,-217.69.LCMS(ESI,m/z):602.2(M+H)。4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-(2- Fluoroethyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2 - A mixed solution of alcohol (100mg, 0.13mmol), CsF (100mg, 0.66mmol) and DMF (3mL) was heated to 50°C and stirred for 1h. The completion of the reaction was monitored by LCMS, the system was lowered to room temperature, and filtered, and the obtained filtrate was purified by Pre-HPLC (C18E, ACN/(0.1%NH 4 CO 3 /H 2 O)=50-70%) to obtain a white solid 4-( 4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((R)-1-(2-fluoroethyl) -2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (40 mg, yield 51%). 1 H NMR (400MHz, DMSO-d 6 ) δ7.96 (dd, J=9.2, 6.0Hz, 1H), 7.72 (d, J=8.6Hz, 1H), 7.50–7.42 (m, 1H), 7.36( d,J=2.5Hz,1H),7.17(dd,J=8.6,6.8Hz,1H),7.07(d,J=2.5Hz,1H),4.52–4.42(m,1H),4.41–4.26(m ,2H),4.24–4.11(m,3H),3.84(s,1H),3.51(s,2H),3.49–3.40(m,3H),3.08–2.90(m,2H),2.82–2.63(m ,2H),1.96–1.85(m,1H),1.79–1.63(m,6H),1.61–1.51(m,1H),1.06(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ -110.55, -128.39, -217.69. LCMS (ESI, m/z): 602.2 (M+H).
实施例2
Example 2
4-(4-((1R,5S)-3,8-二氮杂环[3.2.1]辛基-3-基)-2-((R)-1-(2,2-二氟乙基)-2-甲基吡咯烷-2-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-((R)-1-(2,2-difluoroethane Base)-2-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
实施例2的合成参照实施例1合成方案进行，在步骤A中使用(R)-(1-(2,2-二氟乙基)-2-甲基吡咯烷-2-基)甲醇(中间体b)代替(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇(中间体a)。1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝9.2,6.0Hz,1H),7.73(d,J＝8.7Hz,1H),7.49–7.42(m,1H),7.36(d,J＝2.6Hz,1H),7.18(dd,J＝8.6,6.8Hz,1H),7.07(d,J＝2.5Hz,1H),6.12–5.75(m,1H),4.38–4.10(m,5H),3.88–3.82(m,1H),3.58(s,2H),3.52–3.43(m,2H),3.19–2.98(m,2H),2.93–2.71(m,2H),1.95–1.85(m,1H),1.83–1.66(m,6H),1.64–1.53(m,1H),1.08(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.54,-118.71,-128.35.LCMS(ESI,m/z):620.3(M+H)。The synthesis of Example 2 was carried out with reference to the synthesis scheme of Example 1, using (R)-(1-(2,2-difluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate Enzyme b) instead of (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a). 1 H NMR (400MHz, DMSO-d 6 ) δ7.96 (dd, J=9.2, 6.0Hz, 1H), 7.73 (d, J=8.7Hz, 1H), 7.49–7.42 (m, 1H), 7.36( d,J=2.6Hz,1H),7.18(dd,J=8.6,6.8Hz,1H),7.07(d,J=2.5Hz,1H),6.12–5.75(m,1H),4.38–4.10(m ,5H),3.88–3.82(m,1H),3.58(s,2H),3.52–3.43(m,2H),3.19–2.98(m,2H),2.93–2.71(m,2H),1.95–1.85 (m,1H),1.83–1.66(m,6H),1.64–1.53(m,1H),1.08(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.54,-118.71,- 128.35. LCMS (ESI, m/z): 620.3 (M+H).
实施例3
Example 3
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1,2-dimethylpyrrolidine- 2-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例3的合成参照实施例1合成方案进行，在步骤A中使用(R)–(1,2-二甲基吡咯烷-2-基)甲醇(中间体c)代替(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇(中间体a)。1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝9.2,6.0Hz,1H),7.81–7.68(m,1H),7.51–7.40(m,1H),7.36(d,J＝2.6Hz,1H),7.25–7.15(m,1H),7.13–7.02(m,1H),4.43–4.11(m,4H),3.91–3.82(m,1H),3.72(s,1H),3.52(dd,J＝12.2,5.5Hz,2H),2.96–2.84(m,1H),2.68–2.55(m,1H),2.30(s,3H),2.07–1.53(m,9H),1.06(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.54,-128.30.LCMS(ESI,m/z):570.3(M+H)。The synthesis of Example 3 was carried out with reference to the synthesis scheme of Example 1. In step A, (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (intermediate c) was used instead of (R)-(1 -(2-Fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a). 1 H NMR (400MHz, DMSO-d 6 ) δ7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.81–7.68 (m, 1H), 7.51–7.40 (m, 1H), 7.36 (d, J ＝2.6Hz,1H),7.25–7.15(m,1H),7.13–7.02(m,1H),4.43–4.11(m,4H),3.91–3.82(m,1H),3.72(s,1H), 3.52(dd,J＝12.2,5.5Hz,2H),2.96–2.84(m,1H),2.68–2.55(m,1H),2.30(s,3H),2.07–1.53(m,9H),1.06( s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -110.54, -128.30. LCMS (ESI, m/z): 570.3 (M+H).
基于通用合成方案所述，并参照上述实施例合成方法，本发明还制备并表征了下列化合物：







Based on the description of the general synthesis scheme, and with reference to the synthesis methods of the above examples, the present invention also prepares and characterizes the following compounds:







实施例36
Example 36
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
步骤A：(1R,5S)-3-(2-(((R)-1-烯丙基-2-甲基吡咯烷-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯Step A: (1R,5S)-3-(2-(((R)-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoro-7 -(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester
在室温条件下，将NaH(215mg,5.38mmol)加入到(R)-(1-烯丙基-2-甲基吡咯烷-2-基)甲醇(中间体d4，418mg,2.69mmol)和THF(30mL)的混合液中，室温搅拌0.5h。将(1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(1.20g,1.34mmol)加入到混合溶液中。室温搅拌1h。LCMS检测反应结束后，将反应液加入饱和氯化铵水溶液(50mL)中，EA(50mL×2)萃取，饱和食盐水(70mL)洗涤，收集有机相浓缩并进一步FCC(SiO2,EA/PE＝0～40％)纯化,得到棕色固体(1R,5S)-3-(2-(((R)-1-烯丙基-2-甲基吡咯烷-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.1g,收率80％)。LCMS(m/z):1026.5(M+H)。NaH (215 mg, 5.38 mmol) was added to (R)-(1-allyl-2-methylpyrrolidin-2-yl)methanol (intermediate d4, 418 mg, 2.69 mmol) and THF at room temperature (30 mL) of the mixture was stirred at room temperature for 0.5 h. (1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl) Oxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.20g, 1.34mmol) was added into the mixed solution. Stir at room temperature for 1 h. After the reaction was detected by LCMS, the reaction solution was added to saturated ammonium chloride aqueous solution (50mL), extracted with EA (50mL×2), washed with saturated brine (70mL), and the organic phase was collected and concentrated and further FCC (SiO 2 , EA/PE =0～40%) purification to obtain brown solid (1R,5S)-3-(2-(((R)-1-allyl-2-methylpyrrolidin-2-yl)methoxy)- 6,8-Difluoro-7-(7-fluoro-8-((triisopropylsilyl)acetylene Base)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - tert-butyl carboxylate (1.1 g, yield 80%). LCMS (m/z): 1026.5 (M+H).
步骤B：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-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Step B: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropyl Silyl)oxy)naphthalen-1-yl)quinazoline
在室温条件下，将(1R,5S)-3-(2-(((R)-1-烯丙基-2-甲基吡咯烷-2-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)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.10g,1.07mmol)和DCM/TFA(V/V＝1:1,10mL)的混合液，在室温条件下搅拌1h。LCMS检测反应结束后，浓缩后加入饱和碳酸氢钠水溶液(70mL)，然后用EA(70mL×2)萃取，收集萃取液，食盐水(70mL)洗涤，无水Na2SO4干燥，浓缩得到的棕色固体4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-环丙基-2-甲基吡咯烷-2-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(1.0g,收率99％)。LCMS(m/z):926.5(M+H)。At room temperature, (1R,5S)-3-(2-(((R)-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-di Fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalene-1-yl)quinazoline- tert-butyl 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.10g, 1.07mmol) and DCM/TFA (V/V=1:1, 10mL) The mixture was stirred at room temperature for 1 h. After the reaction was detected by LCMS, after concentration, add saturated aqueous sodium bicarbonate solution (70mL), then extract with EA (70mL×2), collect the extract, wash with brine (70mL), dry over anhydrous Na 2 SO 4 , and concentrate to obtain Brown solid 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-cyclopropyl-2-methylpyrrole Alk-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylmethyl Silyl)oxy)naphthalen-1-yl)quinazoline (1.0 g, yield 99%). LCMS (m/z): 926.5 (M+H).
步骤C：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚Step C: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
在室温条件下，将CsF(821mg,5.40mmol)加入到4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-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(1.00g,1.08mmol)和DMF(10mL)的混合液中。加热至50℃搅拌1h。降温至室温后过滤，得到的滤液粗产品经过Pre-HPLC纯化，得到白色固体4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚(480mg,收率72％)。1H NMR(400MHz,DMSO-d6)δ8.22(s,2H),8.03–7.95(m,1H),7.55(s,1H),7.52–7.45(m,1H),7.41(d,J＝2.5Hz,1H),7.17–7.10(m,1H),5.84–5.67(m,1H),5.13(d,J＝17.1Hz,1H),5.05–4.91(m,1H),4.36–4.11(m,4H),3.97(d,J＝3.5Hz,1H),3.77(s,2H),3.69–3.48(m,2H),3.43–3.28(m,1H),3.11–2.98(m,1H),2.94–2.80(m,1H),2.59–2.51(m,1H),2.03–1.89(m,1H),1.89–1.65(m,6H),1.66–1.50(m,1H),1.08(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.24,-118.69,-124.53.LCMS(m/z):614.3(M+H)。At room temperature, CsF (821mg, 5.40mmol) was added to 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R )-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl) Ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)quinazoline (1.00g, 1.08mmol) and DMF (10mL). Heat to 50°C and stir for 1h. After cooling down to room temperature and filtering, the obtained filtrate crude product was purified by Pre-HPLC to obtain a white solid 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl )-2-(((R)-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethyne yl-6-fluoronaphthalene-2-ol (480mg, yield 72%). 1 H NMR (400MHz,DMSO-d 6 )δ8.22(s,2H),8.03–7.95(m,1H),7.55(s,1H),7.52–7.45(m,1H),7.41(d,J ＝2.5Hz,1H),7.17–7.10(m,1H),5.84–5.67(m,1H),5.13(d,J＝17.1Hz,1H),5.05–4.91(m,1H),4.36–4.11( m,4H),3.97(d,J＝3.5Hz,1H),3.77(s,2H),3.69–3.48(m,2H),3.43–3.28(m,1H),3.11–2.98(m,1H) ,2.94–2.80(m,1H),2.59–2.51(m,1H),2.03–1.89(m,1H),1.89–1.65(m,6H),1.66–1.50(m,1H),1.08(s, 3H). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.24, -118.69, -124.53. LCMS (m/z): 614.3 (M+H).
实施例36-1和36-2
Examples 36-1 and 36-2
(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)- 6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚或者(Sa)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl- 2-Methylpyrrolidin-2-yl)methoxy)- 6,8-Difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol or (Sa)-4-(4-((1R,5S)-3,8-di Azabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2-methylpyrrolidin-2-yl)methoxy)-6,8-di Fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-烯丙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚经SFC(SFC-150,Waters)拆分(分离柱：AD250*25mm,10um(Daicel)；流动相：CO2/EtOH(0.1％7M NH3in MeOH)＝45/55；流速：70mL/min)，得到首先洗脱出来的异构体1为实施例36-1(保留时间相对较短)。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.02–7.94(m,1H),7.58–7.46(m,2H),7.41(d,J＝2.5Hz,1H),7.16–7.11(m,1H),5.90–5.64(m,1H),5.22–5.07(m,1H),5.02-4.94(m,1H),4.32–4.11(m,4H),3.98(s,1H),3.57–3.36(m,4H),3.28–3.15(m,1H),3.11–2.97(m,1H),2.91–2.80(m,1H),2.60–2.52(m,1H),2.07–1.81(m,1H),1.78–1.56(m,7H),1.07(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.19,-119.24,-124.74.LCMS(m/z):614.3(M+H)。手性分析方法SFC-1，Rt＝4.496。随后洗脱出来的异构体2为实施例36-2(相对保留时间较长)。1H NMR(400MHz,DMSO-d6)δ8.05–7.93(m,1H),7.53(d,J＝10.1Hz,1H),7.51–7.44(m,1H),7.41(d,J＝2.2Hz,1H),7.14(d,J＝2.1Hz,1H),5.83–5.65(m,1H),5.21–5.07(m,1H),4.97(d,J＝9.8Hz,1H),4.39–4.09(m,4H),3.96(s,1H),3.54–3.49(m,4H),3.35–3.31(m,1H),3.07–3.00(m,1H),2.90–2.80(m,1H),2.59–2.52(m,1H),2.00–1.90(m,1H),1.77–1.56(m,7H),1.07(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.16,-119.28,-124.82.LCMS(m/z):614.3(M+H)。手性分析方法SFC-1，Rt＝5.715。Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-allyl-2-methyl ylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol by SFC (SFC-150, Waters) Resolution (separation column: AD250*25mm, 10um (Daicel); mobile phase: CO 2 /EtOH (0.1% 7M NH 3 in MeOH) = 45/55; flow rate: 70mL/min), to obtain the first eluted iso Construct 1 is Example 36-1 (relatively short retention time). 1 H NMR (400MHz,DMSO-d 6 )δ10.19(s,1H),8.02–7.94(m,1H),7.58–7.46(m,2H),7.41(d,J=2.5Hz,1H), 7.16–7.11(m,1H),5.90–5.64(m,1H),5.22–5.07(m,1H),5.02–4.94(m,1H),4.32–4.11(m,4H),3.98(s,1H ),3.57–3.36(m,4H),3.28–3.15(m,1H),3.11–2.97(m,1H),2.91–2.80(m,1H),2.60–2.52(m,1H),2.07–1.81 (m,1H),1.78–1.56(m,7H),1.07(s,3H) .19F NMR(376MHz,DMSO- d6 )δ-110.19,-119.24,-124.74.LCMS(m/z): 614.3 (M+H). Chiral analysis method SFC-1, Rt=4.496. Isomer 2 eluting subsequently was Example 36-2 (relatively longer retention time). 1 H NMR (400MHz, DMSO-d 6 )δ8.05–7.93(m,1H),7.53(d,J=10.1Hz,1H),7.51–7.44(m,1H),7.41(d,J=2.2 Hz,1H),7.14(d,J=2.1Hz,1H),5.83–5.65(m,1H),5.21–5.07(m,1H),4.97(d,J=9.8Hz,1H),4.39–4.09 (m,4H),3.96(s,1H),3.54–3.49(m,4H),3.35–3.31(m,1H),3.07–3.00(m,1H),2.90–2.80(m,1H),2.59 –2.52(m,1H),2.00–1.90(m,1H),1.77–1.56(m,7H),1.07(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.16,-119.28 , -124.82. LCMS (m/z): 614.3 (M+H). Chiral analysis method SFC-1, Rt=5.715.
实施例37
Example 37
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-乙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methylpyrrole Alkyl-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
实施例37的合成参照实施例36合成方法进行，在步骤A中使用(R)-(1-乙基-2-甲基吡咯烷-2-基)甲醇代替(R)-(1-环丙基-2-甲基吡咯烷-2-基)甲醇。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.08–7.87(m,1H),7.54(dd,J＝10.3,1.6Hz,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.15(t,J＝2.7Hz,1H),4.28–4.19(m,2H),4.18–4.11(m,2H),3.99–3.95(m,1H),3.58–3.51(m,2H),3.51–3.45(m,1H),3.45–3.36(m,1H),2.97–2.90(m,1H),2.73–2.63(m,1H),2.60–2.52(m,1H),2.48–2.38(m,1H),1.97–1.87(m,1H),1.81–1.61(m,6H),1.61–1.51(m,1H),1.04(s,3H),1.01–0.92(m,3H).19F NMR(377MHz,DMSO-d6)δ-110.20,-119.26,-124.81.LCMS(m/z):602.3(M+H)。The synthesis of Example 37 was carried out with reference to the synthesis method of Example 36. In Step A, (R)-(1-ethyl-2-methylpyrrolidin-2-yl)methanol was used instead of (R)-(1-cyclopropane yl-2-methylpyrrolidin-2-yl)methanol. 1 H NMR (400MHz, DMSO-d 6 ) δ10.22(s, 1H), 8.08–7.87(m, 1H), 7.54(dd, J=10.3, 1.6Hz, 1H), 7.48(t, J=9.0 Hz,1H),7.41(d,J=2.5Hz,1H),7.15(t,J=2.7Hz,1H),4.28–4.19(m,2H),4.18–4.11(m,2H),3.99–3.95 (m,1H),3.58–3.51(m,2H),3.51–3.45(m,1H),3.45–3.36(m,1H),2.97–2.90(m,1H),2.73–2.63(m,1H) ,2.60–2.52(m,1H),2.48–2.38(m,1H),1.97–1.87(m,1H),1.81–1.61(m,6H),1.61–1.51(m,1H),1.04(s, 3H), 1.01 - 0.92 (m, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -110.20, -119.26, -124.81. LCMS (m/z): 602.3 (M+H).
实施例37-1和37-2
Examples 37-1 and 37-2
(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-乙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚或者(Sa)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-乙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2 -Methylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol or (Sa)-4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methylpyrrolidine- 2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1-乙基-2-甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚经SFC(SFC-150,Waters)拆分(分离柱：AD250*25mm,10um(Daicel)；流动相：CO2/IPA(0.1％7M NH3in MeOH)＝45/55；流速：70mL/min)，得到首先洗脱出来的异构体1为实施例37-1(保留时间相对较小)。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.99(dd,J＝9.2,5.8Hz,1H),7.59–7.44(m,2H),7.44–7.35(m,1H),7.15(s,1H),4.33–4.19(m,2H),4.19–4.10(m,2H),3.97(s,1H),3.60–3.47(m,4H),3.01–2.87(m,1H),2.77–2.63(m,1H),2.63–2.55(m,1H),2.49–2.38(m,1H),2.01–1.86(m,1H),1.85–1.61(m,6H),1.60–1.49(m,1H),1.04(s,3H),0.97(t,J＝7.1Hz,3H).19F NMR(376MHz,DMSO-d6)δ-110.19,-119.22,-124.79.LCMS(m/z):602.3(M+H)。手性分析方法SFC-2，Rt＝0.978。随后洗脱出来的异构体2为实施例37-2(相对保留时间较大)。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.04(dd,J＝9.2,5.9Hz,1H),7.65–7.50(m,2H),7.47(d,J＝2.4Hz,1H),7.20(d,J＝2.5Hz,1H),4.34–4.26(m,2H),4.26–4.14(m,2H),4.02(s,1H),3.61–3.48(m,4H),3.04–2.92(m,1H),2.82–2.67(m,1H),2.65–2.58(m,1H),2.53–2.43(m,1H),2.04–1.92(m,1H),1.84–1.66(m,6H),1.66–1.55(m,1H),1.09(s,3H),1.01(t,J＝7.0Hz,3H).19F NMR(376MHz,DMSO-d6)δ-110.19,-119.28,-124.81.LCMS(m/z):602.3(M+H)。手性分析方法SFC-2，Rt＝3.292。









Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1-ethyl-2-methyl Pyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol was resolved by SFC (SFC-150, Waters) (separation column: AD250*25mm, 10um (Daicel); mobile phase: CO 2 /IPA (0.1% 7M NH 3 in MeOH) = 45/55; flow rate: 70mL/min), to obtain the isomeric Body 1 is Example 37-1 (retention time is relatively small). 1 H NMR (400MHz,DMSO-d 6 )δ10.22(s,1H),7.99(dd,J＝9.2,5.8Hz,1H),7.59–7.44(m,2H),7.44–7.35(m,1H ),7.15(s,1H),4.33–4.19(m,2H),4.19–4.10(m,2H),3.97(s,1H),3.60–3.47(m,4H),3.01–2.87(m,1H ),2.77–2.63(m,1H),2.63–2.55(m,1H),2.49–2.38(m,1H),2.01–1.86(m,1H),1.85–1.61(m,6H),1.60–1.49 (m,1H),1.04(s,3H),0.97(t,J=7.1Hz,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.19,-119.22,-124.79.LCMS(m/ z): 602.3 (M+H). Chiral analysis method SFC-2, Rt=0.978. Isomer 2 eluting subsequently was Example 37-2 (relatively longer retention time). 1 H NMR (400MHz, DMSO-d 6 ) δ10.30(s, 1H), 8.04(dd, J=9.2, 5.9Hz, 1H), 7.65–7.50(m, 2H), 7.47(d, J=2.4 Hz,1H),7.20(d,J=2.5Hz,1H),4.34–4.26(m,2H),4.26–4.14(m,2H),4.02(s,1H),3.61–3.48(m,4H) ,3.04–2.92(m,1H),2.82–2.67(m,1H),2.65–2.58(m,1H),2.53–2.43(m,1H),2.04–1.92(m,1H),1.84–1.66( m,6H),1.66–1.55(m,1H),1.09(s,3H),1.01(t,J＝7.0Hz,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.19,-119.28 , -124.81. LCMS (m/z): 602.3 (M+H). Chiral analysis method SFC-2, Rt=3.292.









实施例61
Example 61
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((R)-1,2-二甲基吡咯烷-2-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((R)-1,2-dimethylpyrrolidine- 2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例61的合成参照实施例1合成方案进行，在步骤A中使用(1R,5S)-3-(7-溴-2-氯-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(中间体C-I)代替(1R,5S)-3-(7-溴-2-氯-8-氟喹唑啉-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯(中间体A-I)，并使用(R)-(1,2-二甲基吡咯烷-2-基)甲醇(中间体c)代替(R)-(1-(2-氟乙基)-2-甲基吡咯烷-2-基)甲醇(中间体a)。LCMS(ESI,m/z):571.3(M+H)。





Example 61 was synthesized with reference to the synthesis scheme of Example 1, using (1R,5S)-3-(7-bromo-2-chloro-8-fluoropyridino[4,3-d]pyrimidine-4- Base)-3,8-diazacyclo[3.2.1]octane-8-carboxylate tert-butyl ester (intermediate CI) instead of (1R,5S)-3-(7-bromo-2-chloro-8 -Fluoroquinazolin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (intermediate AI), and using (R)-(1,2 -Dimethylpyrrolidin-2-yl)methanol (intermediate c) instead of (R)-(1-(2-fluoroethyl)-2-methylpyrrolidin-2-yl)methanol (intermediate a) . LCMS (ESI, m/z): 571.3 (M+H).





实施例89
Example 89
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((R)-1-(2-羟基-2-甲基丙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((R)-1-( 2-Hydroxy-2-methylpropyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
步骤A：(R)-1-(2-羟基-2-甲基丙基)-2-甲基吡咯烷-2-羧酸甲酯Step A: (R)-methyl 1-(2-hydroxy-2-methylpropyl)-2-methylpyrrolidine-2-carboxylate
室温下，把三乙胺(3.90g,39.0mmol)加入到(R)-2-甲基吡咯烷-2-羧酸甲酯盐酸盐(1.0g,5.6mmol)、2,2-二甲基环氧乙烷(2.00g,27.8mmol)和MeOH(20mL)的混合溶液中，升温至75℃反应搅拌过夜。TLC监测反应结束后，反应液冷至室温，减压浓缩后FCC(SiO2,EA/PE＝0-20％)纯化，得到无色液体(R)-1-(2-羟基-2-甲基丙基)-2-甲基吡咯烷-2-羧酸甲酯(600mg,收率50％)。LC-MS(m/z):216.1(M+H)。At room temperature, triethylamine (3.90g, 39.0mmol) was added to (R)-2-methylpyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 5.6mmol), 2,2-dimethyl In a mixed solution of oxirane (2.00 g, 27.8 mmol) and MeOH (20 mL), the temperature was raised to 75° C. and the reaction was stirred overnight. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by FCC (SiO 2 , EA/PE=0-20%) to obtain a colorless liquid (R)-1-(2-hydroxy-2-methanol propyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester (600mg, yield 50%). LC-MS (m/z): 216.1 (M+H).
步骤B：(R)-1-(2-(羟甲基)-2-甲基吡咯烷-1-基)-2-甲基丙-2-醇Step B: (R)-1-(2-(Hydroxymethyl)-2-methylpyrrolidin-1-yl)-2-methylpropan-2-ol
冰浴条件下，将LiAlH4(2.79mL,1M THF溶液，2.79mmol)滴入(R)-1-(2-羟基-2-甲基丙基)-2-甲基吡咯烷-2-羧酸甲酯(600mg,2.79mmol)和THF(20mL)的混合溶液中，并在0℃条件下反应20分钟。TLC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(R)-1-(2-(羟甲基)-2-甲基吡咯烷-1-基)-2-甲基丙-2-醇(300mg,收率57％)。LC-MS(m/z):188.1(M+H)。Under ice-bath conditions, drop LiAlH 4 (2.79mL, 1M THF solution, 2.79mmol) into (R)-1-(2-hydroxy-2-methylpropyl)-2-methylpyrrolidine-2-carboxy Acetate methyl ester (600mg, 2.79mmol) and THF (20mL) mixed solution, and reacted at 0°C for 20 minutes. After the reaction was monitored by TLC, 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 (R)- 1-(2-(Hydroxymethyl)-2-methylpyrrolidin-1-yl)-2-methylpropan-2-ol (300 mg, yield 57%). LC-MS (m/z): 188.1 (M+H).
步骤C～步骤E：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((R)-1-(2-羟基-2-甲基丙基)-2-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-酚Step C～Step E: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( R)-1-(2-hydroxyl-2-methylpropyl)-2-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol
实施例89的后续合成步骤C至步骤E参照实施例36合成方法进行。1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),7.99(dd,J＝9.2,5.9Hz,1H),7.57(d,J＝10.0Hz,1H),7.51–7.45(m,1H),7.42(d,J＝2.5Hz,1H),7.17(d,J＝2.5Hz,1H),4.31(d,J＝12.6Hz,2H),4.25–4.06(m,2H),3.97(d,J＝2.6Hz,1H),3.88(s,2H),3.64(dd,J＝25.4,12.9Hz,2H),3.23–3.09(m,1H),2.76(q,J＝8.0Hz,1H),2.56(dd,J＝13.3,5.3Hz,1H),2.35(dd,J＝13.2,2.8Hz,1H),2.00–1.80(m,6H),1.74(p,J＝7.3Hz,2H),1.65–1.46(m,1H),1.14–0.98(m,9H).19F NMR(376MHz,DMSO-d6)δ-110.28,-118.39,-124.43.LC-MS(m/z):646.2(M+H)。




























The subsequent synthesis steps C to E of Example 89 were carried out referring to the synthesis method of Example 36. 1 H NMR (400MHz, DMSO-d 6 ) δ8.30(s, 2H), 7.99(dd, J=9.2, 5.9Hz, 1H), 7.57(d, J=10.0Hz, 1H), 7.51–7.45( m,1H),7.42(d,J=2.5Hz,1H),7.17(d,J=2.5Hz,1H),4.31(d,J=12.6Hz,2H),4.25–4.06(m,2H), 3.97(d, J=2.6Hz, 1H), 3.88(s, 2H), 3.64(dd, J=25.4, 12.9Hz, 2H), 3.23–3.09(m, 1H), 2.76(q, J=8.0Hz ,1H),2.56(dd,J＝13.3,5.3Hz,1H),2.35(dd,J＝13.2,2.8Hz,1H),2.00–1.80(m,6H),1.74(p,J＝7.3Hz, 2H),1.65–1.46(m,1H),1.14–0.98(m,9H) .19F NMR(376MHz,DMSO-d 6 )δ-110.28,-118.39,-124.43.LC-MS(m/z) :646.2(M+H).




























实施例154-1
Example 154-1
(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2S, 3S)-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol· Diformate
实施例154-1的合成参照实施例36合成方法进行，在步骤A中使用中间体B-III-2代替中间体B-III((1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯)；并使用中间体k1b(((2S,3S)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇)代替中间体d4((R)-(1-烯丙基-2-甲基吡咯烷-2-基)甲醇)。LCMS(m/z):618.1(M+H).1H NMR(400MHz,DMSO-d6)δ8.21(s,2H),8.02–7.96(m,1H),7.54(d,J＝10.4Hz,1H),7.51–7.44(m,1H),7.41(d,J＝2.5Hz,1H),7.15(d,J＝2.4Hz,1H),4.32–4.25(m,1H),4.28–4.20(m,3H),3.98(s,1H),3.57–3.51(m,5H),3.25(s,3H),2.95–2.84(m,1H),2.63–2.57(m,1H),2.27(s,3H),2.13–2.06(m,1H),1.83–1.65(m,5H),1.07(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.20,-119.05,-124.64.The synthesis of Example 154-1 was carried out with reference to the synthesis method of Example 36. In step A, intermediate B-III-2 was used instead of intermediate B-III ((1R,5S)-3-(2,6,8-three Fluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1-yl)quinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl); and intermediate k1b (((2S,3S)-3-methoxy-1,2- Dimethylpyrrolidin-2-yl)methanol) instead of intermediate d4 ((R)-(1-allyl-2-methylpyrrolidin-2-yl)methanol). LCMS (m/z): 618.1 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.21 (s, 2H), 8.02–7.96 (m, 1H), 7.54 (d, J=10.4 Hz,1H),7.51–7.44(m,1H),7.41(d,J=2.5Hz,1H),7.15(d,J=2.4Hz,1H),4.32–4.25(m,1H),4.28–4.20 (m,3H),3.98(s,1H),3.57–3.51(m,5H),3.25(s,3H),2.95–2.84(m,1H),2.63–2.57(m,1H),2.27(s ,3H),2.13–2.06(m,1H),1.83–1.65(m,5H),1.07(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.20,-119.05,-124.64.
实施例154-2
Example 154-2
(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3R)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐实施例154-1的合成参照实施例36合成方法进行，在步骤A中使用中间体B-III-2代替中间体B-III((1R,5S)-3-(2,6,8-三氟-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)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯)；并使用中间体k1a(((2S,3R)-3-甲氧基-1,2-二甲基吡咯烷-2-基)甲醇)代替中间体d4((R)-(1-烯丙基-2-甲基吡咯烷-2-基)甲醇)。1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.02–7.93(m,1H),7.55(d,J＝10.3,1H),7.50–7.44(m,1H),7.41(d,J＝2.6Hz,1H),7.15(d,J＝2.5Hz,1H),4.31–4.25(m,3H),4.16–4.14(m,1H),3.97(s,1H),3.74–3.71(m,2H),3.61–3.51(m,3H),3.23(s,3H),2.85–2.77(m,1H),2.58–2.51(m,1H),2.23(s,3H),2.12–2.02(m,1H),1.85–1.70(m,4H),1.63–1.53(m,1H),0.88(s,3H).

(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2S, 3R)-3-methoxy-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol· The synthesis of dicarboxylic acid salt Example 154-1 was carried out with reference to the synthetic method of Example 36, and in step A, intermediate B-III-2 was used instead of intermediate B-III ((1R,5S)-3-(2,6 ,8-Trifluoro-7-(7-fluoro-8-(triisopropylsilyl)ethynyl)-3-(triisopropylsilyl)oxy)naphthalene-1-yl)quinazoline- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl); and using intermediate k1a (((2S,3R)-3-methoxy- 1,2-Dimethylpyrrolidin-2-yl)methanol) instead of intermediate d4 ((R)-(1-allyl-2-methylpyrrolidin-2-yl)methanol). 1 H NMR (400MHz,DMSO-d 6 )δ8.30(s,2H),8.02–7.93(m,1H),7.55(d,J=10.3,1H),7.50–7.44(m,1H),7.41 (d,J=2.6Hz,1H),7.15(d,J=2.5Hz,1H),4.31–4.25(m,3H),4.16–4.14(m,1H),3.97(s,1H),3.74– 3.71(m,2H),3.61–3.51(m,3H),3.23(s,3H),2.85–2.77(m,1H),2.58–2.51(m,1H),2.23(s,3H),2.12– 2.02(m,1H),1.85–1.70(m,4H),1.63–1.53(m,1H),0.88(s,3H).

实施例156-1
Example 156-1
(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2S, 3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
步骤A：(Ra)-(1R,5S)-3-(6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁基酯Step A: (Ra)-(1R,5S)-3-(6,8-Difluoro-2-(((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl )Methoxy)-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazolin-4-yl)-3,8 - tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate
室温条件下，将NaH(17.5mg,0.44mmol,60％)加入到(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲醇(32mg,0.22mmol)和THF(3mL)的混合溶液中，并在室温条件下搅拌0.5h,然后加入(Ra)-(1R,5S)-3-(2,6,8-三氟-7-(7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-(三异丙基乙硅烷基)氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮双环[3.2.1]辛烷-8-羧酸叔丁基酯(中间体B-III-2，130mg,0.15mmol)，所得混合物室温搅拌过夜。LCMS检测反应结束后，把反应液倒入饱和NH4Cl水溶液(20mL)中，EA(30mL×3)萃取，合并的有机相用饱和NaCl水溶液(20mL)洗涤，无水硫酸钠干燥，过滤。滤液浓缩后，得到黄色固体(Ra)-(1R,5S)-3-(6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁基酯(110mg,收率87％)。LCMS(m/z):431.8(M/2+H)。At room temperature, NaH (17.5 mg, 0.44 mmol, 60%) was added to (((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol (32 mg, 0.22 mmol ) and THF (3mL), and stirred at room temperature for 0.5h, then added (Ra)-(1R,5S)-3-(2,6,8-trifluoro-7-(7-fluoro -8-((triisopropylsilyl)ethynyl)-3-(triisopropyldisilyl)oxy)naphthalene-1-yl)quinazolin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester (Intermediate B-III-2, 130 mg, 0.15 mmol), and the resulting mixture was stirred at room temperature overnight. After the reaction was detected by LCMS, the reaction solution was poured into saturated NH 4 Cl aqueous solution (20 mL), extracted with EA (30 mL×3), and the combined organic phases were washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated, (Ra)-(1R,5S)-3-(6,8-difluoro-2-(((2S,3S)-3-fluoro-1,2-dimethylpyrrolidine) was obtained as a yellow solid -2-yl)methoxy)-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazolin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110mg, yield 87%). LCMS (m/z): 431.8 (M/2+H).
步骤B：(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基 吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇Step B: (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(( (2S,3S)-3-fluoro-1,2-dimethyl Pyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol
室温条件下，将CF3COOH(10mL)加入到(Ra)-(1R,5S)-3-(6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁基酯(110mg,0.13mmol)并搅拌1h，浓缩除去酸液，加入EA(30mL)稀释，饱和NaHCO3溶液(20mL)调节pH到8左右,加入水(30mL)，分液，水相用EA(30mL×2)萃取。合并的有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到黄色固体(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(90mg,收率92％)。CF 3 COOH (10 mL) was added to (Ra)-(1R,5S)-3-(6,8-difluoro-2-(((2S,3S)-3-fluoro-1,2 -Dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)quinazole (Phenyl-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110mg, 0.13mmol) and stirred for 1h, concentrated to remove the acid solution, added EA (30mL ) diluted with saturated NaHCO 3 solution (20mL) to adjust the pH to about 8, add water (30mL), separate the layers, and extract the aqueous phase with EA (30mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[ 3.2.1] Oct-3-yl)-6,8-difluoro-2-(((2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy) Quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (90 mg, yield 92%).
步骤C：(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇Step C: (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(( (2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
将(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(90mg,0.12mmol)、CsF(179mg,1.2mmol)和DMF(2mL)的混合物升温至50℃搅拌1h。LCMS监测反应结束，冷至室温，过滤除去不溶物，得到粗产品的DMF溶液，经过Pre-HPLC(C18,CAN/(0.1％NH4CO3/H2O)＝35-45％)制备得到黄色固体(Ra)-4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2S,3S)-3-氟-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(20mg,收率35％)。LCMS(m/z):606.3(M+H)。1H NMR(400MHz,Methanol-d4)δ7.87(dd,J＝9.1,5.8Hz,1H),7.52(dd,J＝10.0,1.8Hz,1H),7.39–7.29(m,2H),7.14(d,J＝2.6Hz,1H),4.74–4.56(m,2H),4.54–4.41(m,3H),3.76–3.56(m,4H),3.35(d,J＝1.0Hz,1H),3.28–3.17(m,1H),2.72–2.60(m,1H),2.47–2.26(m,4H),2.15–1.84(m,5H),1.14(d,J＝1.8Hz,3H).19F NMR(376MHz,Methanol-d4)δ-111.57,-119.31,-125.29,-180.42。



(Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2S ,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl A mixture of )ethynyl)naphthalen-2-ol (90mg, 0.12mmol), CsF (179mg, 1.2mmol) and DMF (2mL) was heated to 50°C and stirred for 1h. LCMS monitored the completion of the reaction, cooled to room temperature, and filtered to remove insoluble matter to obtain a DMF solution of the crude product, which was prepared by Pre-HPLC (C18, CAN/(0.1%NH 4 CO 3 /H 2 O)=35-45%) Yellow solid (Ra)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-((( 2S,3S)-3-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ( 20mg, yield 35%). LCMS (m/z): 606.3 (M+H). 1 H NMR (400MHz, Methanol-d 4 )δ7.87(dd, J=9.1,5.8Hz,1H),7.52(dd,J=10.0,1.8Hz,1H),7.39–7.29(m,2H), 7.14(d,J=2.6Hz,1H),4.74–4.56(m,2H),4.54–4.41(m,3H),3.76–3.56(m,4H),3.35(d,J=1.0Hz,1H) 19 F NMR (376 MHz, Methanol-d 4 ) δ-111.57, -119.31, -125.29, -180.42.



实施例165
Example 165
4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐
4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2R,3S)-1-ethyl -2,3-Dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol·dicarboxylate
步骤A：(1R,5S)-3-(6,8-二氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,3S)- 1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯Step A: (1R,5S)-3-(6,8-Difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl )-2-(((2R,3S)- 1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- tert-butyl carboxylate
将化合物((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b,42mg,0.27mmol)溶于5mL无水THF中，在冰浴条件下，加入NaH(11mg,0.27mmol)。0℃下反应20min后，加入(1R,5S)-3-(2,6,8-三氟-7-((R)-7-氟-8-((三异丙基甲硅烷基)乙炔基)-3-(三异丙基甲硅氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(B-III-2,120mg,0.13mmol)，所得反应液在室温条件下继续搅拌2h。LCMS监测反应结束后，向反应液中加入20mL水，用EtOAc萃取，合并的有机相经无水硫酸钠干燥、过滤、浓缩后，得到黄色油状粗产物(1R,5S)-3-(6,8-二氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,收率85％)。LCMS(m/z):1029.6(M+H).The compound ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b, 42 mg, 0.27 mmol) was dissolved in 5 mL of anhydrous THF, and the Under conditions, NaH (11 mg, 0.27 mmol) was added. After reacting at 0°C for 20 minutes, add (1R,5S)-3-(2,6,8-trifluoro-7-((R)-7-fluoro-8-((triisopropylsilyl)acetylene Base)-3-(triisopropylsilyloxy)naphthalene-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Acetyl tert-butyl ester (B-III-2, 120mg, 0.13mmol), the resulting reaction solution was stirred at room temperature for 2h. After the LCMS monitoring reaction was completed, 20 mL of water was added to the reaction solution, extracted with EtOAc, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily crude product (1R,5S)-3-(6, 8-Difluoro-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,3S)-1- Ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Tert-butyl ester (100mg, yield 85%). LCMS(m/z):1029.6(M+H).
步骤B：4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇Step B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3S )-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl) Ethynyl)naphth-2-ol
将(1R,5S)-3-(6,8-二氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,0.11mmol)溶于二氯甲烷(2mL)，再加入三氟乙酸(2mL)，所得反应液在室温条件下搅拌1h。LCMS监测反应结束后，加入饱和碳酸氢钠溶液(20mL)，所得反应混合物经乙酸乙酯萃取，有机相经无水硫酸钠干燥、过滤、浓缩，得到黄色固体粗产物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(80mg,收率90％)。LCMS(m/z):928.5(M+H).(1R,5S)-3-(6,8-difluoro-7-(7-fluoro-3-hydroxyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo [3.2.1] Octane-8-carboxylic acid tert-butyl ester (100mg, 0.11mmol) was dissolved in dichloromethane (2mL), then trifluoroacetic acid (2mL) was added, and the resulting reaction solution was stirred at room temperature for 1h. After the reaction was monitored by LCMS, saturated sodium bicarbonate solution (20 mL) was added, and the resulting reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid crude product 4-(4-(( 1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3S)-1-ethyl-2,3 -Dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (80mg , yield 90%). LCMS(m/z):928.5(M+H).
步骤C：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐Step C: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2R,3S)-1 -Ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol·dicarboxylate
将4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(80mg,0.1mmol)和氟化铯(157mg，1mmol)溶于DMF(2mL)中，在50℃下搅拌30分钟。LCMS监测反应结束后，反应液经pre-HPLC(C18,CAN/(0.1％FA/H2O)＝15-95％)分离，得到4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐(20mg,收率31％)。1H NMR(400MHz,DMSO-d6)δ8.28(s,2H),7.99(dd,J＝9.2,6.0Hz,1H),7.54(d,J＝10.0Hz,1H),7.51–7.45(m,1H),7.41(d,J＝2.5Hz,1H),7.15(d,J＝2.5Hz,1H),4.29–4.21(m,3H),4.15–4.08(m,1H),3.97(s,1H),3.70–3.64(m,2H),3.59–3.49(m,2H),2.91–2.82(m,1H),2.80–2.71(m,1H),2.69–2.51(m,2H),1.97–1.66(m,6H),1.62–1.49(m,1H),1.09–0.92(m,9H).19F NMR(376MHz,DMSO-d6)δ-73.44,-110.26,-118.89,-124.61.LCMS(m/z):616.3(M+H).4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3S)- 1-ethyl-2,3-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl ) naphthalene-2-ol (80 mg, 0.1 mmol) and cesium fluoride (157 mg, 1 mmol) were dissolved in DMF (2 mL), and stirred at 50° C. for 30 minutes. After the reaction was monitored by LCMS, the reaction solution was separated by pre-HPLC (C18, CAN/(0.1%FA/H 2 O)=15-95%) to obtain 4-(4-(1R,5S)-3,8- Diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl) Methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol·dicarboxylate (20 mg, yield 31%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.28 (s, 2H), 7.99 (dd, J=9.2, 6.0Hz, 1H), 7.54 (d, J=10.0Hz, 1H), 7.51–7.45 ( m,1H),7.41(d,J=2.5Hz,1H),7.15(d,J=2.5Hz,1H),4.29–4.21(m,3H),4.15–4.08(m,1H),3.97(s ,1H),3.70–3.64(m,2H),3.59–3.49(m,2H),2.91–2.82(m,1H),2.80–2.71(m,1H),2.69–2.51(m,2H),1.97 –1.66(m,6H),1.62–1.49(m,1H),1.09–0.92(m,9H) .19F NMR(376MHz,DMSO-d 6 )δ-73.44,-110.26,-118.89,-124.61. LCMS(m/z):616.3(M+H).
实施例166
Example 166
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2R,3R)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3R)-3 -(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例166的合成参照实施例165进行，在步骤A中使用((2R,3R)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇(中间体k6a)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):620.3(M+H).Example 166 was synthesized with reference to Example 165, using ((2R,3R)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol in step A (intermediate k6a ) instead of ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS(m/z):620.3(M+H).
实施例167
Example 167
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(((2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·甲酸盐4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(((2R,3S)-3 -(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol·formic acid Salt
实施例167的合成参照实施例165进行，在步骤A中使用((2R,3S)-3-(氟甲基)-1,2-二甲基吡咯烷-2-基)甲醇(中间体k6b)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):620.3(M+H).1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.55(dd,J＝10.3,1.6Hz,1H),7.52–7.44(m,1H),7.41(d,J＝2.6Hz,1H),7.15(d,J＝2.5Hz,1H),4.74–4.67(m,0.5H),4.62–4.50(m,1H),4.45–4.39(m,0.5H),4.34–4.22(m,3H),4.19–4.14(m,1H),3.99–3.94(m,1H),3.71–3.64(m,2H),3.60–3.50(m,2H),2.93–2.86(m,1H),2.74–2.65(m,1H),2.35–2.18(m,4H),1.97–1.60(m,6H),1.11(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.18,-118.75,-124.54,-218.24.Example 167 was synthesized with reference to Example 165, using ((2R,3S)-3-(fluoromethyl)-1,2-dimethylpyrrolidin-2-yl)methanol in step A (intermediate k6b ) instead of ((2R,3S)-1-ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 620.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (s, 1H), 7.99 (dd, J=9.2, 5.9Hz, 1H), 7.55 ( dd,J=10.3,1.6Hz,1H),7.52–7.44(m,1H),7.41(d,J=2.6Hz,1H),7.15(d,J=2.5Hz,1H),4.74–4.67(m ,0.5H),4.62–4.50(m,1H),4.45–4.39(m,0.5H),4.34–4.22(m,3H),4.19–4.14(m,1H),3.99–3.94(m,1H) ,3.71–3.64(m,2H),3.60–3.50(m,2H),2.93–2.86(m,1H),2.74–2.65(m,1H),2.35–2.18(m,4H),1.97–1.60( m,6H),1.11(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ-110.18,-118.75,-124.54,-218.24.
实施例168
Example 168
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,3S)-1-allyl-2, 3-Dimethylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例168的合成参照实施例165进行，在步骤A中使用((2R,3S)-1-烯丙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2c)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):314.7(M/2+H).1H NMR(400MHz,Chloroform-d)δ7.67(dd,J＝9.2,5.8Hz,1H),7.30–7.27(m,2H),7.22–7.12(m,2H),5.97–5.70(m,1H),5.07(d,J＝17.1Hz,1H),4.93(d,J＝10.1Hz,1H),4.51(d,J＝12.7Hz,1H),4.32–4.15(m,3H),3.72–3.56(m,3H),3.44(d,J＝12.4Hz,1H),3.39–3.26(m,2H),3.06–2.90(m,1H),2.88–2.66(m,2H),2.16–1.96(m,1H),1.94–1.74(m,4H),1.74–1.48(m,2H),1.19(s,3H),1.02(d,J＝7.0Hz,3H).19F NMR(376MHz,Chloroform-d)δ-110.05,-116.37,-121.85。The synthesis of Example 168 was carried out with reference to Example 165, using ((2R,3S)-1-allyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2c) in step A instead of ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 314.7 (M/2+H). 1 H NMR (400MHz, Chloroform-d) δ7.67 (dd, J=9.2, 5.8Hz, 1H), 7.30–7.27 (m, 2H) ,7.22–7.12(m,2H),5.97–5.70(m,1H),5.07(d,J=17.1Hz,1H),4.93(d,J=10.1Hz,1H),4.51(d,J=12.7 Hz,1H),4.32–4.15(m,3H),3.72–3.56(m,3H),3.44(d,J＝12.4Hz,1H),3.39–3.26(m,2H),3.06–2.90(m, 1H),2.88–2.66(m,2H),2.16–1.96(m,1H),1.94–1.74(m,4H),1.74–1.48(m,2H),1.19(s,3H),1.02(d, J = 7.0 Hz, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -110.05, -116.37, -121.85.
实施例169
Example 169
4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,3S)-1-环丙基-2,3-二甲基吡咯烷-2-基)甲氧基)-6,8-二氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,3S)-1-cyclopropyl-2, 3-Dimethylpyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
实施例169的合成参照实施例165进行，在步骤A中使用((2R,3S)-1-环丙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2d)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):628.3(M+H)。The synthesis of Example 169 was carried out with reference to Example 165, using ((2R,3S)-1-cyclopropyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2d) in step A instead of ((2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 628.3 (M+H).
实施例170
Example 170
4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-6,8-二氟-2-(2R,3S)-1,2,3-三甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇·二甲酸盐4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6,8-difluoro-2-(2R,3S)-1,2, 3-Trimethylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol·dicarboxylate
实施例170的合成参照实施例165进行，在步骤A中使用((2R,3S)-1,2,3-三甲基吡咯烷-2-基)甲醇(中间体k2a)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):602.3(M+H).1H NMR(400MHz,DMSO-d6)δ8.31(s,2H),7.98(dd,J＝9.2,5.9Hz,1H),7.54(dd,J＝10.3,1.6Hz,1H),7.51–7.44(m,1H),7.41(d,J＝2.6Hz,1H),7.16(d,J＝2.5Hz,1H),4.30–4.20(m,3H),4.15–4.10(m,1H),3.99–3.96(m,1H),3.55–3.46(m,4H),2.89–2.81(m,1H),2.73–2.66(m,1H),2.30(s,3H),1.97–1.87(m,2H),1.84–1.63(m,4H),1.58–1.42(m,1H),1.09–0.93(m,6H).19F NMR(376MHz,DMSO-d6)δ-110.29,-118.95,-124.65. The synthesis of Example 170 was carried out with reference to Example 165, using ((2R,3S)-1,2,3-trimethylpyrrolidin-2-yl)methanol (intermediate k2a) in step A instead of ((2R, 3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 602.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.31 (s, 2H), 7.98 (dd, J=9.2, 5.9Hz, 1H), 7.54 ( dd,J=10.3,1.6Hz,1H),7.51–7.44(m,1H),7.41(d,J=2.6Hz,1H),7.16(d,J=2.5Hz,1H),4.30–4.20(m ,3H),4.15–4.10(m,1H),3.99–3.96(m,1H),3.55–3.46(m,4H),2.89–2.81(m,1H),2.73–2.66(m,1H),2.30 (s,3H), 1.97–1.87(m,2H), 1.84–1.63(m,4H), 1.58–1.42(m,1H), 1.09–0.93(m,6H). 19 F NMR (376MHz, DMSO- d 6 )δ-110.29,-118.95,-124.65.
实施例171
Example 171
(2R,3S)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-2-基)氧基)甲基)-1,2-二甲基吡咯烷-3-腈·三甲酸盐(2R,3S)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-1,2-dimethylpyrrolidine-3-carbonitrile tricarboxylate
实施例171的合成参照实施例165进行，在步骤A中使用(2R,3S)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈(中间体k4a)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):613.3(M+H).1H NMR(400MHz,DMSO-d6)δ8.39(brs,3H),7.98(dd,J＝9.2,6.0Hz,1H),7.56(d,J＝10.2Hz,1H),7.51-7.44(m,1H),7.41(d,J＝2.6Hz,1H),7.15(d,J＝2.5Hz,1H),4.39–4.32(m,1H),4.30–4.18(m,3H),3.97(s,1H),3.62–3.51(m,4H),2.95–2.88(m,1H),2.75–2.68(m,1H),2.31–2.21(m,4H),2.02–1.93(m,1H),1.78–1.61(m,4H),1.44–1.42(m,1H),1.16(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.25,-118.94,-124.68.The synthesis of Example 171 was carried out with reference to Example 165, using (2R,3S)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4a) in step A instead of ( (2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 613.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (brs, 3H), 7.98 (dd, J=9.2, 6.0Hz, 1H), 7.56 ( d,J=10.2Hz,1H),7.51-7.44(m,1H),7.41(d,J=2.6Hz,1H),7.15(d,J=2.5Hz,1H),4.39–4.32(m,1H ),4.30–4.18(m,3H),3.97(s,1H),3.62–3.51(m,4H),2.95–2.88(m,1H),2.75–2.68(m,1H),2.31–2.21(m ,4H),2.02–1.93(m,1H),1.78–1.61(m,4H),1.44–1.42(m,1H),1.16(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ -110.25, -118.94, -124.68.
实施例172
Example 172
(2R,3R)-2-(((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-6,8-二氟喹唑啉-2-基)氧基)甲基)-1,2-二甲基吡咯烷-3-腈(2R,3R)-2-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7- Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-1,2-dimethylpyrrolidine-3-carbonitrile
实施例172的合成参照实施例165进行，在步骤A中使用(2R,3R)-2-(羟甲基)-1,2-二甲基吡咯烷-3-腈(中间体k4b)代替((2R,3S)-1-乙基-2,3-二甲基吡咯烷-2-基)甲醇(中间体k2b)。LCMS(m/z):613.3(M+H).1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.56(d,J＝10.4Hz,1H),7.52-7.45(m,1H),7.41(d,J＝2.6Hz,1H),7.14(d,J＝2.6Hz,1H),4.39–4.32(m,1H),4.31–4.16(m,3H),3.97(s,1H),3.55–3.44(m,5H),2.96–2.88(m,1H),2.75–2.69(m,1H),2.31–2.20(m,4H),2.02–1.92(m,1H),1.78–1.58(m,4H),1.46–1.37(m,1H),1.16(s,3H).19F NMR(376MHz,DMSO-d6)δ-110.16,-118.99,-124.70.The synthesis of Example 172 was carried out with reference to Example 165, using (2R,3R)-2-(hydroxymethyl)-1,2-dimethylpyrrolidine-3-carbonitrile (intermediate k4b) in step A instead of ( (2R,3S)-1-Ethyl-2,3-dimethylpyrrolidin-2-yl)methanol (intermediate k2b). LCMS (m/z): 613.3 (M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.19 (s, 1H), 7.99 (dd, J=9.2, 5.9Hz, 1H), 7.56 ( d,J=10.4Hz,1H),7.52-7.45(m,1H),7.41(d,J=2.6Hz,1H),7.14(d,J=2.6Hz,1H),4.39–4.32(m,1H ),4.31–4.16(m,3H),3.97(s,1H),3.55–3.44(m,5H),2.96–2.88(m,1H),2.75–2.69(m,1H),2.31–2.20(m ,4H),2.02–1.92(m,1H),1.78–1.58(m,4H),1.46–1.37(m,1H),1.16(s,3H). 19 F NMR(376MHz,DMSO-d 6 )δ -110.16, -118.99, -124.70.
根据上述合成方案及适当条件变化，本发明合成下述化合物：











According to above-mentioned synthetic scheme and appropriate condition change, the present invention synthesizes following compound:











活性实施例active example
实施例1:本发明化合物对KRAS G12D突变的AGS细胞的增殖抑制效果Embodiment 1: the compound of the present invention is to the proliferation inhibitory effect of the AGS cell of 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 representative compounds of the present invention on KRAS G12D mutant AGS cells.
本实验使用如下细胞系：
The following cell lines were used in this experiment:
将其置于37℃、5％CO2、95％湿度条件下培养。Place it under the conditions of 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 clear flat-bottom black wall plate ( Cat#3603); Envision multifunctional microplate reader, PE, 2104; CO 2 incubator, Thermo Scientific, Model 3100 Series; biological safety cabinet, Sujing Antai, Model 1300 Series A2; inverted microscope, Chongqing Optoelectronics, XDS- 1B. AGS cell line was purchased from ATCC, catalog number is CRL-1739.
该实验如下进行：The experiment was performed 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: Cells in logarithmic growth phase were harvested and counted using a platelet counter. The cell viability was detected by the trypan blue exclusion method to ensure that the cell viability was 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% CO 2 .
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。Drug dilution and dosing were carried out as follows: single-point inhibition rate determination drug preparation: prepare 10-fold drug solution, add 10 μL of 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. multiple holes. Drug preparation for IC50 determination: prepare a 10-fold drug solution, add 10 μL of 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 96-well plate that had been dosed were placed at 37° C. and 5% CO 2 to continue culturing 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。Thaw 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 vibrate 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。GraphPad Prism 8.0 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated accordingly.
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 solution control )/(Lum cell control -Lum culture solution 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 exhibit satisfactory anti-proliferation activity on AGS human gastric adenocarcinoma cells with KRAS G12D mutation, and some activity data are shown in the table below.

实施例2:本发明化合物的大鼠盒式给药(Cassette)药代动力学特性Embodiment 2: the rat box type administration (Cassette) pharmacokinetic characteristic of compound of the present invention
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 by rat Cassette pharmacokinetic experiments (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)。The study used male SD rats, age: 6-8 weeks, body weight 220-250g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and the following reagents were used: tolbutamide (Tolbutamide) (Aladdin, Product No. H1401054); sulfobutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biology, Product No. 20191013); Propylene glycol (15) stearate (Solutol, Meilun Bio, product No. S0206A); DMSO (Vetec Company, product No. WXBD0293V ); Acetonitrile (Sigma-Aldrich, Product No. WXBD1744V); Methanol (Sigma-Aldrich, Product No. 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 is formulated into the solvent of 5%DMSO/10%Solutol/85% (20%Captisol), and finally each compound The concentration of the drug was 1mg/mL, and the drug preparation was injected into the tail vein of SD rats according to the injection volume of 1mL/kg, and blood was collected from the external jugular vein at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h respectively. After centrifugation for 20 minutes, the plasma was collected and stored at -20°C until testing.
如下建立化合物LC-MS/MS分析方法：The compound LC-MS/MS analysis method was 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: draw 20 μL of 1mg/mL DMSO stock solution for each compound, transfer to 900 μL of 50% methanol working solution, and serially dilute to obtain a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, then draw 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 quantification of 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 unknown plasma sample and standard curve sample, add 250 μL acetonitrile containing tolbutamide as internal standard as precipitant, precipitate plasma protein, extract the compound to be tested in plasma, centrifuge at low temperature for 20 minutes, take supernatant, The supernatant was mixed with an aqueous solution of 0.1% formic acid, 5 μL was drawn and injected, and the blood drug concentration of the drug was analyzed by LC-MS.
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 standard curve was drawn with the mass spectrometry software Analyst 1.6.1, the unknown samples were quantified, and the pharmacokinetic parameters were calculated with Winnonlin 8.2 according to the drug concentration at each time point of the unknown samples.
实验结果显示,在盒式给药药代动力学评价中，本发明化合物显示良好的药代动力学性质。The experimental results show that the compound of the present invention exhibits good pharmacokinetic properties in the pharmacokinetic evaluation of cassette administration.
实施例3:本发明化合物对细胞色素P450抑制试验Embodiment 3: the compounds of the present invention inhibit test of cytochrome P450
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。The following reagents were used in this experiment: human liver microsomes (Corning Company, product number 452161); reduced nicotinamide adenine dinucleotide phosphate (NADPH, MCE Company, product number HY-F0003/CS-4998); phenacetin , diclofenac, α-naphthoflavone, omeprazole and ketoconazole were purchased from TCI Company; S-Mephenytoin and testosterone were purchased from CAYMAN Company; midazolam was purchased from Bioreclamation IVT; quinidine was purchased from from Damas-beta; sulfabenzopyrazole was purchased from MCE; bufurolol 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) with 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8μL 100mM的奥美拉唑DMSO溶液溶于12μL乙腈中。Prepare the test compound solution: dissolve 8 μL of 10 mM test compound stock solution in 12 μL acetonitrile; prepare the mixed solution of CYP1A2, CYP2C9 and CYP2D6 inhibitors: mix 12 μL 1mM α-naphthoflavone, 10 μL 40mM sulfabenzopyrazole, 10 μL 10mM quinolone Mix nicotine and 8 μL DMSO solution; prepare CYP3A4 inhibitor solution: dissolve 8 μL 2.5 mM ketoconazole DMSO solution in 12 μL acetonitrile; prepare CYP2C19 inhibitor solution: dissolve 8 μL 100 mM omeprazole DMSO solution in 12 μl of 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: use 10mL 0.1M K-buffer to prepare 4 times the concentration of each substrate according to the concentration requirements A solution is required.
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。Prepare 0.2 mg/mL human liver microsome (HLM) solution: add 10 μL of 20 mg/mL human liver microsome to 990 μL K-buffer, store in ice bath until 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 a 96-well plate, add 3 μL of a 400-fold test compound solution; add 200 μL of 0.2 mg/mL HLM to a 96-well plate, and add 1 μL of diluted positive control inhibitor solution. Dispense 30 μL of the compound solution mixed with human liver microsomes into a 96-well plate, and then add 15 μL of the substrate solution. The solution obtained above and the prepared NADPH solution were preheated at 37° C. for 5 min. 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, 2D6 reacts 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. Samples were vortexed for 10 minutes, centrifuged at 5594g for 15 minutes, and samples were prepared for LC-MS/MS analysis.
实验结果显示，在测试浓度下，本发明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 compound of the present invention has no significant inhibitory effect on key CYP subtypes of drug metabolism, showing better drug-drug interaction safety.
实施例4:本发明化合物对KRAS G12D突变的AGS(3D)细胞的增殖抑制效果Embodiment 4: the compound of the present invention is to the proliferation inhibitory effect of the AGS (3D) cell of KRAS G12D mutation
通过在甲基纤维素3D培养基中不贴壁，成球形生长，来评价代表性化合物对AGS细胞系3D增殖的抑制作用。The inhibitory effect of representative compounds on the 3D proliferation of AGS cell lines was evaluated by non-adherent and spherical growth in methylcellulose 3D medium.
本实验中使用如下材料、仪器和试剂：培养基RPMI1640(HyClone，Cat#SH30809.01)；胎牛血清FBS(GBICO,Cat#10099-141)；Luminescent Cell Viability Assay(南京诺唯赞，Cat#DD1101-04)；96孔聚苯乙烯微孔板(黑壁)(Greiner Bio one，Cat.#655096)；甲基纤维素(SIGMA,CAS:9004-67-5)；AGS细胞(KC-0405，康源博创生物科技(北京)有限公司)；多功能酶标仪(BMG LABTECH,Plus)；CO2培养箱(Thermo Scientific，Model 3100 Series)。The following materials, instruments and reagents were used in this experiment: culture medium RPMI1640 (HyClone, Cat#SH30809.01); fetal bovine serum FBS (GBICO, Cat#10099-141); Luminescent Cell Viability Assay (Nanjing Novizyme, Cat#DD1101-04); 96-well polystyrene microplate (black wall) (Greiner Bio one, Cat.#655096); methylcellulose (SIGMA, CAS: 9004 -67-5); AGS cells (KC-0405, Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.); multi-functional microplate reader (BMG LABTECH, Plus); CO incubator (Thermo Scientific, Model 3100 Series).
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，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，使得甲基纤维素终浓度为0.65％，细胞数为2400/孔。将96孔板中的细胞置于37℃、5％CO2、95％湿度条件下培养过夜。Cell Culture and Seeding: Cells in logarithmic growth phase were harvested and counted using a platelet counter. The cell viability was detected by the trypan blue exclusion method to ensure that the cell viability was above 90%. Adjust the cell concentration, add 180 μL of the cell suspension to the 96-well plate after there is no visible gas in the cell suspension, so that the final concentration of methylcellulose is 0.65%, and the number of cells is 2400/well. The cells in the 96-well plate were cultured overnight at 37° C., 5% CO 2 , and 95% humidity.
如下进行药物稀释和加药：用培养基配制10倍浓度药物溶液，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，3.16×稀释，共9个浓度，每个药物浓度设置三个复孔，DMSO含量为0.1％；将已加药的96孔板中的细胞置于37℃、5％CO2、95％湿度条件下继续培养120h，之后进行CTG分析。Drug dilution and dosing were carried out as follows: prepare a 10-fold drug solution with the culture medium, add 20 μL of the 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, a total of 9 concentrations, Three replicate wells were set up for each drug concentration, and the DMSO content was 0.1%. The cells in the 96-well plate that had been dosed were placed at 37°C, 5% CO 2 , and 95% humidity for 120 hours, and then CTG analysis 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，然后读取冷光值。Thaw 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 vibrate 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 then read the luminescence value.
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。 GraphPad Prism 7.0 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated accordingly.
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 solution control )/(Lum cell control -Lum culture solution control )×100%.
本发明化合物对3D培养AGS细胞系显示出令人满意的对KRas G12D突变细胞的增殖抑制活性，IC50值为0.01～0.5μM，例如0.01～0.1μM、0.01～0.05μM。The compounds of the present invention exhibit satisfactory inhibitory activity on the proliferation of KRas G12D mutant cells on 3D cultured AGS cell lines, with IC50 values of 0.01-0.5 μM, such as 0.01-0.1 μM, 0.01-0.05 μM.
代表性化合物的具体数据见下表。
Specific data for representative compounds are given in the table below.
实施例5:本发明化合物的小鼠盒式给药(Cassette)药代动力学特性Embodiment 5: the mouse box type administration (Cassette) pharmacokinetic characteristic of compound of the present invention
通过小鼠Cassette药代动力学实验(Nagilla R.等人,J.Pharm.Sci.2011,100,3862–3874.)评价了本发明代表性化合物的药代动力学特征。The pharmacokinetic characteristics of representative compounds of the present invention were evaluated by mouse Cassette pharmacokinetic experiments (Nagilla R. et al., J. Pharm. Sci. 2011, 100, 3862-3874.).
该研究使用雄性CD-1小鼠，周龄：6-8周，体重18-22g,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)；MC(甲基纤维素，阿拉丁，货号M112866)；DMSO(Sigma-Aldrich，货号186403)；乙腈(Sigma-Aldrich，货号WXBD547V)；甲醇(Sigma-Aldrich，货号F22M67201)。This study used male CD-1 mice, age: 6-8 weeks, body weight 18-22g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; and used the following reagents: Tolbutamide (A Latin, Cat. No. H1401054); MC (Methylcellulose, Aladdin, Cat. No. M112866); DMSO (Sigma-Aldrich, Cat. No. 186403); Acetonitrile (Sigma-Aldrich, Cat. No. WXBD547V); Methanol (Sigma-Aldrich, Cat. No. F22M67201).
将化合物组合配制到5％DMSO+95％(0.5％MC)的溶剂中，最终每个化合物的浓度为1mg/mL,将药物制备物按照10mL/kg的体积灌胃给CD-1小鼠，分别在15min、30min、1h、2h、4h、6h、8h、24h从后肢隐静脉采血，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+95% (0.5% MC), and the final concentration of each compound was 1 mg/mL, and the drug preparation was intragastrically administered to CD-1 mice at a volume of 10 mL/kg, Blood was collected from the saphenous vein of the hindlimb at 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h, and centrifuged at low temperature for 20 minutes to collect plasma, which was stored at -20°C for testing.
如下建立化合物LC-MS/MS分析方法Establish the compound LC-MS/MS analysis method 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2μL标准曲线工作液与18μL小鼠空白血浆混合，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。Preparation of standard curve: draw 20 μL of 1mg/mL DMSO stock solution for each compound, transfer to 900 μL of 50% methanol working solution, and serially dilute to obtain a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, and then draw 2μL standard curve working solution and mix with 18μL mouse blank plasma to obtain a standard with a concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL Curve for quantification of unknown samples.
样品前处理：20μL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1:1混合，吸取10μL进样，采用LC-MS分析药物血药浓度。Sample pretreatment: 20 μL unknown plasma sample and standard curve sample, add 250 μL acetonitrile containing tolbutamide as internal standard as precipitant, precipitate plasma protein, extract the compound to be tested in plasma, centrifuge at low temperature for 20 minutes, take supernatant, The supernatant was mixed with 0.1% formic acid aqueous solution 1:1, 10 μL was drawn and injected, and the blood drug concentration of the drug was analyzed by LC-MS.
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 standard curve was drawn with the mass spectrometry software Analyst 1.6.1, the unknown samples were quantified, and the pharmacokinetic parameters were calculated with Winnonlin 8.2 according to the drug concentration at each time point of the unknown samples.
实验结果显示,在盒式给药药代动力学评价中，本发明化合物显示良好的药代动力学性质。
The experimental results show that the compound of the present invention exhibits good pharmacokinetic properties in the pharmacokinetic evaluation of cassette administration.

Claims (23)

  1. 式(A)的化合物或它们药学上可接受的盐或溶剂合物，
    compounds of formula (A) or their pharmaceutically acceptable salts or solvates,
    其中：in:
    X选自N、CH、C-F、C-Cl和C-CF3；X is selected from N, CH, CF, C-Cl and C- CF3 ;
    Y选自O、S和NRb；Y is selected from O, S and NR b ;
    Ra选自卤素、C1-6烷基或-O-C1-6烷基，其中C1-6烷基任选被卤素取代；R is selected from halogen, C 1-6 alkyl or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by halogen;
    Rb在每次出现时独立地选自H和任选被卤素取代的C1-6烷基； R at each occurrence is independently selected from H and C 1-6 alkyl optionally substituted by halogen;
    R1选自H、CN、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基和-(CH2)p-4-7元杂环烷基，其中的-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和4-7元杂环烷基各自独立地任选被卤素、CN、-C1-6烷基、-ORb或-N(Rb)2取代；或R 1 is selected from H, CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p -C 3-6 cycloalkyl and -(CH 2 ) p -4-7 membered heterocycloalkyl, wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and 4- Each 7-membered heterocycloalkyl group is independently optionally substituted by halogen, CN, -C 1-6 alkyl, -OR b or -N(R b ) 2 ; or
    R1和连接于邻位环碳原子上的R3与它们所连接的环碳原子一起形成稠合的C3-6环烷基；R 1 and R 3 connected to the adjacent ring carbon atoms form a fused C 3-6 cycloalkyl group with the ring carbon atoms to which they are connected;
    R2选自H、-C1-6烷基和-C3-6环烷基，其中的C1-6烷基和C3-6环烷基各自独立地任选被卤素、-C1-6烷基、-ORb或-N(Rb)2取代；或当n为2时，两个R2与它们所连接的碳原子一起形成C3-6环烷基；R 2 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally replaced by halogen, -C 1 -6 alkyl, -OR b or -N(R b ) 2 substituted; or when n is 2, two R 2 together with the carbon atoms they are connected to form a C 3-6 cycloalkyl;
    R3选自H、卤素、-CN、-OH、-OC1-6烷基、-O-(CH2)p-C3-6环烷基、-O-(CH2)p-4-7元杂环烷基、-O-(CH2)p-5-10元杂芳基、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷基、-(CH2)p-5-10元杂芳基、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2和-O-C(O)-N(Rb)2，其中的-C1-6烷基、C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、氧代、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2、-O-C(O)-N(Rb)2取代；或R 3 is selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -O-(CH 2 ) p -C 3-6 cycloalkyl, -O-(CH 2 ) p -4- 7-membered heterocycloalkyl, -O-(CH 2 ) p -5-10 membered heteroaryl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -( CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkyl, -(CH 2 ) p -5-10 membered heteroaryl, -N(R b ) 2. -C(O)-OR b , -C(O)-N(R b ) 2 and -OC(O)-N(R b ) 2 , where -C 1-6 alkyl, C 3- 6- cycloalkyl, 4-7-membered heterocycloalkyl and 5-10-membered heteroaryl are each independently optionally replaced by halogen, -CN, oxo, -C 1-6 alkyl, -OR b , -N( R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 , -OC(O)-N(R b ) 2 substituted; or
    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；或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 each R c is independently selected from H, Halogen and -C 1-6 alkyl optionally substituted by halogen; or
    连接于相邻环碳原子上的两个R3与它们所连接的环碳原子一起形成稠合C3-6环烷基或稠合4-7元杂环烷基；Two R3s connected to adjacent ring carbon atoms form a fused C3-6 cycloalkyl group or a fused 4-7 membered heterocycloalkyl group together with the ring carbon atoms to which they are connected;
    R4选自H、-C1-6烷基、-C2-6烯基、-C2-6炔基、-(CH2)p-C3-6环烷基、-(CH2)p-4-7元杂环烷 基、-(CH2)p-5-10元杂芳基、-C(O)-ORb和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基、4-7元杂环烷基和5-10元杂芳基各自独立地任选被卤素、-CN、-C1-6烷基、-ORb、-N(Rb)2、-C(O)-ORb、-C(O)-N(Rb)2或-O-C(O)-N(Rb)2取代；R 4 is selected from H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , -(CH 2 ) p -C 3-6 cycloalkyl, -(CH 2 ) p -4-7 membered heterocycloalkane -(CH 2 ) p -5-10 membered heteroaryl, -C(O)-OR b and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, - C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl and 5-10 membered heteroaryl are each independently optionally replaced by halogen, -CN , -C 1-6 alkyl, -OR b , -N(R b ) 2 , -C(O)-OR b , -C(O)-N(R b ) 2 or -OC(O)-N (R b ) 2 substitution;
    Z选自其中Z from in
    R5和R7各自独立地选自H或卤素；R and R are each independently selected from H or halogen;
    R6和R8各自独立地选自H、卤素、-C1-6烷基和-C2-6炔基；R 6 and R 8 are each independently selected from H, halogen, -C 1-6 alkyl and -C 2-6 alkynyl;
    m和p各自独立地选自0-3的整数；m and p are each independently selected from an integer of 0-3;
    n是选自0-2的整数。n is an integer selected from 0-2.
  2. 权利要求1的化合物或其药学上可接受的盐或溶剂合物，其中Ra为F。The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R a is F.
  3. 权利要求1或2的化合物或其药学上可接受的盐或溶剂合物，其中Y为O。The compound of claim 1 or 2, wherein Y is O, or a pharmaceutically acceptable salt or solvate thereof.
  4. 权利要求1-3任一项的化合物或其药学上可接受的盐或溶剂合物，其中R1选自-C1-6烷基和-C3-6环烷基。The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl.
  5. 权利要求1-4任一项的化合物或其药学上可接受的盐或溶剂合物，其中R2为H。The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H.
  6. 权利要求1-5任一项的化合物或其药学上可接受的盐或溶剂合物，其中R3为H。The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is H.
  7. 权利要求1-5任一项的化合物或其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、-ORb或-O-C(O)-N(Rb)2取代，或R3为卤素，优选F。The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C 1-6 alkyl, optionally replaced by halogen, -OR b or -OC(O)- N(R b ) 2 substituted, or R 3 is halogen, preferably F.
  8. 权利要求1-7任一项的化合物或其药学上可接受的盐或溶剂合物，其中R4选自-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2-6烯基、-C2- 6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代。The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein R is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkyne -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , where -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl is each independently optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 .
  9. 权利要求8的化合物或其药学上可接受的盐或溶剂合物，其中R4为-C1-6烷基，任选被卤素或-ORb取代。The compound of claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is -C 1-6 alkyl, optionally substituted by halogen or -OR b .
  10. 权利要求1的化合物或其药学上可接受的盐或溶剂合物，其具有式I： 其中X、Y、R1、R2、R3、R4、R5、R6、n和m各自如权利要求1-9相应所定义，优选
    The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having formula I: wherein X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and m are each as defined in claims 1-9, preferably
  11. 权利要求10的化合物或其药学上可接受的盐或溶剂合物，其中The compound of claim 10 or a pharmaceutically acceptable salt or solvate thereof, wherein
    Y为O；Y is O;
    R1选自H、-C1-6烷基和-C3-6环烷基；R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
    R2为H； R2 is H;
    R3选自H、卤素、-ORb或被-O-C(O)-N(Rb)2取代的-C1-6烷基；或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；优选R3选自F、-CH2F、-CHF2、＝CHF；R 3 is selected from H, halogen, -OR b or -C 1-6 alkyl substituted by -OC(O)-N(R b ) 2 ; or two R 3 connected to the same carbon atom form = C(R c ) 2 , wherein each R c is independently selected from H, F, Cl, Br, I, -C 1-6 alkyl optionally substituted by halogen; preferably R 3 is selected from F, -CH 2 F , -CHF 2 , =CHF;
    R4选自-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2- 6烯基、-C2-6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代，优选任选被卤素、-ORb或-O-C(O)-N(Rb)2取代的-C1-6烷基。R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 .
  12. 权利要求10或11的化合物或其药学上可接受的盐或溶剂合物，其中R5为F，且R6为 The compound of claim 10 or 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R is F, and R is
  13. 权利要求1的化合物或其药学上可接受的盐或溶剂合物，其具有式II：其中X、Y、R1、R2、R3、R4、R7、R8、n和m各自如权利要求1-9相应所定义，优选
    The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having formula II: wherein X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , n and m are each as defined in claims 1-9, preferably
  14. 权利要求13的化合物或其药学上可接受的盐或溶剂合物，其中The compound of claim 13 or a pharmaceutically acceptable salt or solvate thereof, wherein
    Y为O；Y is O;
    R1选自H、-C1-6烷基和-C3-6环烷基；R 1 is selected from H, -C 1-6 alkyl and -C 3-6 cycloalkyl;
    R2为H； R2 is H;
    R3选自H、卤素、-ORb或被-O-C(O)-N(Rb)2取代的-C1-6烷基；R 3 is selected from H, halogen, -OR b or -C 1-6 alkyl substituted by -OC(O)-N(R b ) 2 ;
    R4选自-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-6环烷基和-C(O)-N(Rb)2，其中的-C1-6烷基、-C2- 6烯基、-C2-6炔基和-C3-6环烷基各自独立地任选被卤素、-ORb或-O-C(O)-N(Rb)2取代，优选任选被卤素、-ORb或-O-C(O)-N(Rb)2取代的-C1-6烷基。R 4 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl and -C(O)-N(R b ) 2 , Wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -C 3-6 cycloalkyl are each independently optionally replaced by halogen, -OR b or -OC(O )-N(R b ) 2 substituted, preferably -C 1-6 alkyl optionally substituted by halogen, -OR b or -OC(O)-N(R b ) 2 .
  15. 权利要求13或14的化合物或其药学上可接受的盐或溶剂合物，其中R7为H，且R8为卤素。The compound of claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is H, and R 8 is halogen.
  16. 化合物或其药学上可接受的盐或溶剂合物，其为实施例1-232的化合物。 A compound or a pharmaceutically acceptable salt or solvate thereof is the compound of Embodiment 1-232.
  17. 权利要求1-16任一项的化合物或其药学上可接受的盐或溶剂合物，用作药物，用于治疗和/或预防由KRas突变、优选KRas G12D突变介导的疾病。The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, is used as a medicine for treating and/or preventing diseases mediated by KRas mutation, preferably KRas G12D mutation.
  18. 药物组合物，包含根据权利要求1-16任一项的化合物或其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。A pharmaceutical composition comprising a compound according to any one of claims 1-16 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  19. 权利要求1-16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18或19的药物组合物在制备用于预防或治疗由KRas突变、优选KRas G12D突变介导的疾病的用药物中的用途。The compound according to any one of claims 1-16 or its pharmaceutically acceptable salt or solvate, or the pharmaceutical composition according to claim 18 or 19 is used in the preparation for prevention or treatment mediated by KRas mutation, preferably KRas G12D mutation The use of medicines for diseases.
  20. 权利要求19的用途，其中由KRas突变、优选KRas G12D突变介导的疾病选自：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 19, wherein the disease mediated by the KRas mutation, preferably the KRas G12D mutation, is selected from the group consisting of: pancreatic cancer, lung cancer, lung adenocarcinoma, bone cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer , ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophagus cancer, small bowel cancer, endocrine system Carcinoma, 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 tumor (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma.
  21. 权利要求20的用途，其中由KRas突变、优选KRas G12D突变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 purposes of claim 20, wherein the disease mediated by KRas mutation, preferably KRas G12D mutation is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most It is preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, cholangiocarcinoma.
  22. 治疗和/或预防由Ras突变蛋白、尤其是KRas突变蛋白、优选KRas G12D突变蛋白介导的疾病的方法，包括向有需要的对象施用治疗有效量的根据权利要求1-16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18或19的药物组合物。A method for treating and/or preventing a disease mediated by a Ras mutein, especially a KRas mutein, preferably a KRas G12D mutein, comprising administering a therapeutically effective amount of a compound according to any one of claims 1-16 to a subject in need Or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 18 or 19.
  23. 权利要求22的方法，其中由KRas突变、优选KRas G12D突变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 22, wherein the disease mediated by the KRas mutation, preferably the KRas G12D mutation, is selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, lung cancer, bile duct cancer, endometrial cancer, ovarian cancer, leukemia; most It is preferably selected from pancreatic cancer, colon cancer, rectal cancer, lung adenocarcinoma, cholangiocarcinoma.
PCT/CN2023/075209 2022-02-11 2023-02-09 Compound having anti-kras mutant tumor activity WO2023151621A1 (en)

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