WO2023151621A1 - Composé ayant une activité tumorale mutante anti-kras - Google Patents

Composé ayant une activité tumorale mutante anti-kras Download PDF

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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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English (en)
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/fr

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

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Abstract

La présente invention concerne des composés pouvant être utilisés en tant qu'inhibiteurs de KRAS et ayant une structure de formule (A), une composition pharmaceutique comprenant de tels composés, un procédé de préparation de tels composés, et une utilisation des composés dans le traitement de cancers.
PCT/CN2023/075209 2022-02-11 2023-02-09 Composé ayant une activité tumorale mutante anti-kras WO2023151621A1 (fr)

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
CN115109078A (zh) * 2021-03-22 2022-09-27 苏州泽璟生物制药股份有限公司 嘧啶并吡啶类抑制剂及其制备方法和应用

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WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
CN115109078A (zh) * 2021-03-22 2022-09-27 苏州泽璟生物制药股份有限公司 嘧啶并吡啶类抑制剂及其制备方法和应用

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DATABASE REGISTRY ANONYMOUS : "- 2-Naphthalenol, 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2- [[(2R,4R)-4-fluoro-1,2-dimethyl-2-pyrrolidinyl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]-5-ethynyl-6-fluoro- (CA INDEX NAME)", XP093085586, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "- 2-Naphthalenol, 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-[[(2R)-1- methyl-2-pyrrolidinyl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]- (CA INDEX NAME)", XP093085590, retrieved from STN *

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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