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WO2023020347A1 - 嘧啶并吡啶类化合物及其制备方法和医药用途 - Google Patents

嘧啶并吡啶类化合物及其制备方法和医药用途 Download PDF

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Publication number
WO2023020347A1
WO2023020347A1 PCT/CN2022/111402 CN2022111402W WO2023020347A1 WO 2023020347 A1 WO2023020347 A1 WO 2023020347A1 CN 2022111402 W CN2022111402 W CN 2022111402W WO 2023020347 A1 WO2023020347 A1 WO 2023020347A1
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Prior art keywords
alkyl
aryl
phenyl
nhc
heterocyclyl
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PCT/CN2022/111402
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English (en)
French (fr)
Inventor
闫旭
宗利斌
刘国标
陈彬
尚飞
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China Resources Pharmaceutical Research Institute Shenzhen Co Ltd
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China Resources Pharmaceutical Research Institute Shenzhen Co Ltd
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Priority to CN202280005876.8A priority Critical patent/CN116669740A/zh
Publication of WO2023020347A1 publication Critical patent/WO2023020347A1/zh
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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
    • A61K31/519—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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medical technology, and in particular relates to a pyrimidopyridine compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a KRAS-G12D inhibitor in the treatment and/or prevention of diseases related to KRAS-G12D activity use in .
  • KRAS mutations are the most common oncogenic mutations in cancer, especially prevalent in pancreatic cancer, colorectal cancer, and lung cancer, with mutation rates of 95%, 45%, and 35%, respectively (Christensen et al., J Intern Med, 2020, 288( 2), 183-191).
  • KRAS protein is a kind of guanine nucleotide-binding protein with GTP hydrolase activity. In vivo, it binds to GTP (activated) and GDP (inactivated) to switch between active and inactive states, and regulates the downstream RAF-MEK- ERK, PI3K-AKT-mTOR and other signaling pathways (Moore et al., Nat Rev Drug Discov, 2020, 19(8), 533-552).
  • KRAS mutations occur at codon 12, including G12C, G12D, and G12V mutation types; for example, G12C mutations will form steric hindrance, thereby preventing GAP protein from binding to KRAS, reducing GTP hydrolysis, and increasing the level of GTP-bound forms, making downstream Signaling pathways are continuously activated, inducing the occurrence of tumors and various diseases (Simanshu et al., Cell, 2017, 170(1), 17-33).
  • the drug Sotorasib showed significant anticancer activity in patients with advanced solid tumors with KRAS p.G12C mutation and has been approved by the FDA for the treatment of cancer patients with G12C mutation (Skoulidis et al., N Engl J Med, 2021, 384(25), 2371-2381).
  • G12D mutation type there are currently no directly targeted drugs that have entered the clinical stage.
  • KRAS-G12D mutation is the driving factor of many cancers.
  • the incidence rate of pancreatic ductal carcinoma is 25.0%, and the incidence rate of colorectal cancer, kidney cancer, and lung cancer is 13.3%, 10.1%, and 4.1%, respectively (AACR Project GENIE, Cancer Discov, 2017, 7(8), 818-831). Efforts have been made to suppress this type of mutation.
  • GEFs such as SOS protein, and specific SOS1 inhibitors, by binding to SOS1 protein, can inhibit all KRAS mutant types.
  • BI1701963 is a pan-KRAS inhibitor that has entered the clinical phase as monotherapy and in combination with the MEK inhibitor trametinib for the treatment of patients with KRAS-mutated advanced solid tumors (Gerlach et al., Cancer Research, 2020, 80(16), 1091-1091).
  • MRTX1133 is a selective and reversible KRAS-G12D inhibitor that can directly target G12D mutant cells without inhibiting KRAS wild-type cells. Preclinical data have shown that it can effectively inhibit a variety of tumor models with G12D mutations. The molecule is currently in clinical trials Pre-development phase (Mirati.Inc,). In conclusion, the development of KRAS inhibitors, especially the KRAS-G12D mutation is still the direction of people's continuous attention and efforts.
  • the object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 7-12 membered nitrogen-containing bridge ring, 4-12 membered heterocyclic group, cycloalkyl, aryl and heteroaryl; wherein the 7-12 membered nitrogen-containing bridged ring, 4-12 membered heterocyclic ring Base, cycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 5 ; the 7-12 membered nitrogen-containing bridged ring is not
  • the 4-12 membered heterocyclic group is preferably a 7-12 membered spiro heterocyclic group;
  • Y is selected from bond, O, S, SO, SO 2 and NR 4 ;
  • Each L is independently C 1 -C 4 alkylene optionally substituted with one or more hydroxy, C 1 -C 4 hydroxyalkyl, or heteroaryl;
  • R 2 is aryl or heteroaryl; wherein said aryl or heteroaryl are each independently optionally substituted by one or more R 7 ;
  • R 3 is selected from hydrogen, halogen and C 1 -C 6 alkyl
  • each R 4 is independently hydrogen or C 1 -C 3 alkyl
  • each Q is independently a key or O
  • Ring A is selected from 7-12 membered nitrogen-containing bridged rings, 7-12 membered spiro heterocyclic groups, C 3 -C 12 cycloalkyl groups, C 6 -C 14 aryl groups and 5-14 membered heteroaryl groups; wherein the Each of the 7-12 membered nitrogen-containing bridged ring, the 7-12 membered spiro heterocyclic group, the C 3 -C 12 cycloalkyl group, the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group is optionally replaced by a or multiple R 5 substitutions;
  • the 7-12 membered nitrogen-containing bridging ring is preferably selected from more preferred
  • the 7-12 membered spiroheterocyclyl is preferably selected from more preferred
  • Each Q is independently a bond or O.
  • Y is selected from a bond, O, S, SO and SO2 , preferably O and S.
  • Each L is independently C 1 -C 4 alkylene optionally substituted with one or more hydroxy, C 1 -C 4 hydroxyalkyl or heteroaryl; preferably, each L is independently C 1 - C 4 alkylene;
  • each R 4 is independently hydrogen or C 1 -C 3 alkyl
  • each Q is independently a bond or O
  • R 2 is C 6 -C 14 aryl or 5-14 membered heteroaryl, preferably C 6 -C 10 aryl, more preferably phenyl or naphthyl; wherein each of the aryl or heteroaryl is independently optional is substituted by one or more R 7 , and
  • R 3 is selected from hydrogen, halogen and C 1 -C 3 alkyl, preferably halogen.
  • the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (II) or a tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring A is selected from
  • R3 is halogen
  • each R is independently halogen
  • Each R 7 is independently C 2 -C 4 alkynyl, cyano or hydroxyl
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer Construct, or its mixture form, its prodrug or the method for pharmaceutically acceptable salt thereof, it comprises the following steps:
  • compound Ij and compound Perform a coupling reaction to obtain a compound of general formula (I), wherein the high temperature condition is preferably 100°C, the basic reagent is preferably cesium carbonate, and the catalyst is preferably 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride;
  • ring A, R 1 , R 2 , R 3 and Y are as defined in general formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer Constituents, diastereoisomers, or mixtures thereof, prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a KRAS-G12D inhibitor.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and/or treating diseases related to KRAS-G12D activity.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which is used as a medicine.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a KRAS-G12D inhibitor.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, used as a medicine for preventing and/or treating diseases related to KRAS-G12D activity.
  • the present invention further provides a method for preventing and/or treating diseases related to KRAS-G12D activity, which comprises administering a preventive or therapeutically effective amount of the general formula (I) according to the present invention to a subject in need.
  • a preventive or therapeutically effective amount of the general formula (I) according to the present invention to a subject in need.
  • the diseases related to KRAS-G12D activity according to the present invention may be: pancreatic ductal carcinoma, colorectal cancer, renal cancer, lung cancer, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid.
  • the acids include inorganic acids and organic acids, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid , trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the present invention also includes prodrugs of the compound represented by the general formula (I) of the present invention.
  • Prodrugs of the present invention are derivatives of compounds shown in general formula (I), they themselves may have weak activity or even no activity, but after administration, under physiological conditions (such as by metabolism, solvolysis) or otherwise) into the corresponding biologically active form.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the compounds of this invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to KRAS-G12D activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogens involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C, and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C, and 14 C
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom, an alkyl group containing 1 to 4 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms Alkynyl such as ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms or contain 4 to 12 carbon atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1-2 or 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 12 yuan, even more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • the present invention adopts the following technical solutions.
  • the medicinal salt can be prepared by the following scheme, and the specific preparation method is as follows.
  • Step 1 In the presence of high temperature and alkaline reagents, compound Ia is rearranged with tert-butanol and diphenylphosphoryl azide to obtain compound Ib, wherein the high temperature condition is preferably 100°C, and the basic reagent is preferably triethylamine;
  • Step 2 Deprotecting Compound Ib at room temperature in the presence of an acidic reagent to obtain Compound Ic, wherein the acidic reagent is preferably dioxane hydrochloride;
  • Step 3 react compound Ic with N-iodosuccinimide at high temperature and in the presence of a catalyst to obtain compound Id, wherein the high temperature condition is preferably 70°C, and the catalyst is preferably p-toluenesulfonic acid;
  • Step 4 In the presence of high temperature, alkaline reagent and catalyst, compound Id is reacted with carbon monoxide to obtain compound Ie, wherein the high temperature condition is preferably 50°C, the basic reagent is preferably N,N-diisopropylethylamine, and the catalyst is preferably 1 ,1'-bisdiphenylphosphinoferrocene palladium dichloride;
  • Step 5 react Compound Ie with trichloroacetyl isocyanate at 0°C to obtain Compound If;
  • Step 6 react compound If with methanol solution of ammonia at 0°C to obtain compound Ig;
  • Step 7 React compound Ig with phosphorus oxychloride under high temperature and alkaline conditions to obtain compound I, wherein the high temperature condition is preferably 100°C, and the alkaline reagent is preferably N,N-diisopropylethylamine;
  • Step 8 at 0°C, compound I and compound Carrying out a substitution reaction in the presence of a basic reagent to obtain compound Ik, wherein the basic reagent is preferably N,N-diisopropylethylamine;
  • Step 9 In the presence of high temperature and basic reagents, compound Ik is subjected to a substitution reaction with compound HY-R 1 to obtain compound Ij, wherein the high temperature condition is preferably 90°C, and the basic reagent is preferably N,N-diisopropylethyl amine;
  • Step 10 In the presence of high temperature, alkaline reagent and catalyst, compound Ij and compound The coupling reaction is carried out to obtain the compound of general formula (I), wherein the high temperature condition is preferably 100°C, the basic reagent is preferably cesium carbonate, and the catalyst is preferably 1,1'-bisdiphenylphosphinoferrocenedichloropalladium catalyst.
  • the high temperature condition is preferably 100°C
  • the basic reagent is preferably cesium carbonate
  • the catalyst is preferably 1,1'-bisdiphenylphosphinoferrocenedichloropalladium catalyst.
  • ring A, R 1 , R 2 , R 3 and Y are as defined in claim 1 .
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS uses 1100Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).
  • the lc3000 high performance liquid chromatograph and the lc6000 high performance liquid chromatograph were used for the preparative liquid phase.
  • the chromatographic column is Daisogel C18 10 ⁇ m 60A (20mm ⁇ 250mm).
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm mm.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Wanghuamall, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Yinuokai, Nanjing Yaoshi, Anaiji Chemical and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the microwave reaction uses a CEM Discover SP microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin-layer chromatography
  • the eluent system of column chromatography and the developer system of thin-layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum
  • A dichloromethane and methanol system
  • B petroleum ether, ethyl acetate and dichloromethane system
  • C petroleum
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Example 1 5-ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- Preparation of 4-(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol (1)
  • Step 1 Preparation of (bromoethynyl)triisopropylsilane (1b).
  • ethynyltriisopropylsilane 1a (5.00g, 27.4mmol), acetone (100mL), and silver nitrate (4.66g, 27.4mmol) were successively added to a dry 250mL three-necked flask, and added in batches under nitrogen protection.
  • N-bromosuccinimide (5.86g, 32.9mmol) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched by adding ice water, extracted with petroleum ether, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1b as a colorless oil, 6.00 g, with a yield of 84.0%.
  • Step 2 Preparation of 8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (1d).
  • naphthalene-1,3-diol 1c (5.00g, 31.3mmol) and compound 1b (9.79g, 37.5mmol) into a dry 250mL three-necked flask, add 1,4-dioxane (75mL ), dichloro(p-cymenyl)ruthenium(II) dimer (1.91g, 3.12mmol) and potassium acetate (6.13g, 62.5mmol) were added under nitrogen protection, and the temperature was raised to 110°C and stirred for 12 hours.
  • Step 3 Preparation of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (1e).
  • compound 1d (200mg, 0.588mmol) was dissolved in dichloromethane (5mL), added to a 50mL dry three-necked flask, N,N-diisopropylethylamine (228mg, 1.77mmol) was added, nitrogen protection At 0°C, bromomethyl methyl ether (110mg, 0.880mmol) was added dropwise, and reacted at 0°C for half an hour after the dropwise addition.
  • Step 4 Preparation of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yltrifluoromethanesulfonic acid (1f).
  • Step 5 Triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Preparation of naphthalen-1-yl)ethynyl)silane (1 g).
  • compound 1f 200mg, 0.388mmol
  • toluene 5mL
  • pinacol diborate 19mg, 0.776mmol
  • potassium acetate 133mg, 1.36mmol
  • 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride 28.0mg, 0.0383mmol
  • Step 6 Preparation of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (1i).
  • Step 8 Preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine (1k).
  • Step 9 Preparation of methyl 4-amino-6-chloro-5-fluoronicotinate (11).
  • Step 10 Preparation of methyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (1m).
  • Step 11 Preparation of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1n).
  • Step 12 Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1o).
  • Step 13 7-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid Preparation of tert-butyl ester (1p).
  • compound 1o 500mg, 1.99mmol was dissolved in tetrahydrofuran (5.0mL), and 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (422mg, 1.99mmol) was added at 0°C , N,N-diisopropylethylamine (515mg, 3.98mmol) was added dropwise, and reacted at room temperature for 2 hours.
  • Step 14 tert-Butyl 7-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) Preparation of pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1r).
  • compound 1p 500 mg, 1.17 mmol was dissolved in 1,4-dioxane (5.0 mL), and ((2R, 7aS)-2-fluorotetrahydrohydrogen-1H-pyrrolizine-7a was added at room temperature (5H)-yl)methanol (372mg, 2.34mmol) was added dropwise with N,N-diisopropylethylamine (302mg, 2.34mmol), and the reaction was stirred at 80°C for 16 hours.
  • Step 15 7-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-( Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-4,7-di
  • tert-butyl azaspiro[2.5]octane-4-carboxylate (1s).
  • compound 1r 200 mg, 0.364 mmol was dissolved in 1,4-dioxane (2.0 mL) and water (0.2 mL), and triisopropyl ((6-(methoxymethoxy )-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)silane (180mg, 0.364mmol), 1 , 1'-bisdiphenylphosphinoferrocene palladium dichloride (26.6mg, 0.0364mmol), cesium carbonate (237mg, 0.727mmol), nitrogen protection, 100 °C reaction overnight.
  • Step 16 4-(8-Fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4,7- Diazaspiro[2.5]octane-7-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol ( 1t) Preparation.
  • Step 17 5-Ethynyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4 Preparation of -(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol (1).
  • Example 2 4-(4-(2,5-diazabicyclo[2.2.2]octane-2-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro- Preparation of 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol (2)
  • Example 3 4-(4-((1R,5S,8R)-8-amino-3-azabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalene-2- Preparation of Alcohol (3)
  • the preparation method is the same as in Example 1, except that tert-butyl carbamate is used to replace 4,7-diazaspiro[2.5]octane-4- tert-Butyl carboxylate, the title compound 3 was obtained.
  • Example 5 4-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro- Preparation of 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol (5)
  • Test Example 1 Inhibitory level of the compound of the present invention on the binding of KRAS-G12D-CRAF
  • the biochemical activity of the compound was evaluated by detecting the inhibitory level of the compound on the binding of the RAS protein and the downstream kinase RAF.
  • KRAS-G12D/cRAF Binding Kit was purchased from Cisbio, Cat. No. 63ADK000CB21PEG, and the required buffer and reaction solution were prepared according to the instructions of the kit.
  • Compounds were diluted with DMSO, with an initial concentration of 10 ⁇ M, 10 concentration gradients, and 3-fold dilutions.
  • Pipette 0.1 ⁇ L of the compound into a 384-well plate (Corning, 3657) with an ECHO pipette (Labcyte); add 5 ⁇ L of Tag2-KRASG12D-GTP mixture, centrifuge at 1000 rpm for 1 minute. Add 5 ⁇ L Tag1-cRAF to the reaction plate, and centrifuge at 1000 rpm for 1 min.
  • X is the log value of the compound concentration
  • Y is the fluorescence intensity ratio at 665/615 wavelength
  • Top and Bottom are the Y values of the highest and lowest platform of the curve
  • HillSlope is the Hill constant.
  • Test Example 2 Compounds of the present invention inhibit KRAS-G12D-mediated ERK phosphorylation
  • KRAS-G12D mutant AGS cells were from ATCC, using F-12K medium (Gibco, 30-2004) + 10% FBS (Ausgenex, FBS500-S) + 1% penicillin-streptomycin (Gibco, 15140-122) for subculture.
  • F-12K medium Gibco, 30-2004
  • FBS Ausgenex, FBS500-S
  • penicillin-streptomycin Gibco, 15140-122
  • 5,000 AGS cells were seeded in a 384-well plate (Corning, 3657), and placed in a 5% incubator at 37°C overnight to allow the cells to adhere to the wall. The next day, add the compound to be tested in the experiment, dissolve the compound in DMSO, and dilute it. The initial concentration of the experiment starts from 10 mM, and it is diluted 3 times. Set up 10 concentration gradients, and each gradient has 2 replicate wells.
  • GAPDH D4C6R mouse mAb, CST, 97166S
  • X logarithm of compound concentration
  • Y average value (relative to pERK)
  • Top and Bottom are the Y values of the highest and lowest plateau of the curve
  • Hillslope is the Hill constant.

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Abstract

通式(I)所示的嘧啶并吡啶类化合物、其制备方法及含有该化合物的药物组合物，及其作为KRAS-G12D抑制剂的用途，该化合物及含有该化合物的药物组合物可以用于治疗和/或预防与KRAS-G12D活性相关的疾病，例如胰腺导管癌、结直肠癌、肾癌、肺癌等。

Description

嘧啶并吡啶类化合物及其制备方法和医药用途 技术领域
本发明属于医药技术领域，具体涉及一种嘧啶并吡啶类化合物、其制备方法及含有其的药物组合物，以及其作为KRAS-G12D抑制剂在治疗和/或预防与KRAS-G12D活性相关的疾病中的用途。
背景技术
KRAS突变是癌症中最常见的致癌突变，尤其在胰腺癌、结直肠癌和肺癌中普遍出现，突变率分别为95％、45％和35％(Christensen等人，J Intern Med，2020，288(2)，183-191)。KRAS蛋白是一类鸟嘌呤核苷酸结合蛋白，且具有GTP水解酶活性，在体内通过与GTP(活化)和GDP(失活)结合，处于活性与非活性状态转换，调控下游RAF-MEK-ERK，PI3K-AKT-mTOR等信号通路(Moore等人，Nat Rev Drug Discov，2020，19(8)，533-552)。大多数KRAS突变发生在12密码子上，包括G12C、G12D、G12V突变类型；如G12C突变会形成空间位阻，从而阻止GAP蛋白与KRAS结合，减少GTP水解，增加GTP结合形式的水平，使得下游信号通路处于持续活化状态，诱导肿瘤及多种疾病的发生(Simanshu等人，Cell，2017，170(1)，17-33)。药物Sotorasib对KRAS p.G12C突变的晚期实体瘤患者显示出显著的抗癌活性，已被FDA批准用于治疗G12C突变的癌症患者(Skoulidis等人，N Engl J Med，2021，384(25)，2371-2381)。然而，对于G12D突变类型，目前没有进入临床阶段的直接靶向药物。
KRAS-G12D突变是多种癌症的驱动因素，在胰腺导管癌的发生率为25.0％，在结直肠癌、肾癌、肺癌的发生率分别是13.3％、10.1％、4.1％(AACR Project GENIE，Cancer Discov，2017，7(8)，818-831)。对于抑制该类型突变，研究人员已做出努力尝试。KRAS在GDP与GTP的转换需要GEFs的参与，如SOS蛋白，而特异性SOS1抑制剂，通过与SOS1蛋白结合，来抑制所有的KRAS突变类型。BI1701963是一种泛KRAS抑制剂，已进入临床阶段，作为单一疗法以及与MEK抑制剂曲美替尼联合治疗KRAS突变的晚期实体瘤患者(Gerlach等人，Cancer Research，2020，80(16)，1091-1091)。MRTX1133是选择性可逆的KRAS-G12D抑制剂，可直接靶向G12D突变的细胞，而不抑制KRAS野生型细胞，临床前数据显示可有效抑制G12D突变型的多种肿瘤模型，该分子目前处于临床前开发阶段(Mirati.Inc，)。总之，开发KRAS抑制剂，尤其是KRAS-G12D突变仍旧是人们持续关注和努力的方向。
发明内容
本发明人经过潜心研究，设计合成了一系列取代的嘧啶并吡啶类化合物，并 对其进行了KRAS-G12D活性的筛选，研究结果显示该类化合物具有突出的KRAS-G12D抑制活性，并且可以被开发为治疗和/或预防与KRAS-G12D活性相关的疾病的药物。
因此，本发明的目的为提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2022111402-appb-000001
其中：
环A选自7-12元含氮桥环、4-12元杂环基、环烷基、芳基和杂芳基；其中所述7-12元含氮桥环、4-12元杂环基、环烷基、芳基和杂芳基各自独立地任选地被一个或多个R 5取代；所述7-12元含氮桥环不为
Figure PCTCN2022111402-appb-000002
所述4-12元杂环基优选为7-12元螺杂环基；
Y选自键、O、S、SO、SO 2和NR 4；
R 1选自氢、-N(R 4) 2、杂环基、C 1-C 6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-LN(R 4) 2、-L-NHC(＝NH)NH 2、-L-C(＝O)N(R 4) 2、-L-C 1-C 6卤代烷基、-L-OR 4、-L-(CH 2OR 4)(CH 2) nOR 4、-L-NR 4C(＝O)芳基、-L-COOH和-L-C(＝O)OC 1-C 6烷基，其中-L-NR 4C(＝O)-芳基的芳基部分和-L-杂环基的杂环基部分和-L-环烷基的环烷基部分任选地被一个或多个R 5取代，并且其中-L-芳基和-L-杂芳基的芳基或杂芳基任选地被一个或多个R 6取代；
每个L独立地为任选被一个或多个羟基、C 1-C 4羟烷基或杂芳基取代的C 1-C 4亚烷基；
R 2为芳基或杂芳基；其中所述芳基或杂芳基各自独立地任选被一个或多个R 7取代；
R 3选自氢、卤素和C l-C 6烷基；
每个R 4独立地为氢或C l-C 3烷基；
每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷 基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；
每个Q独立地为键或O；
每个R 6独立地选自卤素、羟基、HC(＝O)-、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、C 1-C 4羟烷基和-N(R 4) 2；且
每个R 7独立地选自卤素、氰基、羟基、C 1-C 4烷基、-S-C l-C 3烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4羟基炔基、C l-C 3氰基烷基、三唑基、C l-C 3卤代烷基、-O-C l-C 3卤代烷基、-S-C l-C 3卤代烷基、C l-C 3烷氧基、羟基C l-C 3烷基、-CH 2C(＝O)N(R 4) 2、-C 3-C 4炔基(NR 4) 2、-N(R 4)) 2、氘代C 2-C 4炔基、(C l-C 3烷氧基)卤代C l-C 3烷基-和C 3-C 6环烷基，其中所述C 3-C 6环烷基任选被一个或多个卤素或C l-C 3烷基取代。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
环A选自7-12元含氮桥环、7-12元螺杂环基、C 3-C 12环烷基、C 6-C 14芳基和5-14元杂芳基；其中所述7-12元含氮桥环、7-12元螺杂环基、C 3-C 12环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地任选地被一个或多个R 5取代；
所述7-12元含氮桥环优选选自
Figure PCTCN2022111402-appb-000003
Figure PCTCN2022111402-appb-000004
更优选
Figure PCTCN2022111402-appb-000005
Figure PCTCN2022111402-appb-000006
所述7-12元螺杂环基优选选自
Figure PCTCN2022111402-appb-000007
Figure PCTCN2022111402-appb-000008
更优选
Figure PCTCN2022111402-appb-000009
每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；且
每个Q独立地为键或O。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
Y选自键、O、S、SO和SO 2，优选O和S。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 1选自-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-LN(R 4) 2、-L-NHC(＝NH)NH 2、-LC(＝O)N(R 4) 2、-L-C 1-C 6卤代烷基、-L-OR 4、-L-(CH 2OR 4)(CH 2) nOR 4、-L-NR 4C(＝O)-芳基、-L-COOH和-LC(＝O)OC 1-C 6烷基，其中-L-NR 4C(＝O)-芳基的芳基部分和-L-杂环基的杂环基部分和-L-环烷基的环烷基部分任选地被一个或多个R 5取代，并且其中-L-芳基和-L-杂芳基的芳基或杂芳基任选地被一个或多个R 6取代，优选-L-杂环基、-L-环烷基、-L-C 1-C 6卤代烷基；所述杂环基特别地为6-14元稠杂环基，更特别地选自
Figure PCTCN2022111402-appb-000010
Figure PCTCN2022111402-appb-000011
甚至更特别地为
Figure PCTCN2022111402-appb-000012
每个L独立地为任选被一个或多个羟基、C 1-C 4羟烷基或杂芳基取代的C 1-C 4亚烷基；优选地，每个L独立地为C 1-C 4亚烷基；
每个R 4独立地为氢或C l-C 3烷基；
每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；优选地，每个R 5独立地为卤素；
每个Q独立地为键或O；且
每个R 6独立地选自卤素、羟基、HC(＝O)-、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、C 1-C 4羟烷基和-N(R 4) 2。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 2为C 6-C 14芳基或5-14元杂芳基，优选C 6-C 10芳基，更优选苯基或萘基；其中所述芳基或杂芳基各自独立地任选被一个或多个R 7取代，且
每个R 7独立地选自卤素、氰基、羟基、C 1-C 4烷基、-S-C l-C 3烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4羟基炔基、C l-C 3氰基烷基、三唑基、C l-C 3卤代烷基、-O-C l-C 3卤代烷基、-S-C l-C 3卤代烷基、C l-C 3烷氧基、羟基C l-C 3烷基、-CH 2C(＝O)N(R 4) 2、-C 3-C 4炔基(NR 4) 2、-N(R 4)) 2、氘代C 2-C 4炔基、(C l-C 3烷氧基)卤代C l-C 3烷基-和C 3-C 6环烷基，其中所述C 3-C 6环烷基任选被一个或多个卤素或C l-C 3烷基取代；优选地，每个R 7独立地为C 2-C 4炔基、氰基或羟基。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 3选自氢、卤素和C l-C 3烷基，优选卤素。
在本发明一些优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2022111402-appb-000013
环A选自
Figure PCTCN2022111402-appb-000014
R 3为卤素；
每个R 5独立地为卤素；
每个R 7独立地为C 2-C 4炔基、氰基或羟基；
m为0、1、2或3；且
n为0、1、2或3。
本发明的典型化合物，包括但不限于：
Figure PCTCN2022111402-appb-000015
Figure PCTCN2022111402-appb-000016
其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2022111402-appb-000017
在高温、碱性试剂和催化剂存在下，将化合物Ij与化合物
Figure PCTCN2022111402-appb-000018
进行偶联反应，得到通式(I)化合物，其中，高温条件优选100℃，碱性试剂优选碳酸铯，催化剂优选1,1'-双二苯基膦二茂铁二氯化钯；
其中，环A、R 1、R 2、R 3和Y如通式(I)所定义。
本发明另一方面提供一种药物组合物，其含有根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，以及药学上可接受的载体。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，在制备KRAS-G12D抑制剂中的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，在制备预防和/或治疗与KRAS-G12D活性相关的疾病的药物中的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，其用作药物的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，其用作KRAS-G12D抑制剂的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，其用作药物的用途，所述药物用于预防和/或治疗与KRAS-G12D活性相关的疾病。
本发明进一步提供一种预防和/或治疗与KRAS-G12D活性相关的疾病的方法，其包括向有需要的受试者施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物。
在本发明的一个优选的实施方案中，根据本发明所述的与KRAS-G12D活性相关的疾病可以为：胰腺导管癌、结直肠癌、肾癌、肺癌等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱生 成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。
此外，本发明还包括本发明通式(I)所示的化合物的前药。本发明所述的前药是通式(I)所示的化合物的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活 性成分，也可以与其它治疗与KRAS-G12D活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
术语定义
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，即本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基、含有1至4个碳原子的烷基或含有1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，优选含有2至4个碳原子的烯基，例如乙烯基、1-丙烯基、2-丙烯基、1-、 2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，优选含有2至4个碳原子的炔基或优选含有3至4个碳原子的炔基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2022111402-appb-000019
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2022111402-appb-000020
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三 环。桥环烷基的非限制性实例包括：
Figure PCTCN2022111402-appb-000021
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子或包含4至12个碳原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至12元，甚至更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2022111402-appb-000022
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优 选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2022111402-appb-000023
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2022111402-appb-000024
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022111402-appb-000025
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022111402-appb-000026
Figure PCTCN2022111402-appb-000027
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022111402-appb-000028
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案。
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐可通过以下方案制备，具体制备方法如下。
Figure PCTCN2022111402-appb-000029
步骤1：在高温、碱性试剂存在下，将化合物Ia与叔丁醇和叠氮磷酸二苯酯进行重排反应得到化合物Ib，其中，高温条件优选100℃，碱性试剂优选三乙胺；
步骤2：在室温、酸性试剂存在下，将化合物Ib脱保护得到化合物Ic，其中，酸性试剂优选盐酸二氧六环；
步骤3：在高温、催化剂存在下，将化合物Ic与N-碘代丁二酰亚胺反应得到化合物Id，其中，高温条件优选70℃，催化剂优选对甲苯磺酸；
步骤4：在高温、碱性试剂和催化剂存在下，将化合物Id与一氧化碳反应得到化合物Ie，其中，高温条件优选50℃，碱性试剂优选N,N-二异丙基乙胺，催化剂优选1,1'-双二苯基膦二茂铁二氯化钯；
步骤5：在0℃条件下，将化合物Ie与三氯乙酰基异氰酸酯反应得到化合物If；
步骤6：在0℃条件下，将化合物If与氨的甲醇溶液反应得到化合物Ig；
步骤7：在高温、碱性条件下，将化合物Ig与三氯氧磷反应得到化合物I，其中，高温条件优选100℃，碱性试剂优选N,N-二异丙基乙胺；
步骤8：在0℃条件下，将化合物I与化合物
Figure PCTCN2022111402-appb-000030
在碱性试剂存在下进行取代反应，得到化合物Ik，其中，碱性试剂优选N,N-二异丙基乙胺；
步骤9：在高温、碱性试剂存在下，将化合物Ik与化合物HY-R 1进行取代反应，得到化合物Ij，其中，高温条件优选90℃，碱性试剂优选N,N-二异丙基乙胺；
步骤10：在高温、碱性试剂和催化剂存在下，将化合物Ij与化合物
Figure PCTCN2022111402-appb-000031
进行偶联反应，得到通式(I)化合物，其中，高温条件优选100℃，碱性试剂优选碳酸铯，催化剂优选1,1'-双二苯基膦二茂铁二氯化钯催化剂。
其中，环A、R 1、R 2、R 3和Y如权利要求1所定义。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用1100Series LC/MSD Trap(ESI)质谱仪(生产商：Agilent)。
GC-MS测定使用GCMS-QP2010SE。
制备液相使用lc3000高效液相色谱仪以及lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为Daisogel C18 10μm 60A(20mm×250mm)。
HPLC的测定使用岛津LC-20AD高压液相色谱仪(Agilent TC-C18 250×4.6mm 5μm色谱柱)和岛津LC-2010AHT高压液相色谱仪(Phenomenex C18 250×4.6mm 5μm色谱柱)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京耦合、Sigma、百灵威、易世明、上海书亚、伊诺凯、南京药石、安耐吉化学等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
微波反应使用CEM Discover SP型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚、乙酸乙酯和二氯甲烷体系，C：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
实施例1：5-乙炔基-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-(4,7-二氮杂螺[2.5]辛烷-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(1)的制备
Figure PCTCN2022111402-appb-000032
步骤1：(溴乙炔基)三异丙基硅烷(1b)的制备。
于室温，向干燥的250mL三口烧瓶中依次加入乙炔基三异丙基硅烷1a(5.00g，27.4mmol)，丙酮(100mL)，硝酸银(4.66g，27.4mmol)，氮气保护下分批次加入N-溴代丁二酰亚胺(5.86g，32.9mmol)，室温搅拌反应2小时。反应结束后，反应液加入冰水淬灭，石油醚萃取，干燥，过滤，滤液减压浓缩，得无色油状标题化合物1b，6.00g，收率84.0％。
GC-MS:m/z 261.2[M+H] +。
步骤2：8-((三异丙基甲硅烷基)乙炔基)萘-1,3-二酚(1d)的制备。
于室温，将萘-1,3-二酚1c(5.00g，31.3mmol)和化合物1b(9.79g，37.5mmol)加入到干燥的250mL三口烧瓶中，加入1,4-二氧六环(75mL)，氮气保护下加入二氯(对-甲异丙苯)钌(II)二聚体(1.91g，3.12mmol)和醋酸钾(6.13g，62.5mmol)，升温至110℃搅拌反应12小时。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝3：1)，得淡棕色固体状标题化合物1d，5.80g，收率54.6％。
LC-MS:m/z 340.9[M+H] +。
步骤3：3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-酚(1e)的制备。
于室温，将化合物1d(200mg，0.588mmol)溶于二氯甲烷(5mL)，加入到50mL干燥的三口瓶中，加入N,N-二异丙基乙胺(228mg，1.77mmol)，氮气保护下，于0℃滴加溴甲基甲基醚(110mg，0.880mmol)，滴加完后0℃反应半小时。反应结束后，加入冰水淬灭，二氯甲烷萃取，干燥，过滤，滤液减压浓缩，残余物柱层析纯化(流动相：石油醚：乙酸乙酯＝30：1)得淡黄色油状标题化合物1e，200mg，收率88.5％。
LC-MS:m/z 385.0[M+H] +。
步骤4：3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基三氟甲磺酸(1f)的制备。
于室温，将化合物1e(190mg，0.495mmol)溶于二氯甲烷(5mL)，加入到50mL干燥的三口瓶中，加入N,N-二异丙基乙胺(191mg，1.48mmol)，氮气保护下，于-40℃滴加三氟甲磺酸酐(209mg，0.741mmol)，滴加完后-40℃反应半小时。反应结束后，加入冰水淬灭，二氯甲烷萃取，干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得淡黄色油状标题化合物1f，150mg，收率58.8％。
LC-MS:m/z 516.9[M+H] +。
步骤5：三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)硅烷(1g)的制备。
于室温，向干燥的50mL三口烧瓶中依次加入化合物1f(200mg，0.388mmol)，甲苯(5mL)，联硼酸频那醇酯(197mg，0.776mmol)，氮气保护下，加入醋酸钾(133mg，1.36mmol)和1,1'-双二苯基膦二茂铁二氯化钯(28.0mg，0.0383mmol)，升温至110℃搅拌反应12小时。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝30：1)，得淡黄色固体状标题化合物1g，100mg，收率52.1％。
LCMS:m/z 495.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.69-7.65(m,2H),7.45(d,J＝2.8Hz,1H),7.36-7.31(m,2H),5.27(s,2H),3.49(s,3H),1.42(s,12H),1.15-1.13(m,21H)。
步骤6：(2-氯-3-氟吡啶-4-基)氨基甲酸叔丁酯(1i)的制备。
于室温，将2-氯-3-氟异烟酸1h(18.0g，103mmol)、叔丁醇(130mL)、甲苯(130mL)、三乙胺(31.2g，309mmol)加到三口瓶中，氮气保护，升温至100℃，反应0.5h，降至室温，滴加叠氮磷酸二苯酯(42.4g，155mmol)，滴加完后，升温至100℃，继续反应3h。反应结束后，反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得棕色油状标题化合物1i，25g，收率：98％。
LC-MS：m/z 247[M+H]+。
步骤7：2-氯-3-氟吡啶-4-胺(1j)的制备。
于室温，将化合物1i(25.0g，101mmol)、盐酸/1,4-二氧六环(102mL，404mmol，4N)、乙腈(250mL)加到反应瓶中，室温搅拌反应16小时。反应结束后，反应液抽滤，收集滤饼，滤饼用饱和碳酸钠(100mL)游离，用乙酸乙酯(100mL x 3)萃取，合并的有机相用无水硫酸钠干燥，过滤、减压浓缩，得黄棕色固体状标题化合物1j，8.0g，收率：53.7％。
LC-MS：m/z 147[M+H]+。
步骤8：2-氯-3-氟-5-碘吡啶-4-胺(1k)的制备。
于室温，将化合物1j(7.0g，47.9mmol)、N-碘代丁二酰亚胺(12.95g，57.5mmol)，对甲苯磺酸(413mg，2.40mmol)、乙腈(70mL)加到反应瓶中，70℃搅拌反应16小时。反应结束后，反应液加入饱和碳酸钠(150mL)，用乙酸乙酯(100mL x 3)萃取，合并有机相，饱和亚硫酸钠(150mL)洗涤有机相，无水硫酸钠干燥，过滤、减压浓缩，得浅棕色固体状标题化合物1k，12.0g，收率：92.3％。
LC-MS：m/z 273[M+H]+。
步骤9：4-氨基-6-氯-5-氟烟酸甲酯(1l)的制备。
于室温，将化合物1k(10.0g，36.8mmol)、1,1'-双二苯基膦二茂铁二氯化钯(1.34g，1.8mmol)、N,N-二异丙基乙胺(14.2g，110mmol)、甲醇(100mL)加入封管中，通一氧化碳，0.4MPa，50℃搅拌反应16小时。反应结束后，反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1：5)， 得深棕色固体状标题化合物1l，6.0g，收率：80％。
LC-MS：m/z 205[M+H]+。
步骤10：6-氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)烟酸甲酯(1m)的制备。
于室温，将化合物1l(5.0g，24.5mmol)溶于四氢呋喃(50mL)中，0℃滴加三氯乙酰基异氰酸酯(6.90g，36.8mmol)，室温搅拌反应16小时。反应结束后，反应液用甲基叔丁基醚(100mL)打浆，抽滤，干燥滤饼，得浅棕色固体状标题化合物1m，3.5g，收率：36.5％。
LC-MS：m/z 394[M+H]+。
步骤11：7-氯-8-氟吡啶并[4,3-d]嘧啶-2,4-二醇(1n)的制备。
于室温，将化合物1m(3.50g，8.90mmol)溶于甲醇(35mL)中，0℃滴加氨的甲醇溶液(3.5mL，7N)，室温搅拌反应16小时。反应结束后，反应液甲基叔丁基醚(100mL)打浆，抽滤，干燥滤饼，得浅棕色固体状标题化合物1n，1.4g，收率：73.68％。
LC-MS：m/z 216[M+H]+。
步骤12：2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(1o)的制备。
于室温，将化合物1n(1.00g，4.65mmol)溶于三氯氧磷(5.0mL)中，0℃滴加N,N-二异丙基乙胺(3.00g，23.3mmol)，90℃搅拌反应16小时。反应结束后，反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得浅黄色固体状标题化合物1o，500mg，收率：43.1％。
LC-MS：m/z 251[M+H]+。
步骤13：7-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯(1p)的制备。
于室温，化合物1o(500mg，1.99mmol)溶于四氢呋喃(5.0mL)中，0℃加入4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯(422mg,1.99mmol)，滴加N,N-二异丙基乙胺(515mg，3.98mmol)，室温反应2小时。反应结束后，反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝1：4)，得浅黄色固体状标题化合物1p，500mg，收率：58％。
LC-MS：m/z 428[M+H]+。
步骤14：叔丁基7-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-4-羧酸酯(1r)的制备。
于室温，化合物1p(500mg,1.17mmol)溶于1,4-二氧六环(5.0mL)中，室温加入((2R,7aS)-2-氟四氢氢-1H-吡咯里嗪-7a(5H)-基)甲醇(372mg,2.34mmol),滴加N,N-二异丙基乙胺(302mg，2.34mmol)，80℃搅拌反应16小时。反应结束后，反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷：甲醇＝1：5)，得浅黄色固体状标题化合物1r，500mg，收率：77.6％。
LC-MS：m/z 551[M+H]+。
步骤15：7-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯(1s)的制备。
于室温,化合物1r(200mg,0.364mmol)溶于1,4-二氧六环(2.0mL)和水(0.2mL)中，室温加入三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)硅烷(180mg,0.364mmol)，1,1'-双二苯基膦二茂铁二氯化钯(26.6mg，0.0364mmol)，碳酸铯(237mg，0.727mmol)，氮气保护，100℃反应过夜。反应结束后，反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷：甲醇＝1：5)，得浅黄色固体标题化合物1s，150mg，收率：46.9％。
LC-MS：m/z 883[M+H]+。
步骤16：4-(8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-(4,7-二氮杂螺[2.5]辛烷-7-基)吡啶并[4,3-d]嘧啶-7-基)-5-((三异丙基硅基)乙炔基)萘-2-醇(1t)的制备。
于室温，化合物1s(150mg,0.170mmol)溶于乙腈(2.0mL)中，室温加入盐酸/1,4-二氧六环(0.227mL，0.907mmol，4N)溶液，室温反应1h。反应结束后，减压浓缩，得浅黄色固体标题化合物1t，100mg，收率：79.7％。
LC-MS：m/z 739[M+H]+。
步骤17：5-乙炔基-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-(4,7-二氮杂螺[2.5]辛烷-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(1)的制备。
于室温，化合物1t(100mg,0.136mmol)溶于N,N-二甲基甲酰胺(1.0mL)中，室温加入氟化铯(82.35mg，0.542mmol)溶液，室温反应48h，反应结束后，抽滤，母液残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-100％)，得白色固体状标题化合物1，22mg，收率：27.8％。
LC-MS：m/z 583.0[M+H] +。
1H NMR(400MHz,CD 3OD)δ9.00-8.96(s,1H),7.82(d,J＝8.2Hz,1H),7.51(m,1H),7.42-7.37(m,1H),7.33(d,J＝2.5Hz,1H),7.17(d,J＝2.5Hz,1H),5.40-5.26(m,1H),4.35-4.24(m,2H),4.17-4.09(m,2H),4.01-3.96(m,2H),3.42-3.34(m,1H),3.31-3.22(m,2H),3.13(m,2H),3.09-3.03(m,2H),2.42-2.25(m,2H),2.19-2.14(m,1H),2.07-2.00(m,2H),1.95-1.85(m,1H),0.73-0.67(m,4H)。
实施例2：4-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-醇(2)的制备
Figure PCTCN2022111402-appb-000033
与实施例1的制备方法相同，除了用2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯替代4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯，制得标题化合物2。
LC-MS：m/z 583.0[M+H] +。
1H NMR(400MHz,CD 3OD)δ9.15(s,1H),7.84(d,J＝8.2Hz,1H),7.53(d,J＝7.0Hz,1H),7.43-7.39(m,1H),7.35(d,J＝2.5Hz,1H),7.22-7.15(m,1H),5.39-5.25(m,1H),5.23-4.99(m,2H),4.38-4.20(m,4H),3.48-3.44(m,1H),3.29-3.18(m,5H),3.06-3.00(m,1H),2.35-2.26(m,2H),2.16-2.07(m,3H),2.04-1.85(m,5H)。
实施例3：4-(4-((1R,5S,8R)-8-氨基-3-氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-醇(3)的制备
Figure PCTCN2022111402-appb-000034
与实施例1的制备方法相同，除了用3-氮杂双环[3.2.1]辛基-8-基)氨基甲酸叔丁酯替代4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯，制得标题化合物3。
LC-MS：m/z 597.0[M+H] +。
1H NMR(300MHz,CD 3OD)δ8.98(s,1H),7.81(d,J＝5.4Hz,1H),7.50(d,J＝1.5Hz,1H),7.39(d,J＝6.0Hz,1H),7.32(d,J＝2.1Hz,1H),7.16(d,J＝2.1Hz,1H),5.36-5.23(m,1H),4.78-4.67(m,2H),4.32-4.20(m,2H),3.68-3.60(m,2H),3.34(s,1H),3.23-3.18(m,2H),3.04-2.97(m,2H),2.37-2.11(m,5H),2.01-1.87(m,6H),1.61-1.55(m,2H)。
实施例4：5-乙炔基-4-(8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)-4-(3,9-二氮螺[5.5]十一烷-3-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(4)的制备
Figure PCTCN2022111402-appb-000035
与实施例1的制备方法相同，除了用3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯替代4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯，制得标题化合物4。
LC-MS：m/z 625.0[M+H] +。
1H NMR(300MHz,CD 3OD)δ8.97(s,1H),7.80(d,J＝5.7Hz,1H),7.48(d,J＝5.1Hz,1H),7.3(t,J＝6.0Hz,1H),7.30(d,J＝1.8Hz,1H),7.16(d,J＝2.1Hz,1H),5.36-5.22(m,1H),4.31-4.20(m,2H),4.06-4.03(m,3H),3.27-3.13(m,4H),3.04-2.97(m,2H),2.92-2.89(m,4H),2.36-2.18(m,2H),2.15-2.09(m,1H),2.01-1.86(m,3H),1.80-1.77(m,4H),1.67-1.64(m,4H)。
实施例5：4-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-8-氟-2-((2R,7aS)-2-氟四氢-1H-吡咯里嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-醇(5)的制备
Figure PCTCN2022111402-appb-000036
与实施例1的制备方法相同，除了用3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯替代4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯，制得标题化合物5。
LC-MS：m/z 568.9[M+H] +。
1H NMR(300MHz,CD 3OD)δ9.38(s,1H),7.81(d,J＝6.0Hz,1H),7.49(d,J＝5.4Hz,1H),7.40-7.32(m,2H),7.16(d,J＝1.8Hz,1H),5.37-5.23(m,1H),4.37-4.23(m,5H),3.92(d,J＝4.5Hz,2H),3.23-3.18(m,3H),3.05-2.98(m,2H),2.83-2.77(m,1H),2.37-2.10(m,4H),2.02-1.87(m,3H),1.73(d,J＝7.2Hz,1H)。
本发明化合物的生物学评价
试验例1：本发明化合物对KRAS-G12D-CRAF结合的抑制水平
通过检测化合物对RAS蛋白和下游激酶RAF结合的抑制水平，评估化合物的生化活性。
检测KRAS-G12D/cRAF结合试剂盒，购自Cisbio，货号63ADK000CB21PEG， 按照试剂盒的说明配制所需的缓冲液及反应液。用DMSO稀释化合物，起始浓度10μM，10个浓度梯度，3倍稀释。用ECHO移液器(Labcyte)吸取0.1μL化合物至384孔板(Corning，3657)内；加入5μL的Tag2-KRASG12D-GTP混合液，1000rpm，离心1分钟。再加入5μL Tag1-cRAF至反应板内，1000rpm离心1min。将反应板置于25℃，孵育15分钟。然后再加入10μL anti-Tag1-Tb3和anti-Tag2-XL665混合物，1000rpm离心1分钟，4℃孵育3小时。采用Envision(Perkin Elmer，2104)读取665/615nm波长下的荧光强度比值。通过化合物组与空白对照组的荧光强度比值进行对比，计算化合物在各浓度下的抑制率。利用GraphPad 8.0进行非线性拟合，计算化合物的IC 50数值，抑制率公式如下：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))，
其中：X为化合物浓度的log值，Y为665/615波长下荧光强度比值，Top和Bottom为曲线最高及最低平台的Y值；HillSlope为希尔常数。
在表1中，A是指化合物对KRAS-G12D-CRAF结合抑制活性的IC 50<25nM；B是指IC 50＝25nM至500nM；C是指IC 50>500nM。
表1.本发明化合物对KRAS-G12D-CRAF结合的抑制活性
化合物编号 IC 50(nM)
实施例1 A
实施例2 A
实施例3 A
实施例4 B
实施例5 A
以上数据结果表明，本发明化合物对KRAS-G12D-CRAF结合具有显著抑制作用。
试验例2：本发明化合物抑制KRAS-G12D介导的ERK磷酸化
KRAS-G12D突变的AGS细胞(CRL-1739)来自ATCC，采用F-12K培养基(Gibco，30-2004)+10％FBS(Ausgenex，FBS500-S)+1％青霉素-链霉素(Gibco，15140-122)进行传代培养。5,000个AGS细胞接种在384孔板中(Corning，3657)，置于37℃，5％的培养箱内过夜，使细胞贴壁。第二天，加入实验待测的化合物，化合物用DMSO溶解，稀释，实验起始浓度从10mM开始，3倍稀释，设置10个浓度梯度，每个梯度2个复孔。将细胞板放置培养箱中，37℃，5％CO2。3小时后，去除培养基，加入8％的固定液(Solarbio，P1112)，室温孵育30min。然后，PBS清洗2次，Odyssey Blocking Buffer(LI-COR，927-40000)室温封闭1h；PBS清洗，孵育一抗(phospho-p44/42MAPK(T202/Y204)Rabbit mAb，CST，4370S)，4℃过夜；PBST清洗3次，室温孵育二抗(Goat anti-Rabbit IgG，Li-Cor，926-32211)1h；将培养板倒置，1000转/分，离心1分钟，采用Odyssey CLx(Li-Cor)红外成像系统进行扫描孔板。GAPDH(D4C6R mouse mAb,CST,97166S)作为参照蛋 白，进行蛋白均一化。使用XL-Fit软件进行数据分析，通过非线性拟合，得出化合物浓度与效应关系，利用以下公式计算化合物对细胞pERK抑制的IC 50值：Y＝Bottom+(Top-Bottom)/(1+10((LogIC 50-X)*Hilislope))
X：化合物浓度的对数；Y：平均值(相对pERK)；Top和Bottom为曲线最高及最低平台期的Y值；Hillslope为希尔常数。
在表2中，A是指化合物对KRAS-G12D介导的ERK磷酸化抑制活性的IC 50<25nM；B是指IC 50＝25nM至500nM；C是指IC 50>500nM。
表2.本发明化合物对KRAS-G12D介导的ERK磷酸化抑制活性
化合物编号 IC 50(nM)
实施例1 A
实施例2 A
实施例3 C
实施例5 B
以上数据结果表明，本发明化合物对KRAS-G12D下游的pERK具有显著抑制作用。

Claims (13)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2022111402-appb-100001
    其中：
    环A选自7-12元含氮桥环、4-12元杂环基、环烷基、芳基和杂芳基；其中所述7-12元含氮桥环、4-12元杂环基、环烷基、芳基和杂芳基各自独立地任选地被一个或多个R 5取代；所述7-12元含氮桥环不为
    Figure PCTCN2022111402-appb-100002
    所述4-12元杂环基优选为7-12元螺杂环基；
    Y选自键、O、S、SO、SO 2和NR 4；
    R 1选自氢、-N(R 4) 2、杂环基、C 1-C 6烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-LN(R 4) 2、-L-NHC(＝NH)NH 2、-L-C(＝O)N(R 4) 2、-L-C 1-C 6卤代烷基、-L-OR 4、-L-(CH 2OR 4)(CH 2) nOR 4、-L-NR 4C(＝O)芳基、-L-COOH和-L-C(＝O)OC 1-C 6烷基，其中-L-NR 4C(＝O)-芳基的芳基部分和-L-杂环基的杂环基部分和-L-环烷基的环烷基部分任选地被一个或多个R 5取代，并且其中-L-芳基和-L-杂芳基的芳基或杂芳基任选地被一个或多个R 6取代；
    每个L独立地为任选被一个或多个羟基、C 1-C 4羟烷基或杂芳基取代的C 1-C 4亚烷基；
    R 2为芳基或杂芳基；其中所述芳基或杂芳基各自独立地任选被一个或多个R 7取代；
    R 3选自氢、卤素和C l-C 6烷基；
    每个R 4独立地为氢或C l-C 3烷基；
    每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3 烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；
    每个Q独立地为键或O；
    每个R 6独立地选自卤素、羟基、HC(＝O)-、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、C 1-C 4羟烷基和-N(R 4) 2；且
    每个R 7独立地选自卤素、氰基、羟基、C 1-C 4烷基、-S-C l-C 3烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4羟基炔基、C l-C 3氰基烷基、三唑基、C l-C 3卤代烷基、-O-C l-C 3卤代烷基、-S-C l-C 3卤代烷基、C l-C 3烷氧基、羟基C l-C 3烷基、-CH 2C(＝O)N(R 4) 2、-C 3-C 4炔基(NR 4) 2、-N(R 4)) 2、氘代C 2-C 4炔基、(C l-C 3烷氧基)卤代C l-C 3烷基-和C 3-C 6环烷基，其中所述C 3-C 6环烷基任选被一个或多个卤素或C l-C 3烷基取代。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    环A选自7-12元含氮桥环、7-12元螺杂环基、C 3-C 12环烷基、C 6-C 14芳基和5-14元杂芳基；其中所述7-12元含氮桥环、7-12元螺杂环基、C 3-C 12环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地任选地被一个或多个R 5取代；
    所述7-12元含氮桥环优选选自
    Figure PCTCN2022111402-appb-100003
    Figure PCTCN2022111402-appb-100004
    更优选
    Figure PCTCN2022111402-appb-100005
    Figure PCTCN2022111402-appb-100006
    所述7-12元螺杂环基优选选自
    Figure PCTCN2022111402-appb-100007
    Figure PCTCN2022111402-appb-100008
    更优选
    Figure PCTCN2022111402-appb-100009
    每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、 C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；且
    每个Q独立地为键或O。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y选自键、O、S、SO和SO 2，优选O和S。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 1选自-L-杂环基、-L-芳基、-L-杂芳基、-L-环烷基、-LN(R 4) 2、-L-NHC(＝NH)NH 2、-LC(＝O)N(R 4) 2、-L-C 1-C 6卤代烷基、-L-OR 4、-L-(CH 2OR 4)(CH 2) nOR 4、-L-NR 4C(＝O)-芳基、-L-COOH和-LC(＝O)OC 1-C 6烷基，其中-L-NR 4C(＝O)-芳基的芳基部分和-L-杂环基的杂环基部分和-L-环烷基的环烷基部分任选地被一个或多个R 5取代，并且其中-L-芳基和-L-杂芳基的芳基或杂芳基任选地被一个或多个R 6取代，优选-L-杂环基、-L-环烷基、-L-C 1-C 6卤代烷基；所述杂环基特别地为6-14元稠杂环基，更特别地选自
    Figure PCTCN2022111402-appb-100010
    Figure PCTCN2022111402-appb-100011
    甚至更特别地为
    Figure PCTCN2022111402-appb-100012
    每个L独立地为任选被一个或多个羟基、C 1-C 4羟烷基或杂芳基取代的C 1-C 4亚烷基；优选地，每个L独立地为C 1-C 4亚烷基；
    每个R 4独立地为氢或C l-C 3烷基；
    每个R 5独立地选自卤素、羟基、C l-C 3羟烷基、C l-C 3烷基、C l-C 3卤代烷基、C l-C 3烷氧基、氰基、-Q-苯基、-Q-苯基SO 2F、-NHC(＝O)苯基、-NHC(＝O)苯基SO 2F、C l-C 3烷基取代的吡唑基、芳基-C l-C3烷基-、叔丁基二甲基甲硅烷氧基CH 2-、-N(R 4) 2、(C l-C 3烷氧基)C l-C 3烷基-、(C l-C 3烷基)C(＝O)、氧代基、(C l-C 3卤代烷基)C(＝O)-,-SO 2F、(C l-C 3烷氧基)C l-C 3烷氧基、-CH 2OC(＝O)N(R 4) 2、-CH 2NHC(＝O)OC 1-C 6烷基、-CH 2NHC(＝O)N(R 4) 2、-CH 2NHC(＝O)C 1-C 6烷基、-CH 2(吡唑基)、-CH 2NHSO 2C 1-C 6烷基、-CH 2OC(＝O)三环基、-OC(＝O)N(R 4) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基(C l-C 3烷基)N(CH 3)) 2、-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基、-OC(＝O)杂环基和-CH 2杂环基，其中-NHC(＝O)苯基或-OC(＝O)NH(C l-C 3烷基)O(C l-C 3烷基)苯基的苯基任选地被-C(＝O)OH或OH取代并且其中-CH 2杂环基的杂环基任选地被一个或多个氧代基取代；优选地，每个R 5独立地为卤素；
    每个Q独立地为键或O；且
    每个R 6独立地选自卤素、羟基、HC(＝O)-、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4卤代烷基、C 1-C 4羟烷基和-N(R 4) 2。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 2为C 6-C 14芳基或5-14元杂芳基，优选C 6-C 10芳基，更优选苯基或萘基；其中所述芳基或杂芳基各自独立地任选被一个或多个R 7取代，且
    每个R 7独立地选自卤素、氰基、羟基、C 1-C 4烷基、-S-C l-C 3烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4羟基炔基、C l-C 3氰基烷基、三唑基、C l-C 3卤代烷基、-O-C l-C 3卤代烷基、-S-C l-C 3卤代烷基、C l-C 3烷氧基、羟基C l-C 3烷基、-CH 2C(＝O)N(R 4) 2、-C 3-C 4炔基(NR 4) 2、-N(R 4)) 2、氘代C 2-C 4炔基、(C l-C 3烷氧基)卤代C l-C 3烷基-和C 3-C 6环烷基，其中所述C 3-C 6环烷基任选被一个或多个卤素或C l-C 3烷基取代；优选地，每个R 7独立地为C 2-C 4炔基、氰基或羟基。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 3选自氢、卤素和C l-C 3烷基，优选卤素。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、 对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2022111402-appb-100013
    环A选自
    Figure PCTCN2022111402-appb-100014
    R 3为卤素；
    每个R 5独立地为卤素；
    每个R 7独立地为C 2-C 4炔基、氰基或羟基；
    m为0、1、2或3；且
    n为0、1、2或3。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，所述化合物选自：
    Figure PCTCN2022111402-appb-100015
  9. 一种制备根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
    Figure PCTCN2022111402-appb-100016
    在高温、碱性试剂和催化剂存在下，将化合物Ij与化合物
    Figure PCTCN2022111402-appb-100017
    进行偶联反应，得到通式(I)化合物，其中，高温条件优选100℃，碱性试剂优选碳酸铯，催化剂优选1,1'-双二苯基膦二茂铁二氯化钯；
    其中，环A、R 1、R 2、R 3和Y如权利要求1所定义。
  10. 一种药物组合物，其含有根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体。
  11. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求10所述的药物组合物在制备KRAS-G12D抑制剂中的用途。
  12. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求10所述的药物组合物在制备预防和/或治疗与KRAS-G12D活性相关的疾病的药物中的用途。
  13. 根据权利要求12所述的用途，其中所述与KRAS-G12D活性相关的疾病选自胰腺导管癌、结直肠癌、肾癌和肺癌。
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024119277A1 (en) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Kras inhibitors and pharmaceutical uses thereof
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080593A1 (en) 2023-10-09 2025-04-17 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
WO2025080592A1 (en) 2023-10-09 2025-04-17 Incyte Corporation Combination comprising a kras g12d inhibitor and an egfr inhibitor for use in the treatment of cancer
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2021106231A1 (en) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. A compound having inhibitory activity against kras g12d mutation
WO2022042630A1 (en) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022061251A1 (en) * 2020-09-18 2022-03-24 Plexxikon Inc. Compounds and methods for kras modulation and indications therefor
WO2022098625A1 (en) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Kras g12d inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104470921B (zh) * 2013-05-17 2017-05-03 上海恒瑞医药有限公司 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
CR20210307A (es) * 2017-12-21 2021-07-27 Boehringer Ingelheim Int NUEVAS PIRIDOPIRIMIDINONAS SUSTITUIDAS CON BENCILAMINO Y DERIVADOS COMO INHIBIDORES DE SOS1 (Divisional 2020-312)
JP7349456B2 (ja) * 2018-07-03 2023-09-22 ジエンス ヘンルイ メデイシンカンパニー リミテッド ピリドピリミジン誘導体、その調製方法およびその医学的使用
US11648221B2 (en) * 2019-09-27 2023-05-16 Emory University KRAS agonists, pharmaceutical compositions, and uses in managing cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2021106231A1 (en) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. A compound having inhibitory activity against kras g12d mutation
WO2022042630A1 (en) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022061251A1 (en) * 2020-09-18 2022-03-24 Plexxikon Inc. Compounds and methods for kras modulation and indications therefor
WO2022098625A1 (en) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Kras g12d inhibitors

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024119277A1 (en) * 2022-12-08 2024-06-13 Risen (Suzhou) Pharma Tech Co., Ltd. Kras inhibitors and pharmaceutical uses thereof
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080593A1 (en) 2023-10-09 2025-04-17 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
WO2025080592A1 (en) 2023-10-09 2025-04-17 Incyte Corporation Combination comprising a kras g12d inhibitor and an egfr inhibitor for use in the treatment of cancer
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors

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