WO2023020347A1 - Composé de pyrimidopyridine ainsi que son procédé de préparation et utilisation médicale s'y rapportant - Google Patents

Composé de pyrimidopyridine ainsi que son procédé de préparation et utilisation médicale s'y rapportant 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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alkyl
aryl
phenyl
nhc
heterocyclyl
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PCT/CN2022/111402
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English (en)
Chinese (zh)
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闫旭
宗利斌
刘国标
陈彬
尚飞
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华润医药研究院（深圳）有限公司
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Priority to CN202280005876.8A priority Critical patent/CN116669740A/zh
Publication of WO2023020347A1 publication Critical patent/WO2023020347A1/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
    • A61K31/519—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.

Abstract

L'invention concerne un composé de pyrimidopyridine représenté par la formule générale (I), un procédé de préparation s'y rapportant, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de KRAS-G12D. Le composé et la composition pharmaceutique contenant le composé peuvent être utilisés dans le traitement et/ou la prévention de maladies associées à l'activité KRAS-G12D, tels que le cancer du conduit pancréatique, le cancer colorectal, le cancer du rein et le cancer du poumon.
PCT/CN2022/111402 2021-08-16 2022-08-10 Composé de pyrimidopyridine ainsi que son procédé de préparation et utilisation médicale s'y rapportant WO2023020347A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques

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WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
WO2022042630A1 (fr) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Composés hétéroaryle, leurs procédés de préparation et leurs utilisations
WO2022061251A1 (fr) * 2020-09-18 2022-03-24 Plexxikon Inc. Composés et procédés pour la modulation de kras et leurs indications
WO2022098625A1 (fr) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d

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Publication number Priority date Publication date Assignee Title
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2021106231A1 (fr) * 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. Composé ayant une activité inhibitrice contre la mutation kras g12d
WO2022042630A1 (fr) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Composés hétéroaryle, leurs procédés de préparation et leurs utilisations
WO2022061251A1 (fr) * 2020-09-18 2022-03-24 Plexxikon Inc. Composés et procédés pour la modulation de kras et leurs indications
WO2022098625A1 (fr) * 2020-11-03 2022-05-12 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques

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