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WO2023025116A1 - Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine Download PDF

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Publication number
WO2023025116A1
WO2023025116A1 PCT/CN2022/114084 CN2022114084W WO2023025116A1 WO 2023025116 A1 WO2023025116 A1 WO 2023025116A1 CN 2022114084 W CN2022114084 W CN 2022114084W WO 2023025116 A1 WO2023025116 A1 WO 2023025116A1
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Prior art keywords
alkyl
group
cycloalkyl
heteroaryl
pharmaceutically acceptable
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PCT/CN2022/114084
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English (en)
Chinese (zh)
Inventor
陈友喜
黄贤贵
龚亮
李文朋
毛文涛
叶成
钱文建
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Priority to CN202280006450.4A priority Critical patent/CN116323625A/zh
Publication of WO2023025116A1 publication Critical patent/WO2023025116A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
    • C07C53/16—Halogenated acetic acids
    • C07C53/18—Halogenated acetic acids containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the invention relates to a heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a K-Ras GTPase inhibitor.
  • RAS represent a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal development or physiological conditions, RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration and differentiation. RAS functions as a molecular switch, the on/off state of RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When the RAS contains bound GDP it is dormant or resting or off and is "inactive". When cells are exposed to certain growth-promoting stimuli in response, RAS is induced to convert bound GDP to GTP.
  • GTPase activating proteins GTPase activating proteins
  • RAS proteins contain a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTPase reaction). It also includes a C-terminal extension known as the CAAX box, which can be post-translationally modified and targets the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop).
  • P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein, since this dynamic part switches between the resting and loaded states This capability is often expressed as a "spring-loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the ⁇ -phosphate of GTP, which maintains the switch I and switch II regions in their active conformations, respectively. Following hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.
  • KRAS mutations are prevalent in the three most deadly cancer types in the United States: pancreatic (95%), colorectal (45%), and lung (25%), including cardiac myxoma, prostate, hepatocellular carcinoma, chondrosarcoma, Seminoma, malignant melanoma, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B KRAS mutations are also found in other cancer types, including lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, and testicular germ cell carcinoma, but rarely in breast, ovarian, and brain cancers ( ⁇ 2 %).
  • KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D.
  • the increased mutation frequency of specific alleles is mostly from the classic smoking-induced mutations (G:C to T:A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutation.
  • KRAS mutations including G12C
  • other known driver oncogenic mutations in NSCLC including EGFR, ALK, ROS1, RET, and BRAF
  • KRAS mutations often co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.
  • KRas G12D inhibitors At present, there is fierce competition for the clinical development of KRas G12D inhibitors at home and abroad. Among them, the KRas G12D inhibitor MRTX-1133 developed by Mirati Therapeutics Inc. has entered the preclinical stage and is used to treat diseases such as colorectal tumors, non-small cell lung cancer and pancreatic cancer. . There are currently a handful of published patent applications for KRas G12D inhibitors, including WO2021041671 by Mirati Therapeutics Inc. Although some progress has been made in the research and application of KRas G12D inhibitors, there is still huge room for improvement, and it is still necessary to continue research and development of new KRas G12D inhibitors.
  • the object of the present invention is to provide a heterocyclic derivative represented by general formula (I), or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • Ring A is a 4- to 12-membered heterocyclic group, wherein the heterocyclic group contains at least one nitrogen atom;
  • Ring B is aryl, heteroaryl, heterocyclyl or cycloalkyl
  • Q is N or CR a ;
  • R a is a hydrogen atom, halogen, hydroxyl, amino, alkyl, alkoxy or cyano; wherein the alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkane Substituents of radicals and alkoxy groups;
  • L is a bond, -O- or -NR b ;
  • R b is a hydrogen atom or an alkyl group
  • R c is absent or a hydrogen atom
  • Each of L 1 is independently a bond or -C 1 -C 6 alkylene, wherein said alkylene is optionally further substituted by one or more R A ;
  • RA is each independently a hydrogen atom, halogen, hydroxyl or hydroxymethyl
  • two RAs connected to the same carbon atom form a cycloalkyl group together with the connected carbon atoms; preferably cyclopropyl;
  • R 2 are the same or different, each independently a hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further selected by one or more selected from halogen, hydroxyl , cyano and alkoxy substituents;
  • any two R 2 form a cycloalkyl or heterocyclic group together with the atoms they are connected to;
  • R 2 and R a form a 6-8 membered heterocyclic group together with the atoms they are connected to; the heterocyclic group is optionally further substituted by one or more R B ;
  • R B is a hydrogen atom, halogen, alkyl, deuterated alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkyl and Substituents of alkoxy groups are substituted;
  • RB is preferably a hydrogen atom, methyl or deuteromethyl;
  • R 2 and R 3 together form a heteroaryl or heterocyclic group with the atoms they are connected to;
  • R 4 are the same or different, each independently hydrogen atom, halogen, cyano, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring, wherein the alkyl , cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring optionally further substituted by one or more R C ;
  • two R 4 form a fused ring together with the same carbon atom to which they are attached; the fused ring is optionally further substituted by one or more R C ;
  • R 2 and R 4 together form a 6-8 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more R D ;
  • R D is a hydrogen atom, halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, alkyl and alkoxy Substituted by group; R D is preferably a hydrogen atom;
  • R 8 , R 9 and R 10 are each independently a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, Aryl or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, Carboxyl and carboxylate substituents are substituted;
  • each m is independently 0, 1, 2, 3 or 4;
  • each k is independently 0, 1, 2, 3 or 4;
  • r is each independently 0, 1 or 2.
  • heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof which are general formula ( The compound shown in II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • Ring C is each independently aryl, heteroaryl or fused ring
  • R 4 are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy, wherein the alkyl, cycloalkyl or alkoxy are optionally further selected from one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is preferably halogen, more preferably fluorine or chlorine;
  • each n is independently 0, 1, 2 or 3;
  • Ring A, W, R 1 to R 3 , R C , L, Q and m are defined as described in general formula (I).
  • heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof which are general formula ( Compounds shown in IV) or (V) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring C is each independently aryl, heteroaryl or fused ring
  • each n is independently 0, 1, 2 or 3;
  • Ring A, W, R 1 to R 3 , R C , L, Q and m are defined as described in general formula (I).
  • heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof which are general formula ( The compound shown in VI) or (VII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • Ring C is each independently aryl, heteroaryl or fused ring
  • R 4 are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy are optionally further selected by one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is preferably halogen, more preferably fluorine or chlorine;
  • RB is a hydrogen atom or a methyl group
  • each n is independently 0, 1, 2 or 3;
  • each p is independently 0, 1, 2 or 3;
  • Ring A, W, R 1 to R 3 , R C , L and Q are as defined in the general formula (I).
  • heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof which are general formula ( The compound shown in VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • Ring D is a fused ring
  • n 0, 1, 2 or 3;
  • Ring A, W, R 1 to R 3 , R C , L, Q and m are defined as described in general formula (I).
  • R 5 is a hydrogen atom or an alkyl group; wherein the alkyl group is preferably a methyl group;
  • R 3 is as described in the general formula (I).
  • R 3 is defined as described in general formula (VI).
  • heterocyclic derivatives described in general formula (VII) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof wherein:
  • R 3 is defined as described in general formula (VII)
  • R 3 is cycloalkyl, heteroaryl, -C(O)-heterocyclyl, -C(O)-heteroaryl, -(CH2)q-heterocyclyl, -(CH 2 )q-OR 5 Or -(CH2)q-NR 6 R 7 ; wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further replaced by one or more selected from alkyl, halogen, cycloalkyl and alkoxy Substituents are substituted;
  • R 5 is a hydrogen atom or an alkyl group; R 5 is preferably a hydrogen atom;
  • R 6 and R 7 are each independently an alkyl group, preferably a methyl group
  • q 0, 1 or 2.
  • heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) Class derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 3 is the following groups:
  • Q is CR a ;
  • R a is a hydrogen atom or a cyano group.
  • R 1 is -L 1 -heterocyclyl
  • halogen is preferably fluorine
  • heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) Class derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 is:
  • heterocyclic derivatives described in general formula (II), (III), (IV), (V), (VI) or (VII) or their stereoisomers Body, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is:
  • Naphthyl is preferred.
  • the compounds include, but are not limited to:
  • the present invention provides a pharmaceutical composition, which contains an effective dose of the general formula (I), (II), (III), (IV), (V), (VI), The compound described in (VII) or (VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or their combination.
  • the present invention provides a method for inhibiting KRas G12D enzyme, wherein said method comprises, administering to a patient a pharmaceutical composition, said pharmaceutical composition containing an effective dose of the general formula (I), (II) , (III), (IV), (V), (VI), (VII) or (VIII) compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and Pharmaceutical carrier, excipient or their combination.
  • the present invention also provides a compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer , a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating a disease mediated by a KRas G12D mutation, wherein the disease mediated by a KRas G12D mutation Cancer is preferred, wherein said cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine Carcinoma, cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblasto
  • the present invention provides a compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereo Isomers, tautomers or pharmaceutically acceptable salts thereof, or the use of pharmaceutical compositions thereof in the preparation of KRas G12D inhibitors.
  • Another aspect of the present invention relates to a method for preventing and/or treating diseases mediated by KRas G12D mutations, comprising administering to patients a therapeutically effective dose of the general formula (I), (II), (III), (IV) , (V), (VI), (VII) or (VIII) described compound or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also provides the compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, mutual Variant or pharmaceutically acceptable salt thereof
  • the cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, Cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, colorectal tumor, rectal cancer and lung cancer; wherein said lung cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer
  • the present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof
  • the present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof
  • the cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, Seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, colorectal tumors, rectal cancer and lung cancer;
  • the present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof
  • the compounds or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are used as KRas G12D inhibitors.
  • the present invention also provides a method for preventing and/or treating cancer, which comprises administering the general formula (I), (II), (III), (IV), (V), (VI), (VII) to a subject in need Or the compound described in (VIII) or its stereoisomer, tautomer or its pharmaceutically acceptable salt
  • the described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present invention also provides a method for inhibiting KRas G12D in a subject, comprising administering general formula (I), (II), (III), (IV), (V), (VI), (VII) or The compound described in (VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof The compound described above or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition.
  • the pharmaceutical formulations of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonarily, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intravesically, intradermally , intraperitoneally, subcutaneously, subkeratinally or by inhalation.
  • 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. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • the formulations of the invention are suitably presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form generally refers to that amount of the compound which produces a therapeutic effect.
  • Dosage forms for the topical or transdermal administration of a compound of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, in admixture with any preservatives, buffers or propellants which may be required.
  • the compound of the present invention when administered to humans and animals in the form of medicine, the compound can be provided alone or in the form of a pharmaceutical composition containing Active ingredient, such as 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient.
  • Active ingredient such as 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxy Sodium methylcellulose, ethylcellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and Suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol , mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) seaweed
  • antioxidants examples include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; ( 2) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
  • Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluen
  • Solid dosage forms may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or the following Any one of: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, Gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorption (9) lubricants
  • fillers or bulking agents such as starch, lactose, sucrose, glucose, mannito
  • Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, THF, polyethylene glycol Fatty acid esters of diols and sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers such as ethanol, isopropanol
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and gum tragacanth and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and gum tragacanth and mixtures thereof.
  • Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyesters, etc. Glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • the sprays can contain other customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.
  • “Bond” means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.
  • Alkyl when taken as a group or a part of a group means to include C 1 -C 20 straight chain or branched aliphatic hydrocarbon groups (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). It is preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups can be substituted or unsubstituted.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl etc. (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl, more preferably C 2 -C 6 alkynyl, most preferably C 2 -C 4 alkynyl (comprising e.g. 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • Cycloalkyl means saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings (containing, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atom). It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings A polycyclic group with a carbon-like structure, and the single rings share a carbon atom (called a spiro atom) with each other.
  • the ring contains one or more double bonds, but none of the rings has an aromatic system with fully conjugated ⁇ electrons.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
  • spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more An all-carbon polycyclic group in which the ring structures share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 yuan, more preferably 7 to 10 yuan.
  • 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 include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.
  • “Bridged cycloalkyl” refers to 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more A ring structure, an all-carbon polycyclic group that shares two carbon atoms that are not directly attached to each other, an aromatic system in which one or more rings may contain one or more double bonds, but none of the rings has fully conjugated ⁇ -electrons , preferably 6 to 12 yuan, more preferably 7 to 10 yuan. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more (eg 1, 2, 3 or 4)
  • the atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic rings, condensed rings, bridged rings and spiro rings.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl , thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, dihydropyrrolyl, dihydrothiazole Dihydroisothiazolyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • a heterocyclyl group can be substituted or unsubstituted.
  • “Spiroheterocyclyl” means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings Like structure, and the single rings share one atom with each other, the ring contains 1 or more double bonds, but none of the rings has a fully conjugated ⁇ -electron aromatic system, one or more ( For example 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group 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.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Heteraspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has complete conjugation Aromatic system of ⁇ electrons in which one or more (for example 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2) heteroatoms , and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13, 14 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 heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine or
  • “Bridged heterocyclic group” means 5 to 14 members, 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two A polycyclic group of one or more ring structures sharing two atoms not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has fully conjugated ⁇ electrons
  • the aromatic system of wherein one or more (eg 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[2.2.2]octyl Cyclo[3.3.2]decyl.
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered (e.g. 8, 9, 10 membered) bicyclic ring, which may contain 1 to 4 (e.g. 1, 2, 3, 4) optional from nitrogen, oxygen and/or sulfur atoms. Bicyclic heteroaryl is preferred.
  • heteroaryl examples include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl Adiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl , Indazolyl, Benzisothiazolyl, Benzoxazolyl, Benzisoxazolyl,
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have complete conjugation Aromatic system of ⁇ electrons, wherein the ring atoms are selected from 0, one or more (eg 1, 2, 3, 4) selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2), the remaining ring atoms are carbon.
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan (for example, 7, 8, 9, 10, 11, 12, 13, 14 yuan), more preferably 8 to 10 yuan. Examples of "fused rings” include, but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl means an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
  • Hydroalkyl means an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • Hydromethyl refers to a group in which the methyl group is optionally further substituted with one or more hydroxy groups.
  • Haloalkoxy refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted by one or more halogens, wherein alkoxy is as defined herein.
  • Haldroxy means an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl means -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylate group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.
  • DMSO dimethylsulfoxide
  • Ts refers to p-toluenesulfonyl.
  • T3P refers to propylphosphoric anhydride.
  • DPPA diphenylphosphoryl azide
  • DEA diethylamine
  • X-PHOS Pd G2 refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- 1,1'-biphenyl)]palladium(II).
  • 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.
  • R 8' , R 9' and R 10' are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, Heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituents of heteroaryl, carboxyl or carboxylate;
  • r 0, 1 or 2.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and Mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
  • structures depicted herein also include all isomeric (eg, diastereoisomers, enantiomers, and atropisomers) and geometric (conformational) isomeric forms of such structures; e.g. , the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • isomeric e.g. diastereoisomers, enantiomers, and atropisomers
  • geometric (conformational) isomeric forms of such structures e.g. , the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • the individual stereoisomers of the compounds of the present invention and the pair Mixtures of enantiomers, diastereoisomers and geometric (conformational) isomers are within the scope of the present invention.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • 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.
  • the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao 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.
  • CD 3 OD deuterated methanol.
  • the solution in the reaction refers to an aqueous solution.
  • 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (600mg, 2.38mmol, prepared according to published patent WO2020146613) was added to dichloromethane (3.44mL), N, N-Diisopropylethylamine (3.07g, 23.77mmol, 4.14mL), cooled to -40°C, added 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 1b (234.15 mg, 1.90 mmol, prepared according to the published patent US20140336182) in dichloromethane solution (3 mL), and continued to react and stir for 20 minutes at -40°C.
  • reaction solution was cooled to room temperature, filtered to remove molecular sieves, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 7-chloro-4-(5,6-dihydro Imidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine 1e (220 mg, 476.61 ⁇ mol), yield 62%.
  • tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2a (882.98 mg, 7.07 mmol)
  • 2-bromoethan-1-ol 2b 1 g, 4.71 mmol
  • triethylamine 953.33 mg, 9.42 mmol
  • reaction solution was lowered to room temperature, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate (30 mL), the water layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 8-(2-hydroxyl Ethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester 2c (1.2 g, 4.68 mmol), yield 99.38%.
  • reaction liquid was distilled off under reduced pressure to remove the organic solvent, and saturated aqueous sodium bicarbonate solution was added to the obtained residue until no bubbles were generated, ethyl acetate (30 mL) was added for extraction, liquid separation, the organic phase was concentrated under reduced pressure, and the aqueous phase was freeze-dried to obtain the product Combined and dried, 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol 2d (340 mg, 2.18 mmol) was obtained with a yield of 92.98%.
  • reaction solution was distilled off under reduced pressure to remove the organic solvent, and the resulting residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2mm I.D.; 5 ⁇ m, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B : CH3CN), to obtain 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol 3d (63.36mg, 86.24 ⁇ mol ), yield 18.28%.
  • reaction liquid was distilled off under reduced pressure to remove the organic solvent, and the residue was added to saturated aqueous sodium bicarbonate until no bubbles were generated.
  • the system was extracted with ethyl acetate (5 mL), the organic phase was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid phase separation ( Separation column AKZONOBEL Kromasil; 250 ⁇ 21.2mm I.D.; 5 ⁇ m, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 4-(8-(D-prolyl)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]
  • reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: system A) to obtain 4-(2,7-dichloro-8-fluoropyrido[4,3-d] Pyrimidin-4-yl)-1-imino-1 ⁇ 6 -thiomorpholine 1-oxide 4b (130 mg, 371.22 ⁇ mol), yield 20.90%.
  • reaction solution was lowered to room temperature, concentrated under reduced pressure, and the resulting residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN) to give 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine And[4,3-d]pyrimidin-4-yl)-1-imino-1 ⁇ 6 -thiomorpholine 1-oxide 4c (30 mg, 61.43 ⁇ mol), the yield was 17%.
  • Test example 1 The compound of the present invention is to the determination of p-ERK1/2 inhibitory activity in AGS (human gastric adenocarcinoma) cell
  • the following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in AGS cells.
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio, and the detailed experimental operation can refer to the kit instruction manual.
  • AGS cells (containing the KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • AGS cells were plated in 96-well plates at 40,000 per well, and the medium was complete medium, and cultured overnight at 37° C. in a 5% CO2 incubator.
  • the test compound was dissolved in DMSO to prepare a 10mM stock solution, and then diluted with F12K complete medium, and 100uL of F12K complete medium containing the corresponding concentration of the test compound was added to each well.
  • 1 ⁇ cell phospho/total protein lysis buffer Advanced phospho-ERK1 /2 kit components
  • the fluorescence intensity of each well with emission wavelengths of 620nM and 665nM was measured on a microplate reader in TF-FRET mode at an excitation wavelength of 304nM, and the ratio of the fluorescence intensity of each well at 665/620 was calculated.
  • the percentage inhibition rate of the test compound at each concentration was calculated, and the non-linear regression analysis was carried out with the concentration of the test compound on the value-inhibition rate by GraphPad Prism 5 software , to obtain the IC50 value of the compound.
  • the preferred compound of the present invention has obvious inhibitory effect on the activity of p-ERK1/2 in AGS cells, the IC50 of the preferred compound is ⁇ 500nM, and the IC50 of the more optimal compound is ⁇ 200nM.
  • Test example 2 The compounds of the present invention inhibit the proliferation of AsPC-1 cells
  • AsPC-1 human metastatic pancreatic adenocarcinoma
  • AsPC-1 cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100 ⁇ g/mL streptomycin and 1mM Sodium Pyruvate middle. cell viability through Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for determination.
  • test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample.
  • concentration of the compound ranges from 1000nM to 0.015nM .
  • Cells in the logarithmic growth phase were inoculated into 96-well cell culture plates at a density of 800 cells per well, cultivated overnight at 37°C in a 5% CO2 incubator, and then continued to cultivate for 120 hours after adding the test compound.
  • the preferred compound of the present invention has obvious inhibitory effect on the proliferation of AsPC-1 cells, the IC50 of the preferred compound is ⁇ 500nM, and the IC50 of the more optimal compound is ⁇ 200nM.
  • Test example 3 Determination of the inhibitory ability of the compound of the present invention to KRAS G12D:RAF1 protein interaction
  • the following method is used to determine the ability of the compound of the present invention to block KRAS G12D:RAF1 protein interaction in vitro.
  • This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (63ADK000CB21PEG) from Cisbio.
  • Kit instruction manual For detailed experimental operations, please refer to the kit instruction manual.
  • the experimental procedure is briefly described as follows: use diluent buffer (Product No. 62DLBDDF) to prepare Tag1-RAF1 and Tag2-KRAS-G12D proteins at a working solution concentration of 5X for later use.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with diluent buffer for use.
  • the compound of the present invention has a good inhibitory effect on the inhibitory activity of KRAS G12D: RAF1 protein interaction.

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Abstract

La présente invention concerne un dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente invention concerne un dérivé hétérocyclique représenté par la formule générale (I), son procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, ainsi que son utilisation en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de KRas G12D ; les définitions de chaque substituant dans la formule générale (I) sont les mêmes que leurs définitions dans la description.
PCT/CN2022/114084 2021-08-25 2022-08-23 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine Ceased WO2023025116A1 (fr)

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Cited By (23)

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WO2023198078A1 (fr) * 2022-04-11 2023-10-19 杭州英创医药科技有限公司 Composés polycycliques en tant qu'inhibiteurs de kras g12d
WO2023213269A1 (fr) * 2022-05-06 2023-11-09 Zai Lab (Shanghai) Co., Ltd. Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale
WO2024054926A1 (fr) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Inhibiteurs de kras g12d
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024153116A1 (fr) * 2023-01-18 2024-07-25 Suzhou Zanrong Pharma Limited Inhibiteurs de kras g12d et leurs utilisations
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
EP4361157A4 (fr) * 2021-06-21 2024-10-16 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine
WO2024227091A1 (fr) * 2023-04-26 2024-10-31 Ranok Therapeutics (Hangzhou) Co. Ltd. Inhibiteurs diazabicyclooctanes de kras g12d et utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
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WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
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WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
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EP4361157A4 (fr) * 2021-06-21 2024-10-16 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine
WO2023198078A1 (fr) * 2022-04-11 2023-10-19 杭州英创医药科技有限公司 Composés polycycliques en tant qu'inhibiteurs de kras g12d
WO2023213269A1 (fr) * 2022-05-06 2023-11-09 Zai Lab (Shanghai) Co., Ltd. Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale
WO2024054926A1 (fr) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Inhibiteurs de kras g12d
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024153116A1 (fr) * 2023-01-18 2024-07-25 Suzhou Zanrong Pharma Limited Inhibiteurs de kras g12d et leurs utilisations
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024227091A1 (fr) * 2023-04-26 2024-10-31 Ranok Therapeutics (Hangzhou) Co. Ltd. Inhibiteurs diazabicyclooctanes de kras g12d et utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025016432A1 (fr) * 2023-07-18 2025-01-23 泰励生物科技（上海）有限公司 Composé présentant une activité anti-tumeur à mutation de kras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
CN119684315A (zh) * 2024-01-26 2025-03-25 苏州盛迪亚生物医药有限公司 一种苯并噻吩取代稠环化合物的结晶形式及其制备方法
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025245127A1 (fr) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques

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