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WO2021057256A1 - Composé azoté hétérocyclique, composition pharmaceutique le contenant, son procédé de préparation et utilisation associée - Google Patents

Composé azoté hétérocyclique, composition pharmaceutique le contenant, son procédé de préparation et utilisation associée Download PDF

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Publication number
WO2021057256A1
WO2021057256A1 PCT/CN2020/106080 CN2020106080W WO2021057256A1 WO 2021057256 A1 WO2021057256 A1 WO 2021057256A1 CN 2020106080 W CN2020106080 W CN 2020106080W WO 2021057256 A1 WO2021057256 A1 WO 2021057256A1
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group
membered
compound
alkyl
aryl
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PCT/CN2020/106080
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English (en)
Chinese (zh)
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游泽金
何云
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202080055686.8A priority Critical patent/CN114269753B/zh
Publication of WO2021057256A1 publication Critical patent/WO2021057256A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention requires an invention patent application filed in China on September 29, 2019 under the name "a nitrogen-containing hexacyclic compound, a pharmaceutical composition containing it, its preparation method and its use", and the application number of 201910932795.2 Priority, the entire content of the patent application is incorporated herein by reference.
  • the present invention belongs to the field of medicinal chemistry, and relates to a novel nitrogen-containing hexacyclic compound with NLRP3 regulating activity, a preparation method thereof, a pharmaceutical composition containing the same, and medical use thereof.
  • NLRP3 (NLR family pyrin domain containing 3) belongs to the NLR (NOD-like receptors) family and is one of the most studied intracellular pattern recognition receptors in recent years. It is mainly expressed on macrophages and neutrophils and participates in the body's inherent Immunity, resistance to pathogen infection and stress damage. The role of NLRP3 inflammasomes in inflammatory and metabolic diseases is very clear, and its excessive activation can lead to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has anti-tumor effects that inhibit tumor growth and metastasis.
  • NLRP3 protein After the NLRP3 protein recognizes PAMP (pathogen-associated molecular patterns) or DAMP (damage-associated molecular patterns), its NOD domain undergoes oligomerization and recruits proteins such as ASC and pro-caspase-1 to form a functional NLRP3 with minimal inflammation. body. After pro-caspase-1 is cleaved and activated to caspase-1, caspase-1 cleaves pro-IL-1 ⁇ and pro-IL-18 in a large amount to convert them into active forms of IL-1 ⁇ and IL-18 and release them to Extracellular, amplify the inflammatory response.
  • PAMP pathogen-associated molecular patterns
  • DAMP damage-associated molecular patterns
  • NLRP3 inflammasome can significantly increase the levels of the immune factors IL-1 ⁇ and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent adaptive immune responses to exert its anti-tumor effects.
  • IL-1 ⁇ can induce CD8+ T cells to secrete interferon ⁇ (IFN- ⁇ ), and it can also induce CD4+ T cells to secrete IL-17, leading to effective anti-tumor immune effects; while IL-18 can promote NK Cells mature, activate the downstream signaling pathway of STAT1 in immune cells, and enhance the killing function of immune cells.
  • IFN- ⁇ interferon ⁇
  • IL-18 can promote NK Cells mature, activate the downstream signaling pathway of STAT1 in immune cells, and enhance the killing function of immune cells.
  • Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of liver cancer patients.
  • NLRP3-deficient mice have a higher rate of colorectal tumor formation, and colorectal cancer liver metastasis worsens. It can be seen that NLRP3 plays an important role in the tumor microenvironment and can be used as a key target of tumor immunotherapy, and it can also be used as a tumor prognostic marker.
  • NLRP3 modulators Although NLRP3 agonists have the potential for tumor immunotherapy, only one compound is currently in clinical phase I studies. Therefore, it is necessary to develop new, high-efficiency and low-toxicity NLRP3 agonists to meet the needs of clinical treatment.
  • the present invention aims to provide a novel nitrogen-containing cyclic compound with a regulatory effect on NLRP3, which can directly bind or modify NLRP3 at the protein level, and enhance the function of NLRP3 inflammasomes by activating, stabilizing, and changing the distribution of NLRP3. .
  • the present invention provides a compound having the structure of formula II or a pharmaceutically acceptable form thereof,
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • R 4 is NR 41a R 41b ;
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, Cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 ;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 aryl, and C 1-8 alkylene-(5-10 membered heteroaryl), wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 Alkylene-C 6-12 aryl and C 1-8 alkylene-(5-10 membered heteroaryl) are each optionally substituted by one or more substituents, each of which is independently Selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalk
  • R 31 , R 32 , R 33 and R 34 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, or R 31 and R 32 together with the N atom to which they are connected to form a 4-8 membered heterocyclic group, or R 33 and R 34 together with the N atom to which they are connected correspondingly and The C atoms together form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 membered
  • the heterocyclic group, the C 6-12 aryl group and the 5-10 membered heteroaryl group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from hydroxyl, cyano, halogen, nitro
  • R 36a and R 36b are each independently selected from hydrogen, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted by one Or multiple substituents, each of said substituents is independently selected from hydroxyl, cyano, halogen, amino, methylamino and dimethylamino, or R 36a and R 36b together with the C atom to which they are attached form 3- 7-membered cycloalkyl or heterocyclic group;
  • each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 and/or R 40 are the same or different from each other;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, co-crystals, solvates, N-oxides, Isotope markers, metabolites and prodrugs.
  • the present invention provides specific compounds having the structure of formula II, formula IV, formula IV-A or formula V, which include:
  • the preparation method which comprises the following steps:
  • Step 1 Compound IV-1 is halogenated to produce compound IV-2;
  • X represents a halogen atom, selected from chlorine and bromine
  • Step 2 Compound IV-2 is reacted by iodine to generate compound IV-3;
  • Step 3 Compound IV-3 is oxidized to produce compound IV-4;
  • Step 4 Reaction of compound IV-4 with R 4 H to produce compound IV-5, wherein R 4 is connected to thienopyridine through a nitrogen atom;
  • Step 5 Compound IV-5 is coupled to produce compound IV-6;
  • Step 6-1 Compound IV-6 undergoes substitution reaction to generate compound IV-A-1;
  • Step 6-2 Compound IV-6 is coupled to produce compound IV-B-1;
  • R 1, R 3a, R 3b , R 4, L a and L b are as defined herein.
  • the preparation method of the compound and the compound of formula IV-B-2 which comprises the following steps:
  • Step 7 Compound IV-A-1' and compound IV-B-1' are deprotected to produce compound IV-A-2 and compound IV-B-2, respectively;
  • the present invention provides a method for preparing a compound of formula V, which comprises the following steps:
  • Step 1 Compound IV-6 is substituted or coupled to produce compound V;
  • R 1 , R 3 , R 4 , R 33 , L 2 , L 3 , p and q are as defined herein.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the structure of Formula II, Formula IV, Formula IV-A or Formula V, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound having the structure of formula II, formula IV, formula IV-A or formula V, or a pharmaceutically acceptable form or pharmaceutical composition thereof, which is used as an NLRP3 modulator, preferably as an NLRP3 agonist Agent.
  • this application provides a compound having the structure of Formula II, Formula IV, Formula IV-A, or Formula V, or a pharmaceutically acceptable form or pharmaceutical composition thereof when prepared for prevention and/or treatment at least in part by NLRP3 Use in medicine for mediated diseases.
  • the present invention provides a method for preventing and/or treating diseases mediated at least in part by NLRP3, which comprises the following steps: a preventive and/or therapeutically effective amount of formula II, formula IV, formula The compound of structure IV-A or formula V, or a pharmaceutically acceptable form or pharmaceutical composition thereof, is administered to an individual in need thereof.
  • the present invention provides a drug combination composition
  • a drug combination composition comprising a compound having the structure of formula II, formula IV, formula IV-A or formula V, or a pharmaceutically acceptable form or pharmaceutical composition thereof, and at least One other co-directional NLRP3 modulator.
  • the present invention provides a method for the prevention and/or treatment of cancer, which comprises the following steps: a preventive and/or therapeutically effective amount of the NLRP3 agonist having formula II, formula IV, and formula IV -A compound of the structure of formula V or its pharmaceutically acceptable form or pharmaceutical composition or combination of drugs is administered to an individual in need thereof.
  • the present invention provides a method for the prevention and/or treatment of immune diseases, which comprises the following steps: a preventive and/or therapeutically effective amount of a NLRP3 antagonist of formula II and formula IV ,
  • a preventive and/or therapeutically effective amount of a NLRP3 antagonist of formula II and formula IV a preventive and/or therapeutically effective amount of a NLRP3 antagonist of formula II and formula IV .
  • the compound of formula IV-A or formula V or its pharmaceutically acceptable form or pharmaceutical composition or drug combination composition is administered to individuals in need thereof.
  • the compound of the present invention has obvious agonistic activity on NLRP3 and its signal pathway, has no obvious toxic and side effects, and can be used for the treatment of abnormal cell proliferation diseases (such as cancer).
  • compositions, methods, or devices that includes a series of elements is not necessarily limited to the explicitly listed elements, but may also include other elements that are not explicitly listed or elements inherent in the above-mentioned composition, method, or device.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is substantially non-toxic to living organisms.
  • Pharmaceutically acceptable salts generally include (but are not limited to) the salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also called acid addition salts or Base addition salt. Examples of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002.
  • isomers refers to compounds that have the same molecular weight because of the same number of atoms and atomic types, but differ in the arrangement or configuration of the atoms in space.
  • stereoisomer refers to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) resulting in a vertical asymmetric plane, So that it can rotate the stable isomer of plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can be in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers Form exists. Generally, these compounds can be prepared as racemates.
  • stereoisomers that is, single enantiomers or diastereomers, or enrichment of single stereoisomers (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%).
  • a single stereoisomer of a compound is synthetically prepared from an optically active starting material containing the desired chiral center, or is prepared by preparing a mixture of enantiomeric products and then separating or resolving.
  • the obtained for example, is converted into a mixture of diastereomers and then subjected to separation or recrystallization, chromatographic treatment, chiral resolution reagents, or direct separation of the enantiomers on a chiral chromatography column.
  • Starting compounds with specific stereochemistry are either commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art.
  • enantiomers refers to a pair of stereoisomers that have non-superimposable mirror images of each other.
  • diastereomer or “diastereomer” refers to optical isomers that do not constitute mirror images of each other.
  • racemic mixture or “racemate” refers to a mixture containing equal parts of a single enantiomer (ie, a mixture of two R and S enantiomers in equimolar amounts).
  • non-racemic mixture refers to a mixture containing unequal parts of single enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
  • tautomers refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers include (but are not limited to) interconversion through proton migration, such as keto-enol isomerization, imine-enamine isomerization Isomerization, nitroso-oxime isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • cis-trans isomer refers to the stereoisomers formed by the atoms (or groups) located on both sides of the double bond or the ring system due to different positions relative to the reference plane; in the cis-isomer, the atom ( Or group) is located on the same side of the double bond or ring system, and the atom (or group) is located on the opposite side of the double bond or ring system in the trans isomer. Unless otherwise indicated, all cis-trans isomer forms of the compounds of the present invention are within the scope of the present invention.
  • polymorph refers to the solid crystal form of a compound or complex, which can be a single polymorph or more than one polymorph in any ratio mixture.
  • Those skilled in the art can obtain polymorphs by known methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor phase diffusion, and sublimation.
  • well-known techniques can be used to detect, classify and identify polymorphs.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • XRPD X-ray Powder Diffraction
  • SCXRD Single crystal X-ray diffraction
  • NMR solid-state nuclear magnetic resonance
  • IR infrared spectroscopy
  • Raman spectroscopy and scanning electron microscopy (SEM), etc.
  • solvate refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, etc.), ethanolate, acetonate, and the like.
  • N-oxide refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound.
  • Common N-oxides include (but are not limited to) trimethylamine-N-oxide, 4-methylmorpholine-N-oxide, pyridine-N-oxide and the like.
  • the 1a position in the nucleus of the formula I compound of the present invention is a tertiary amine nitrogen atom, which can form the corresponding N-oxide; in addition, when the group directly connected to the nitrogen atom at the 3 position in the nucleus is not a (sulfon) acyl , Then the 3-position is also a tertiary amine nitrogen atom, which can also form the corresponding N-oxide.
  • isotopic label refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom (having the same atomic number but different atomic mass or mass number).
  • the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 11 C, 13 C, 14 C , 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S, 37 Cl, 123 I and 125 I.
  • metabolite refers to a derivative compound formed after the compound of the present invention is metabolized.
  • metabolites see Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th ed.) [M], McGraw-Hill International Editions, 1996.
  • prodrug refers to a derivative compound capable of directly or indirectly providing the compound of the present invention after administration to an individual.
  • Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (for example, more easily absorbed into the blood), or promote delivery of the parent compound to the site of action (for example, the lymphatic system) compound of.
  • all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.
  • prodrugs see Pro-drugs as Novel Drug Delivery Systems (14 th ed.) [M], ACS Symposium Series, 1975 and Bioreversible Carriers in Drug Design [M], Pergamon Press, 1987.
  • the present invention also encompasses the compounds of the present invention containing protecting groups.
  • protecting groups In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups. Examples of suitable protecting groups can be found in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie [M], Plenum Press, 1973 and Protective Groups in Organic Synthesis [M], John Wiley & Sons, 1991. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl.
  • the substituent Y can be either hydrogen or halogen. Hydroxy, cyano, alkyl or aryl; in the same way, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.
  • each optionally means that at least two groups (or ring systems) present in the structure may have the same or different handling methods under certain circumstances.
  • the substituent X and the substituent Y are each optionally substituted by an alkyl group, which actually includes the following multiple treatment methods: (1) only X is substituted by an alkyl group; (2) only Y is substituted by an alkyl group; (3) ) X and Y are both substituted by alkyl; (4) X and Y are both unsubstituted.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • halo refers to substitution by a halogen atom.
  • cyano refers to the -CN group.
  • nitro refers to the -NO 2 group.
  • hydroxyl refers to the -OH group.
  • alkyl refers to a linear or branched monovalent saturated aliphatic hydrocarbon group.
  • C 1-15 alkyl means having 1 to 15 carbon atoms, 1-8 Carbon atoms, straight or branched chain alkyl groups of 1 to 6 carbon atoms and 1-4 carbon atoms.
  • Common alkyl groups include (but are not limited to) methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3) ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), isobutyl (-CH 2 CH(CH 3 ) 2 ), Tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyl (-CH 2 C(CH 3 ) 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) and so on.
  • alkylene refers to a divalent saturated aliphatic hydrocarbon group obtained by removing two hydrogen atoms from a linear or branched saturated aliphatic hydrocarbon group.
  • Common alkylene groups include (but are not limited to) methylene (-CH 2 -), 1,2-ethylene (-CH 2 CH 2 -), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1-methyl-1,2-ethylene (-CH(CH 3 )CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), 1- Methyl-1,3-propylene (-CH(CH 3 )CH 2 CH 2 -), 1,1-dimethyl-1,2-ethylene (-C(CH 3 ) 2 CH 2- ), 1,2-dimethyl-1,2-ethylene (-CH(CH 3 )CH(CH 3 )-), etc.
  • haloalkyl refers to a straight or branched alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms.
  • C 1-8 haloalkyl refers to having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively ⁇ haloalkyl.
  • Common haloalkyl groups include (but are not limited to) fluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), 1-fluoroethyl (-CHFCH 3 ) , 2-fluoroethyl (-CH 2 CH 2 F), 1,2-difluoroethyl (-CHFCH 2 F), 2,2-difluoroethyl (-CH 2 CHF 2 ), 1, 2, 2-trifluoroethyl (-CHFCHF 2 ), 2,2,2-trifluoroethyl (-CH 2 CF 3 ), 1,1,2,2,2-pentafluoroethyl (-CF 2 CF 3 ), 3,3,3-trifluoropropyl (-CH 2 CH 2 CF 3 ), chloromethyl (-CH 2 Cl), etc.
  • hydroxyalkyl refers to a straight or branched alkyl group substituted with one or more (such as 1 to 3) hydroxyl groups.
  • C 1-4 hydroxyalkyl and “C 1-3 hydroxyalkyl” refer to hydroxyalkyl groups having 1 to 4 carbon atoms and 1 to 3 carbon atoms, respectively.
  • Common hydroxyalkyl groups include (but are not limited to) hydroxymethyl (-CH 2 OH), 2-hydroxyethyl (-CH 2 CH 2 OH), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH) , 4-hydroxybutyl (-CH 2 CH 2 CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), etc.
  • alkenylene refers to a straight or branched divalent aliphatic hydrocarbon group containing one or more (such as 1 to 3) carbon-carbon double bonds.
  • alkynyl refers to a linear or branched monovalent aliphatic hydrocarbon group having one or more (such as 1 to 3) carbon-carbon triple bonds.
  • Common alkenylene groups include (but are not limited to) ethynyl 2-propyn-1-yl 2-butyn-1-yl 1,3-butadiynyl Wait.
  • alkynylene refers to a straight or branched divalent aliphatic hydrocarbon group having one or more (such as 1 to 3) carbon-carbon triple bonds.
  • Common alkynylene groups include (but are not limited to) 1,2-ethynylene 1,3-propylene-1-propynyl 1,3-Butynylene-1-butynyl 1,4-ylidene-2-butynyl Wait.
  • alkoxy refers to a monovalent linear or branched alkyl-O- group and is connected to other groups through a single bond to an oxygen atom.
  • Common alkoxy groups include (but are not limited to) methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy ( -OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 C( CH 3 ) 3 ), n-hexyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), etc.
  • alkyleneoxy refers to a divalent linear or branched alkylene-O- group, and is connected to the group by a single bond connected to an oxygen atom and another single bond connected to an alkylene group.
  • Other groups. Common alkyleneoxy groups include (but are not limited to) -OCH 2 -, -OCH(CH 3 )CH 2 -, -CH 2 CH 2 O-, and the like.
  • condensed ring or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spirocyclic ring refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkyl refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic) monovalent non-aromatic cyclic hydrocarbon group.
  • Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; and ring (fused Cyclo)cycloalkanes, such as decahydronaphthyl (also known as decalinyl, naphthyl), bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[5.1.0] Octyl, bicyclo[2.2.0]hexyl, bicyclo[4.2.0]octyl, etc.; spirocyclic cycloalkyl, such as
  • cycloalkylene refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic) divalent non-aromatic cyclic hydrocarbon group, which has the same carbon atom or two different carbons from the parent cycloalkyl group Two monovalent group centers obtained by removing two hydrogen atoms from the atom.
  • Common cycloalkylene groups include (but are not limited to) cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylidene, cyclohexene Base and so on.
  • heterocyclic group refers to a saturated or unsaturated, monocyclic or polycyclic (including fused ring, bridged ring, and spiro ring) monovalent non-aromatic ring system, the ring atoms of which consist of carbon atoms and are selected from boron, Heteroatoms of nitrogen, oxygen, sulfur, phosphorus and arsenic
  • 3-14 membered heterocyclic group refers to a heterocyclic group containing 3-14 ring atoms, including (but not limited to) 4-10 membered heterocyclic group, 4-7 membered heterocyclic group (e.g.
  • nitrogen-containing heterocyclic group 4-7 Membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered sulfur-containing heterocyclic group), 5-6 membered heterocyclic group (e.g. 5-6 membered nitrogen-containing heterocyclic group, 5-6 Membered oxygen-containing heterocyclic group, 5-6 membered sulfur-containing heterocyclic group), etc.
  • nitrogen-containing heterocyclic group “oxygen-containing heterocyclic group” and “sulfur-containing heterocyclic group” each optionally contain one or more A heteroatom selected from nitrogen, oxygen, and sulfur.
  • Common monocyclic heterocyclic groups include (but are not limited to) oxirane, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone, imidazolidine Group, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiaalkyl, trithiaalkyl, etc.; common cyclic heterocyclic groups include ( But not limited to) heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, etc., such as pyrrolidinocyclopropyl, Pyrrolidinocyclobutyl, pyrrolidinocyclohexyl, cyclopentylaza
  • the nitrogen atom on the heterocyclic group in the present invention is optionally oxidized to form nitrogen oxide (NH ⁇ O).
  • heterocyclylene refers to a saturated or unsaturated, monocyclic or polycyclic (such as bicyclic) divalent non-aromatic ring system, the ring atoms of which consist of carbon atoms and are selected from boron, nitrogen, oxygen, sulfur, Phosphorus and arsenic heteroatoms are composed of two monovalent group centers obtained by removing two hydrogen atoms from two carbon atoms, two heteroatoms or one carbon atom and one heteroatom of the parent heterocyclic group.
  • Common heterocyclylenes include (but are not limited to) oxetane-2,2-ylidene, oxetane-2,3-ylidene, azetidine-2,2-ylidene, nitrogen Etidine-2,3-subunit, azetidine-2,4-subunit, tetrahydrofuran-2,5-subunit, tetrahydro-2H-pyran-2,3-subunit, tetrahydrofuran-2,3-subunit Hydrogen-2H-pyran-2,4-subunit, tetrahydro-2H-pyran-2,5-subunit, tetrahydro-2H-pyran-2,6-subunit, pyrrolidine-1,2 -Subunit, pyrrolidine-1,3-subunit, pyrrolidine-2,3-subunit, pyrrolidine-2,4-subunit, pyrrolidine-2,5-subunit, piperidine-1,2 -Subunit, piperidine-1,2 -Subunit
  • the nitrogen atom on the heterocyclylene in the present invention is optionally oxidized, that is, nitrogen oxide (NH ⁇ O) is formed.
  • aryl refers to an all-carbon monocyclic or fused polycyclic monovalent aromatic ring system with a conjugated ⁇ -electron system.
  • C 6-12 aryl and C 6-10 aryl refer to aryl groups containing 6 to 12 and 6 to 10 carbon atoms, respectively. Common aryl groups include (but are not limited to) phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl and the like.
  • arylene refers to a bivalent aromatic ring system with a conjugated ⁇ -electron system, all-carbon monocyclic or fused polycyclic ring, which has two hydrogen atoms removed from the two carbon atoms of the parent aryl group And the obtained two monovalent group centers.
  • Common aryl groups include (but are not limited to) phenylene, naphthylene and the like.
  • aryl and cycloalkyl refers to a monovalent fused ring group formed by an aryl group and a cycloalkyl group (such as a monocyclic cycloalkyl group) sharing two adjacent atoms with each other, which is combined with other groups (or ring groups). The attachment point of the system) may be on the aryl group or on the cycloalkyl group.
  • aryl and cycloalkyl refers to an aryl and cycloalkyl containing 9 to 12 ring atoms.
  • Common aryl and cycloalkyl groups include, but are not limited to, phenyl and cyclopentyl, phenyl and cyclohexyl, and the like.
  • aryl and heterocyclic group refers to a monovalent fused ring group formed by an aryl group and a heterocyclic group (such as a monocyclic heterocyclic group) sharing two adjacent atoms with each other, which is combined with other groups (or ring groups). The point of attachment of) may be on an aryl group or a heterocyclic group.
  • 9-12 membered aryl and heterocyclic group refers to an aryl and heterocyclic group containing 9-12 ring atoms, such as benzo 5-6 membered nitrogen-containing heterocyclic group, benzo 5- 6-membered oxygen-containing heterocyclic group, benzo 5-6 membered sulfur-containing heterocyclic group, etc., "nitrogen-containing heterocyclic group”, “oxygen-containing heterocyclic group” and “sulfur-containing heterocyclic group” each optionally contain one Or more heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Common aryl and cycloalkyl groups include (but are not limited to) indazolidinyl, benzomorpholinyl, dihydroisoquinolinone, benzo[1,4]dioxanyl, dihydrobenzo Furanyl.
  • the nitrogen atom on the heterocyclic group in the present invention is optionally oxidized to form nitrogen oxide (NH ⁇ O).
  • heteroaryl refers to a monocyclic or fused polycyclic monovalent aromatic ring system with a conjugated ⁇ -electron system, the ring atoms of which consist of carbon atoms and are selected from boron, nitrogen, oxygen, sulfur, phosphorus and
  • the heteroatom structure of arsenic preferably has 2 or more (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (for example 1, 2, 3 or 4) heteroatom monocyclic or fused polycyclic group.
  • 5-10 membered heteroaryl refers to a heteroaryl group containing 5 to 10 ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered Thioaryl groups, preferably 5-6 membered nitrogen-containing heteroaryl groups, 5-6 membered oxygen-containing heteroaryl groups, 5-6 membered sulfur-containing heteroaryl groups, more preferably 5-6 membered nitrogen-containing monoheteroaryl groups, 5 -6 membered oxygen-containing monoheteroaryl group, 5-6 membered sulfur-containing monoheteroaryl group.
  • nitrogen-containing heteroaryl group each optionally contain one or more heteroatoms selected from oxygen, nitrogen, and sulfur.
  • Common heterocyclic groups include (but are not limited to) acridinyl, carbazolyl, indazolyl, indazinyl, indolyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazole Base, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quine Linyl, isoquinolyl, quinoxalinyl, phenazinyl, phenoxazinyl, phenothiazin
  • heteroarylene refers to a monocyclic or fused polycyclic divalent aromatic ring system with a conjugated ⁇ -electron system, the ring atoms of which consist of carbon atoms and are selected from boron, nitrogen, oxygen, sulfur, and phosphorus And arsenic heteroatoms, preferably having 2 or more (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more ( For example, 1, 2, 3, or 4) heteroatom monocyclic or fused polycyclic group, which has two carbon atoms or one carbon atom and one heteroatom removed from the parent heteroaryl group. Two monovalent group centers derived from hydrogen atoms. Common heteroarylene groups include (but are not limited to) pyrazolylidene, imidazolylidene and the like.
  • aryl and heteroaryl refers to a monovalent bicyclic group formed by sharing two adjacent atoms between an aryl group (such as a phenyl group) and a heteroaryl group (such as a 5-6 membered monocyclic heteroaryl group). , The point of attachment to other groups (or ring systems) can be on the aromatic ring or heteroaromatic ring.
  • aryl and heteroaryl group refers to an aryl and heteroaryl group containing 9 to 12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monocyclic heteroaryl group.
  • heteroaryl and cycloalkyl means that a heteroaryl group (such as a 5-6 membered monocyclic heteroaryl group) and a cycloalkyl group (such as a C 4-6 cycloalkyl group) share two adjacent atoms with each other to form The point of attachment of the monovalent cyclic group with other groups (or ring system) can be on the heteroaryl group or cycloalkyl group.
  • 9-10 membered heteroaryl and cycloalkyl refers to a heteroaryl and cycloalkyl group containing 9-10 ring atoms, such as 4-6 membered nitrogen-containing monocyclic heteroaryl and C 4-6 monocyclic Cyclocycloalkyl.
  • substituted means that one or more (for example, 1, 2, 3, or 4) hydrogen atoms on the designated atom (or group) are replaced by other atoms (or groups), provided that no Exceeds the normal valence of the specified atom in the current situation and forms a stable compound. If a certain substituent is described as "optionally substituted by (by) --, the substituent can be (1) unsubstituted or (2) substituted. If a certain type of substituent is described as "each independently selected from", then any one of the plurality of such substituents simultaneously present is selected independently of the other; in other words, among the plurality of such substituents One can be the same or different from the other.
  • one or more refers to one or more than one under reasonable conditions, such as two, three, four, five, six, seven, eight, nine or ten.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention provides a compound of formula X or a pharmaceutically acceptable form thereof,
  • A is selected from
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl group Heterocyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • ⁇ R 2 is -NR 41a R 41b ;
  • Each R 5 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group are each optionally substituted with one or more substituents, each of which is independent Ground is selected from halogen, hydroxy, cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 ; m is 0, 1 or 2;
  • ⁇ R 4 is -NR 41a R 41b ;
  • ⁇ R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl , C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group are each optionally substituted by one or more substituents, each of which is independently selected from halogen, Hydroxy, cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 ;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 aryl, and C 1-8 alkylene-(5-10 membered heteroaryl), wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 Alkylene-C 6-12 aryl and C 1-8 alkylene-(5-10 membered heteroaryl) are each optionally substituted by one or more substituents, each of which is independently Selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalk
  • R 31 , R 32 , R 33 and R 34 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, or R 31 and R 32 together with the N atom to which they are connected to form a 4-8 membered heterocyclic group, or R 33 and R 34 together with the N atom to which they are connected correspondingly and The C atoms together form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 membered
  • the heterocyclic group, the C 6-12 aryl group and the 5-10 membered heteroaryl group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from hydroxyl, cyano, halogen, nitro
  • R 36a and R 36b are each independently selected from hydrogen, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted by one Or multiple substituents, each of said substituents is independently selected from hydroxyl, cyano, halogen, amino, methylamino and dimethylamino, or R 36a and R 36b together with the C atom to which they are attached form 3- 7-membered cycloalkyl or heterocyclic group;
  • each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 and/or R 40 are the same or different from each other;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, co-crystals, solvates, N-oxides, Isotope markers, metabolites and prodrugs.
  • the compound of formula X above is a compound of formula I
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • R 2 is NR 41a R 41b ;
  • Each R 5 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group, wherein the C 1- 6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more substituents, each of which is independently selected From halogen, hydroxy, cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 ; m is 0, 1 or 2;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 aryl, and C 1-8 alkylene-(5-10 membered heteroaryl), wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 Alkylene-C 6-12 aryl and C 1-8 alkylene-(5-10 membered heteroaryl) are each optionally substituted by one or more substituents, each of which is independently Selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalk
  • R 31 , R 32 , R 33 and R 34 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, or R 31 and R 32 together with the N atom to which they are connected to form a 4-8 membered heterocyclic group, or R 33 and R 34 together with the N atom to which they are connected correspondingly and The C atoms together form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 membered
  • the heterocyclic group, the C 6-12 aryl group and the 5-10 membered heteroaryl group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from hydroxyl, cyano, halogen, nitro
  • R 36a and R 36b are each independently selected from hydrogen, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted by one Or multiple substituents, each of said substituents is independently selected from hydroxyl, cyano, halogen, amino, methylamino and dimethylamino, or R 36a and R 36b together with the C atom to which they are attached form 3- 7-membered cycloalkyl or heterocyclic group;
  • each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 and/or R 40 are the same or different from each other.
  • the above-mentioned compound of formula X or formula I is a compound of formula III,
  • R 1 , R 2 , R 3 , R 5 , L and m are as defined above.
  • the above-mentioned compound of formula X, formula I or formula III is a compound of formula III-A,
  • R 1 and R 2 are as defined above;
  • R 5a is selected from hydrogen, C 1-3 alkyl, fluorine and chlorine;
  • L a is -L 1a - (L 2) p - (L 3) q -, wherein L 1a is selected from -O -, - S-, and -NR 33 -, and L 2, L 3, p and q are as hereinbefore Defined
  • R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 37 are as defined above.
  • the above-mentioned compound of formula X, formula I or formula III is a compound of formula III-B,
  • R 1 and R 2 are as defined above;
  • R 5a is selected from hydrogen, C 1-3 alkyl, fluorine and chlorine;
  • the compound of formula X above is a compound of formula II
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • R 4 is NR 41a R 41b ;
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more substituents, each of which is independently selected from halogen, hydroxyl, Cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 ;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkylene-C 6-12 aryl, and C 1-8 alkylene-(5-10 membered heteroaryl), wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 Alkylene-C 6-12 aryl and C 1-8 alkylene-(5-10 membered heteroaryl) are each optionally substituted by one or more substituents, each of which is independently Selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalk
  • R 31 , R 32 , R 33 and R 34 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, or R 31 and R 32 together with the N atom to which they are connected to form a 4-8 membered heterocyclic group, or R 33 and R 34 together with the N atom to which they are connected correspondingly and The C atoms together form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10 membered
  • the heterocyclic group, the C 6-12 aryl group and the 5-10 membered heteroaryl group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from hydroxyl, cyano, halogen, nitro
  • R 36a and R 36b are each independently selected from hydrogen, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each optionally substituted by one Or multiple substituents, each of said substituents is independently selected from hydroxyl, cyano, halogen, amino, methylamino and dimethylamino, or R 36a and R 36b together with the C atom to which they are attached form 3- 7-membered cycloalkyl or heterocyclic group;
  • each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 and/or R 40 are the same or different from each other.
  • the above-mentioned compound of formula X or formula II is a compound of formula IV,
  • R 1 , R 3 , R 4 , X 1 and L are as defined above.
  • the above-mentioned compound of formula X, formula II or formula IV is a compound of formula IV-A,
  • R 1 , R 4 and R 6 are as defined above;
  • L a is -L 1a - (L 2) p - (L 3) q -, wherein L 1a is selected from -O -, - S-, and -NR 33 -, and L 2, L 3, p and q are as hereinbefore Defined
  • R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 37 are as defined above.
  • the above-mentioned compound of formula X, formula II or formula IV is a compound of formula IV-B,
  • R 1 , R 4 and R 6 are as defined above;
  • the above-mentioned compound of formula X, formula II, formula IV or formula IV-A is a compound of formula V,
  • R 1 , R 3 , R 4 , L 2 , L 3 , p and q are as defined above;
  • R 33 is selected from hydrogen and C 1-6 alkyl.
  • R 3 in the compound of formula I, formula II, formula III, formula IV or formula V is selected from cyclobutyl, hydroxy, oxetan-3-yl Methoxy, methyl, morpholin-4-yl 2-oxopyrrolidin-1-yl Cyclopropyl, cyclopropylamino, difluoromethyl, fluorine, isopropyl, (1R,5S,6s)-1,5-dimethyl-3-azabicyclo[3.1.0]hex-6- base Isobutyl, hydroxymethyl and tetrahydro-2H-pyran-4-yl
  • the aryl group and the 4-10 membered heterocyclylene are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxy, cyano, nitro, C 1-6 alkane Group, C 1-4 haloalkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy.
  • -LR 3 in the compound of formula I, formula II, formula III or formula IV or -L a -R 3a in the compound of formula III-A or formula IV-A or formula -L b -R 3b in the compound of III-B or formula IV-B or -N(R 33 )-(L 2 ) p -(L 3 ) q -R 3 in the compound of formula V is selected from:
  • R 1 in the compound of Formula I, Formula II, Formula III, Formula IV, Formula III-A, Formula IV-A, Formula III-B, Formula IV-B, or Formula V Selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclic group, C 6-10 aryl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, Each of C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl is optionally substituted by one or more substituents, each of which is individually Independently selected from halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl and C 1-4 hydroxyalkyl.
  • R in the compound of formula I, formula II, formula III, formula IV, formula III-A, formula IV-A, formula III-B, formula IV-B or formula V 1 is selected from 5-6 membered heteroaryl groups and 4-7 membered heterocyclic groups, especially 5-6 membered nitrogen-containing heteroaryl groups (such as pyrazolyl or pyridyl) and 6-membered oxygen-containing heterocyclic groups (such as four Hydrogen-2H-pyran-2-yl), which is optionally substituted by one or more substituents, each of which is independently selected from halogen (preferably fluorine), C 1-3 alkyl (preferably Methyl) and 4-7 membered heterocyclic group (preferably tetrahydro-2H-pyran-2-yl).
  • 5-6 membered nitrogen-containing heteroaryl groups such as pyrazolyl or pyridyl
  • 6-membered oxygen-containing heterocyclic groups such as four Hydrogen-2H-pyran-2-yl
  • substituents each of which
  • R in the compound of formula I, formula II, formula III, formula IV, formula III-A, formula IV-A, formula III-B, formula IV-B or formula V 1 is 5-6 membered heteroaryl (preferably 5-6 membered nitrogen-containing heteroaryl, more preferably pyrazolyl or pyridyl), which is optionally substituted by one or more substituents, each of said substituents Each is independently selected from halogen (preferably fluorine), C 1-3 alkyl (preferably methyl) and 4-7 membered heterocyclic group (preferably tetrahydro-2H-pyran-2-yl).
  • R in the compound of formula I, formula II, formula III, formula IV, formula III-A, formula IV-A, formula III-B, formula IV-B or formula V 1 is selected from pyrazolyl, 1,3-dimethyl-1H-pyrazolyl, picoline and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolyl; preferably , R 1 is selected from 1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-5-yl, 2-picoline-6-yl and 1-(tetrahydro-2H-pyridine (Pyran-2-yl)-1H-pyrazol-2-yl; more preferably, R 1 is selected from 1H-pyrazol-5-yl and 2-picoline-6-yl.
  • R 4 in the compound of formula II, formula IV, formula IV-A, formula IV-B or formula V is -NR 41a R 41b , wherein R 41a and R 41b are each independently Selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl, and R 41a and R 41b are not hydrogen at the same time, or R 41a and R 41b together with the N atom to which they are connected form a 4-6 membered heterocyclic ring Group, wherein the C 1-4 alkyl group, C 3-6 cycloalkyl group and 4-6 membered heterocyclic group are each optionally substituted with one or more substituents, and each of the substituents is independently selected From C 1-4 alkyl, C 1-4 hydroxyalkyl and carboxyl.
  • R 4 in the compound of formula II, formula IV, formula IV-A, formula IV-B or formula V is -NR 41a R 41b , wherein R 41a and R 41b are each independently Ground is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, and R 41a and R 41b are not hydrogen at the same time, or R 41a and R 41b together with the N atom to which they are attached form a pyrrolidine -1-yl, wherein the methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and pyrrolidin-1-yl are each optionally substituted with one or more substituents, each of which is substituted
  • the groups are each independently selected from methyl, tert-butyl, hydroxymethyl and carboxyl groups.
  • R 4 in the compound of formula II, formula IV, formula IV-A, formula IV-B or formula V is selected from -N(H)-C(CH 3 ) 3 , -N(H)-CH 3 , -N(H)-C 2 H 5 , -N(H)-isopropyl, -N(H)-cyclopropyl, -N(CH 3 ) 2 , -N (C 2 H 5 ) 2 , -N(H)-CH 2 -COOH, -N(H)-C 2 H 4 -OH, -N(H)-1-methylcyclopropyl, -N(H ) -C(CH 3 ) 2 -CH 2 -C(CH 3 ) 3 and pyrrolidin-1-yl; preferably, R 4 is -N(H)-C(CH 3 ) 3 .
  • m in the compound of formula I or formula III is 0 or 1
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl and C 3-6 cycloalkyl, wherein The C 1-4 alkyl group and the C 3-6 cycloalkyl group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 hydroxyalkyl and -NR 31 R 32 .
  • R 6 in the compound of formula II, formula IV, formula IV-A, formula IV-B or formula V is selected from hydrogen, halogen (preferably chlorine), C 1-4 alkyl (Preferably methyl) and C 3-6 cycloalkyl. In some more preferred embodiments of the present invention, R 6 in the compound of formula II, formula IV, formula IV-A, formula IV-B or formula V is hydrogen.
  • R 33 in the compound of formula V is selected from hydrogen, methyl and or ethyl; preferably; R 33 is hydrogen.
  • the present invention also provides specific compounds having the structure of formula X, formula II, formula IV, formula IV-A or formula V or their pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans Isomers, polymorphs, solvates, N-oxides, isotope markers, metabolites or prodrugs, including (but not limited to) compounds with structures and names as shown in the table below:
  • the present invention provides a method for preparing the compound of formula III-A and compound of formula III-B (when R 5 in formula III is hydrogen, it is the compound of formula III-A-1 and compound of formula III-B-1, respectively), It includes the following steps:
  • Step 1 Compound III-1 is halogenated to produce compound III-2;
  • X represents a halogen atom, selected from chlorine, bromine and iodine
  • Step 2 Compound III-2 is oxidized to generate compound III-3;
  • Step 3 Reaction of compound III-3 with R 2 H to produce compound III-4, wherein R 2 is connected to quinoline through a nitrogen atom;
  • Step 4 Compound III-4 is coupled to produce compound III-5;
  • Step 5-1 Compound III-5 is substituted to generate compound III-A-1;
  • Step 5-2 Compound III-5 is coupled to produce compound III-B-1;
  • R 1, R 2, R 3a , R 3b, L a and L b are as hereinbefore defined.
  • the halogenating agent that can be used in the halogenation reaction in step 1 includes phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, etc.; solvents that can be used Including 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, etc.; the reaction temperature is -20°C to 100°C.
  • the oxidizing agent that can be used in the oxidation reaction in the second step includes m-chloroperoxybenzoic acid, hydrogen peroxide, carbamide peroxide, etc.; the solvent that can be used includes dichloromethane, chloroform, 1, 2-Dichloroethane, 1,4-dioxane, etc.; the reaction temperature is -20°C to 100°C.
  • the solvent that can be used in the reaction in step 3 includes tetrahydrofuran, 1,4-dioxane, toluene, etc.; the reaction temperature is -20°C to 100°C.
  • the coupling reaction in step 4 includes Suzuki reaction, Stille reaction, etc.
  • R 1 passes through the boronic acid (for example, R 1 -B(OH) 2 ), boronic acid ester ( E.g ) Or organotin compounds (such as R 1 -Sn(n-Bu) 3 ) participate in the reaction
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2, etc.
  • usable bases include cesium carbonate (Cs 2 CO 3 ), potassium phosphate (K 3 PO 4 ), sodium carbonate (Na 2 CO 3 ), potassium acetate (AcOK), sodium bicarbonate (NaHCO 3 ), potassium carbonate (K 2 CO 3) 3 ) etc.
  • usable solvents are 1,4-dioxane/water (the slash indicates a combination of the two), N,N-dimethylformamide/water, dimethyl sulfoxide/
  • the solvent that can be used in the substitution reaction in step 5-1 is N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, etc.;
  • Alkaline reagents that can be used include triethylamine, N,N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.; the reaction temperature is -20°C to 180°C.
  • the coupling reaction in step 5-2 includes Suzuki reaction, Stille reaction, etc.
  • R 3b -L b is passed through the boronic acid containing it (for example, R 3b -L b -B(OH ) 2 ), borate (e.g.
  • organotin compounds such as R 3b -L b -Sn(n-Bu) 3
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 etc.
  • the alkaline reagents used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, etc.
  • the solvents that can be used are 1,4-dioxane/water, N,N-dimethylformaldehyde Amide/water, dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.
  • the reaction temperature is 60°C to 180°C.
  • the present invention provides the above-mentioned compound of formula III-A and compound of formula III-B (when R 5 in formula III is fluorine and m is 1, they are respectively the compound of formula III-A-2 and the compound of formula III-B-2)
  • the preparation method includes the following steps:
  • Step 1 Compound III-6 reacts with Meldrum's acid under the catalysis of Lewis acid to produce compound III-7;
  • Step 2 Compound III-7 undergoes condensation reaction to produce compound III-8;
  • Y represents a sulfonyl group, selected from the group consisting of methanesulfonyl (Ms), p-toluenesulfonyl (Ts) and trifluoromethanesulfonyl (Tf);
  • Step 3-1 Compound III-8 is substituted to generate compound III-9-1;
  • Step 3-2 Compound III-8 is coupled to produce compound I-9-2;
  • Step 4 Compounds III-9-1 and III-9-2 are halogenated to generate compounds III-10-1 and III-10-2, respectively;
  • X represents a halogen atom, selected from chlorine, bromine and iodine
  • Step 5 Compounds III-10-1 and III-10-2 are respectively reacted with R 2 H to generate compounds III-11-1 and III-11-2, wherein R 2 is connected to quinoline through a nitrogen atom;
  • Step 6 Compounds III-11-1 and III-11-2 are respectively coupled to generate compounds III-A-2 and III-B-2;
  • R 1, R 2, R 3a , R 3b, L a and L b are as hereinbefore defined.
  • the Lewis acid that can be used in the reaction in step 1 includes Eaton's reagent, aluminum trichloride, boron trifluoride, iron bromide, etc.; the solvent that can be used includes Tetrahydrofuran, 1,4-dioxane, toluene, etc.; the reaction temperature is 20°C to 100°C.
  • the basic reagents that can be used in the substitution reaction in step 2 include triethylamine, N,N-diisopropylethylamine, potassium carbonate, etc.; the solvent that can be used is tetrahydrofuran , 1,4-dioxane, toluene, etc.; the reaction temperature is 20°C to 100°C.
  • the solvent that can be used in the substitution reaction in step 3-1 includes N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, etc.;
  • Alkaline reagents that can be used include triethylamine, N,N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.; the reaction temperature is -20°C to 180°C.
  • the coupling reaction in step 3-2 includes Suzuki reaction, Stille reaction, etc., R 3b -L b is passed through the boronic acid containing it (for example, R 3b -L b -B(OH ) 2 ), borate (e.g.
  • organotin compounds such as R 3b -L b -Sn(n-Bu) 3
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 etc.
  • the alkaline reagents used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, etc.
  • the solvent that can be used is 1,4-dioxane/water (the slash indicates the combination of the two) , N,N-dimethylformamide/water, dimethylsulfoxide/water, acetonitrile/water, toluene/water, etc.
  • the reaction temperature is 60°C to 180°C.
  • the halogenating agent that can be used in the halogenation reaction in step 4 includes phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, etc.; solvents that can be used Including 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, etc.; the reaction temperature is -20°C to 100°C.
  • the solvent that can be used in the reaction in Step 5 includes tetrahydrofuran, 1,4-dioxane, toluene, etc.; the reaction temperature is -20°C to 100°C.
  • the coupling reaction in step 6 includes Suzuki reaction, Stille reaction, etc.
  • R 1 is passed through the boronic acid (for example, R 1 -B(OH) 2 ), boronic acid ester ( E.g ) Or organotin compounds (such as R 1 -Sn(n-Bu) 3 ) participate in the reaction
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2, etc.
  • usable bases include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, etc.
  • solvents that can be used are 1,4-dioxane/water, N,N-dimethylformamide/water , Dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.
  • the reaction temperature is 60°C to 180°C.
  • the method includes the following steps:
  • Step 1 Compound IV-1 is halogenated to produce compound IV-2;
  • X represents a halogen atom, selected from chlorine and bromine
  • Step 2 Compound IV-2 is reacted by iodine to generate compound IV-3;
  • Step 3 Compound IV-3 is oxidized to produce compound IV-4;
  • Step 4 Reaction of compound IV-4 with R 4 H to produce compound IV-5, wherein R 4 is connected to thienopyridine through a nitrogen atom;
  • Step 5 Compound IV-5 is coupled to produce compound IV-6;
  • Step 6-1 Compound IV-6 undergoes substitution reaction to generate compound IV-A-1;
  • Step 6-2 Compound IV-6 is coupled to produce compound IV-B-1;
  • R 1, R 3a, R 3b , R 4, L a and L b are as hereinbefore defined.
  • the halogenating agent that can be used in the halogenation reaction in step 1 includes phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, hydrogen bromide, etc.; solvents that can be used It is 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, etc.; the reaction temperature is -20°C to 100°C.
  • the iodinating agent that can be used in the iodination reaction in step 2 includes elemental iodine, N-iodosuccinimide (NIS), hydrogen iodide, etc.; solvents that can be used Including acetic acid, 1,4-dioxane, N,N-dimethylformamide, ethyl acetate, etc.; the reaction temperature is -20°C to 100°C.
  • the oxidants that can be used in the oxidation reaction in step 3 include m-chloroperoxybenzoic acid, hydrogen peroxide, carbamide peroxide, etc.; the solvents that can be used are dichloromethane, chloroform, 1, 2-Dichloroethane, 1,4-dioxane, etc.; the reaction temperature is -20°C to 100°C.
  • the solvent that can be used in the reaction in step 4 is tetrahydrofuran, 1,4-dioxane, toluene, etc.; the reaction temperature is -20°C to 100°C.
  • the coupling reaction in step 5 includes Suzuki reaction, Stille reaction, etc.
  • R 1 passes through the boronic acid (for example, R 1 -B(OH) 2 ), boronic acid ester ( E.g ) Or organotin compounds (such as R 1 -Sn(n-Bu) 3 ) participate in the reaction
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2, etc.
  • usable bases include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, etc.
  • solvents that can be used are 1,4-dioxane/water, N,N-dimethylformamide/water , Dimethyl sulfoxide/water, acetonitrile/water, toluene/water, etc.
  • the reaction temperature is 60°C to 180°C.
  • the solvent that can be used in the substitution reaction in step 6-1 includes N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, etc.;
  • Alkaline reagents that can be used include triethylamine, N,N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.; the reaction temperature is -20°C to 180°C.
  • the coupling reaction in step 6-2 includes Suzuki reaction, Stille reaction, etc., R 3b -L b is passed through the boronic acid containing it (for example, R 3b -L b -B(OH ) 2 ), borate (e.g.
  • organotin compounds such as R 3b -L b -Sn(n-Bu) 3
  • usable catalysts include Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 etc.
  • the alkaline reagents used include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, etc.
  • the solvent that can be used is 1,4-dioxane/water (the slash indicates the combination of the two) , N,N-dimethylformamide/water, dimethylsulfoxide/water, acetonitrile/water, toluene/water, etc.
  • the reaction temperature is 40°C to 180°C.
  • the preparation method of the compound and the compound of formula IV-B-2 which comprises the following steps:
  • Step 7 Compound IV-A-1' and compound IV-B-1' are deprotected to produce compound IV-A-2 and compound IV-B-2, respectively;
  • R 3a, R 3b, R 4 , L a and L b are as hereinbefore defined;
  • PG 1 and PG 2 represents a protecting group, each independently selected from tetrahydro -2H- pyran-2-yl (of THP), t Butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • the acids that can be used in the deprotection reaction in steps 7-1 and 7-2 include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aluminum chloride (Lewis acid) , P-toluenesulfonic acid, etc.; usable solvents are dichloromethane, ethyl acetate, 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, etc.; the reaction temperature is -10°C to 180°C.
  • the present invention provides a preparation method of the compound of the above formula V, which uses the intermediate compound IV-6 in the preparation method of the compound of the formula IV-A and the compound of the formula IV-B as a raw material, and specifically includes the following steps:
  • Step 1 Compound IV-6 is substituted or coupled to produce compound V;
  • R 1 , R 3 , R 4 , R 33 , L 2 , L 3 , p and q are as defined above.
  • the solvent that can be used in the substitution reaction in step 1 includes N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, etc.;
  • the alkaline reagents include triethylamine, N,N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.; the reaction temperature is -20°C to 180°C.
  • the coupling reaction in step 1 includes the Buchwald-Hartwig reaction;
  • the catalysts that can be used include Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 etc.
  • usable ligands include PPh 3 , BINAP, Xphos, Davephos, Brettphos, etc.
  • usable alkaline reagents include cesium carbonate, potassium phosphate, sodium carbonate, potassium acetate, Sodium bicarbonate, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, sodium hydroxide, etc.
  • solvents that can be used are 1,4-dioxane, N,N-dimethyl Formamide, dimethyl sulfoxide, acetonitrile, toluene, etc.
  • the reaction temperature is 40°C to 180°C
  • composition refers to a composition that can be used as a medicine, which comprises a pharmaceutical active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a pharmaceutical excipient that is compatible with the active ingredients of the drug and is administered together, and is harmless to the subject, and is suitable for contact with humans and/or other substances within the scope of reasonable medical judgment. Animal tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Common pharmaceutically acceptable carriers include (but are not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, Flavoring agents, preservatives, antioxidants, pH regulators, solvents, co-solvents, surfactants, etc. Examples of suitable pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences[M], Mack Printing Company, 1990.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V
  • the compound or a pharmaceutically acceptable form thereof comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V
  • the compound or a pharmaceutically acceptable form thereof comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V
  • the compound or a pharmaceutically acceptable form thereof comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V
  • the compound or a pharmaceutically acceptable form thereof comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A
  • the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • agonist refers to a compound that binds to a receptor and activates it to trigger a downstream biological effect or response, including full agonist and partial agonist Agent (partial agonist).
  • Full agonists can activate the receptor and produce the greatest effect (maximal effect or Emax).
  • a partial agonist can bind to the receptor and activate it, but compared to a full agonist, it only produces a partial effect.
  • the potency (potency, measured by EC 50 ) of a partial agonist may be higher or lower than the potency of a full agonist.
  • the NLRP3 agonists of the present invention include NLRP3 full agonists and NLRP3 partial agonists.
  • NLRP3 NLR family pyrin domain containing 3, which is an inflammasome.
  • the meaning includes NLRP3 nucleic acid, polynucleotide, oligonucleotide, sense and antisense polynucleotide chain, complementary sequence, short peptide, Polypeptides, proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various splicing bodies, alleles, different species and activated fragments, etc.
  • the compound of formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V or a pharmaceutically acceptable form thereof can also exhibit a regulatory effect (especially agonistic activity) on NLRP3, and can be used as NLRP3 modulators. Therefore, the present invention provides the above-mentioned compound of formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V or its pharmaceutically acceptable compounds.
  • the application also provides the above-mentioned compounds of formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V or their pharmaceutically
  • NLRP3 disease mediated at least in part by NLRP3 refers to a disease whose pathogenesis includes at least some of the factors related to NLRP3.
  • diseases include (but are not limited to) cancers (such as leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, etc.). Cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, colorectal cancer, stomach cancer, esophageal cancer, oral cancer, pancreatic cancer, liver cancer, lung cancer, kidney cancer, skin cancer, bone cancer, brain cancer, nerve glue Plasma, melanoma, etc.).
  • cancers such as leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, etc.
  • Cancer cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, colorectal cancer, stomach cancer, esophageal cancer, oral cancer, pancreatic cancer, liver cancer, lung cancer, kidney cancer, skin cancer, bone cancer, brain cancer, nerve glue Plasma
  • the present invention provides a method for preventing and/or treating diseases mediated at least in part by NLRP3, which comprises the following steps: a preventive and/or therapeutically effective amount of the above formula X, formula I, formula II, and formula III , Formula IV, Formula III-A, Formula III-B, Formula IV-A, Formula IV-B, or Formula V compound or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition is administered to an individual in need thereof.
  • preventive and/or therapeutically effective amount refers to the dose of the pharmaceutically active ingredient that can induce a biological or medical response in cells, tissues, organs, or organisms (for example, individuals) to achieve preventive and/or therapeutic effects.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered or several divided doses can be administered over time. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration).
  • the total is about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day.
  • a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose can still be used without causing any harmful side effects, provided that the larger dose is set in advance.
  • the dose is divided into several smaller doses and administered in divided doses throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition is about 0.01-1000 mg.
  • the term “treat/treating/treatment” refers to reversing, alleviating, or inhibiting the disorder or condition targeted, or the progression of one or more symptoms of such a disorder or condition.
  • administration refers to applying pharmaceutical active ingredients (such as the compound of the present invention) or a pharmaceutical composition containing the pharmaceutical active ingredient (such as the pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc. , In order to make the active ingredient of the medicine or the medicine composition come into contact with the individual or its cells, tissues, organs, biological fluids and other parts.
  • Suitable dosage forms include (but are not limited to) tablets, capsules, lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, suspensions, injections, elixirs, Syrup etc.
  • the term "has a need for it" refers to the doctor's or other nursing staff's judgment on the individual's needs or will benefit from the prevention and/or treatment process. This judgment is based on the doctor's or other nursing staff's expertise in their field of expertise. kind of factors.
  • the term "individual" refers to a human or non-human animal (e.g., a mammal).
  • exemplary human individuals include both human individuals suffering from diseases and normal human individuals.
  • exemplary animal individuals include all vertebrates, such as non-mammals (such as amphibians, reptiles, birds, etc.) and mammals (non-human primates, rodents, domestic animals, and/or domesticated animals, etc.).
  • the present invention provides a drug combination composition
  • a drug combination composition comprising the above formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or The compound of formula V or its pharmaceutically acceptable form or the above-mentioned pharmaceutical composition, and at least one other co-directional NLRP3 modulator.
  • the term "in the same direction" means that when at least two modulators are administered to a certain target, their adjustment directions should be substantially the same, or both exhibit agonistic effects or simultaneously exhibit antagonistic effects.
  • the above-mentioned drug combination composition contains Formula X, Formula I, Formula II, Formula III, Formula IV, Formula III-A, Formula III-B, Formula IV-A, Formula IV-
  • the pharmaceutical combination composition is suitable for the prevention and/or treatment of cancer; the same applies when
  • the above-mentioned drug combination composition comprises a compound of formula X, formula I, formula II, formula III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V as an NLRP3 antagonist
  • the drug combination composition is suitable for the prevention and/or treatment of immune diseases.
  • the present invention provides a method for preventing and/or treating cancer, which comprises the following steps: a preventive and/or therapeutically effective amount of the above formula X, formula I, formula II, formula III, and NLRP3 agonists
  • a preventive and/or therapeutically effective amount of the above formula X, formula I, formula II, formula III, and NLRP3 agonists The compound of formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical combination composition is applied to it Individuals in need.
  • the present invention provides a method for the prevention and/or treatment of immune diseases, which comprises the following steps: a preventive and/or therapeutically effective amount of the above formula X, formula I, formula II, and formula as an NLRP3 antagonist III, formula IV, formula III-A, formula III-B, formula IV-A, formula IV-B or formula V compound or its pharmaceutically acceptable form or the above-mentioned pharmaceutical composition or the above-mentioned drug combination composition is applied Individuals who need it.
  • the structure of the compound of the present invention is identified by hydrogen nuclear magnetic resonance spectroscopy ( 1 H-NMR) and/or mass spectrometry (MS).
  • 1 H-NMR chemical shifts ( ⁇ ) are recorded in parts per million (ppm). 1 H-NMR is measured by AVANCE III HD 400MHz nuclear magnetic instrument, the solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ), the internal standard is four Methylsilane (TMS). Common abbreviations have the following meanings: s: singlet; d: doublet; t: triplet; q: quartet; dd: doublet; qd: quartet; m: multiplet; br: Broad; J: Coupling constant; Hz: Hertz.
  • the monitoring of the reaction is carried out by TLC or LC-MS.
  • TLC uses silica gel GF 254 (Qingdao Ocean) as the stationary phase.
  • LC-MS uses Aglient 1260 Infinity/Aglient 6120 Quadrupole mass spectrometer.
  • the compound of the present invention can be separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography).
  • Prep-HPLC uses Agilent 1260 preparative liquid chromatograph, the detection wavelength is 214nm or 254nm; the chromatographic column is Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); the column temperature is 25°C, and the elution conditions are as follows:
  • Condition 1 10%-90% acetonitrile and 90%-10% ammonium formate aqueous solution (0.05%, w/v), 0-16min; flow rate: 24mL/min;
  • Condition 3 10%-90% acetonitrile and 90%-10% formic acid aqueous solution (0.05%, w/v), 0-16min; flow rate: 28mL/min;
  • Condition 4 10%-90% acetonitrile and 90%-10% ammonium bicarbonate aqueous solution (0.05%, w/v), 0-16min; flow rate: 28mL/min;
  • the flash column chromatography uses the Biotage flash column chromatograph.
  • the microwave reaction is carried out using a Biotage Initiator + microwave reactor.
  • reaction temperature is room temperature (15°C to 30°C).
  • the reagents used in this application are purchased from companies such as Acros Organics, Aldrich Chemical Company, or Terbo Chemical.
  • Step 1 Synthesis of 7-bromothieno[3,2-b]pyridine (compound 2b).
  • Step 2 Synthesis of 7-bromo-2-iodothieno[3,2-b]pyridine (compound 2c).
  • Step 3 Synthesis of 7-bromo-2-iodothieno[3,2-b]pyridine 4-oxide (compound 2d).
  • Step 4 Synthesis of 7-bromo-N-tert-butyl-2-iodothieno[3,2-b]pyridine-5-amine (compound 2e).
  • Step 5 7-Bromo-N-tert-butyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b ] Synthesis of pyridine-5-amine (compound 2f).
  • Example 1 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol (compound 2).
  • the first step 3-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2- b] Synthesis of pyridin-7-ylamino)-1-propanol (1b).
  • the first step 7-bromo-N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5-amine (2a )Synthesis.
  • the first step N 5 -tert-butyl-N 7 -(oxetan-3-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- Synthesis of 5-yl)thieno[3,2-b]pyridine-5,7-diamine (3a).
  • the first step N 5 -tert-butyl-N 7 -((R)-1-methoxyprop-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)- Synthesis of 1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (5a).
  • the first step N 5 -tert-butyl-N 7 -((3-methylpyridin-2-yl)methyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H -Pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (6a) synthesis.
  • Example 7 N 5 -tert-butyl-N 7 -(2-morpholinoethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine (Compound 8).
  • the first step N 5 -tert-butyl-N 7 -(2-morpholinoethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- Synthesis of phenyl)thieno[3,2-b]pyridine-5,7-diamine (7a).
  • Example 8 1-(2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)ethyl)- 2-pyrrolidone (compound 9).
  • the first step 1-(2-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3 ,2-b]Pyridin-7-ylamino)ethyl)-2-pyrrolidone (8a) synthesis.
  • the first step N 5 -tert-butyl-N 7 -(cyclopropylmethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) Synthesis of thieno[3,2-b]pyridine-5,7-diamine (9a).
  • the first step 3-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2- b] Synthesis of pyridin-7-ylamino)-2,2-dimethyl-1-propanol (10a).
  • the second step 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl Synthesis of propyl-1-propanol (Compound 11).
  • the first step N 5 -tert-butyl-N 7 -(2,2-difluoroethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5 -Yl)thieno[3,2-b]pyridine-5,7-diamine (11a).
  • Example 12 N 5 -tert-butyl-N 7 -isobutyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (compound 13 ).
  • the first step N 5 -tert-butyl-N 7 -isobutyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3 ,2-b]pyridine-5,7-diamine (12a).
  • Example 13 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2-(methoxymethyl Yl)-1-propanol (Compound 14).
  • the first step N 5 -tert-butyl-N 7 -(oxetan-3-ylmethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyridine Synthesis of azol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (13a).
  • the first step (3-((5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3, Synthesis of 2-b]pyridin-7-ylamino)methyl)oxetan-3-yl)methanol (14a).
  • the first step 2-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2- b] Synthesis of pyridin-7-ylamino)-N-cyclopropylacetamide (15a).
  • Example 16 2-((5-tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)(methyl)amino)ethanol ( Compound 17).
  • the first step 2-((5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2 -b] Synthesis of pyridin-7-yl)(methyl)amino)ethanol (16a).
  • the second step 2-((5-tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)(methyl)amino)ethanol( Compound 17) Synthesis.
  • Example 17 N 5 -tert-butyl-N 7 -(2-methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7- Diamine (Compound 18).
  • Example 18 N 7 -((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-N 5 -tert-butyl-2-(1H-pyrazole-5- Yl)thieno[3,2-b]pyridine-5,7-diamine (compound 19).
  • the first step (1R,5S,6s)-tert-butyl 6-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- Synthesis of 5-yl)thieno[3,2-b]pyridin-7-ylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (18a).
  • the first step ((1r,4r)-4-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) Synthesis of thieno[3,2-b]pyridin-7-ylamino)cyclohexanol (20a).
  • Step 2 (1r,4r)-4-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino) ring Synthesis of Hexanol (Compound 21).
  • Example 21 N 5 -tert-butyl-N 7 -((3-methyloxetan-3-yl)methyl)-2-(1H-pyrazol-5-yl)thieno[3 ,2-b]pyridine-5,7-diamine (compound 22).
  • the first step N 5 -tert-butyl-N 7 -((3-methyloxetan-3-yl)methyl)-2-(1-(tetrahydro-2H-pyran-2- Yl)-1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (21a).
  • Example 22 3-(5-(tert-butylamino)-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol ( Compound 23).
  • the first step Synthesis of 7-bromo-N-tert-butyl-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-5-amine (22a).
  • the first step N 5 -tert-butyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N 7 -((tetrahydro-2H- Synthesis of pyran-4-yl)methyl)thieno[3,2-b]pyridine-5,7-diamine (23a).
  • the first step Synthesis of 7-bromo-2-iodo-N-isopropylthieno[3,2-b]pyridine-5-amine (23a).
  • the third step 3-(5-(isopropylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2- b] Synthesis of pyridin-7-ylamino)-2,2-dimethyl-1-propanol (23c).
  • the fourth step 3-(5-(isopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl Synthesis of propyl-1-propanol (Compound 35).
  • the first step Synthesis of 7-bromo-2-iodo-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridine (25a).
  • trifluoromethanesulfonic anhydride (1190 mg) was added to 2d (500 mg) in dichloromethane (10 mL), and then tetrahydropyrrole (699.26 mg) was slowly added dropwise, and the reaction was stirred at 25°C for 2 hours. After quenching with water, the system was spin-dried, followed by flash column chromatography (eluent system A) to obtain compound 25a (240 mg).
  • the second step 7-bromo-5-(pyrrolidin-1-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[ 3,2-b] Synthesis of pyridine (25b).
  • the third step 2,2-Dimethyl-3-(5-(pyrrolidin-1-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- Synthesis of 5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol (25c).
  • the first step Synthesis of 7-bromo-2-iodo-N-(2,4,4-trimethylpent-2-yl)thieno[3,2-b]pyridin-5-amine (26a).
  • the compound has no MS response.
  • the second step 7-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(2,4,4-trimethylpentan Synthesis of -2-yl)thieno[3,2-b]pyridine-5-amine (26b).
  • the third step 2,2-Dimethyl-3-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-(2,4 Synthesis of ,4-Trimethylpent-2-ylamino)thieno[3,2-b]pyridin-7-ylamino)-1-propanol (26c).
  • the fourth step 3-(2-(1H-pyrazol-5-yl)-5-(2,4,4-trimethylpent-2-ylamino)thieno[3,2-b]pyridine- Synthesis of 7-ylamino)-2,2-dimethyl-1-propanol (Compound 75).
  • Example 27 3-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2- b] Pyridin-7-ylamino)-1-propanol (Compound 76).
  • Experimental Example 1 The agonistic effect of the compound of the present invention on IL-1 ⁇ expression in THP-1 cells after PMA-induced differentiation.
  • the HTRF homogeneous time-resolved fluorescence detection method was used to test the effect of the compound of the present invention on the level of NLRP3 downstream cytokine IL-1 ⁇ , in order to evaluate the effect of the compound on the hNLRP3 inflammasome or hNLRP3 inflammasome pathway at the cellular level The excitatory effect.
  • RPMI 1640 Hyclone
  • FBS fetal bovine serum
  • PMA phorbol myristyl acetate
  • Kit IL-1 ⁇ detection kit (CISBIO).
  • THP-1 cells in the logarithmic growth phase were seeded in a T75 culture flask at a density of 5 ⁇ 10 5 cells/well, and then cultured in a 37°C, 5% CO 2 cell incubator for 24 hours.
  • 1 ⁇ M PMA induces THP-1 suspension cells to become adherent macrophages;
  • the medium is RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM ⁇ -mercaptoethanol;
  • Experimental Example 2 The agonistic effect of the compound of the present invention on IL-1 ⁇ expression in NLRP3-deficient THP1 cells (THP1- def NLRP3 cells) after PMA-induced differentiation.
  • the HTRF detection method was used to test the effect of the compound of the present invention on the level of IL-1 ⁇ in THP1-def NLRP3 cells to evaluate the specificity of the compound on hNLRP3 inflammasome or hNLRP3 inflammasome pathway agonism.
  • THP1-def NLRP3 cells in the logarithmic growth phase were seeded in a T75 culture flask at a density of 5 ⁇ 10 5 cells/well, and then cultured in an incubator at 37°C and 5% CO 2 for 24 hours.
  • 1 ⁇ M PMA induces THP1- def NLRP3 suspension cells to become adherent macrophages; the medium is RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM ⁇ -mercaptoethanol;
  • the luciferase in HEK-hTLR7-NF- ⁇ B-reporter cells was tested to test the activating effect of the compound of the present invention on the TLR7 signaling pathway, so as to evaluate the specificity of the compound's agonistic effect on the NLRP3 pathway.
  • DMEM High glucose
  • FBS fetal bovine serum
  • HEK-hTLR7-NF- ⁇ B-Luciferase gene cells human TLR7NF- ⁇ B-luciferase reporter gene cells (Nanjing Kebai).
  • Kit Bright-Glo TM Luciferase detection kit (Promega).
  • the HEK-hTLR7-NF- ⁇ B-Luciferase gene cells in the logarithmic growth phase were trypsinized, resuspended in culture medium to a concentration of 2 ⁇ 10 6 cells/mL, and 50 ⁇ L/well cell resuspension was added to In a 96-well plate, the number of cells per well is 1 ⁇ 10 6 ; take an appropriate amount of 10 mM DMSO solution of the test compound, prepare 2 ⁇ test concentration with medium, and add 50 ⁇ L/well to the cells in the 96-well plate.
  • the 96-well plate is placed in an incubator at 37°C and 5% CO 2 for 16 hours; the medium is DMEM containing 10% FBS;
  • the secretion of alkaline phosphatase in the HEK-Blue cell line was tested to test the activating effect of the compound of the present invention on the TLR8 signaling pathway, so as to evaluate the specificity of the compound's agonistic effect on the NLRP3 pathway.
  • DMEM High glucose
  • FBS Gabco
  • QUANTI-Blue InvivoGen/rep-qb2.
  • HEK-Blue TM hTLR8 cells human TLR8 cells (InvivoGen).
  • the HEK-Blue TM hTLR8 cells in the logarithmic growth phase were trypsinized, resuspended in culture medium to a concentration of 2 ⁇ 10 6 cells/mL, and 50 ⁇ L/well cell suspension was added to a 96-well plate; An appropriate amount of 10mM DMSO solution of the compound to be tested is prepared with culture medium to 2 ⁇ test concentration, and 50 ⁇ L/well is added to the cells in a 96-well plate; the plate is placed in an incubator at 37°C and 5% CO 2 for 16 hours ; The medium is DMEM containing 10% FBS.
  • the compounds of the present invention represented by the compounds listed in Table 1 have a significant agonistic effect on the expression of IL-1 ⁇ in THP-1 cells after PMA-induced differentiation, but on IL-1 ⁇ in THP-1 def NLRP3 cells.
  • the expression has no agonistic effect even at the highest compound tested concentration (30 ⁇ M). All compounds tested had no activating effect on hTLR7 and hTLR8 at 100 ⁇ M.
  • the compounds of the present invention represented by the compounds listed in Table 1 have obvious specific agonistic activity on hNLRP3 and/or its signal pathway.

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Abstract

La présente invention s'inscrit dans le domaine de la chimie médicinale, et concerne un composé azoté hétérocyclique, et une composition pharmaceutique le contenant, son procédé de préparation et une utilisation associée. En particulier, la présente invention concerne un composé de la structure de formule II, lequel composé a un effet de régulation de NLRP3 significatif, peut être utilisé en tant que régulateur de NLRP3 efficace et a une activité antitumorale.
PCT/CN2020/106080 2019-09-29 2020-07-31 Composé azoté hétérocyclique, composition pharmaceutique le contenant, son procédé de préparation et utilisation associée WO2021057256A1 (fr)

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CN1671714A (zh) * 2002-06-14 2005-09-21 辉瑞大药厂 可用作治疗剂的噻吩并吡啶的苯并稠合杂芳基酰胺衍生物,包括它的药物组合物,及其使用方法
CN1714092A (zh) * 2002-11-25 2005-12-28 惠氏公司 作为蛋白激酶抑制剂的噻吩并[3,2－b]吡啶－6－腈和噻吩并[2,3－b]吡啶－5－腈
EP1724268A1 (fr) * 2004-02-20 2006-11-22 Kirin Beer Kabushiki Kaisha Compose ayant une activite d'inhibition du tgf-beta et composition pharmaceutique contenant celui-ci
CN1993129A (zh) * 2004-06-04 2007-07-04 阿斯利康(瑞典)有限公司 用于药物的噻吩并嘧啶和噻唑并嘧啶
CN104936963A (zh) * 2012-11-20 2015-09-23 Ktb肿瘤研究有限责任公司 作为蛋白激酶抑制剂的硫醚衍生物
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