WO2021057256A1 - Heterocyclic nitrogen compound, pharmaceutical composition containing same, preparation method therefor and use thereof - Google Patents

Heterocyclic nitrogen compound, pharmaceutical composition containing same, preparation method therefor and use thereof Download PDF

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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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French (fr)
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/en
Publication of WO2021057256A1 publication Critical patent/WO2021057256A1/en

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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.

Abstract

The present invention falls within the field of medicinal chemistry, and relates to a heterocyclic nitrogen compound, and a pharmaceutical composition containing same, a preparation method therefor and a use thereof. In particular, provided in the present invention is a compound of the structure of formula II, which compound has a significant NLRP3 regulation effect, can be used as an efficient NLRP3 regulator, and has an anti-tumour activity.

Description

一种含氮并环类化合物，包含其的药物组合物，其制备方法及其用途A nitrogen-containing hexacyclic compound, a pharmaceutical composition containing the same, its preparation method and its use
相关申请的引用References to related applications
本发明要求2019年9月29日在中国提交的，名称为“一种含氮并环类化合物，包含其的药物组合物，其制备方法及其用途”、申请号为201910932795.2的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。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.
技术领域Technical field
本发明属于药物化学领域，涉及一种具有NLRP3调节活性的新型含氮并环类化合物，其制备方法，包含其的药物组合物，及其医药用途。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.
背景技术Background technique
NLRP3(NLR family pyrin domain containing 3)属于NLR(NOD-like receptors)家族，是近年来研究最多的一种细胞内模式识别受体，主要表达于巨噬细胞和嗜中性粒细胞，参与机体固有免疫，抵抗病原体感染和应激损伤。NLRP3炎症小体在炎性和代谢类疾病中的作用十分明确，其过度活化会导致2型糖尿病、类风湿性关节炎和动脉粥样硬化等免疫性疾病。然而，近年来的研究表明，NLRP3有抑制肿瘤生长和转移的抗肿瘤作用。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蛋白在识别PAMP(pathogen-associated molecular patterns)或DAMP(damage-associated molecular patterns)后，其NOD结构域发生寡聚化并招募ASC和pro-caspase-1等蛋白，形成具有功能的NLRP3炎症小体。在pro-caspase-1被剪切活化成caspase-1之后，caspase-1大量剪切pro-IL-1β和pro-IL-18，使之转化成活性形式IL-1β和IL-18并释放到胞外，放大炎性反应。激动的NLRP3炎症小体可以显著提高肿瘤微环境中免疫因子IL-1β和IL-18的水平，启动天然免疫杀伤以及后续的获得性免疫应答，以发挥其抗肿瘤作用。具体地，IL-1β可诱导CD8+T细胞分泌干扰素γ(IFN-γ)，也可诱导CD4+T细胞分泌IL-17，导致有效的抗肿瘤免疫效应；而IL-18则能够促进NK细胞成熟，激活免疫细胞内STAT1下游信号通路，增强免疫细胞的杀伤功能。临床研究显示，NLRP3的下调与肝癌病人的预后呈显著负相关。临床前研究也显示，NLRP3缺陷小鼠结直肠肿瘤的形成率更高，且结直肠癌肝转移更加恶化。由此可见，NLRP3在肿瘤微环境中起着重要作用，可以作为肿瘤免疫治疗的一个关键靶点，也可作为肿瘤预后标志物。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-1β and pro-IL-18 in a large amount to convert them into active forms of IL-1β and IL-18 and release them to Extracellular, amplify the inflammatory response. Agitated NLRP3 inflammasome can significantly increase the levels of the immune factors IL-1β and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent adaptive immune responses to exert its anti-tumor effects. Specifically, IL-1β can induce CD8+ T cells to secrete interferon γ (IFN-γ), 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. Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of liver cancer patients. Preclinical studies have also shown that 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.
WO2017184746、WO2017184735、WO2018152396和WO2019014402公开了NLRP3调节剂。尽管NLRP3激动剂有肿瘤免疫治疗的潜能，但目前仅有一个化合物处于临床I期研究。因此，需要开发新的、高效低毒的NLRP3激动剂来满足临床治疗需求。WO2017184746, WO2017184735, WO2018152396 and WO2019014402 disclose 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.
发明内容Summary of the invention
发明要解决的问题The problem to be solved by the invention
本发明旨在提供对于NLRP3具有调节作用的新型含氮并环类化合物，该化合物可以在蛋白水平上直接结合或修饰NLRP3，通过活化、稳定、改变NLRP3分布等方式来增强NLRP3炎症小体的功能。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. .
用于解决问题的方案Solution to the problem
第一方面，本发明提供了一种具有式II结构的化合物或其药学上可接受的形式，In the first aspect, the present invention provides a compound having the structure of formula II or a pharmaceutically acceptable form thereof,
Figure PCTCN2020106080-appb-000001
Figure PCTCN2020106080-appb-000001
其中，among them,
X 1选自-C(R 6)＝和-N＝； X 1 is selected from -C(R 6 )= and -N=;
X 2选自-C(-L-R 3)＝和-N＝；当同时存在多个L和R 3时，各个L或R 3彼此相同或不同； X 2 is selected from -C(-LR 3 )= and -N=; when there are multiple L and R 3 at the same time, each L or R 3 is the same or different from each other;
R 1选自C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，其中所述C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-OR 37和-SR 37； 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 Each of the heterocyclic groups is optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -OC(= O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -OR 37 and -SR 37 ;
R 4为NR 41aR 41b；R 41a和R 41b各自独立地选自氢、C 1-6烷基、C 1-6烷氧基和C 3-8环烷基，或者R 41a和R 41b连同与其连接的N原子一起形成4-7元杂环基，其中所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-7元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、4-7元杂环基、氰基、硝基、-OR 37、-SR 37、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-C(＝O)OR 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 31R 32，且R 41a和R 41b不同时为氢； R 4 is NR 41a R 41b ; R 41a and R 41b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b together Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is formed, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each any Optionally substituted by one or more substituents, each of the substituents is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 member Heterocyclic group, cyano group, nitro group, -OR 37 , -SR 37 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 ,- C(=O)OR 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 31 R 32 , and R 41a It is not hydrogen at the same time as R 41b;
R 6选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32； 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 ;
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基和-NR 31R 32；n、p和q各自独立地为0、1或2； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from C 1-8 alkylene and C 2-8 alkenylene Group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered Heteroaryl, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, where The C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heteroalkylene group The cyclic group, C 6-12 arylene group and 5-10 membered heteroarylene group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and -NR 31 R 32 ; n, p and q are each independently 0, 1 or 2;
R 3选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40、-P(＝O)(OR 39)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-N＝NR 38、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40和-P(＝O)(OR 39)OR 30； R 3 is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C(=NR 38 )NR 31 R 32 , -P(R 39 ) 2 , -P(OR 39 ) 2 , -P(=O)R 39 R 40 , -P(=O)(OR 39 )OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , where The C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more substituents, each of which is individually Independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy Group, C 1-4 hydroxyalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, -C(=O) OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 ,- OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C (=NR 38 )NR 31 R 32 , -N=NR 38 , -P(R 39 ) 2 , -P(OR 39 ) 2. -P(=O)R 39 R 40 and -P(=O)(OR 39 )OR 30 ;
R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 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 haloalkoxy, -C(=O)O( C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)R 35 , -S(=O ) 2 R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 35选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32； R 35 is selected from 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), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one or more substituents, each of said substituents Each is independently selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, -C(=O )O(C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)CH 3 , -S (=O) 2 CH 3 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 31、R 32、R 33和R 34各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基，或者R 31和R 32连同与其连接的N原子一起形成4-8元杂环基，或者R 33和R 34连同与其对应连接的N原子和C原子一起形成4-8元杂环基，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-8元杂环基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基； 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 Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl;
R 36a和R 36b各自独立地选自氢、C 1-8烷基和C 1-8烷氧基，其中所述C 1-8烷基和C 1-8烷氧基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、氨基、甲氨基和二甲氨基，或者R 36a和R 36b连同与其连接的C原子一起形成3-7元环烷基或杂环基； 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;
R 38选自氢、羟基、氰基、硝基、-S(＝O)R 35和-S(＝O) 2R 35；并且 R 38 is selected from hydrogen, hydroxyl, cyano, nitro, -S(=O)R 35 and -S(=O) 2 R 35 ; and
当同时存在多个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39和/或R 40时，各个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39或R 40彼此相同或不同； When there are multiple 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 at the same time, each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 or R 40 are the same or different from each other;
所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、共晶、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。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.
第二方面，本发明提供了具有式II、式IV、式IV-A或式V结构的具体化合物，其包括：In the second aspect, the present invention provides specific compounds having the structure of formula II, formula IV, formula IV-A or formula V, which include:
(1)4-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2-甲基-2-丁醇；(1) 4-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2-methyl-2- Butanol
(2)3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(2) 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(3)3-(5-(叔丁氨基)-2-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(3) 3-(5-(tert-butylamino)-2-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino) -1-propanol;
(4)N 5-叔丁基-N 7-(氧杂环丁烷-3-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (4) N 5 -tert-butyl-N 7 -(oxetan-3-yl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5, 7-diamine;
(5)N 5-叔丁基-N 7-(环丁基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (5) N 5 -tert-butyl-N 7 -(cyclobutylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine;
(6)(R)-N 5-叔丁基-N 7-(1-甲氧基丙-2-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (6) (R)-N 5 -tert-butyl-N 7 -(1-methoxyprop-2-yl)-2-(1H-pyrazol-5-yl)thieno[3,2-b ]Pyridine-5,7-diamine;
(7)N 5-叔丁基-N 7-((3-甲基吡啶-2-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (7) N 5 -tert-butyl-N 7 -((3-methylpyridin-2-yl)methyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b] Pyridine-5,7-diamine;
(8)N 5-叔丁基-N 7-(2-吗啉基乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (8) N 5 -tert-butyl-N 7 -(2-morpholinoethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7- Diamine
(9)1-(2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)乙基)-2-吡咯烷酮；(9) 1-(2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)ethyl)-2 -Pyrrolidone;
(10)N 5-叔丁基-N 7-(环丙基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (10) N 5 -tert-butyl-N 7 -(cyclopropylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine ；
(11)3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(11) 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol;
(12)N 5-叔丁基-N 7-(2,2-二氟乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (12) N 5 -tert-butyl-N 7 -(2,2-difluoroethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine;
(13)N 5-叔丁基-N 7-异丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (13) N 5 -tert-butyl-N 7 -isobutyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine;
(14)3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2-(甲氧甲基)-1-丙醇；(14) 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2-(methoxymethyl )-1-propanol;
(15)(3-((5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)甲基)氧杂环丁烷-3-基)甲醇；(15)(3-((5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)methyl)oxyheterocycle Butane-3-yl)methanol;
(16)2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-N-环丙基乙酰胺；(16) 2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-N-cyclopropylacetamide ；
(17)2-((5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基)(甲基)氨基)乙醇；(17) 2-((5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)(methyl)amino)ethanol;
(18)N 5-叔丁基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (18) N 5 -tert-butyl-N 7 -(2-methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-di amine;
(19)N 7-((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)-N 5-叔丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (19) N 7 -((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-N 5 -tert-butyl-2-(1H-pyrazol-5-yl ) Thieno[3,2-b]pyridine-5,7-diamine;
(20)(R)-2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-4-甲基-1-戊醇；(20)(R)-2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-4-methyl -1-pentanol;
(21)(1r,4r)-4-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)环己醇；(21)(1r,4r)-4-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)cyclohexane alcohol;
(22)N 5-叔丁基-N 7-((3-甲基氧杂环丁烷-3-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (22) N 5 -tert-butyl-N 7 -((3-methyloxetan-3-yl)methyl)-2-(1H-pyrazol-5-yl)thieno(3, 2-b]pyridine-5,7-diamine;
(23)3-(5-(叔丁氨基)-2-(6-甲基吡啶-2-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(23) 3-(5-(tert-butylamino)-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(24)N 5-叔丁基-2-(1H-吡唑-5-基)-N 7-((四氢-2H-吡喃-4-基)甲基)噻吩并[3,2-b]吡啶-5,7-二胺； (24) N 5 -tert-butyl-2-(1H-pyrazol-5-yl)-N 7 -((tetrahydro-2H-pyran-4-yl)methyl)thieno(3,2- b] pyridine-5,7-diamine;
(25)2,2-二甲基-3-(5-(甲氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(25) 2,2-Dimethyl-3-(5-(methylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)- 1-propanol;
(26)3-(5-(甲氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(26) 3-(5-(methylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(27)N 7-(2,2-二氟乙基)-N 5-甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (27) N 7 -(2,2-Difluoroethyl)-N 5 -methyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7- Diamine
(28)N 7-(环丙基甲基)-N 5-甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (28) N 7 -(cyclopropylmethyl)-N 5 -methyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine;
(29)N 7-(2-甲氧乙基)-N 5-甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (29) N 7 -(2-methoxyethyl)-N 5 -methyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine ；
(30)3-(5-(乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(30) 3-(5-(Ethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl- 1-propanol;
(31)3-(5-(乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(31) 3-(5-(Ethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(32)N 7-(2,2-二氟乙基)-N 5-乙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (32) N 7 -(2,2-difluoroethyl)-N 5 -ethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7- Diamine
(33)N 7-(环丙基甲基)-N 5-乙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (33) N 7 -(cyclopropylmethyl)-N 5 -ethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine;
(34)N 5-乙基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (34) N 5 -Ethyl-N 7 -(2-Methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine ；
(35)3-(5-(异丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(35) 3-(5-(Isopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol;
(36)3-(5-(异丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(36) 3-(5-(isopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(37)N 7-(2,2-二氟乙基)-N 5-异丙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (37) N 7 -(2,2-Difluoroethyl)-N 5 -isopropyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine;
(38)N 7-(环丙基甲基)-N 5-异丙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (38) N 7 -(Cyclopropylmethyl)-N 5 -isopropyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine ；
(39)N 5-异丙基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (39) N 5 -isopropyl-N 7 -(2-methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-di amine;
(40)3-(5-(环丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(40) 3-(5-(Cyclopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol;
(41)3-(5-(环丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(41) 3-(5-(Cyclopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(42)N 5-环丙基-N 7-(2,2-二氟乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (42) N 5 -Cyclopropyl-N 7 -(2,2-Difluoroethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine;
(43)N 5-环丙基-N 7-(环丙基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (43) N 5 -Cyclopropyl-N 7 -(Cyclopropylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine ；
(44)N 5-环丙基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (44) N 5 -Cyclopropyl-N 7 -(2-Methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-di amine;
(45)3-(5-(二甲氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(45) 3-(5-(Dimethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol;
(46)3-(5-(二甲氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(46) 3-(5-(Dimethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(47)N 7-(2,2-二氟乙基)-N 5,N 5-二甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (47) N 7 -(2,2-difluoroethyl)-N 5 ,N 5 -dimethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine- 5,7-diamine;
(48)N 7-(环丙基甲基)-N 5,N 5-二甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (48) N 7 -(cyclopropylmethyl)-N 5 ,N 5 -dimethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine;
(49)N 7-(2-甲氧乙基)-N 5,N 5-二甲基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (49) N 7 -(2-methoxyethyl)-N 5 ,N 5 -dimethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5, 7-diamine;
(50)3-(5-(二乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(50) 3-(5-(Diethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol;
(51)3-(5-(二乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(51) 3-(5-(Diethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(52)N 7-(2,2-二氟乙基)-N 5,N 5-二乙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (52) N 7 -(2,2-difluoroethyl)-N 5 ,N 5 -diethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine- 5,7-diamine;
(53)N 7-(环丙基甲基)-N 5,N 5-二乙基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (53) N 7 -(cyclopropylmethyl)-N 5 ,N 5 -diethyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Diamine;
(54)N 5,N 5-二乙基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (54) N 5 , N 5 -Diethyl-N 7 -(2-methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5, 7-diamine;
(55)3-(2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(55) 3-(2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2- Dimethyl-1-propanol;
(56)3-(2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(56) 3-(2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol ；
(57)N-(2,2-二氟乙基)-2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-胺；(57) N-(2,2-Difluoroethyl)-2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridine- 7-amine;
(58)N-(环丙基甲基)-2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-胺；(58) N-(Cyclopropylmethyl)-2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridine-7-amine ；
(59)N-(2-甲氧乙基)-2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-胺；(59) N-(2-Methoxyethyl)-2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridine-7- amine;
(60)2-(7-(3-羟基-2,2-二甲基丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙酸；(60) 2-(7-(3-hydroxy-2,2-dimethylpropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-yl (Amino)acetic acid;
(61)2-(7-(3-羟基丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙酸；(61) 2-(7-(3-hydroxypropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)acetic acid;
(62)2-(7-(2,2-二氟乙基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙酸；(62) 2-(7-(2,2-Difluoroethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)acetic acid;
(63)2-(7-(环丙基甲基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙酸；(63) 2-(7-(Cyclopropylmethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)acetic acid;
(64)2-(7-(2-甲氧乙基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙酸；(64) 2-(7-(2-methoxyethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)acetic acid;
(65)3-(5-(2-羟基乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；(65) 3-(5-(2-Hydroxyethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-di Methyl-1-propanol;
(66)3-(5-(2-羟基乙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(66) 3-(5-(2-hydroxyethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol;
(67)2-(7-(2,2-二氟乙基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙醇；(67) 2-(7-(2,2-Difluoroethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)ethanol;
(68)2-(7-(环丙基甲基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙醇；(68) 2-(7-(Cyclopropylmethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)ethanol;
(69)2-(7-(2-甲氧乙基氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-基氨基)乙醇；(69) 2-(7-(2-methoxyethylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-5-ylamino)ethanol;
(70)2,2-二甲基-3-(5-(1-甲基环丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(70) 2,2-Dimethyl-3-(5-(1-methylcyclopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-7 -Base amino)-1-propanol;
(71)3-(5-(1-甲基环丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇；(71) 3-(5-(1-Methylcyclopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propan alcohol;
(72)N 7-(2,2-二氟乙基)-N 5-(1-甲基环丙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (72)N 7 -(2,2-Difluoroethyl)-N 5 -(1-methylcyclopropyl)-2-(1H-pyrazol-5-yl)thieno(3,2-b ]Pyridine-5,7-diamine;
(73)N 7-(环丙基甲基)-N 5-(1-甲基环丙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (73) N 7 -(cyclopropylmethyl)-N 5 -(1-methylcyclopropyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine- 5,7-diamine;
(74)N 7-(2-甲氧乙基)-N 5-(1-甲基环丙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺； (74) N 7 -(2-methoxyethyl)-N 5 -(1-methylcyclopropyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine -5,7-diamine;
(75)3-(2-(1H-吡唑-5-基)-5-(2,4,4-三甲基戊-2-基氨基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇；和(75) 3-(2-(1H-pyrazol-5-yl)-5-(2,4,4-trimethylpent-2-ylamino)thieno[3,2-b]pyridine-7 -Amino)-2,2-dimethyl-1-propanol; and
(76)3-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇。(76) 3-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b ]Pyridin-7-ylamino)-1-propanol.
第三方面，本发明提供了式IV-A化合物与式IV-B化合物(当式IV中的X 1为-CH＝时，分别为式IV-A-1化合物与式IV-B-1化合物)的制备方法，其包括下列步骤： In the third aspect, the present invention provides a compound of formula IV-A and a compound of formula IV-B (when X 1 in formula IV is -CH=, it is a compound of formula IV-A-1 and a compound of formula IV-B-1, respectively ) The preparation method, which comprises the following steps:
第1步：化合物IV-1经卤代反应生成化合物IV-2；Step 1: Compound IV-1 is halogenated to produce compound IV-2;
Figure PCTCN2020106080-appb-000002
Figure PCTCN2020106080-appb-000002
X代表卤素原子，选自氯和溴；X represents a halogen atom, selected from chlorine and bromine;
第2步：化合物IV-2经碘代反应生成化合物IV-3；Step 2: Compound IV-2 is reacted by iodine to generate compound IV-3;
Figure PCTCN2020106080-appb-000003
Figure PCTCN2020106080-appb-000003
第3步：化合物IV-3经氧化反应生成化合物IV-4；Step 3: Compound IV-3 is oxidized to produce compound IV-4;
Figure PCTCN2020106080-appb-000004
Figure PCTCN2020106080-appb-000004
第4步：化合物IV-4与R 4H反应生成化合物IV-5，其中R 4通过氮原子与噻吩并吡啶相连； 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;
Figure PCTCN2020106080-appb-000005
Figure PCTCN2020106080-appb-000005
第5步：化合物IV-5经偶联反应生成化合物IV-6；Step 5: Compound IV-5 is coupled to produce compound IV-6;
Figure PCTCN2020106080-appb-000006
Figure PCTCN2020106080-appb-000006
第6-1步：化合物IV-6经取代反应生成化合物IV-A-1；Step 6-1: Compound IV-6 undergoes substitution reaction to generate compound IV-A-1;
Figure PCTCN2020106080-appb-000007
Figure PCTCN2020106080-appb-000007
第6-2步：化合物IV-6经偶联反应生成化合物IV-B-1；Step 6-2: Compound IV-6 is coupled to produce compound IV-B-1;
Figure PCTCN2020106080-appb-000008
Figure PCTCN2020106080-appb-000008
其中R 1、R 3a、R 3b、R 4、L a和L b如本文中所定义。 Wherein R 1, R 3a, R 3b , R 4, L a and L b are as defined herein.
本发明还提供了式IV-A化合物与式IV-B化合物(当式IV中的X 1为-CH＝且R 1为1H-吡唑-5-基时，分别为式IV-A-2化合物与式IV-B-2化合物)的制备方法，其包括下列步骤： The present invention also provides a compound of formula IV-A and a compound of formula IV-B (when X 1 in formula IV is -CH= and R 1 is 1H-pyrazol-5-yl, respectively, formula IV-A-2 The preparation method of the compound and the compound of formula IV-B-2), which comprises the following steps:
第7步：化合物IV-A-1’和化合物IV-B-1’分别经脱保护基反应生成化合物IV-A-2和化合物IV-B-2；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;
Figure PCTCN2020106080-appb-000009
Figure PCTCN2020106080-appb-000009
其中R 3a、R 3b、R 4、L a和L b如本文中所定义；PG 1和PG 2代表保护基，各自独立地选自四氢-2H-吡喃-2-基、叔丁氧羰基和苄氧羰基。 Wherein R 3a, R 3b, R 4 , L a and L b as defined herein; PG 1 and PG 2 represents a protecting group, each independently selected from tetrahydro -2H- pyran-2-yl, tert Carbonyl and benzyloxycarbonyl.
第四方面，本发明提供了式V化合物的制备方法，其包括下列步骤：In a fourth aspect, the present invention provides a method for preparing a compound of formula V, which comprises the following steps:
第1步：化合物IV-6经取代或偶联反应生成化合物V；Step 1: Compound IV-6 is substituted or coupled to produce compound V;
Figure PCTCN2020106080-appb-000010
Figure PCTCN2020106080-appb-000010
其中R 1、R 3、R 4、R 33、L 2、L 3、p和q如本文中所定义。 Wherein R 1 , R 3 , R 4 , R 33 , L 2 , L 3 , p and q are as defined herein.
第五方面，本发明提供了一种药物组合物，其包含具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式，以及药学上可接受的载体。In the fifth aspect, the present invention provides 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.
第六方面，本发明提供了具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物，其用作NLRP3调节剂，优选用作NLRP3激动剂。In the sixth aspect, 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.
第七方面，本申请提供了具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物在制备用于预防和/或治疗至少部分由NLRP3介导的疾病的药物中的用途。In the seventh aspect, 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.
第八方面，本发明提供了一种用于预防和/或治疗至少部分由NLRP3介导的疾病的方法，其包括下列步骤：将预防和/或治疗有效量的具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物施用于对其有需求的个体。In the eighth aspect, 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.
第九方面，本发明提供了一种药物联用组合物，其包含具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物，以及至少一种其他的同向NLRP3调节剂。In a ninth aspect, the present invention provides 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.
第十方面，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3激动剂的具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物或者药物联用组合物施用于对其有需求的个体。In a tenth aspect, 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.
第十一方面，本发明提供了一种用于预防和/或治疗免疫性疾病的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3拮抗剂的具有式II、式IV、式IV-A或式V结构的化合物或其药学上可接受的形式或者药物组合物或者药物联用组合物施用于对其有需求的个体。In an eleventh aspect, 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 , 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.
发明的效果The effect of the invention
本发明的化合物对NLRP3及其信号通路具有明显的激动活性，无明显毒副作用，可用于细胞增殖异常性疾病(例如癌症)的治疗。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).
具体实施方式detailed description
在进一步描述本发明之前，应当理解，本发明不限于本文中所述的特定实施方案；还应该理解，文中所使用的术语仅用于描述而非限制特定实施方案。Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein; it should also be understood that the terms used in the text are only used to describe rather than limit the specific embodiments.
[术语定义][Definition of Terms]
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图是指在本领域中通常所理解的技术，包括那些对本领域 技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. Mention of the technology used herein is intended to refer to the technology generally understood in the art, including those technical changes or equivalent technology substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.
术语“包含”、“包括”、“具有”或“含有”或其任何其他变体为包含性的(inclusive)或开放式的(open-ended)，旨在涵盖非排他性的包含内容。例如，包含一系列元素的组合物、方法或装置不一定仅限于已明确列出的元素，而是可能还包含其他未明确列出的元素或上述组合物、方法或装置所固有的元素。The terms "comprising", "including", "having" or "containing" or any other variations thereof are inclusive or open-ended and are intended to cover non-exclusive inclusions. For example, a composition, method, or device 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.
“药学上可接受的盐”是指对生物体基本上无毒性的，本发明的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机/有机酸或无机/有机碱反应而形成的盐，此类盐又被称为酸加成盐或碱加成盐。适合的药学上可接受的盐的实例可参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use[M],Wiley-VCH,2002。"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.
术语“异构体”是指因具有相同的原子数和原子类型而具有相同的分子量，但原子的空间排列或构型不同的化合物。The term "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.
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本发明的化合物存在可能导致立体异构的不对称中心以及其他化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物(或其药学上可接受的盐)包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。如下文中所述，化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂，或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的旋光异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出，本发明的化合物的所有立体异构体形式都在本发明的范围之内。The term "stereoisomer" (or "optical isomer") 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. However, if necessary, such compounds can be prepared or separated to obtain pure stereoisomers, that is, single enantiomers or diastereomers, or enrichment of single stereoisomers (purity ≥ 98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%). As described below, 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. The term "enantiomers" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not constitute mirror images of each other. The term "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). The term "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.
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的，可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、亚硝基-肟异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomers" (or "tautomeric forms") 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. For example, proton tautomers (or proton transfer 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.
术语“顺反异构体”是指位于双键或环系两侧的原子(或基团)因相对于参考平面的位置不同而形成的立体异构体；在顺式异构体中原子(或基团)位于双键或环系的同侧，在反式异构体中原子(或基团)位于双键或环系的异侧。除非另外指出，本发明的化合物的所有顺反异构体形式都在本发明的范围之内。The term "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.
术语“多晶型物”(或称“多晶型形式”)是指化合物或复合物的固体晶体形式，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。本领域技术人员可通过已知方法获得多晶型物。这些方法包括(但不限于)熔融重结晶、熔融冷却、溶剂重结晶、去溶剂化、快速蒸发、快速冷却、慢速冷却、汽相扩散和升华。另外，可用熟知的技术检测、分类和鉴定多晶型物，这些技术包括(但不限于)差示扫描量热法(DSC)、热重分析法(TGA)、X射线粉末衍射法(XRPD)、单晶X射线衍射法(SCXRD)、固态核磁共振(NMR)、红外光谱法(IR)、拉曼光谱法和扫描电镜术(SEM)等。The term "polymorph" (or "polymorph form") 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. In addition, well-known techniques can be used to detect, classify and identify polymorphs. These techniques include (but are not limited to) Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-ray Powder Diffraction (XRPD) , Single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM), etc.
术语“溶剂化物”是指由本发明的化合物(或其药学上可接受的盐)与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。常见的溶剂化物包括(但不限于)水合物(包括半水合物、一水合物、二水合物、三水合物等)、乙醇合物、丙酮合物等。The term "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.
术语“N-氧化物”是指叔胺类或含氮(芳)杂环类化合物结构中的氮原子经氧化而形成的化合物。常 见的N-氧化物包括(但不限于)三甲胺-N-氧化物、4-甲基吗啉-N-氧化物、吡啶-N-氧化物等。本发明的式I化合物母核中1a位是叔胺氮原子，可以形成相应的N-氧化物；另外，当母核中3位上与氮原子直接相连的基团不为(磺)酰基时，则3位也是叔胺氮原子，同样可以形成相应的N-氧化物。The term "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.
术语“同位素标记物”是指将本发明的化合物中的特定原子替换为其同位素原子(具有相同原子序数，但原子质量或质量数不同)而形成的衍生化合物。除非另外指出，本发明的化合物包括H、C、N、O、F、P、S、Cl的各种同位素，如 2H(D)、 3H(T)、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 18F、 31P、 32P、 35S、 36S、 37Cl、 123I和 125I。 The term "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). Unless otherwise indicated, 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.
术语“代谢物”是指本发明的化合物经代谢后形成的衍生化合物。关于代谢物的实例可参见Goodman and Gilman's:The Pharmacological Basis of Therapeutics(9 th ed.)[M],McGraw-Hill International Editions,1996。 The term "metabolite" refers to a derivative compound formed after the compound of the present invention is metabolized. For examples of metabolites, see Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th ed.) [M], McGraw-Hill International Editions, 1996.
术语“前药”是指在施用于个体后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于个体时可以提高本发明的化合物的生物利用度的化合物(例如，更易吸收入血)，或者促进母体化合物向作用位点(例如，淋巴***)递送的化合物。除非另外指出，本发明的化合物的所有前药形式都在本发明的范围之内，且各种前药形式是本领域熟知的。关于前药的其他信息可参见Pro-drugs as Novel Drug Delivery Systems(14 th ed.)[M],ACS Symposium Series,1975和Bioreversible Carriers in Drug Design[M],Pergamon Press,1987。 The term "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. Unless otherwise indicated, 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. For other information about 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.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，适合的保护基的实例可参见Protective Groups in Organic Chemistry,ed.J.F.W.McOmie[M],Plenum Press,1973和Protective Groups in Organic Synthesis[M],John Wiley&Sons,1991。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses the compounds of the present invention containing 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.
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。The term "independently" means that at least two groups (or ring systems) with the same or similar value ranges present in the structure may have the same or different meanings under certain circumstances. For example, the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl. When the substituent X is hydrogen, 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.
术语“各自任选地”是指结构中存在的至少两个基团(或环系)可以在特定情形下具有相同或不同的处置方式。例如，取代基X和取代基Y各自任选地被烷基取代，则实际上包括下列多种处置方式：(1)只有X被烷基取代；(2)只有Y被烷基取代；(3)X和Y均被烷基取代；(4)X和Y均未被取代。The term "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. For example, 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.
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。术语“卤代”是指被卤素原子取代。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term "halo" refers to substitution by a halogen atom.
术语“氰基”是指-CN基团。The term "cyano" refers to the -CN group.
术语“硝基”是指-NO 2基团。 The term "nitro" refers to the -NO 2 group.
术语“羟基”是指-OH基团。The term "hydroxyl" refers to the -OH group.
术语“烷基”是指直链或支链的一价饱和脂肪烃基。术语“C 1-15烷基”、“C 1-8烷基”、“C 1-6烷基”和“C 1- 4烷基”分别指具有1至15个碳原子、1至8个碳原子、1至6个碳原子和1-4个碳原子的直链或支链烷基。常见的烷基包括(但不限于)甲基(-CH 3)、乙基(-CH 2CH 3)、正丙基(-CH 2CH 2CH 3)、异丙基(-CH(CH 3) 2)、正丁基(-CH 2CH 2CH 2CH 3)、仲丁基(-CH(CH 3)CH 2CH 3)、异丁基(-CH 2CH(CH 3) 2)、叔丁基(-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、新戊基(-CH 2C(CH 3) 3)、正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)等。 The term "alkyl" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group. The term "C 1-15 alkyl", "C 1-8 alkyl", "C 1-6 alkyl" and "C 1- 4 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.
术语“亚烷基”是指从直链或支链的饱和脂肪烃基中去掉两个氢原子所得到的二价饱和脂肪烃基。常见的亚烷基包括(但不限于)亚甲基(-CH 2-)、1,2-亚乙基(-CH 2CH 2-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1-甲基-1,2-亚乙基(-CH(CH 3)CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)、1-甲基-1,3-亚丙基(-CH(CH 3)CH 2CH 2-)、1,1-二甲基-1,2-亚乙基(-C(CH 3) 2CH 2-)、1,2-二甲基-1,2-亚乙基(-CH(CH 3)CH(CH 3)-)等。 The term "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.
术语“卤代烷基”是指被一个或多个(诸如1至3个)相同或不同的卤素原子取代的直链或支链的烷基。术语“C 1-8卤代烷基”、“C 1-6卤代烷基”和“C 1-4卤代烷基”分别指具有1至8个碳原子、1至6个碳原子和1至4个碳原子的卤代烷基。常见的卤代烷基包括(但不限于)氟甲基(-CH 2F)、二氟甲基(-CHF 2)、三氟甲基(-CF 3)、1-氟乙基(-CHFCH 3)、2-氟乙基(-CH 2CH 2F)、1,2-二氟乙基(-CHFCH 2F)、2,2-二 氟乙基(-CH 2CHF 2)、1,2,2-三氟乙基(-CHFCHF 2)、2,2,2-三氟乙基(-CH 2CF 3)、1,1,2,2,2-五氟乙基(-CF 2CF 3)、3,3,3-三氟丙基(-CH 2CH 2CF 3)、氯甲基(-CH 2Cl)等。 The term "haloalkyl" refers to a straight or branched alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. The terms "C 1-8 haloalkyl", "C 1-6 haloalkyl" and "C 1-4 haloalkyl" refer to having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively的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.
术语“羟烷基”是指被一个或多个(诸如1至3个)羟基取代的直链或支链的烷基。术语“C 1-4羟烷基”和“C 1-3羟烷基”分别指具有1至4个碳原子和1至3个碳原子的羟烷基。常见的羟烷基包括(但不限于)羟甲基(-CH 2OH)、2-羟乙基(-CH 2CH 2OH)、3-羟丙基(-CH 2CH 2CH 2OH)、4-羟丁基(-CH 2CH 2CH 2CH 2OH)、1-羟乙基(-CH(OH)CH 3)等。 The term "hydroxyalkyl" refers to a straight or branched alkyl group substituted with one or more (such as 1 to 3) hydroxyl groups. The terms "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.
术语“烯基”是指含有一个或多个(诸如1至3个)碳-碳双键的直链或支链的一价脂肪烃基。常见的烯基包括(但不限于)乙烯基(-CH＝CH 2)、2-丙烯-1-基(-CH 2CH＝CH 2)、1-甲基-1-乙烯基(-C(CH 3)＝CH 2)、2-丁烯-1-基(-CH 2-CH＝CH-CH 3)等。 The term "alkenyl" refers to a linear or branched monovalent aliphatic hydrocarbon group containing one or more (such as 1 to 3) carbon-carbon double bonds. Common alkenyl groups include (but are not limited to) vinyl (-CH=CH 2 ), 2-propen-1-yl (-CH 2 CH=CH 2 ), 1-methyl-1-vinyl (-C( CH 3 )=CH 2 ), 2-buten-1-yl (-CH 2 -CH=CH-CH 3 ), etc.
术语“亚烯基”是指含有一个或多个(诸如1至3个)碳-碳双键的直链或支链的二价脂肪烃基。常见的亚烯基包括(但不限于)1,2-亚乙烯基(-CH＝CH-)、1,3-亚-1-丙烯基(-CH 2CH＝CH-)、1,2-亚-1-丙烯基(-C(CH 3)＝CH-)等。 The term "alkenylene" refers to a straight or branched divalent aliphatic hydrocarbon group containing one or more (such as 1 to 3) carbon-carbon double bonds. Common alkenylene groups include (but are not limited to) 1,2-vinylene (-CH=CH-), 1,3--1-propenylene (-CH 2 CH=CH-), 1,2- 1-propenylene (-C(CH 3 )=CH-) and the like.
术语“炔基”是指具有一个或多个(诸如1至3个)碳-碳三键的直链或支链的一价脂肪烃基。常见的亚烯基包括(但不限于)乙炔基
Figure PCTCN2020106080-appb-000011
2-丙炔-1-基
Figure PCTCN2020106080-appb-000012
2-丁炔-1-基
Figure PCTCN2020106080-appb-000013
1,3-丁二炔基
Figure PCTCN2020106080-appb-000014
等。 The term "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
Figure PCTCN2020106080-appb-000011
2-propyn-1-yl
Figure PCTCN2020106080-appb-000012
2-butyn-1-yl
Figure PCTCN2020106080-appb-000013
1,3-butadiynyl
Figure PCTCN2020106080-appb-000014
Wait.
术语“亚炔基”是指具有一个或多个(诸如1至3个)碳-碳三键的直链或支链的二价脂肪烃基。常见的亚炔基包括(但不限于)1,2-亚乙炔基
Figure PCTCN2020106080-appb-000015
1,3-亚-1-丙炔基
Figure PCTCN2020106080-appb-000016
1,3-亚-1-丁炔基
Figure PCTCN2020106080-appb-000017
1,4-亚-2-丁炔基
Figure PCTCN2020106080-appb-000018
等。 The term "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
Figure PCTCN2020106080-appb-000015
1,3-propylene-1-propynyl
Figure PCTCN2020106080-appb-000016
1,3-Butynylene-1-butynyl
Figure PCTCN2020106080-appb-000017
1,4-ylidene-2-butynyl
Figure PCTCN2020106080-appb-000018
Wait.
术语“烷氧基”是指一价的直链或支链的烷基-O-基团，并且通过一个与氧原子相连的单键连接至其他基团。常见的烷氧基包括(但不限于)甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)、正丁氧基(-OCH 2CH 2CH 2CH 3)、仲丁氧基(-OCH(CH 3)CH 2CH 3)、异丁氧基(-OCH 2CH(CH 3) 2)、叔丁氧基(-OC(CH 3) 3)、正戊氧基(-OCH 2CH 2CH 2CH 2CH 3)、新戊氧基(-OCH 2C(CH 3) 3)、正己氧基(-OCH 2CH 2CH 2CH 2CH 2CH 3)等。 The term "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 2 CH 3 ), etc.
术语“亚烷氧基”是指二价的直链或支链的亚烷基-O-基团，并且通过一个与氧原子相连的单键以及另一个与亚烷基相连的单键连接至其他基团。常见的亚烷氧基包括(但不限于)-OCH 2-、-OCH(CH 3)CH 2-、-CH 2CH 2O-等。 The term "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.
术语“并环”或“稠环”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的环系。The term "condensed ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
术语“螺环”指由两个或两个以上环状结构彼此共用一个环原子所形成的环系。The term "spirocyclic ring" refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
术语“桥环”指由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系。The term "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.
术语“环烷基”是指饱和或不饱和的、单环或多环(诸如双环)的一价非芳香族环烃基。常见的环烷基包括(但不限于)单环环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基等；并环(稠环)环烷烃，例如十氢萘基(又称为十氢化萘基、萘烷基)、二环[2.1.0]戊基、二环[3.1.0]己基、二环[5.1.0]辛基、二环[2.2.0]己基、二环[4.2.0]辛基等；螺环环烷基，例如螺戊基、螺[2.4]庚基、螺[2.5]辛基、螺[2.6]壬基、螺[3.3]庚基、螺[3.5]壬基等；桥环环烷基，例如金刚烷基等。本发明中的环烷基上的碳原子任选地被氧代，即形成环羰基(C＝O)。The term "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 spiropentyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[ 2.6] Nonyl, spiro[3.3]heptyl, spiro[3.5]nonyl, etc.; bridged cycloalkyls such as adamantyl and the like. The carbon atom on the cycloalkyl group in the present invention is optionally oxo, that is, a cyclocarbonyl group (C=O) is formed.
术语“亚环烷基”是指饱和或不饱和的、单环或多环(诸如双环)的二价非芳香族环烃基，其具有自母体环烷基的同一个碳原子或两个不同碳原子上去除两个氢原子而得到的两个一价基团中心。常见的亚环烷基包括(但不限于)亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚环辛基、亚环壬基、亚环己烯基等。本发明中的亚环烷基上的碳原子任选地被氧代，即形成环羰基(C＝O)。The term "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. The carbon atom on the cycloalkylene group in the present invention is optionally oxo, that is, a cyclic carbonyl group (C=O) is formed.
术语“杂环基”是指饱和或不饱和的、单环或多环(包括并环、桥环、螺环)的一价非芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成。术语“3-14元杂环基”是指含有3-14个环原子的杂环基，包括(但不限于)4-10元杂环基、4-7元杂环基(例如4-7元含氮杂环基、4-7元含 氧杂环基、4-7元含硫杂环基)、5-6元杂环基(例如5-6元含氮杂环基、5-6元含氧杂环基、5-6元含硫杂环基)等，“含氮杂环基”、“含氧杂环基”、“含硫杂环基”分别任选地含有一个或多个选自氮、氧、硫的杂原子。常见的单环杂环基包括(但不限于)环氧乙烷基、氮丙啶基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫吗啉基、二噻烷基、三噻烷基等；常见的并环杂环基包括(但不限于)杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基等，例如吡咯烷基并环丙基、吡咯烷基并环丁基、吡咯烷基并环己基、环戊基并氮杂环丙基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基等；常见的桥环杂环基包括(但不限于)
Figure PCTCN2020106080-appb-000019
Figure PCTCN2020106080-appb-000020
Figure PCTCN2020106080-appb-000021
等；常见的螺环杂环基包括(但不限于)
Figure PCTCN2020106080-appb-000022
Figure PCTCN2020106080-appb-000023
Figure PCTCN2020106080-appb-000024
等。本发明中的杂环基上的碳原子任选地被氧代，即形成环羰基(C＝O)。本发明中的杂环基上的氮原子任选地被氧化，即形成氮氧化物(NH→O)。本发明中的杂环基上的硫原子任选地被氧化，即形成亚砜(S＝O)或砜(S(＝O) 2)。 The term "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 The term "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. 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, cyclopentylazacyclopropyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, pyrrole Alkyl morpholino, piperidino morpholino, etc.; common bridged heterocyclic groups include (but are not limited to)
Figure PCTCN2020106080-appb-000019
Figure PCTCN2020106080-appb-000020
Figure PCTCN2020106080-appb-000021
Etc.; common spirocyclic heterocyclic groups include (but are not limited to)
Figure PCTCN2020106080-appb-000022
Figure PCTCN2020106080-appb-000023
Figure PCTCN2020106080-appb-000024
Wait. The carbon atom on the heterocyclic group in the present invention is optionally oxo, that is, a cyclic carbonyl group (C=O) is formed. The nitrogen atom on the heterocyclic group in the present invention is optionally oxidized to form nitrogen oxide (NH→O). The sulfur atom on the heterocyclic group in the present invention is optionally oxidized to form sulfoxide (S=O) or sulfone (S(=O) 2 ).
术语“亚杂环基”是指饱和或不饱和的、单环或多环(诸如双环)的二价非芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，其具有自母体杂环基的两个碳原子、两个杂原子或一个碳原子和一个杂原子上去除两个氢原子而得到的两个一价基团中心。常见的亚杂环基包括(但不限于)氧杂环丙烷-2,2-亚基、氧杂环丙烷-2,3-亚基、氮杂环丁烷-2,2-亚基、氮杂环丁烷-2,3-亚基、氮杂环丁烷-2,4-亚基、四氢呋喃-2,5-亚基、四氢-2H-吡喃-2,3-亚基、四氢-2H-吡喃-2,4-亚基、四氢-2H-吡喃-2,5-亚基、四氢-2H-吡喃-2,6-亚基、吡咯烷-1,2-亚基、吡咯烷-1,3-亚基、吡咯烷-2,3-亚基、吡咯烷-2,4-亚基、吡咯烷-2,5-亚基、哌啶-1,2-亚基、哌啶-1,3-亚基、哌啶-1,4-亚基、哌啶-2,3-亚基、哌啶-2,4-亚基、哌啶-2,5-亚基、哌啶-2,6-亚基等。本发明中的亚杂环基上的碳原子任选地被氧代，即形成环羰基(C＝O)。本发明中的亚杂环基上的氮原子任选地被氧化，即形成氮氧化物(NH→O)。本发明中的亚杂环基上的硫原子任选地被氧化，即形成亚砜(S＝O)或砜(S(＝O) 2)。 The term "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-1,3-subunit, piperidine-1,4-subunit, piperidine-2,3-subunit, piperidine-2,4-subunit, piperidine-2,5 -Subunit, piperidine-2,6-subunit, etc. The carbon atom on the heterocyclylene in the present invention is optionally oxo, that is, a cyclic carbonyl group (C=O) is formed. The nitrogen atom on the heterocyclylene in the present invention is optionally oxidized, that is, nitrogen oxide (NH→O) is formed. The sulfur atom on the heterocyclylene in the present invention is optionally oxidized to form sulfoxide (S=O) or sulfone (S(=O) 2 ).
术语“芳基”是指具有共轭π电子***的、全碳单环或稠合多环的一价芳香族环系。术语“C 6-12芳基”和“C 6-10芳基”分别是指含有6至12个和6至10个碳原子的芳基。常见的芳基包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic monovalent aromatic ring system with a conjugated π-electron system. The terms "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.
术语“亚芳基”是指具有共轭π电子***的、全碳单环或稠合多环的二价芳香族环系，其具有自母体芳基的两个碳原子上去除两个氢原子而得到的两个一价基团中心。常见的芳基包括(但不限于)亚苯基、亚萘基等。The term "arylene" refers to a bivalent aromatic ring system with a conjugated π-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.
术语“芳基并环烷基”是指芳基与环烷基(例如单环环烷基)彼此共用两个相邻的原子形成的一价并环基团，其与其他基团(或环系)的连接位点可以在芳基上或在环烷基上。术语“9-12元芳基并环烷基”是指包含9-12个环原子的芳基并环烷基。常见的芳基并环烷基包括(但不限于)苯基并环戊基、苯基并环己基等。本发明中的芳基并环烷基中环烷基上的碳原子任选地被氧代，即形成环羰基(C＝O)。The term "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. The term "9-12 membered 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. The carbon atoms on the cycloalkyl group in the aryl and cycloalkyl group in the present invention are optionally oxo, that is, a cyclic carbonyl group (C=O) is formed.
术语“芳基并杂环基”是指芳基与杂环基(例如单环杂环基)彼此共用两个相邻的原子形成的一价并环基团，其与其他基团(或环系)的连接点在可以在芳基或杂环基上。术语“9-12元芳基并杂环基”是指含有9-12个环原子的芳基并杂环基的基团，例如苯并5-6元含氮杂环基、苯并5-6元含氧杂环基、苯并5-6元含硫杂环基等，“含氮杂环基”、“含氧杂环基”、“含硫杂环基”分别任选地含有一个或多个选自氮、氧、硫的杂原子。常见的芳基并环烷基包括(但不限于)吲唑烷基、苯并吗啉基、二氢异喹啉酮基、苯并[1,4]二氧六环基、二氢苯并呋喃基。本发明中的杂环基上的碳原子任选地被氧代，即形 成环羰基(C＝O)。本发明中的杂环基上的氮原子任选地被氧化，即形成氮氧化物(NH→O)。本发明中的杂环基上的硫原子任选地被氧化，即形成亚砜(S＝O)或砜(S(＝O) 2)。 The term "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. The term "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 carbon atom on the heterocyclic group in the present invention is optionally oxo, that is, a cyclic carbonyl group (C=O) is formed. The nitrogen atom on the heterocyclic group in the present invention is optionally oxidized to form nitrogen oxide (NH→O). The sulfur atom on the heterocyclic group in the present invention is optionally oxidized to form sulfoxide (S=O) or sulfone (S(=O) 2 ).
术语“杂芳基”是指具有共轭π电子***的、单环或稠合多环的一价芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，优选具有2个或2个以上(例如3、4、5、6、7、8、9、10、11、12、13或14个)碳原子以及一个或多个(例如1个、2个、3个或4个)杂原子的单环或稠合多环基团。术语“5-10元杂芳基”是指含有5至10个环原子的杂芳基，包括5-10元含氮杂芳基、5-10元含氧杂芳基、5-10元含硫杂芳基，优选5-6元含氮杂芳基、5-6元含氧杂芳基、5-6元含硫杂芳基，更优选5-6元含氮单杂芳基、5-6元含氧单杂芳基、5-6元含硫单杂芳基。“含氮杂芳基”、“含氧杂芳基”、“含硫杂芳基”分别任选地含有一个或多个选自氧、氮、硫的杂原子。常见的杂环基包括(但不限于)吖啶基、咔唑基、吲唑基、吲嗪基、吲哚基、噻吩基、呋喃基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、***基、四唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、异喹啉基、喹喔啉基、吩嗪基、吩噁嗪基、吩噻嗪基、蝶啶基、嘌呤基等。The term "heteroaryl" refers to a monocyclic or fused polycyclic monovalent aromatic ring system with a conjugated π-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. The term "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. The "nitrogen-containing heteroaryl group", "oxygen-containing heteroaryl group" and "sulfur-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, phenothiazinyl, pterridinyl, purinyl and the like.
术语“亚杂芳基”是指具有共轭π电子***的、单环或稠合多环的二价芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，优选具有2个或2个以上(例如3、4、5、6、7、8、9、10、11、12、13或14个)碳原子以及一个或多个(例如1个、2个、3个或4个)杂原子的单环或稠合多环基团，其具有自母体杂芳基的两个碳原子或者一个碳原子和一个杂原子上去除两个氢原子而得到的两个一价基团中心。常见的亚杂芳基包括(但不限于)亚吡唑基、亚咪唑基等。The term "heteroarylene" refers to a monocyclic or fused polycyclic divalent aromatic ring system with a conjugated π-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.
术语“芳基并杂芳基”是指芳基(例如苯基)与杂芳基(例如5-6元单环杂芳基)彼此共用两个相邻的原子形成的一价并环基团，其与其他基团(或环系)的连接点可以在芳环或杂芳环上。术语“9-12元芳基并杂芳基”是指含有9-12个环原子的芳基并杂芳基，例如苯并5-6元含氮单环杂芳基。The term "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. The term "9-12 membered 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.
术语“杂芳基并环烷基”是指杂芳基(例如5-6元单环杂芳基)与环烷基(例如C 4-6环烷基)彼此共用两个相邻的原子形成的一价并环基团，其与其他基团(或环系)的连接点可以在杂芳基或环烷基上。术语“9-10元杂芳基并环烷基”是指含有9-10个环原子的杂芳基并环烷基，例如4-6元含氮单环杂芳基并C 4-6单环环烷基。 The term "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. The term "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.
术语“取代”是指所指定的原子(或基团)上的一个或多个(例如1个、2个、3个或4个)氢原子被其他原子(或基团)代替，条件是未超过所指定的原子在当前情况下的正常原子价并且形成稳定的化合物。如果某一个取代基被描述为“任选地被(由)……取代”，则该取代基可以(1)未被取代或(2)被取代。如果某一种取代基被描述为“各自独立地选自……”，则同时存在的多个该取代基中的任一者独立于另一者被选择；换言之，多个该取代基中的一个可与另一个相同或不同。术语“一个或多个”是指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。The term "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. The term "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.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.
[通式化合物][General formula compound]
本发明提供了一种式X化合物或其药学上可接受的形式，The present invention provides a compound of formula X or a pharmaceutically acceptable form thereof,
A-L-R 3 ALR 3
XX
其中，among them,
A选自
Figure PCTCN2020106080-appb-000025
A is selected from
Figure PCTCN2020106080-appb-000025
·X 2选自-C(-L-R 3)＝和-N＝；当同时存在多个L和R 3时，各个L或R 3彼此相同或不同； · X 2 is selected from -C(-LR 3 )= and -N=; when there are multiple L and R 3 at the same time, each L or R 3 is the same or different from each other;
·R 1选自C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，其中所述C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、C 1-4烷基、C 3- 8环烷基、C 1-4卤代烷基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-OC(＝O)R 30、-OC(＝O)NR 31R 32、 -NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-OR 37和-SR 37； 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 The cyclyl and heterocyclic groups are each optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, C 1-4 alkyl, C 3 8 cycloalkane Group, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl , -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -OC( ＝O)R 30 , -OC(＝O)NR 31 R 32 , -NR 33 C(＝O)NR 31 R 32 , -NR 33 C(＝O)OR 30 , -S(＝O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -OR 37 and -SR 37 ;
··R 2为-NR 41aR 41b； ··R 2 is -NR 41a R 41b ;
··每一个R 5各自独立地选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32；m为0、1或2； ··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;
··X 1选自-C(R 6)＝和-N＝； ··X 1 is selected from -C(R 6 )= and -N=;
··R 4为-NR 41aR 41b； ··R 4 is -NR 41a R 41b ;
··R 6选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32； ··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 41a和R 41b各自独立地选自氢、C 1-6烷基、C 1-6烷氧基和C 3-8环烷基，或者R 41a和R 41b连同与其连接的N原子一起形成4-7元杂环基，其中所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-7元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、4-7元杂环基、氰基、硝基、-OR 37、-SR 37、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-C(＝O)OR 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 31R 32，并且R 41a和R 41b不同时为氢； ·R 41a and R 41b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b are formed together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally substituted by one or more Substituents are substituted, and each of the substituents is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, cyano, Nitro, -OR 37 , -SR 37 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -C(=O)OR 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 31 R 32 , and R 41a and R 41b are not hydrogen at the same time ；
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基和-NR 31R 32；n、p和q各自独立地为0、1或2； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from C 1-8 alkylene and C 2-8 alkenylene Group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered Heteroaryl, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, where The C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heteroalkylene group The cyclic group, C 6-12 arylene group and 5-10 membered heteroarylene group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and -NR 31 R 32 ; n, p and q are each independently 0, 1 or 2;
R 3选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40、-P(＝O)(OR 39)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-N＝NR 38、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40和-P(＝O)(OR 39)OR 30； R 3 is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C(=NR 38 )NR 31 R 32 , -P(R 39 ) 2 , -P(OR 39 ) 2 , -P(=O)R 39 R 40 , -P(=O)(OR 39 )OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , where The C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more substituents, each of which is individually Independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy Group, C 1-4 hydroxyalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, -C(=O) OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 ,- OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C (=NR 38 )NR 31 R 32 , -N=NR 38 , -P(R 39 ) 2 , -P(OR 39 ) 2. -P(=O)R 39 R 40 and -P(=O)(OR 39 )OR 30 ;
R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 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 haloalkoxy, -C(=O)O( C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)R 35 , -S(=O ) 2 R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 35选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32； R 35 is selected from 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), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one or more substituents, each of said substituents Each is independently selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, -C(=O )O(C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)CH 3 , -S (=O) 2 CH 3 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 31、R 32、R 33和R 34各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基，或者R 31和R 32连同与其连接的N原子一起形成4-8元杂环基，或者R 33和R 34连同与其对应连接的N原子和C原子一起形成4-8元杂环基，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-8元杂环基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基； 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 Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl;
R 36a和R 36b各自独立地选自氢、C 1-8烷基和C 1-8烷氧基，其中所述C 1-8烷基和C 1-8烷氧基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、氨基、甲氨基和二甲氨基，或者R 36a和R 36b连同与其连接的C原子一起形成3-7元环烷基或杂环基； 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;
R 38选自氢、羟基、氰基、硝基、-S(＝O)R 35和-S(＝O) 2R 35；并且 R 38 is selected from hydrogen, hydroxyl, cyano, nitro, -S(=O)R 35 and -S(=O) 2 R 35 ; and
当同时存在多个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39和/或R 40时，各个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39或R 40彼此相同或不同； When there are multiple 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 at the same time, each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 or R 40 are the same or different from each other;
所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、共晶、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。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.
在本发明的一些实施方案中，上述式X化合物为式I化合物，In some embodiments of the present invention, the compound of formula X above is a compound of formula I,
Figure PCTCN2020106080-appb-000026
Figure PCTCN2020106080-appb-000026
其中，among them,
X 2选自-C(-L-R 3)＝和-N＝；当同时存在多个L和R 3时，各个L或R 3彼此相同或不同； X 2 is selected from -C(-LR 3 )= and -N=; when there are multiple L and R 3 at the same time, each L or R 3 is the same or different from each other;
R 1选自C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，其中所述C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-OR 37和-SR 37； 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 Each of the heterocyclic groups is optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -OC(= O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -OR 37 and -SR 37 ;
R 2为NR 41aR 41b；R 41a和R 41b各自独立地选自氢、C 1-6烷基、C 1-6烷氧基和C 3-8环烷基，或者R 41a和R 41b连同与其连接的N原子一起形成4-7元杂环基，其中所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-7元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、4-7元杂环基、氰基、硝基、-OR 37、-SR 37、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-C(＝O)OR 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 31R 32，并且R 41a和R 41b不同时为氢； R 2 is NR 41a R 41b ; R 41a and R 41b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b together Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is formed, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each any Optionally substituted by one or more substituents, each of the substituents is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 member Heterocyclic group, cyano group, nitro group, -OR 37 , -SR 37 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 ,- C(=O)OR 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 31 R 32 , and R 41a It is not hydrogen at the same time as R 41b;
每一个R 5各自独立地选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32；m为0、1或2； 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;
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基和-NR 31R 32；n、p和q各自独立地为0、1或2； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from C 1-8 alkylene and C 2-8 alkenylene Group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered Heteroaryl, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, where The C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heteroalkylene group The cyclic group, C 6-12 arylene group and 5-10 membered heteroarylene group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and -NR 31 R 32 ; n, p and q are each independently 0, 1 or 2;
R 3选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、- C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40、-P(＝O)(OR 39)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-N＝NR 38、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40和-P(＝O)(OR 39)OR 30； R 3 is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 ,-C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C(=NR 38 )NR 31 R 32 , -P(R 39 ) 2 , -P(OR 39 ) 2 , -P(=O)R 39 R 40 , -P(=O)(OR 39 )OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , where The C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more substituents, each of which is individually Independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy Group, C 1-4 hydroxyalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, -C(=O) OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 ,- OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C (=NR 38 )NR 31 R 32 , -N=NR 38 , -P(R 39 ) 2 , -P(OR 39 ) 2. -P(=O)R 39 R 40 and -P(=O)(OR 39 )OR 30 ;
R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 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 haloalkoxy, -C(=O)O( C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)R 35 , -S(=O ) 2 R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 35选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32； R 35 is selected from 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), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one or more substituents, each of said substituents Each is independently selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, -C(=O )O(C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)CH 3 , -S (=O) 2 CH 3 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 31、R 32、R 33和R 34各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基，或者R 31和R 32连同与其连接的N原子一起形成4-8元杂环基，或者R 33和R 34连同与其对应连接的N原子和C原子一起形成4-8元杂环基，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-8元杂环基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基； 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 Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl;
R 36a和R 36b各自独立地选自氢、C 1-8烷基和C 1-8烷氧基，其中所述C 1-8烷基和C 1-8烷氧基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、氨基、甲氨基和二甲氨基，或者R 36a和R 36b连同与其连接的C原子一起形成3-7元环烷基或杂环基； 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;
R 38选自氢、羟基、氰基、硝基、-S(＝O)R 35和-S(＝O) 2R 35；并且 R 38 is selected from hydrogen, hydroxyl, cyano, nitro, -S(=O)R 35 and -S(=O) 2 R 35 ; and
当同时存在多个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39和/或R 40时，各个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39或R 40彼此相同或不同。 When there are multiple 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 at the same time, each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 or R 40 are the same or different from each other.
在本发明的一些实施方案中，上述式X或式I化合物为式III化合物，In some embodiments of the present invention, the above-mentioned compound of formula X or formula I is a compound of formula III,
Figure PCTCN2020106080-appb-000027
Figure PCTCN2020106080-appb-000027
其中R 1、R 2、R 3、R 5、L和m如上文中所定义。 Wherein R 1 , R 2 , R 3 , R 5 , L and m are as defined above.
在本发明的一些实施方案中，上述式X、式I或式III化合物为式III-A化合物，In some embodiments of the present invention, the above-mentioned compound of formula X, formula I or formula III is a compound of formula III-A,
Figure PCTCN2020106080-appb-000028
Figure PCTCN2020106080-appb-000028
其中，among them,
R 1和R 2如上文中所定义； R 1 and R 2 are as defined above;
R 5a选自氢、C 1-3烷基、氟和氯； R 5a is selected from hydrogen, C 1-3 alkyl, fluorine and chlorine;
L a为-L 1a-(L 2) p-(L 3) q-，其中L 1a选自-O-、-S-和-NR 33-，并且L 2、L 3、p和q如上文中所定义； 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 3a选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 33C(＝O)OR 30；并且 R 3a is selected from 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, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC( ＝O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4 -10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl group and 9-12 membered aryl group The cycloalkyl groups are each optionally substituted with one or more substituents, each of which is independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 ring Alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 33 C(=O)OR 30 ; and
R 30、R 31、R 32、R 33、R 34、R 35和R 37如上文中所定义。 R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 37 are as defined above.
在本发明的一些实施方案中，上述式X、式I或式III化合物为式III-B化合物，In some embodiments of the present invention, the above-mentioned compound of formula X, formula I or formula III is a compound of formula III-B,
Figure PCTCN2020106080-appb-000029
Figure PCTCN2020106080-appb-000029
其中，among them,
R 1和R 2如上文中所定义； R 1 and R 2 are as defined above;
R 5a选自氢、C 1-3烷基、氟和氯； R 5a is selected from hydrogen, C 1-3 alkyl, fluorine and chlorine;
L b为-(L 1b) n-(L 2b) p-(L 3b) q-，其中L 1b、L 2b和L 3b各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；n、p和q各自独立地为0或1； L b is -(L 1b ) n -(L 2b ) p -(L 3b ) q -, wherein L 1b , L 2b and L 3b are each independently selected from C 1-8 alkylene, C 2-8 alkylene Alkenyl, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 member Heteroarylene, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, Wherein said C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered alkylene The heterocyclic group, the C 6-12 arylene group and the 5-10 membered heteroarylene group are each optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, hydroxy, and cyano. , Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; n, p and q are each independently 0 or 1;
R 3b选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 33C(＝O)OR 30；并且 R 3b is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-8 alkyl group, C 1-8 alkoxy group , C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and Heteroaryl and 9-12 membered aryl and cycloalkyl are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, hydroxy, C 1 -4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocycle Group, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, -C(=O)OR 30 , -C(=O)R 30 , -C(= O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(= O)NR 31 R 32 and -NR 33 C(=O)OR 30 ; and
条件是：requirement is:
当n+p+q≥1时，-(L 1b) n-(L 2b) p-(L 3b) q-中与式III-B中的喹啉连接的L 1b或L 2b或L 3b不为-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-或-C(＝O)-； When n+p+q≥1, -(L 1b ) n -(L 2b ) p -(L 3b ) q -in which L 1b or L 2b or L 3b connected to the quinoline in formula III-B is not It is -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -or -C(=O)-;
当n+p+q＝0时，R 3b不为氢、卤素、氰基、硝基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32或-S(＝O) 2NR 31R 32。 When n+p+q=0, R 3b is not hydrogen, halogen, cyano, nitro, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(= O) R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC(=O)R 30 , -OC( ＝O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 or -S(=O) 2 NR 31 R 32 .
在本发明的一些实施方案中，上述式X化合物为式II化合物，In some embodiments of the present invention, the compound of formula X above is a compound of formula II,
Figure PCTCN2020106080-appb-000030
Figure PCTCN2020106080-appb-000030
其中，among them,
X 1选自-C(R 6)＝和-N＝； X 1 is selected from -C(R 6 )= and -N=;
X 2选自-C(-L-R 3)＝和-N＝；当同时存在多个L和R 3时，各个L或R 3彼此相同或不同； X 2 is selected from -C(-LR 3 )= and -N=; when there are multiple L and R 3 at the same time, each L or R 3 is the same or different from each other;
R 1选自C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，其中所述C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-OR 37和-SR 37； 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 Each of the heterocyclic groups is optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -OC(= O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -OR 37 and -SR 37 ;
R 4为NR 41aR 41b；R 41a和R 41b各自独立地选自氢、C 1-6烷基、C 1-6烷氧基和C 3-8环烷基，或者R 41a和R 41b连同与其连接的N原子一起形成4-7元杂环基，其中所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-7元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、4-7元杂环基、氰基、硝基、-OR 37、-SR 37、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-C(＝O)OR 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 31R 32，且R 41a和R 41b不同时为氢； R 4 is NR 41a R 41b ; R 41a and R 41b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b together Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is formed, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each any Optionally substituted by one or more substituents, each of the substituents is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 member Heterocyclic group, cyano group, nitro group, -OR 37 , -SR 37 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 ,- C(=O)OR 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 31 R 32 , and R 41a It is not hydrogen at the same time as R 41b;
R 6选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32； 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 ;
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基和-NR 31R 32；n、p和q各自独立地为0、1或2； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from C 1-8 alkylene and C 2-8 alkenylene Group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered Heteroaryl, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, where The C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heteroalkylene group The cyclic group, C 6-12 arylene group and 5-10 membered heteroarylene group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and -NR 31 R 32 ; n, p and q are each independently 0, 1 or 2;
R 3选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40、-P(＝O)(OR 39)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-N＝NR 38、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40和-P(＝O)(OR 39)OR 30； R 3 is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C(=NR 38 )NR 31 R 32 , -P(R 39 ) 2 , -P(OR 39 ) 2 , -P(=O)R 39 R 40 , -P(=O)(OR 39 )OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , where The C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more substituents, each of which is individually Independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy Group, C 1-4 hydroxyalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, -C(=O) OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 ,- OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C (=NR 38 )NR 31 R 32 , -N=NR 38 , -P(R 39 ) 2 , -P(OR 39 ) 2. -P(=O)R 39 R 40 and -P(=O)(OR 39 )OR 30 ;
R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元 杂芳基)各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 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 haloalkoxy, -C(=O)O( C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)R 35 , -S(=O ) 2 R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 35选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32； R 35 is selected from 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), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one or more substituents, each of said substituents Each is independently selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, -C(=O )O(C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)CH 3 , -S (=O) 2 CH 3 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
R 31、R 32、R 33和R 34各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基，或者R 31和R 32连同与其连接的N原子一起形成4-8元杂环基，或者R 33和R 34连同与其对应连接的N原子和C原子一起形成4-8元杂环基，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-8元杂环基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基； 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 Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl;
R 36a和R 36b各自独立地选自氢、C 1-8烷基和C 1-8烷氧基，其中所述C 1-8烷基和C 1-8烷氧基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、氨基、甲氨基和二甲氨基，或者R 36a和R 36b连同与其连接的C原子一起形成3-7元环烷基或杂环基； 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;
R 38选自氢、羟基、氰基、硝基、-S(＝O)R 35和-S(＝O) 2R 35；并且 R 38 is selected from hydrogen, hydroxyl, cyano, nitro, -S(=O)R 35 and -S(=O) 2 R 35 ; and
当同时存在多个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39和/或R 40时，各个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39或R 40彼此相同或不同。 When there are multiple 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 at the same time, each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 or R 40 are the same or different from each other.
在本发明的一些实施方案中，上述式X或式II化合物为式IV化合物，In some embodiments of the present invention, the above-mentioned compound of formula X or formula II is a compound of formula IV,
Figure PCTCN2020106080-appb-000031
Figure PCTCN2020106080-appb-000031
其中R 1、R 3、R 4、X 1和L如上文中所定义。 Wherein R 1 , R 3 , R 4 , X 1 and L are as defined above.
在本发明的一些实施方案中，上述式X、式II或式IV化合物为式IV-A化合物，In some embodiments of the present invention, the above-mentioned compound of formula X, formula II or formula IV is a compound of formula IV-A,
Figure PCTCN2020106080-appb-000032
Figure PCTCN2020106080-appb-000032
其中，among them,
R 1、R 4和R 6如上文中所定义； R 1 , R 4 and R 6 are as defined above;
L a为-L 1a-(L 2) p-(L 3) q-，其中L 1a选自-O-、-S-和-NR 33-，并且L 2、L 3、p和q如上文中所定义； 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 3a选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 33C(＝O)OR 30；并且 R 3a is selected from 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, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC( ＝O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4 -10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl group and 9-12 membered aryl group The cycloalkyl groups are each optionally substituted with one or more substituents, each of which is independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 ring Alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 33 C(=O)OR 30 ; and
R 30、R 31、R 32、R 33、R 34、R 35和R 37如上文中所定义。 R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 37 are as defined above.
在本发明的一些实施方案中，上述式X、式II或式IV化合物为式IV-B化合物，In some embodiments of the present invention, the above-mentioned compound of formula X, formula II or formula IV is a compound of formula IV-B,
Figure PCTCN2020106080-appb-000033
Figure PCTCN2020106080-appb-000033
其中，among them,
R 1、R 4和R 6如上文中所定义； R 1 , R 4 and R 6 are as defined above;
L b为-(L 1b) n-(L 2b) p-(L 3b) q-，其中L 1b、L 2b和L 3b各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；n、p和q各自独立地为0或1； L b is -(L 1b ) n -(L 2b ) p -(L 3b ) q -, wherein L 1b , L 2b and L 3b are each independently selected from C 1-8 alkylene, C 2-8 alkylene Alkenyl, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 member Heteroarylene, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, Wherein said C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered alkylene The heterocyclic group, the C 6-12 arylene group and the 5-10 membered heteroarylene group are each optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, hydroxy, and cyano. , Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; n, p and q are each independently 0 or 1;
R 3b选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 33C(＝O)OR 30；并且 R 3b is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-8 alkyl group, C 1-8 alkoxy group , C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and Heteroaryl and 9-12 membered aryl and cycloalkyl are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, hydroxy, C 1 -4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocycle Group, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, -C(=O)OR 30 , -C(=O)R 30 , -C(= O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(= O)NR 31 R 32 and -NR 33 C(=O)OR 30 ; and
条件是：requirement is:
当n+p+q≥1时，-(L 1b) n-(L 2b) p-(L 3b) q-中与式IV-B中的噻吩并吡啶连接的L 1b或L 2b或L 3b不为-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-或-C(＝O)-； When n+p+q≥1, -(L 1b ) n -(L 2b ) p -(L 3b ) q -L 1b or L 2b or L 3b connected to the thienopyridine in formula IV-B Not -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -or -C(=O)-;
当n+p+q＝0时，R 3b不为氢、卤素、氰基、硝基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32或-S(＝O) 2NR 31R 32。 When n+p+q=0, R 3b is not hydrogen, halogen, cyano, nitro, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(= O) R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC(=O)R 30 , -OC( ＝O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 or -S(=O) 2 NR 31 R 32 .
在本发明的一些实施方案中，上述式X、式II、式IV或式IV-A化合物为式V化合物，In some embodiments of the present invention, the above-mentioned compound of formula X, formula II, formula IV or formula IV-A is a compound of formula V,
Figure PCTCN2020106080-appb-000034
Figure PCTCN2020106080-appb-000034
其中，among them,
R 1、R 3、R 4、L 2、L 3、p和q如上文中所定义； R 1 , R 3 , R 4 , L 2 , L 3 , p and q are as defined above;
R 33选自氢和C 1-6烷基。 R 33 is selected from hydrogen and C 1-6 alkyl.
在本发明的一些优选的实施方案中，式I、式II、式III、式IV或式V化合物中的R 3选自氢、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-NR 33C(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、4-7元杂环基、C 6- 10芳基和5-6元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 3-6环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-OR 37、-SR 37和-NR 33C(＝O)OR 30。 In some preferred embodiments of the present invention, R 3 in the compound of formula I, formula II, formula III, formula IV or formula V is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl, -C(=O)OR 30 , -C(=O) NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 ,- OC(=O)R 30 , -NR 33 C(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-6 alkyl group, C 1-6 alkoxy group , C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6- 10 aryl, and 5-6 membered heteroaryl are each optionally substituted with one or more substituents, the substituents each Each is independently selected from halogen, cyano, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-7 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl, -C(=O)OR 30 , -C(=O)R 30 ,- C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -OR 37 , -SR 37 and -NR 33 C(=O)OR 30 .
在本发明的一些优选的实施方案中，式I、式II、式III、式IV或式V化合物中的R 3选自环丁基、羟基、氧杂环丁烷-3-基
Figure PCTCN2020106080-appb-000035
甲氧基、甲基、吗啉-4-基
Figure PCTCN2020106080-appb-000036
2-氧代吡咯烷-1-基
Figure PCTCN2020106080-appb-000037
环丙基、环丙基氨基、二氟甲基、氟、异丙基、(1R,5S,6s)-1,5-二甲基-3-氮杂双环[3.1.0]己-6-基
Figure PCTCN2020106080-appb-000038
异丁基、羟甲基和四氢-2H-吡喃-4-基
Figure PCTCN2020106080-appb-000039
 In some preferred embodiments of the present invention, 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
Figure PCTCN2020106080-appb-000035
Methoxy, methyl, morpholin-4-yl
Figure PCTCN2020106080-appb-000036
2-oxopyrrolidin-1-yl
Figure PCTCN2020106080-appb-000037
Cyclopropyl, cyclopropylamino, difluoromethyl, fluorine, isopropyl, (1R,5S,6s)-1,5-dimethyl-3-azabicyclo[3.1.0]hex-6- base
Figure PCTCN2020106080-appb-000038
Isobutyl, hydroxymethyl and tetrahydro-2H-pyran-4-yl
Figure PCTCN2020106080-appb-000039
在本发明的一些优选的实施方案中，式I、式II、式III或式IV化合物中的L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自-NR 33- 、-C(＝O)-、5-10元亚杂芳基、C 1-6亚烷基和C 3-6亚环烷基，其中所述5-10元亚杂环基、C 1-6亚烷基和C 3-6亚环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、C 1-6烷基、C 1-4羟烷基和C 1-4烷氧基。 In some preferred embodiments of the present invention, L in the compound of formula I, formula II, formula III or formula IV is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from -NR 33- , -C(=O)-, 5-10 membered heteroarylene, C 1-6 alkylene and C 3-6 cycloalkylene, Wherein the 5-10 membered heterocyclylene, C 1-6 alkylene and C 3-6 cycloalkylene are each optionally substituted by one or more substituents, and each of the substituents is independently It is selected from hydroxy, C 1-6 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy.
在本发明的一些优选的实施方案中，式V化合物中的L 2和L 3各自独立地选自C 1-6亚烷基、C 3-6亚环烷基、5-10元亚杂芳基、4-10元亚杂环基、-C(＝O)-和-NR 33-，其中所述C 1-6亚烷基、C 3-6亚环烷基、5-10元亚杂芳基和4-10元亚杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基。 In some preferred embodiments of the present invention, L 2 and L 3 in the compound of formula V are each independently selected from C 1-6 alkylene, C 3-6 cycloalkylene, 5-10 membered heteroarylene Group, 4-10 membered heterocyclylene, -C(=O)- and -NR 33 -, wherein the C 1-6 alkylene, C 3-6 cycloalkylene, 5-10 membered heterocyclylene 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.
在本发明的一些更优选的实施方案中，式I、式II、式III或式IV化合物中的-L-R 3或者式III-A或式IV-A化合物中的-L a-R 3a或者式III-B或式IV-B化合物中的-L b-R 3b或者式V化合物中的-N(R 33)-(L 2) p-(L 3) q-R 3选自： In some more preferred embodiments of the present invention, -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:
Figure PCTCN2020106080-appb-000040
Figure PCTCN2020106080-appb-000040
优选：Preferred:
Figure PCTCN2020106080-appb-000041
Figure PCTCN2020106080-appb-000041
在本发明的一些优选的实施方案中，式I、式II、式III、式IV、式III-A、式IV-A、式III-B、式IV-B或式V化合物中的R 1选自C 1-6烷基、C 3-6环烷基、4-7元杂环基、C 6-10芳基和5-6元杂芳基，其中所述C 1-6烷基、C 3-6环烷基、4-7元杂环基、C 6-10芳基和5-6元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、C 1-4烷基、C 3-6环烷基、C 1-4卤代烷基和C 1-4羟烷基。 In some preferred embodiments of the present invention, 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.
在本发明的一些更优选的实施方案中，式I、式II、式III、式IV、式III-A、式IV-A、式III-B、式IV-B或式V化合物中的R 1选自5-6元杂芳基和4-7元杂环基，特别是5-6元含氮杂芳基(例如吡唑基或吡啶 基)和6元含氧杂环基(例如四氢-2H-吡喃-2-基)，其任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素(优选氟)、C 1-3烷基(优选甲基)和4-7元杂环基(优选四氢-2H-吡喃-2-基)。 In some more preferred embodiments of the present invention, 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).
在本发明的一些更优选的实施方案中，式I、式II、式III、式IV、式III-A、式IV-A、式III-B、式IV-B或式V化合物中的R 1为5-6元杂芳基(优选5-6元含氮杂芳基，更优选吡唑基或吡啶基)，其任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素(优选氟)、C 1-3烷基(优选甲基)和4-7元杂环基(优选四氢-2H-吡喃-2-基)。 In some more preferred embodiments of the present invention, 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).
在本发明的一些更优选的实施方案中，式I、式II、式III、式IV、式III-A、式IV-A、式III-B、式IV-B或式V化合物中的R 1选自吡唑基、1,3-二甲基-1H-吡唑基、甲基吡啶基和1-(四氢-2H-吡喃-2-基)-1H-吡唑基；优选地，R 1选自1H-吡唑-5-基、1,3-二甲基-1H-吡唑-5-基、2-甲基吡啶-6-基和1-(四氢-2H-吡喃-2-基)-1H-吡唑-2-基；更优选地，R 1选自1H-吡唑-5-基和2-甲基吡啶-6-基。 In some more preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，式I、式III、式III-A或式III-B化合物中的R 2为-NR 41aR 41b，其中R 41a和R 41b各自独立地选自氢、C 1-4烷基和C 3-6环烷基，且R 41a和R 41b不同时为氢，或者R 41a和R 41b连同与其连接的N原子一起形成4-6元杂环基，其中所述C 1-4烷基、C 3-6环烷基和4-6元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自C 1-4烷基、C 1-4羟烷基和-C(＝O)OH。 In some preferred embodiments of the present invention, R 2 in the compound of formula I, formula III, formula III-A or formula III-B 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 attached form a 4-6 membered heterocyclic group, wherein The C 1-4 alkyl group, C 3-6 cycloalkyl group and 4-6 membered heterocyclic group are each optionally substituted by one or more substituents, and each of the substituents is independently selected from C 1 -4 alkyl, C 1-4 hydroxyalkyl and -C(=O)OH.
在本发明的一些优选的实施方案中，式II、式IV、式IV-A、式IV-B或式V化合物中的R 4为-NR 41aR 41b，其中R 41a和R 41b各自独立地选自氢、C 1-4烷基和C 3-6环烷基，且R 41a和R 41b不同时为氢，或者R 41a和R 41b连同与其连接的N原子一起形成4-6元杂环基，其中所述C 1-4烷基、C 3-6环烷基和4-6元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自C 1-4烷基、C 1-4羟烷基和羧基。 In some preferred embodiments of the present invention, 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.
在本发明的一些更优选的实施方案中，式II、式IV、式IV-A、式IV-B或式V化合物中的R 4为-NR 41aR 41b，其中R 41a和R 41b各自独立地选自氢、甲基、乙基、异丙基、叔丁基和环丙基，且R 41a和R 41b不同时为氢，或者R 41a和R 41b连同与其连接的N原子一起形成吡咯烷-1-基，其中所述甲基、乙基、异丙基、叔丁基、环丙基和吡咯烷-1-基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自甲基、叔丁基、羟甲基和羧基。 In some more preferred embodiments of the present invention, 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.
在本发明的一些更优选的实施方案中，式II、式IV、式IV-A、式IV-B或式V化合物中的R 4选自-N(H)-C(CH 3) 3、-N(H)-CH 3、-N(H)-C 2H 5、-N(H)-异丙基、-N(H)-环丙基、-N(CH 3) 2、-N(C 2H 5) 2、-N(H)-CH 2-COOH、-N(H)-C 2H 4-OH、-N(H)-1-甲基环丙基、-N(H)-C(CH 3) 2-CH 2-C(CH 3) 3和吡咯烷-1-基；优选地，R 4为-N(H)-C(CH 3) 3。 In some more preferred embodiments of the present invention, 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 .
在本发明的一些优选的实施方案中，式I或式III化合物中的m为0或1，R 5选自氢、卤素、C 1-4烷基和C 3-6环烷基，其中所述C 1-4烷基和C 3-6环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32。 In some preferred embodiments of the present invention, m in the compound of formula I or formula III is 0 or 1, and 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 .
在本发明的一些优选的实施方案中，式II、式IV、式IV-A、式IV-B或式V化合物中的R 6选自氢、卤素(优选氯)、C 1-4烷基(优选甲基)和C 3-6环烷基。在本发明的一些更优选的实施方案中，式II、式IV、式IV-A、式IV-B或式V化合物中的R 6为氢。 In some 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 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.
在本发明的一些优选的实施方案中，式V化合物中的R 33选自氢、甲基和或乙基；优选地；R 33为氢。 In some preferred embodiments of the present invention, R 33 in the compound of formula V is selected from hydrogen, methyl and or ethyl; preferably; R 33 is hydrogen.
另外，本发明还提供了具有式X、式II、式IV、式IV-A或式V结构的具体化合物或其药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药，包括(但不限于)结构及名称如下表所示的化合物：In addition, 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:
Figure PCTCN2020106080-appb-000042
Figure PCTCN2020106080-appb-000042
Figure PCTCN2020106080-appb-000043
Figure PCTCN2020106080-appb-000043
Figure PCTCN2020106080-appb-000044
Figure PCTCN2020106080-appb-000044
Figure PCTCN2020106080-appb-000045
Figure PCTCN2020106080-appb-000045
Figure PCTCN2020106080-appb-000046
Figure PCTCN2020106080-appb-000046
Figure PCTCN2020106080-appb-000047
Figure PCTCN2020106080-appb-000047
Figure PCTCN2020106080-appb-000048
Figure PCTCN2020106080-appb-000048
Figure PCTCN2020106080-appb-000049
Figure PCTCN2020106080-appb-000049
Figure PCTCN2020106080-appb-000050
Figure PCTCN2020106080-appb-000050
Figure PCTCN2020106080-appb-000051
Figure PCTCN2020106080-appb-000051
[制备方法][Preparation]
本发明提供了上述式III-A化合物与式III-B化合物(当式III中的R 5为氢时，分别为式III-A-1化合物与式III-B-1化合物)的制备方法，其包括下列步骤： 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:
第1步：化合物III-1经卤代反应生成化合物III-2；Step 1: Compound III-1 is halogenated to produce compound III-2;
Figure PCTCN2020106080-appb-000052
Figure PCTCN2020106080-appb-000052
X代表卤素原子，选自氯、溴和碘；X represents a halogen atom, selected from chlorine, bromine and iodine;
第2步：化合物III-2经氧化反应生成化合物III-3；Step 2: Compound III-2 is oxidized to generate compound III-3;
Figure PCTCN2020106080-appb-000053
Figure PCTCN2020106080-appb-000053
第3步：化合物III-3与R 2H反应生成化合物III-4，其中R 2通过氮原子与喹啉相连； 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;
Figure PCTCN2020106080-appb-000054
Figure PCTCN2020106080-appb-000054
第4步：化合物III-4经偶联反应生成化合物III-5；Step 4: Compound III-4 is coupled to produce compound III-5;
Figure PCTCN2020106080-appb-000055
Figure PCTCN2020106080-appb-000055
第5-1步：化合物III-5经取代反应生成化合物III-A-1；Step 5-1: Compound III-5 is substituted to generate compound III-A-1;
Figure PCTCN2020106080-appb-000056
Figure PCTCN2020106080-appb-000056
第5-2步：化合物III-5经偶联反应生成化合物III-B-1；Step 5-2: Compound III-5 is coupled to produce compound III-B-1;
Figure PCTCN2020106080-appb-000057
Figure PCTCN2020106080-appb-000057
其中R 1、R 2、R 3a、R 3b、L a和L b如上文中所定义。 Wherein R 1, R 2, R 3a , R 3b, L a and L b are as hereinbefore defined.
在本发明的一些优选的实施方案中，第1步中的卤代反应可使用的卤代剂包括三氯氧磷、五氯化磷、三溴氧磷、溴化氢等；可使用的溶剂包括1,4-二氧六环、N,N-二甲基甲酰胺和乙酸乙酯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第2步中的氧化反应可使用的氧化剂包括间氯过氧苯甲酸、双氧水、过氧化脲等；可使用的溶剂包括二氯甲烷、氯仿、1,2-二氯乙烷、1,4-二氧六环等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第3步中的反应可使用的溶剂包括四氢呋喃、1,4-二氧六环、甲苯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第4步中的偶联反应包括Suzuki反应、Stille反应等，R 1通过包含其的硼酸(例如R 1-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000058
)或有机锡化合物(例如R 1-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯(Cs 2CO 3)、磷酸钾(K 3PO 4)、碳酸钠(Na 2CO 3)、醋酸钾(AcOK)、碳酸氢钠(NaHCO 3)、碳酸钾(K 2CO 3)等；可使用的溶剂为1,4-二氧六环/水(斜杠表述二者的组合)、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为60℃至180℃。 In some preferred embodiments of the present invention, 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
Figure PCTCN2020106080-appb-000058
) 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 Sexual reagents 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/water, acetonitrile /Water, toluene/water, etc.; the reaction temperature is 60°C to 180°C.
在本发明的一些优选的实施方案中，第5-1步中的取代反应可使用的溶剂为N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈、二氯甲烷等；可使用的碱性试剂包括三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等；反应温度为-20℃至180℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第5-2步中的偶联反应包括Suzuki反应、Stille反应等，R 3b-L b通过包含其的硼酸(例如R 3b-L b-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000059
)或有机锡化合物(例如R 3b-L b-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、碳酸钾等；可使用的溶剂为1,4-二氧六环/水、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为60℃至180℃。 In some preferred embodiments of the present invention, 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.
Figure PCTCN2020106080-appb-000059
) Or organotin compounds (such as R 3b -L b -Sn(n-Bu) 3 ) participate in the reaction; 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.
本发明提供了上述式III-A化合物与式III-B化合物(当式III中的R 5为氟且m为1时，分别为式III-A-2化合物与式III-B-2化合物)的制备方法，其包括下列步骤： 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:
第1步：化合物III-6在路易斯酸催化下与米氏酸(Meldrum’s acid)反应生成化合物III-7；Step 1: Compound III-6 reacts with Meldrum's acid under the catalysis of Lewis acid to produce compound III-7;
Figure PCTCN2020106080-appb-000060
Figure PCTCN2020106080-appb-000060
第2步：化合物III-7经缩合反应生成化合物III-8；Step 2: Compound III-7 undergoes condensation reaction to produce compound III-8;
Figure PCTCN2020106080-appb-000061
Figure PCTCN2020106080-appb-000061
其中Y代表磺酰基，选自甲磺酰基(Ms)、对甲苯磺酰基(Ts)和三氟甲磺酰基(Tf)；Wherein Y represents a sulfonyl group, selected from the group consisting of methanesulfonyl (Ms), p-toluenesulfonyl (Ts) and trifluoromethanesulfonyl (Tf);
第3-1步：化合物III-8经取代反应生成化合物III-9-1；Step 3-1: Compound III-8 is substituted to generate compound III-9-1;
Figure PCTCN2020106080-appb-000062
Figure PCTCN2020106080-appb-000062
第3-2步：化合物III-8经偶联反应生成化合物I-9-2；Step 3-2: Compound III-8 is coupled to produce compound I-9-2;
Figure PCTCN2020106080-appb-000063
Figure PCTCN2020106080-appb-000063
第4步：化合物III-9-1和III-9-2分别经卤代反应生成化合物III-10-1和III-10-2；Step 4: Compounds III-9-1 and III-9-2 are halogenated to generate compounds III-10-1 and III-10-2, respectively;
Figure PCTCN2020106080-appb-000064
Figure PCTCN2020106080-appb-000064
其中X代表卤素原子，选自氯、溴和碘；Wherein X represents a halogen atom, selected from chlorine, bromine and iodine;
第5步：化合物III-10-1和III-10-2分别与R 2H反应生成化合物III-11-1和III-11-2，其中R 2通过氮原子与喹啉相连； 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;
Figure PCTCN2020106080-appb-000065
Figure PCTCN2020106080-appb-000065
第6步：化合物III-11-1和III-11-2分别经偶联反应生成化合物III-A-2和III-B-2；Step 6: Compounds III-11-1 and III-11-2 are respectively coupled to generate compounds III-A-2 and III-B-2;
Figure PCTCN2020106080-appb-000066
Figure PCTCN2020106080-appb-000066
其中R 1、R 2、R 3a、R 3b、L a和L b如上文中所定义。 Wherein R 1, R 2, R 3a , R 3b, L a and L b are as hereinbefore defined.
在本发明的一些优选的实施方案中，第1步中的反应可使用的路易斯酸包括伊顿试剂(Eaton’s reagent)、三氯化铝、三氟化硼、溴化铁等；可使用的溶剂包括四氢呋喃、1,4-二氧六环、甲苯等；反应温度为20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第2步中的取代反应可使用的碱性试剂包括三乙胺、N,N-二异丙基乙胺、碳酸钾等；可使用的溶剂为四氢呋喃、1,4-二氧六环、甲苯等；反应温度为20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第3-1步中的取代反应可使用的溶剂包括N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈、二氯甲烷等；可使用的碱性试剂包括三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等；反应温度为-20℃至180℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第3-2步中的偶联反应包括Suzuki反应、Stille反应等，R 3b-L b通过包含其的硼酸(例如R 3b-L b-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000067
)或有机锡化合物(例如R 3b-L b-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、碳酸钾等；可使用的溶剂为1,4-二氧六环/水(斜杠表述二者的组合)、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为60℃至180℃。 In some preferred embodiments of the present invention, 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.
Figure PCTCN2020106080-appb-000067
) Or organotin compounds (such as R 3b -L b -Sn(n-Bu) 3 ) participate in the reaction; 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.
在本发明的一些优选的实施方案中，第4步中的卤代反应可使用的卤代剂包括三氯氧磷、五氯化磷、三溴氧磷、溴化氢等；可使用的溶剂包括1,4-二氧六环、N,N-二甲基甲酰胺、乙酸乙酯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第5步中的反应可使用的溶剂包括四氢呋喃、1,4-二氧六环、甲苯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第6步中的偶联反应包括Suzuki反应、Stille反应等，R 1通过包含其的硼酸(例如R 1-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000068
)或有机锡化合物(例如R 1-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、碳酸钾等；可使用的溶剂为1,4-二氧六环/水、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为60℃至180℃。 In some preferred embodiments of the present invention, 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
Figure PCTCN2020106080-appb-000068
) 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 Sexual reagents 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.
本发明提供了上述式IV-A化合物与式IV-B化合物(当式IV中的X 1为-CH＝时，分别为式IV-A-1化合物与式IV-B-1化合物)的制备方法，其包括下列步骤： The present invention provides the preparation of the above compound of formula IV-A and compound of formula IV-B (when X 1 in formula IV is -CH=, the compound of formula IV-A-1 and compound of formula IV-B-1 respectively) The method includes the following steps:
第1步：化合物IV-1经卤代反应生成化合物IV-2；Step 1: Compound IV-1 is halogenated to produce compound IV-2;
Figure PCTCN2020106080-appb-000069
Figure PCTCN2020106080-appb-000069
X代表卤素原子，选自氯和溴；X represents a halogen atom, selected from chlorine and bromine;
第2步：化合物IV-2经碘代反应生成化合物IV-3；Step 2: Compound IV-2 is reacted by iodine to generate compound IV-3;
Figure PCTCN2020106080-appb-000070
Figure PCTCN2020106080-appb-000070
第3步：化合物IV-3经氧化反应生成化合物IV-4；Step 3: Compound IV-3 is oxidized to produce compound IV-4;
Figure PCTCN2020106080-appb-000071
Figure PCTCN2020106080-appb-000071
第4步：化合物IV-4与R 4H反应生成化合物IV-5，其中R 4通过氮原子与噻吩并吡啶相连； 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;
Figure PCTCN2020106080-appb-000072
Figure PCTCN2020106080-appb-000072
第5步：化合物IV-5经偶联反应生成化合物IV-6；Step 5: Compound IV-5 is coupled to produce compound IV-6;
Figure PCTCN2020106080-appb-000073
Figure PCTCN2020106080-appb-000073
第6-1步：化合物IV-6经取代反应生成化合物IV-A-1；Step 6-1: Compound IV-6 undergoes substitution reaction to generate compound IV-A-1;
Figure PCTCN2020106080-appb-000074
Figure PCTCN2020106080-appb-000074
第6-2步：化合物IV-6经偶联反应生成化合物IV-B-1；Step 6-2: Compound IV-6 is coupled to produce compound IV-B-1;
Figure PCTCN2020106080-appb-000075
Figure PCTCN2020106080-appb-000075
其中R 1、R 3a、R 3b、R 4、L a和L b如上文中所定义。 Wherein R 1, R 3a, R 3b , R 4, L a and L b are as hereinbefore defined.
在本发明的一些优选的实施方案中，第1步中的卤代反应可使用的卤代剂包括三氯氧磷、五氯化磷、三溴氧磷、溴化氢等；可使用的溶剂为1,4-二氧六环、N,N-二甲基甲酰胺、乙酸乙酯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第2步中的碘代反应可使用的碘代剂包括单质碘、N-碘代琥珀酰亚胺(NIS)、碘化氢等；可使用的溶剂包括乙酸、1,4-二氧六环、N,N-二甲基甲酰胺、乙酸乙酯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第3步中的氧化反应可使用的氧化剂包括间氯过氧苯甲酸、双氧水、过氧化脲等；可使用的溶剂为二氯甲烷、氯仿、1,2-二氯乙烷、1,4-二氧六环等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第4步中的反应可使用的溶剂为四氢呋喃、1,4-二氧六环、甲苯等；反应温度为-20℃至100℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第5步中的偶联反应包括Suzuki反应、Stille反应等，R 1通过包含其的硼酸(例如R 1-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000076
)或有机锡化合物(例如R 1-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、碳酸钾等；可使用的溶剂为1,4-二氧六环/水、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为60℃至180℃。 In some preferred embodiments of the present invention, 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
Figure PCTCN2020106080-appb-000076
) 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 Sexual reagents 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.
在本发明的一些优选的实施方案中，第6-1步中的取代反应可使用的溶剂包括N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈、二氯甲烷等；可使用的碱性试剂包括三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等；反应温度为-20℃至180℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第6-2步中的偶联反应包括Suzuki反应、Stille反应等，R 3b-L b通过包含其的硼酸(例如R 3b-L b-B(OH) 2)、硼酸酯(例如
Figure PCTCN2020106080-appb-000077
)或有机锡化合物(例如R 3b-L b-Sn(n-Bu) 3)参与反应；可使用的催化剂包括Pd(PPh 3) 4、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、碳酸钾等；可使用的溶剂为1,4-二氧六环/水(斜杠表述二者的组合)、N,N-二甲基甲酰胺/水、二甲基亚砜/水、乙腈/水、甲苯/水等；反应温度为40℃至180℃。 In some preferred embodiments of the present invention, 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.
Figure PCTCN2020106080-appb-000077
) Or organotin compounds (such as R 3b -L b -Sn(n-Bu) 3 ) participate in the reaction; 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.
本发明提供了上述式IV-A化合物与式IV-B化合物(当式IV中的X 1为-CH＝且R 1为1H-吡唑-5-基时，分别为式IV-A-2化合物与式IV-B-2化合物)的制备方法，其包括下列步骤： The present invention provides the compound of formula IV-A and the compound of formula IV-B (when X 1 in formula IV is -CH= and R 1 is 1H-pyrazol-5-yl, respectively, formula IV-A-2 The preparation method of the compound and the compound of formula IV-B-2), which comprises the following steps:
第7步：化合物IV-A-1’和化合物IV-B-1’分别经脱保护基反应生成化合物IV-A-2和化合物IV-B-2；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;
Figure PCTCN2020106080-appb-000078
Figure PCTCN2020106080-appb-000078
其中R 3a、R 3b、R 4、L a和L b如上文中所定义；PG 1和PG 2代表保护基，各自独立地选自四氢-2H-吡喃-2-基(THP)、叔丁氧羰基(Boc)和苄氧羰基(Cbz)。 Wherein 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).
在本发明的一些优选的实施方案中，第7-1步和第7-2步中的脱保护基反应可使用的酸包括盐酸、氢溴酸、硫酸、硝酸、氯化铝(路易斯酸)、对甲苯磺酸等；可使用的溶剂为二氯甲烷、乙酸乙酯、1,4-二氧六环、二甲基亚砜、乙腈、甲苯等；反应温度为-10℃至180℃。In some preferred embodiments of the present invention, 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.
本发明提供了上述式V化合物的制备方法，其利用上述式IV-A化合物与式IV-B化合物的制备方法中的中间体——化合物IV-6作为原料，具体包括下列步骤：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:
第1步：化合物IV-6经取代或偶联反应生成化合物V；Step 1: Compound IV-6 is substituted or coupled to produce compound V;
Figure PCTCN2020106080-appb-000079
Figure PCTCN2020106080-appb-000079
其中R 1、R 3、R 4、R 33、L 2、L 3、p和q如上文中所定义。 Wherein R 1 , R 3 , R 4 , R 33 , L 2 , L 3 , p and q are as defined above.
在本发明的一些优选的实施方案中，第1步中的取代反应可使用的溶剂包括N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈、二氯甲烷等；可使用的碱性试剂包括三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等；反应温度为-20℃至180℃。In some preferred embodiments of the present invention, 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.
在本发明的一些优选的实施方案中，第1步中的偶联反应包括Buchwald-Hartwig反应；可使用的催化剂包括Pd(PPh 3) 4、Pd 2(dba) 3、Pd(OAc) 2、Pd(dppf)Cl 2·CH 2Cl 2等；可使用的配体包括PPh 3、BINAP、Xphos、Davephos、Brettphos等；可使用的碱性试剂包括碳酸铯、磷酸钾、碳酸钠、醋酸钾、碳酸氢钠、叔丁醇钾、三乙胺、N,N-二异丙基乙胺、氢氧化钠等；可使用的溶剂为1,4-二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、乙腈、甲苯等；反应温度为40℃至180℃。 In some preferred embodiments of the present invention, 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.
[药物组合物][Pharmaceutical composition]
术语“药物组合物”是指可以用作药物的组合物，其包含药物活性成分(API)以及可选的一种或多种药学上可接受载体。术语“药学上可接受的载体”是指与药物活性成分相容而一同施用，并且对受试者无害的药用辅料，其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或者与合理的益处/风险比相应的其它问题或并发症。常见的药学上可接受的载体包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。适合的药学上可接受的载体的实例可参见Remington’s Pharmaceutical Sciences[M],Mack Printing Company,1990。The term "pharmaceutical 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. The term "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.
本发明提供了一种药物组合物，其包含上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式。The present invention provides 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.
在本发明的一些实施方案中，上述药物组合物还包含药学上可接受的载体。In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[医药用途][Medicine use]
术语“激动剂(agonist)”是指一种与受体结合并将其激活而引发下游的生物学效应(biological effect)或应答(response)的化合物，包括完全激动剂(full agonist)和部分激动剂(partial agonist)。完全激动剂能激活受体并产生最大的效应(maximal effect或Emax)。部分激动剂可以和受体结合并将其激活，但相对于完全激动剂而言，只产生部分的效应(partial effect)。当完全激动剂和部分激动剂共存时，部分激动剂有时可以通过与完全激动剂竞争受体上的结合位点或其他机制而成为部分拮抗剂。一个部分激动剂的效力(potency，可由EC 50衡量)有可能高于或低于一个全激动剂的效力。本发明的NLRP3激动剂包括NLRP3完全激动剂和NLRP3部分激动剂。 The term "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. When a full agonist and a partial agonist coexist, the partial agonist can sometimes become a partial antagonist by competing with the full agonist for binding sites on the receptor or by other mechanisms. 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.
术语“NLRP3”的全称是NLR family pyrin domain containing 3，是一种炎症小体。在本发明中，当提及“NLRP3”时，所指的含义包括NLRP3的核酸、多聚核苷酸、寡核苷酸、正义和反义多聚核苷酸链、互补序列、短肽、多肽、蛋白、同源或异源分子、亚型、前体、突变体、变体、衍生物、各种剪接体、等位基因、不同种属以及活化片段等。The full name of the term "NLRP3" is NLR family pyrin domain containing 3, which is an inflammasome. In the present invention, when referring to "NLRP3", 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.
无论是上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式，还是上述药物组合物，都能够对NLRP3表现出调节作用(尤其是激动活性)，可以用作NLRP3调节剂。因此，本发明提供了上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物用作NLRP3调节剂的用途。No matter 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, The above-mentioned pharmaceutical compositions 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 accepted form or use of the above-mentioned pharmaceutical composition as a modulator of NLRP3.
另外，本申请还提供了上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物在制备用于预防和/或治疗至少部分由NLRP3介导的疾病的药物中的用途。In addition, 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 The acceptable form or the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of diseases mediated at least in part by NLRP3.
术语“至少部分由NLRP3介导的疾病”是指发病机理中至少包含一部分与NLRP3有关的因素的疾病，这些疾病包括(但不限于)癌症(例如白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、***、***癌、膀胱癌、结肠癌、直肠癌、结直肠癌、胃癌、食管癌、口腔癌、胰腺癌、肝癌、肺癌、肾癌、皮肤癌、骨癌、脑癌、神经胶质瘤、黑色素瘤等)。The term "disease mediated at least in part by NLRP3" refers to a disease whose pathogenesis includes at least some of the factors related to NLRP3. These 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.).
[治疗方法][treatment method]
本发明提供了一种用于预防和/或治疗至少部分由NLRP3介导的疾病的方法，其包括下列步骤：将预防和/或治疗有效量的上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物施用于对其有需求的个体。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.
术语“预防和/或治疗有效量”是指能够诱发细胞、组织、器官或生物体(例如个体)产生生物或医学反应以实现预防和/或治疗效果的药物活性成分的剂量。The term "preventively 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.
可调整给药方案以提供最佳所需响应。例如，可给药单次推注或可随时间给药数个分剂量。要注 意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。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.
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，合计约为0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是预先将所述较大剂量分成数个较小剂量并且在一整天中分次给药。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. Generally, 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). For a 70 kg person, 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. In some cases, 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.
本发明的化合物在药物组合物中的含量或用量约为0.01-1000mg。The content or amount of the compound of the present invention in the pharmaceutical composition is about 0.01-1000 mg.
除非另外说明，术语“治疗(treat/treating/treatment)”是指逆转、减轻、抑制所针对的病症或病况，或者这样的病症或病况的一或多种症状的进展。术语“施用”是指将药物活性成分(比如本发明的化合物)或包含药物活性成分的药物组合物(例如本发明的药物组合物)应用于个体或其细胞、组织、器官、生物流体等部位，以便使药物活性成分或药物组合物与个体或其细胞、组织、器官、生物流体等部位接触的过程。常见的施用方式包括(但不限于)口服施用、皮下施用、肌内施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直肠施用、***施用等。对于上述施用(给药)途径，可以通过适合的剂型使用本发明的药物组合物。适合的剂型包括(但不限于)片剂、胶囊剂、锭剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、混悬剂、注射剂、酏剂、糖浆剂等。Unless otherwise stated, 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. The term "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. Common modes of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration and the like. For the above-mentioned administration (administration) route, the pharmaceutical composition of the present invention can be used in a suitable dosage form. 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.
术语“对其有需求”是指医生或其他护理人员对个体需要或者将要从预防和/或治疗过程中获益的判断，该判断的得出基于医生或其他护理人员在其专长领域中的各种因素。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.
术语“个体”(或称受试者)是指人类或非人类的动物(例如哺乳动物)。示例性的人类个体既包括患有疾病的人类个体，也包括正常的人类个体。示例性的动物个体包括所有脊椎动物，例如非哺乳动物(例如两栖类、爬行类、鸟类等)和哺乳动物(非人灵长类、啮齿类、家畜和/或驯化动物等)。The term "individual" (or subject) 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.).
[联合用药][Combination medication]
本发明提供了一种药物联用组合物，其包含上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物，以及至少一种其他的同向NLRP3调节剂。The present invention provides 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.
术语“同向”是指当针对某一靶点施用至少两种调节剂时，其调节方向应大体相同，或者同时表现出激动作用，或者同时表现出拮抗作用。具体而言，当上述药物联用组合物包含作为NLRP3激动剂的式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者药物组合物时，其还包含至少一种其他的NLRP3激动剂，该药物联用组合物适用于预防和/或治疗癌症；同理，当上述药物联用组合物包含作为NLRP3拮抗剂的式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者药物组合物时，其还包含至少一种其他的NLRP3拮抗剂，该药物联用组合物适用于预防和/或治疗免疫性疾病。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. Specifically, when 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- When the compound of B or formula V or its pharmaceutically acceptable form or pharmaceutical composition, it also contains at least one other NLRP3 agonist, 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 In its pharmaceutically acceptable form or pharmaceutical composition, it also contains at least one other NLRP3 antagonist, and the drug combination composition is suitable for the prevention and/or treatment of immune diseases.
本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3激动剂的上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的个体。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 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.
本发明提供了一种用于预防和/或治疗免疫性疾病的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3拮抗剂的上述式X、式I、式II、式III、式IV、式III-A、式III-B、式IV-A、式IV-B或式V化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的个体。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.
以下将结合具体的实施例来进一步阐述本发明。应当理解，这些实施例仅用于说明本发明，而并不旨在限制本发明的范围。如果下列实施例中的实验方法未注明具体条件，则通常按照常规条件或生产厂商所建议的条件(例如，室温为20～30℃)。所使用的试剂购自Acros Organics、Aldrich Chemical Company、上海特伯化学科技有限公司等。除非另外说明，下列实施例中出现的百分比和份数均以重 量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention, and are not intended to limit the scope of the present invention. If the experimental methods in the following examples do not indicate specific conditions, they usually follow the conventional conditions or the conditions recommended by the manufacturer (for example, the room temperature is 20-30°C). The reagents used were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., etc. Unless otherwise specified, the percentages and parts appearing in the following examples are calculated by weight.
本发明上下文中的缩写具有以下含义：The abbreviations in the context of the present invention have the following meanings:
Figure PCTCN2020106080-appb-000080
Figure PCTCN2020106080-appb-000080
本发明的化合物的结构通过核磁共振氢谱( 1H-NMR)和/或质谱(MS)鉴定。 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).
1H-NMR化学位移(δ)以百万分之一(ppm)记录。 1H-NMR通过AVANCE III HD 400MHz核磁 仪测定，溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)。常见缩写形式具有如下含义：s：单峰；d：二重峰；t：三重峰；q：四重峰；dd：双二重峰；qd：四二重峰；m：多重峰；br：宽峰(broad)；J：偶合常数；Hz：赫兹。 1 H-NMR chemical shifts (δ) 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.
反应的监测采用TLC或LC-MS进行。The monitoring of the reaction is carried out by TLC or LC-MS.
TLC采用硅胶GF 254(青岛海洋)作为固定相。TLC uses silica gel GF 254 (Qingdao Ocean) as the stationary phase.
LC-MS使用Aglient 1260 Infinity/Aglient 6120 Quadrupole质谱仪。LC-MS uses Aglient 1260 Infinity/Aglient 6120 Quadrupole mass spectrometer.
本发明的化合物可通过制备TLC、硅胶柱层析、Prep-HPLC和/或快速柱层析(Flash柱层析)分离纯化。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使用Agilent 1260制备液相色谱仪，检测波长为214nm或254nm；色谱柱为Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；柱温为25℃，并且洗脱条件如下：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×5.0μm); the column temperature is 25℃, and the elution conditions are as follows:
条件1：10％-90％乙腈和90％-10％甲酸铵水溶液(0.05％，w/v)，0-16min；流速：24mL/min；Condition 1: 10%-90% acetonitrile and 90%-10% ammonium formate aqueous solution (0.05%, w/v), 0-16min; flow rate: 24mL/min;
条件2：10％-46％乙腈和90％-54％碳酸氢铵水溶液(0.05％，w/v)，0-7.2min；流速：24mL/min；Condition 2: 10%-46% acetonitrile and 90%-54% ammonium bicarbonate aqueous solution (0.05%, w/v), 0-7.2min; flow rate: 24mL/min;
条件3：10％-90％乙腈和90％-10％甲酸水溶液(0.05％，w/v)，0-16min；流速：28mL/min；Condition 3: 10%-90% acetonitrile and 90%-10% formic acid aqueous solution (0.05%, w/v), 0-16min; flow rate: 28mL/min;
条件4：10％-90％乙腈和90％-10％碳酸氢铵水溶液(0.05％，w/v)，0-16min；流速：28mL/min；Condition 4: 10%-90% acetonitrile and 90%-10% ammonium bicarbonate aqueous solution (0.05%, w/v), 0-16min; flow rate: 28mL/min;
条件5：30％-90％乙腈和70％-10％碳酸氢铵水溶液(0.05％，w/v)，0-16min；流速：24mL/min；Condition 5: 30%-90% acetonitrile and 70%-10% ammonium bicarbonate aqueous solution (0.05%, w/v), 0-16min; flow rate: 24mL/min;
条件6：10％-70％乙腈和90％-30％碳酸氢铵水溶液(0.05％，w/v)，0-18min；流速：24mL/min。Condition 6: 10%-70% acetonitrile and 90%-30% ammonium bicarbonate aqueous solution (0.05%, w/v), 0-18 min; flow rate: 24 mL/min.
柱色谱法一般使用200～300目硅胶(青岛海洋)为固定相。洗脱剂体系A：二氯甲烷和甲醇；洗脱剂体系B：石油醚和乙酸乙酯。根据化合物的极性不同而调节两种洗脱剂体系的体积比。Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase. Eluent system A: dichloromethane and methanol; eluent system B: petroleum ether and ethyl acetate. Adjust the volume ratio of the two eluent systems according to the polarity of the compound.
快速柱层析使用Biotage快速柱色谱仪。The flash column chromatography uses the Biotage flash column chromatograph.
微波反应使用Biotage Initiator+微波反应器进行。The microwave reaction is carried out using a Biotage Initiator + microwave reactor.
在以下实施例中，如无特殊说明，反应的温度为室温(15℃～30℃)。In the following examples, unless otherwise specified, the reaction temperature is room temperature (15°C to 30°C).
本申请中所使用的试剂购自Acros Organics、Aldrich Chemical Company或特伯化学等公司。The reagents used in this application are purchased from companies such as Acros Organics, Aldrich Chemical Company, or Terbo Chemical.
中间体制备例1：(7-溴-N-叔丁基-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-胺(化合物2f)。Intermediate preparation example 1: (7-bromo-N-tert-butyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3, 2-b] Pyridin-5-amine (Compound 2f).
Figure PCTCN2020106080-appb-000081
Figure PCTCN2020106080-appb-000081
第1步：7-溴噻吩并[3,2-b]吡啶(化合物2b)的合成。Step 1: Synthesis of 7-bromothieno[3,2-b]pyridine (compound 2b).
将三溴氧磷(158.90g，555.61mmol)加热到60℃至融化状态，将化合物1a(14g，92.60mmol)加入其中，升温到100℃反应2小时。将反应液缓慢倒入冰水中，用氢氧化钠调节pH>8。DCM萃取，有机层干燥浓缩。通过柱层析纯化(洗脱剂体系B)，得到化合物2b(18.5g)。Phosphorus oxybromide (158.90 g, 555.61 mmol) was heated to 60° C. to a molten state, compound 1a (14 g, 92.60 mmol) was added to it, and the temperature was raised to 100° C. to react for 2 hours. The reaction solution was slowly poured into ice water, and the pH was adjusted to >8 with sodium hydroxide. It was extracted with DCM and the organic layer was dried and concentrated. Purification by column chromatography (eluent system B) gave compound 2b (18.5 g).
MS(ESI):m/z 213.9[M+H] +。 MS (ESI): m/z 213.9 [M+H] + .
第2步：7-溴-2-碘噻吩并[3,2-b]吡啶(化合物2c)的合成。Step 2: Synthesis of 7-bromo-2-iodothieno[3,2-b]pyridine (compound 2c).
-65℃下，将LDA(4M，14.2mL)缓慢加入到化合物2b(10g，46.71mmol)的THF(100mL)溶液中，低温搅拌反应1小时。将碘单质(14.18g，56.05mmol)的THF(80mL)溶液缓慢加入到反应体系中，低温反应2小时。缓慢升到室温反应2小时。加饱和氯化铵水溶液淬灭反应。EA萃取，有机层干燥浓缩。通过柱层析纯化(洗脱剂体系B)，得到化合物2c(13.5g)。At -65°C, LDA (4M, 14.2 mL) was slowly added to the compound 2b (10 g, 46.71 mmol) in THF (100 mL) solution, and the reaction was stirred at low temperature for 1 hour. A solution of elemental iodine (14.18 g, 56.05 mmol) in THF (80 mL) was slowly added to the reaction system, and reacted at low temperature for 2 hours. Slowly rise to room temperature and react for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution. EA extraction, the organic layer was dried and concentrated. Purification by column chromatography (eluent system B) gave compound 2c (13.5 g).
MS(ESI):m/z 339.9[M+H] +。 MS (ESI): m/z 339.9 [M+H] + .
第3步：7-溴-2-碘噻吩并[3,2-b]吡啶4-氧化物(化合物2d)的合成。Step 3: Synthesis of 7-bromo-2-iodothieno[3,2-b]pyridine 4-oxide (compound 2d).
室温下，将间氯过氧苯甲酸(3.57g，17.65mmol)加入到化合物2c(4.08g，11.77mmol)的DCM(50mL)溶液中，室温反应4小时。加饱和碳酸钠水溶液淬灭反应，DCM萃取。有机层干燥浓缩，加DCM打浆，过滤，得到化合物2d(3.0g)。At room temperature, m-chloroperoxybenzoic acid (3.57 g, 17.65 mmol) was added to a solution of compound 2c (4.08 g, 11.77 mmol) in DCM (50 mL), and reacted at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium carbonate solution, and extracted with DCM. The organic layer was dried and concentrated, slurried with DCM, and filtered to obtain compound 2d (3.0 g).
MS(ESI):m/z 355.9[M+H] +。 MS (ESI): m/z 355.9 [M+H] + .
第4步：7-溴-N-叔丁基-2-碘噻吩并[3,2-b]吡啶-5-胺(化合物2e)的合成。Step 4: Synthesis of 7-bromo-N-tert-butyl-2-iodothieno[3,2-b]pyridine-5-amine (compound 2e).
0℃下，依次将叔丁胺(3.22g，44.12mmol)、对甲苯磺酸酐(7.19g，22.06mmol)加入到化合物2d(3.0g，8.82mmol)的氯仿(15mL)/三氟甲苯(15mL)溶液中。0℃反应1小时。过滤反应液，母液浓缩。通过柱层析纯化(洗脱剂体系B)，得到化合物2e(2.3g)。At 0°C, tert-butylamine (3.22g, 44.12mmol) and p-toluenesulfonic anhydride (7.19g, 22.06mmol) were added to the chloroform (15mL)/benzotrifluoride (15mL) solution of compound 2d (3.0g, 8.82mmol) in sequence in. React at 0°C for 1 hour. The reaction liquid was filtered, and the mother liquor was concentrated. Purification by column chromatography (eluent system B) gave compound 2e (2.3g).
MS(ESI):m/z 435.0[M+Na] +。 MS (ESI): m/z 435.0 [M+Na] + .
第5步：7-溴-N-叔丁基-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-胺(化合物2f)的合成。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).
室温下，依次将碳酸钾(1.54g，11.19mmol)、Pd(dppf)Cl 2(204.49mg，279.74μmol)加入到化合物1f(1.87g，6.71mmol)和化合物2e(2.3g，5.59mmol)的1,4-二氧六环(20mL)/水(2mL)溶液中，然后保持50℃搅拌反应8小时。加水淬灭反应，EA萃取(40mL×3)。有机层干燥浓缩，通过柱层析分离纯化(PE:EA＝5:1)，得到化合物2f(2.0g)。 At room temperature, potassium carbonate (1.54g, 11.19mmol), Pd(dppf)Cl 2 (204.49mg, 279.74μmol) were added to compound 1f (1.87g, 6.71mmol) and compound 2e (2.3g, 5.59mmol). In 1,4-dioxane (20 mL)/water (2 mL) solution, the mixture was kept at 50° C. and stirred for 8 hours. The reaction was quenched by adding water, and extracted with EA (40 mL×3). The organic layer was dried and concentrated, and separated and purified by column chromatography (PE:EA=5:1) to obtain compound 2f (2.0 g).
MS(ESI):m/z 435.0[M+H] +。 MS (ESI): m/z 435.0 [M+H] + .
实施例1：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物2)。Example 1: 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol (compound 2).
Figure PCTCN2020106080-appb-000082
Figure PCTCN2020106080-appb-000082
第一步：3-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(1b)的合成。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).
将3-氨基丙醇(69mg)、2f(200mg)、Brettphos(49.31mg)、Pd 2(dba) 3(42.07mg)和叔丁醇钾(154.64mg)加入1,4-二氧六环(8mL)中，氮气保护，110℃搅拌10小时。冷却，过滤，滤液浓缩后经层析硅胶板纯化分离(洗脱剂体系B)，得到1b(23mg)。 Add 3-aminopropanol (69mg), 2f (200mg), Brettphos (49.31mg), Pd 2 (dba) 3 (42.07mg) and potassium tert-butoxide (154.64mg) to 1,4-dioxane ( 8mL), under nitrogen protection, and stirred at 110°C for 10 hours. After cooling, filtering, the filtrate was concentrated and purified and separated by chromatography on a silica gel plate (eluent system B) to obtain 1b (23 mg).
MS(ESI):m/z 430.2[M+H] +。 MS (ESI): m/z 430.2 [M+H] + .
第二步：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物2)的合成。The second step: 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol (compound 2) Synthesis.
将1b(15mg)和对甲苯磺酸(8mg)加入甲醇(5mL)中，25℃搅拌3小时，减压浓缩，通过Prep-HPLC分离纯化(洗脱条件2)，冻干得到化合物2(12mg)。1b (15mg) and p-toluenesulfonic acid (8mg) were added to methanol (5mL), stirred at 25°C for 3 hours, concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to give compound 2 (12mg ).
MS(ESI):m/z 346.2[M+H] +。 MS (ESI): m/z 346.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),5.96(s,1H),5.68-5.71(m,2H),4.53-4.55(m,1H),3.51-3.52(m,2H),3.16-3.35(m,2H),1.75-1.76(m,2H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.79 (s, 1H), 7.36 (s, 1H), 6.77 (s, 1H), 5.96 (s, 1H), 5.68-5.71(m,2H),4.53-4.55(m,1H),3.51-3.52(m,2H),3.16-3.35(m,2H),1.75-1.76(m,2H),1.41(s,9H) ).
实施例2：3-(5-叔丁氨基)-2-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物3)。Example 2: 3-(5-tert-butylamino)-2-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino) -1-Propanol (Compound 3).
Figure PCTCN2020106080-appb-000083
Figure PCTCN2020106080-appb-000083
第一步：7-溴-N-叔丁基-2-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-胺(2a)的合成。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.
将2e(71.31mg)、1,3-二甲基-1H-吡唑-5-硼酸频哪醇酯(35.59mg)、碳酸钾(73.85mg)、Pd(dppf)Cl 2(21.83mg)加入1,4-二氧六环(5mL)和水(0.5mL)的混合体系中，N 2置换后50℃反应4小时。将反应液降至室温，过滤，滤液减压浓缩后经薄层层析(洗脱剂体系B)，得到2a(90mg)。 Add 2e (71.31mg), 1,3-dimethyl-1H-pyrazole-5-boronic acid pinacol ester (35.59mg), potassium carbonate (73.85mg), Pd(dppf)Cl 2 (21.83mg) In a mixed system of 1,4-dioxane (5 mL) and water (0.5 mL), the reaction was carried out at 50°C for 4 hours after N 2 replacement. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and then subjected to thin layer chromatography (eluent system B) to obtain 2a (90 mg).
MS(ESI):m/z 379[M+H] +。 MS (ESI): m/z 379 [M+H] + .
第二步：3-(5-叔丁氨基)-2-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物3)的合成。The second step: 3-(5-tert-butylamino)-2-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino) Synthesis of -1-propanol (Compound 3).
将3-氨基-1-丙醇(128.71mg)、2a(130mg)、Pd 2(dba) 3(62.77mg)、BrettPhos(73.58mg)、叔丁醇钾(115.37mg)加入1,4-二氧六环(5mL)，N 2置换后110℃反应5小时。过滤，滤饼用二氧六环洗涤，滤液减压浓缩后通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物3(30mg)。 Add 3-amino-1-propanol (128.71mg), 2a (130mg), Pd 2 (dba) 3 (62.77mg), BrettPhos (73.58mg), potassium tert-butoxide (115.37mg) to 1,4-bis Oxane (5 mL) was replaced with N 2 and reacted at 110°C for 5 hours. After filtration, the filter cake was washed with dioxane, the filtrate was concentrated under reduced pressure and then separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 3 (30 mg).
MS(ESI):m/z 374.1[M+H] +。 MS (ESI): m/z 374.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ7.25(s,1H),6.30(s,1H),6.11-6.08(m,1H),5.83(s,1H),5.73(s,1H),4.52(t,J＝5.0Hz,1H),3.92(s,3H),3.52(dd,J＝11.3,6.1Hz,2H),3.18(dd,J＝12.6,6.7Hz,2H),2.16(s,3H),1.80-1.72(m,2H),1.41(s,9H)。 1 H-NMR(DMSO-d 6 ,400MHz): δ7.25(s,1H), 6.30(s,1H), 6.11-6.08(m,1H), 5.83(s,1H), 5.73(s,1H) ), 4.52 (t, J = 5.0Hz, 1H), 3.92 (s, 3H), 3.52 (dd, J = 11.3, 6.1 Hz, 2H), 3.18 (dd, J = 12.6, 6.7 Hz, 2H), 2.16 (s, 3H), 1.80-1.72 (m, 2H), 1.41 (s, 9H).
实施例3：N 5-叔丁基-N 7-(氧杂环丁烷-3-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物4)。 Example 3: N 5 -tert-Butyl-N 7 -(oxetan-3-yl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5 ,7-Diamine (Compound 4).
Figure PCTCN2020106080-appb-000084
Figure PCTCN2020106080-appb-000084
第一步：N 5-叔丁基-N 7-(氧杂环丁烷-3-基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(3a)的合成。 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).
将氧杂环丁烷-3-胺(67mg)、2f(200mg)、Brettphos(49.31mg)、Pd 2(dba) 3(42.07mg)和叔丁醇钾(154.64mg)加入1,4-二氧六环(8mL)中，氮气保护，110℃搅拌10小时。冷却，过滤，滤液浓缩后经层析硅胶板纯化分离(洗脱剂体系B)，得到3a(30mg)。 Add oxetane-3-amine (67mg), 2f (200mg), Brettphos (49.31mg), Pd 2 (dba) 3 (42.07mg) and potassium tert-butoxide (154.64mg) to 1,4-bis In oxane (8 mL), under nitrogen protection, stir at 110°C for 10 hours. After cooling, filtering, the filtrate was concentrated and purified and separated by chromatography on a silica gel plate (eluent system B) to obtain 3a (30 mg).
MS(ESI):m/z 428.2[M+H] +。 MS (ESI): m/z 428.2 [M+H] + .
第二步：N 5-叔丁基-N 7-(氧杂环丁烷-3-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物4)的合成。 The second step: N 5 -tert-butyl-N 7 -(oxetan-3-yl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5 , Synthesis of 7-diamine (Compound 4).
将3a(30mg)和对甲苯磺酸(16mg)加入甲醇(5mL)中，25℃搅拌3小时，减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物4(4mg)。3a (30mg) and p-toluenesulfonic acid (16mg) were added to methanol (5mL), stirred at 25°C for 3 hours, concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 4 (4mg ).
MS(ESI):m/z 344.2[M+H] +。 MS (ESI): m/z 344.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.93(s,1H),7.80(s,1H),7.38(s,1H),6.71-6.79(m,2H),5.78(s,1H),5.39(s,1H),4.82-4.84(m,2H),4.51-4.58(m,3H),1.40(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.93 (s, 1H), 7.80 (s, 1H), 7.38 (s, 1H), 6.71-6.79 (m, 2H), 5.78 (s, 1H) ), 5.39 (s, 1H), 4.82-4.84 (m, 2H), 4.51-4.58 (m, 3H), 1.40 (s, 9H).
实施例4：N 5-叔丁基-N 7-(环丁基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物5)。 Example 4: N 5 -tert-butyl-N 7 -(cyclobutylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine( Compound 5).
Figure PCTCN2020106080-appb-000085
Figure PCTCN2020106080-appb-000085
第一步：N 5-叔丁基-N 7-(环丁基甲基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(4a)的合成。 The first step: N 5 -tert-butyl-N 7 -(cyclobutylmethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno [3,2-b] Synthesis of pyridine-5,7-diamine (4a).
将2f(70mg)、环丁基甲胺(68.5mg)、Pd 2(dba) 3(30.3mg)、BrettPhos(30.3mg)、叔丁醇钾(83mg)加入到1,4-二氧六环(3mL)中，氮气置换后加热至120℃反应4小时。体系过滤，滤液浓缩后用 少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到4a(62mg)。 Add 2f (70mg), cyclobutyl methylamine (68.5mg), Pd 2 (dba) 3 (30.3mg), BrettPhos (30.3mg), potassium tert-butoxide (83mg) to 1,4-dioxane (3mL In ), after nitrogen replacement, it is heated to 120°C for reaction for 4 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 4a (62 mg).
MS(ESI):m/z 440.2[M+H] +。 MS (ESI): m/z 440.2 [M+H] + .
第二步：N 5-叔丁基-N 7-(环丁基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物5)的合成。 The second step: N 5 -tert-butyl-N 7 -(cyclobutylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine( Compound 5) Synthesis.
将4a(62mg)加入到无水甲醇(3mL)中，加入对甲苯磺酸(73mg)，室温下反应0.5小时，反应液通过Prep-HPLC分离纯化(洗脱条件2)，冻干得到化合物5(16mg)。4a (62mg) was added to anhydrous methanol (3mL), p-toluenesulfonic acid (73mg) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 5. (16mg).
MS(ESI):m/z 356.2[M+H] +。 MS (ESI): m/z 356.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.91(s,1H),7.79(s,1H),7.35(s,1H),6.77(s,1H),6.01(s,1H),5.72(s,1H),5.67(s,1H),3.57(t,J＝6.4Hz,2H),2.71-2.60(m,1H),2.09-1.99(m,2H),1.91-1.81(m,2H),1.76-1.65(m,2H),1.40(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.79 (s, 1H), 7.35 (s, 1H), 6.77 (s, 1H), 6.01 (s, 1H), 5.72(s,1H),5.67(s,1H),3.57(t,J=6.4Hz,2H),2.71-2.60(m,1H),2.09-1.99(m,2H),1.91-1.81(m, 2H), 1.76-1.65 (m, 2H), 1.40 (s, 9H).
实施例5：(R)-N 5-叔丁基-N 7-(1-甲氧基丙-2-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物6)。 Example 5: (R)-N 5 -tert-butyl-N 7 -(1-methoxyprop-2-yl)-2-(1H-pyrazol-5-yl)thieno[3,2- b] Pyridine-5,7-diamine (Compound 6).
Figure PCTCN2020106080-appb-000086
Figure PCTCN2020106080-appb-000086
第一步：N 5-叔丁基-N 7-((R)-1-甲氧基丙-2-基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(5a)的合成。 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).
将2f(70mg)、(R)-1-甲氧基-2-丙胺(71.7mg)、Pd 2(dba) 3(30.3mg)、BrettPhos(30.3mg)、叔丁醇钾(83mg)加入到1,4-二氧六环(3mL)中，氮气置换后加热至120℃反应4小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到5a(25mg)。 Add 2f (70mg), (R)-1-methoxy-2-propylamine (71.7mg), Pd 2 (dba) 3 (30.3mg), BrettPhos (30.3mg), potassium tert-butoxide (83mg) to After replacing 1,4-dioxane (3 mL) with nitrogen, it was heated to 120° C. and reacted for 4 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 5a (25 mg).
MS(ESI):m/z 444.2[M+H] +。 MS (ESI): m/z 444.2 [M+H] + .
第二步：(R)-N 5-叔丁基-N 7-(1-甲氧基丙-2-基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物6)的合成。 The second step: (R)-N 5 -tert-butyl-N 7 -(1-methoxyprop-2-yl)-2-(1H-pyrazol-5-yl)thieno[3,2- b] Synthesis of pyridine-5,7-diamine (compound 6).
将5a(25mg)加入到无水甲醇(3mL)中，加入对甲苯磺酸(29mg)，室温下反应0.5小时，反应液通过Prep-HPLC分离纯化(洗脱条件2)，冻干得到化合物6(10mg)。5a (25mg) was added to anhydrous methanol (3mL), p-toluenesulfonic acid (29mg) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 6. (10mg).
MS(ESI):m/z 360.2[M+H] +。 MS (ESI): m/z 360.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.92(s,1H),7.80(s,1H),7.36(s,1H),6.78(s,1H),5.74(s,2H),5.64(s,1H),3.74-3.62(m,1H),3.50-3.43(m,1H),3.31-3.27(m,4H),1.41(s,9H),1.19(d,J＝6.4Hz,3H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.92 (s, 1H), 7.80 (s, 1H), 7.36 (s, 1H), 6.78 (s, 1H), 5.74 (s, 2H), 5.64(s,1H),3.74-3.62(m,1H),3.50-3.43(m,1H),3.31-3.27(m,4H),1.41(s,9H),1.19(d,J=6.4Hz, 3H).
实施例6：N 5-叔丁基-N 7-((3-甲基吡啶-2-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物7)。 Example 6: N 5 -tert-butyl-N 7 -((3-methylpyridin-2-yl)methyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b ] Pyridine-5,7-diamine (Compound 7).
Figure PCTCN2020106080-appb-000087
Figure PCTCN2020106080-appb-000087
第一步：N 5-叔丁基-N 7-((3-甲基吡啶-2-基)甲基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(6a)的合成。 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.
将2f(70mg)、2-氨甲基-3-甲基吡啶盐酸盐(30.14mg)、叔丁醇钾(54.12mg)、Pd(OAc) 2(7.22mg)、BINAP(40.04mg)加入甲苯(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再 经快速柱层析(洗脱剂体系A)，得到6a(50mg)。 Add 2f (70mg), 2-aminomethyl-3-methylpyridine hydrochloride (30.14mg), potassium tert-butoxide (54.12mg), Pd(OAc) 2 (7.22mg), BINAP (40.04mg) In toluene (2mL), heated to 120°C under the protection of N 2 and reacted for 2 hours. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 6a (50 mg).
MS(ESI):m/z 477.1[M+H] +。 MS (ESI): m/z 477.1 [M+H] + .
第二步：N 5-叔丁基-N 7-((3-甲基吡啶-2-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物7)的合成。 The second step: N 5 -tert-butyl-N 7 -((3-methylpyridin-2-yl)methyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b ] Synthesis of pyridine-5,7-diamine (compound 7).
将6a(20mg)、对甲苯磺酸(8.66mg)加入甲醇(2mL)中，室温搅拌反应12小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件5)，冻干得到化合物7。6a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 5), and lyophilized to obtain compound 7.
MS(ESI):m/z 393.1[M+H] +。 MS (ESI): m/z 393.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.96(s,1H),8.44-8.42(m,1H),7.81(s,1H),7.65-7.62(m,1H),7.41(s,1H),7.28-7.25(m,1H),6.81(s,1H),6.44(s,1H),5.80(s,2H),4.45(d,J＝4.4Hz,2H),2.36(s,3H),1.41(s,9H)。 1 H-NMR(DMSO-d 6 ,400MHz): δ12.96(s,1H),8.44-8.42(m,1H),7.81(s,1H),7.65-7.62(m,1H),7.41(s ,1H),7.28-7.25(m,1H),6.81(s,1H),6.44(s,1H),5.80(s,2H), 4.45(d,J=4.4Hz,2H),2.36(s, 3H), 1.41(s, 9H).
实施例7：N 5-叔丁基-N 7-(2-吗啉基乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物8)。 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).
Figure PCTCN2020106080-appb-000088
Figure PCTCN2020106080-appb-000088
第一步：N 5-叔丁基-N 7-(2-吗啉基乙基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(7a)的合成。 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).
将2f(70mg)、N-(2-氨基乙基)吗啉(24.7mg)、叔丁醇钾(54.12mg)、Pd(OAc) 2(7.22mg)、BINAP(40.04mg)加入甲苯(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到7a(50mg)。 Add 2f (70mg), N-(2-aminoethyl)morpholine (24.7mg), potassium tert-butoxide (54.12mg), Pd(OAc) 2 (7.22mg), BINAP (40.04mg) to toluene (2mL) In ), heat to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 7a (50 mg).
MS(ESI):m/z 485.1[M+H] +。 MS (ESI): m/z 485.1 [M+H] + .
第二步：N 5-叔丁基-N 7-(2-吗啉基乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物8)的合成。 The second step: N 5 -tert-butyl-N 7 -(2-morpholinoethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7 -Synthesis of Diamine (Compound 8).
将7a(20mg)、对甲苯磺酸(8.66mg)加入甲醇(2mL)中，室温搅拌反应12小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物8(3mg)。7a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 8 (3 mg).
MS(ESI):m/z 401.1[M+H] +。 MS (ESI): m/z 401.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.92(s,1H),7.79(s,1H),7.37(s,1H),6.78(s,1H),5.81-5.76(m,2H),5.70(s,1H),3.61-3.58(m,4H),3.26-3.22(m,2H),2.57-2.51(m,2H),2.49-2.43(m,4H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.92 (s, 1H), 7.79 (s, 1H), 7.37 (s, 1H), 6.78 (s, 1H), 5.81-5.76 (m, 2H) ), 5.70 (s, 1H), 3.61-3.58 (m, 4H), 3.26-3.22 (m, 2H), 2.57-2.51 (m, 2H), 2.49-2.43 (m, 4H), 1.41 (s, 9H) ).
实施例8：1-(2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)乙基)-2-吡咯烷酮(化合物9)。Example 8: 1-(2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)ethyl)- 2-pyrrolidone (compound 9).
Figure PCTCN2020106080-appb-000089
Figure PCTCN2020106080-appb-000089
第一步：1-(2-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)乙基)-2-吡咯烷酮(8a)的合成。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.
将2f(100mg)、1-(2-氨基乙基)-2-吡咯烷酮(88.32mg)、叔丁醇钾(77.32mg)、Pd(OAc) 2(10.31mg)、BINAP(57.21mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到8a(50mg)。 Add 2f (100mg), 1-(2-aminoethyl)-2-pyrrolidone (88.32mg), potassium tert-butoxide (77.32mg), Pd(OAc) 2 (10.31mg), BINAP (57.21mg) to toluene (3mL), heated to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 8a (50 mg).
MS(ESI):m/z 483.2[M+H] +。 MS (ESI): m/z 483.2 [M+H] + .
第二步：1-(2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)乙基)-2-吡咯烷酮(化合 物9)的合成。The second step: 1-(2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)ethyl)- Synthesis of 2-pyrrolidone (Compound 9).
将8a(30mg)、对甲苯磺酸(11.77mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物9(12mg)。8a (30 mg) and p-toluenesulfonic acid (11.77 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 9 (12 mg).
MS(ESI):m/z 399.2[M+H] +。 MS (ESI): m/z 399.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.95(s,1H),7.79(s,1H),7.37(s,1H),6.77(s,1H),6.07(s,1H),5.72(d,J＝5.2Hz,2H),3.44-3.38(m,4H),3.27(dd,J＝11.8,5.9Hz,2H),2.23(t,J＝8.1Hz,2H),1.97-1.87(m,2H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.95 (s, 1H), 7.79 (s, 1H), 7.37 (s, 1H), 6.77 (s, 1H), 6.07 (s, 1H), 5.72(d,J=5.2Hz,2H),3.44-3.38(m,4H), 3.27(dd,J=11.8,5.9Hz,2H), 2.23(t,J=8.1Hz,2H),1.97-1.87 (m, 2H), 1.41 (s, 9H).
实施例9：N 5-叔丁基-N 7-(环丙基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物10)。 Example 9: N 5 -tert-butyl-N 7 -(cyclopropylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-di Amine (Compound 10).
Figure PCTCN2020106080-appb-000090
Figure PCTCN2020106080-appb-000090
第一步：N 5-叔丁基-N 7-(环丙基甲基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(9a)的合成。 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).
将2f(70mg)、环丙基甲胺(57.99mg)、叔丁醇钾(54.90mg)、Pd 2(dba) 3(29.42mg)、BrettPhos(34.47mg)加入1,4-二氧六环(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到9a(45mg)。 Add 2f (70mg), cyclopropylmethylamine (57.99mg), potassium tert-butoxide (54.90mg), Pd 2 (dba) 3 (29.42mg), BrettPhos (34.47mg) to 1,4-dioxane (2mL), heated to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 9a (45 mg).
MS(ESI):m/z 426.2[M+H] +。 MS (ESI): m/z 426.2 [M+H] + .
第二步：N 5-叔丁基-N 7-(环丙基甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物10)的合成。 The second step: N 5 -tert-butyl-N 7 -(cyclopropylmethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-di Synthesis of Amine (Compound 10).
将9a(45mg)、对甲苯磺酸(20.03mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物10(15mg)。9a (45mg) and p-toluenesulfonic acid (20.03mg) were added to methanol (2mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 10 (15 mg).
MS(ESI):m/z 342.2[M+H] +。 MS (ESI): m/z 342.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.69(s,1H),7.56(s,1H),7.13(s,1H),6.54(s,1H),5.87(s,1H),5.50(s,2H),2.77(t,J＝6.1Hz,2H),1.17(s,9H),0.96-0.87(m,1H),0.27-0.20(m,2H),0.02(q,J＝4.8Hz,2H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ12.69 (s, 1H), 7.56 (s, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.87 (s, 1H), 5.50(s,2H),2.77(t,J=6.1Hz,2H),1.17(s,9H),0.96-0.87(m,1H),0.27-0.20(m,2H),0.02(q,J= 4.8Hz, 2H).
实施例10：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物11)。Example 10: 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-propanol (Compound 11).
Figure PCTCN2020106080-appb-000091
Figure PCTCN2020106080-appb-000091
第一步：3-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(10a)的合成。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).
将2f(70mg)、3-氨基-2,2-二甲基-1-丙醇(49.76mg)、Pd(OAc) 2(3.61mg)、BINAP(20.02mg)、叔丁醇钾(54.12mg)加入到甲苯(7mL)中，N 2保护，加热至120℃反应5小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到10a(45mg)。 Combine 2f (70mg), 3-amino-2,2-dimethyl-1-propanol (49.76mg), Pd(OAc) 2 (3.61mg), BINAP (20.02mg), potassium tert-butoxide (54.12mg) ) Was added to toluene (7 mL), protected by N 2 , and heated to 120° C. for reaction for 5 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 10a (45 mg).
MS(ESI):m/z 458.2[M+H] +。 MS (ESI): m/z 458.2 [M+H] + .
第二步：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物11)的合成。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).
将10a(34mg)加入到甲醇(6mL)中，加入对甲苯磺酸(20.02mg)，于25℃下反应2小时，将 反应体系旋干，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物11(15mg)。10a (34mg) was added to methanol (6mL), p-toluenesulfonic acid (20.02mg) was added, and the reaction was carried out at 25°C for 2 hours. The reaction system was spin-dried and separated and purified by Prep-HPLC (elution condition 4). Lyophilization gave compound 11 (15 mg).
MS(ESI):m/z 374.2[M+H] +。 MS (ESI): m/z 374.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ12.93(s,1H),7.79(s,1H),7.37(s,1H),6.78(s,1H),5.79-5.65(m,3H),4.84(t,J＝5.2Hz,1H),3.27(d,J＝5.2Hz,2H),3.03(d,J＝5.9Hz,2H),1.40(s,9H),0.90(s,6H)。 1 H-NMR (400MHz, DMSO-d 6 ): δ 12.93 (s, 1H), 7.79 (s, 1H), 7.37 (s, 1H), 6.78 (s, 1H), 5.79-5.65 (m, 3H) ), 4.84 (t, J = 5.2 Hz, 1H), 3.27 (d, J = 5.2 Hz, 2H), 3.03 (d, J = 5.9 Hz, 2H), 1.40 (s, 9H), 0.90 (s, 6H) ).
实施例11：N 5-叔丁基-N 7-(2,2-二氟乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物12)。 Example 11: N 5 -tert-butyl-N 7 -(2,2-difluoroethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5, 7-Diamine (Compound 12).
Figure PCTCN2020106080-appb-000092
Figure PCTCN2020106080-appb-000092
第一步：N 5-叔丁基-N 7-(2,2-二氟乙基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(11a)。 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).
将2f(70mg)、2,2-二氟乙胺(39.10mg)、Pd(OAc) 2(3.61mg)、BINAP(20.02mg)、叔丁醇钾(54.12mg)加入到甲苯(7mL)中，N 2保护，加热至120℃反应5小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到11a(55mg)。 Add 2f (70mg), 2,2-difluoroethylamine (39.10mg), Pd(OAc) 2 (3.61mg), BINAP (20.02mg), potassium tert-butoxide (54.12mg) to toluene (7mL) , N 2 protection, heat to 120°C for 5 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 11a (55 mg).
MS(ESI):m/z 436.3[M+H] +。 MS (ESI): m/z 436.3 [M+H] + .
第二步：N 5-叔丁基-N 7-(2,2-二氟乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物12)的合成。 The second step: N 5 -tert-butyl-N 7 -(2,2-difluoroethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5, Synthesis of 7-diamine (Compound 12).
将11a(55mg)加入到甲醇(4mL)中，于25℃下反应2小时，反应结束后，体系浓缩后通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物12(29mg)。11a (55 mg) was added to methanol (4 mL) and reacted at 25° C. for 2 hours. After the reaction, the system was concentrated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 12 (29 mg).
MS(ESI):m/z 352.1[M+H] +。 MS (ESI): m/z 352.1 [M+H] + .
1H-NMR(DMSO-d 6，400MHz):δ12.95(s,1H),7.82(s,1H),7.41(s,1H),6.81(s,1H),6.39(t,J＝7.3Hz,1H),6.17(tt,J＝4.1Hz,1H),5.83(s,1H),5.79(s,1H),3.60-3.50(m,2H),1.43(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.95 (s, 1H), 7.82 (s, 1H), 7.41 (s, 1H), 6.81 (s, 1H), 6.39 (t, J = 7.3 Hz, 1H), 6.17 (tt, J = 4.1 Hz, 1H), 5.83 (s, 1H), 5.79 (s, 1H), 3.60-3.50 (m, 2H), 1.43 (s, 9H).
实施例12：N 5-叔丁基-N 7-异丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物13)。 Example 12: N 5 -tert-butyl-N 7 -isobutyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (compound 13 ).
Figure PCTCN2020106080-appb-000093
Figure PCTCN2020106080-appb-000093
第一步：N 5-叔丁基-N 7-异丁基-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(12a)。 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).
将2f(80mg)、异丁胺(40.28mg)、Pd(OAc) 2(4.12mg)、BINAP(22.88mg)、叔丁醇钾(61.85mg)加入到甲苯(10mL)中，N 2保护，加热至120℃反应5h。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到12a(50mg)。 Add 2f (80mg), isobutylamine (40.28mg), Pd(OAc) 2 (4.12mg), BINAP (22.88mg), potassium tert-butoxide (61.85mg) to toluene (10mL), N 2 protection, Heat to 120°C for 5h. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 12a (50 mg).
MS(ESI):m/z 428.1[M+H] +。 MS (ESI): m/z 428.1 [M+H] + .
第二步：N 5-叔丁基-N 7-异丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物13)的合成。 The second step: N 5 -tert-butyl-N 7 -isobutyl-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7-diamine (compound 13 )Synthesis.
将12a(35mg)加入到甲醇(5mL)中，于25℃下反应2小时，体系浓缩后通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物13(4mg)。12a (35 mg) was added to methanol (5 mL) and reacted at 25° C. for 2 hours. After the system was concentrated, the system was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 13 (4 mg).
MS(ESI):m/z 344.2[M+H] +。 MS (ESI): m/z 344.2 [M+H] + .
1H-NMR(DMSO-d 6，400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),6.09(s,1H),5.72(s,1H),5.66(s,1H),2.91(t,J＝6.0Hz,2H),1.99-1.91(m,1H),1.40(s,9H),0.92(d,J＝6.6Hz,6H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.79 (s, 1H), 7.36 (s, 1H), 6.77 (s, 1H), 6.09 (s, 1H), 5.72(s,1H),5.66(s,1H),2.91(t,J=6.0Hz,2H),1.99-1.91(m,1H),1.40(s,9H),0.92(d,J=6.6Hz ,6H).
实施例13：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2-(甲氧甲基)-1-丙醇(化合物14)。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).
Figure PCTCN2020106080-appb-000094
Figure PCTCN2020106080-appb-000094
第一步：N 5-叔丁基-N 7-(氧杂环丁烷-3-基甲基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(13a)的合成。 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).
将2f(100mg)、3-氨甲基-1-氧杂环丁烷(24.01mg)、叔丁醇钾(77.32mg)、Pd(OAc) 2(10.02mg)、BINAP(57.21mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到13a(80mg)。 Add 2f (100mg), 3-aminomethyl-1-oxetane (24.01mg), potassium tert-butoxide (77.32mg), Pd(OAc) 2 (10.02mg), BINAP (57.21mg) to toluene (3mL), heated to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 13a (80 mg).
MS(ESI):m/z 442.1[M+H] +。 MS (ESI): m/z 442.1 [M+H] + .
第二步：3-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2-(甲氧甲基)-1-丙醇(化合物14)的合成。The second step: 3-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2-(methoxymethyl Yl)-1-propanol (Compound 14).
将13a(20mg)、对甲苯磺酸(8.66mg)加入甲醇(2mL)中，室温搅拌反应12小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件6)，冻干得到化合物14(5mg)。13a (20 mg) and p-toluenesulfonic acid (8.66 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 6), and lyophilized to obtain compound 14 (5 mg).
MS(ESI):m/z 390.1[M+H] +。 MS (ESI): m/z 390.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.91(s,1H),7.79(s,1H),7.36(s,1H),6.77(s,1H),5.95-5.92(m,1H),5.70-5.67(m,2H),4.59-4.57(m,1H),3.51-3.47(m,2H),3.44-3.35(m,2H),3.31(s,3H),3.14-3.11(m,2H),2.11-2.04(m,1H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.79 (s, 1H), 7.36 (s, 1H), 6.77 (s, 1H), 5.95-5.92 (m, 1H) ), 5.70-5.67(m,2H),4.59-4.57(m,1H),3.51-3.47(m,2H),3.44-3.35(m,2H),3.31(s,3H),3.14-3.11(m , 2H), 2.11-2.04 (m, 1H), 1.41 (s, 9H).
实施例14：(3-((5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)甲基)氧杂环丁烷-3-基)甲醇(化合物15)。Example 14: (3-((5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)methyl)oxa Cyclobutan-3-yl)methanol (Compound 15).
Figure PCTCN2020106080-appb-000095
Figure PCTCN2020106080-appb-000095
第一步：(3-((5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)甲基)氧杂环丁烷-3-基)甲醇(14a)的合成。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).
将2f(60mg)、3-氨甲基-3-羟甲基-1-氧杂环丁烷(64.58mg)、叔丁醇钾(46.39mg)、Pd 2(dba) 3(25.24mg)、BrettPhos(29.59mg)加入1,4-二氧六环(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到14a(35mg)。 2f (60mg), 3-aminomethyl-3-hydroxymethyl-1-oxetane (64.58mg), potassium tert-butoxide (46.39mg), Pd 2 (dba) 3 (25.24mg), BrettPhos (29.59mg) was added to 1,4-dioxane (2mL) and heated to 120°C for 2 hours under N 2 protection. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 14a (35 mg).
MS(ESI):m/z 472.2[M+H] +。 MS (ESI): m/z 472.2 [M+H] + .
第二步：(3-((5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)甲基)氧杂环丁烷-3-基)甲醇(化合物15)的合成。The second step: (3-((5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)methyl)oxa Synthesis of cyclobutan-3-yl)methanol (Compound 15).
将14a(35mg)、对甲苯磺酸(14.06mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物15(12mg)。14a (35 mg) and p-toluenesulfonic acid (14.06 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 15 (12 mg).
MS(ESI):m/z 388.2[M+H] +。 MS (ESI): m/z 388.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.93(s,1H),7.80(s,1H),7.37(s,1H),6.78(s,1H),6.04(t,J＝5.7Hz,1H),5.73(d,J＝11.9Hz,2H),5.06(t,J＝5.1Hz,1H),4.39(d,J＝5.9Hz,2H),4.34(d,J＝5.9Hz,2H),3.71(d,J＝5.0Hz,2H),3.39(d,J＝5.7Hz,2H),1.41(s,9H)。 1 H-NMR(DMSO-d 6 ,400MHz): δ12.93(s,1H),7.80(s,1H),7.37(s,1H),6.78(s,1H),6.04(t,J=5.7 Hz, 1H), 5.73 (d, J = 11.9 Hz, 2H), 5.06 (t, J = 5.1 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.71 (d, J=5.0 Hz, 2H), 3.39 (d, J=5.7 Hz, 2H), 1.41 (s, 9H).
实施例15：2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-N-环丙基乙酰胺(化合物16)。Example 15: 2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-N-cyclopropylethyl Amide (Compound 16).
Figure PCTCN2020106080-appb-000096
Figure PCTCN2020106080-appb-000096
第一步：2-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-N-环丙基乙酰胺(15a)的合成。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).
将2f(100mg)、2-氨基-N-环丙基乙酰胺(78.65mg)、叔丁醇钾(77.32mg)、Pd(OAc) 2(10.31mg)、BINAP(57.21mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到15a(70mg)。 Add 2f (100mg), 2-amino-N-cyclopropylacetamide (78.65mg), potassium tert-butoxide (77.32mg), Pd(OAc) 2 (10.31mg), BINAP (57.21mg) to toluene (3mL) ), heat to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 15a (70 mg).
MS(ESI):m/z 469.3[M+H] +。 MS (ESI): m/z 469.3 [M+H] + .
第二步：2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-N-环丙基乙酰胺(化合物16)的合成。The second step: 2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-N-cyclopropylethyl Synthesis of amide (compound 16).
将15a(35mg)、对甲苯磺酸(14.15mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物16(15mg)。15a (35 mg) and p-toluenesulfonic acid (14.15 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 16 (15 mg).
MS(ESI):m/z 399.2[M+H] +。 MS (ESI): m/z 399.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.93(s,1H),7.98(d,J＝4.1Hz,1H),7.80(s,1H),7.38(s,1H),6.79(s,1H),6.10(s,1H),5.79(s,1H),5.52(s,1H),3.69(d,J＝5.8Hz,2H),2.67(tq,J＝7.8,4.0Hz,1H),1.40(s,9H),0.62(td,J＝7.0,4.7Hz,2H),0.48-0.42(m,2H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.93 (s, 1H), 7.98 (d, J = 4.1 Hz, 1H), 7.80 (s, 1H), 7.38 (s, 1H), 6.79 ( s, 1H), 6.10 (s, 1H), 5.79 (s, 1H), 5.52 (s, 1H), 3.69 (d, J = 5.8 Hz, 2H), 2.67 (tq, J = 7.8, 4.0 Hz, 1H ), 1.40 (s, 9H), 0.62 (td, J=7.0, 4.7 Hz, 2H), 0.48-0.42 (m, 2H).
实施例16：2-((5-叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基)(甲基)氨基)乙醇(化合物17)。Example 16: 2-((5-tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-yl)(methyl)amino)ethanol ( Compound 17).
Figure PCTCN2020106080-appb-000097
Figure PCTCN2020106080-appb-000097
第一步：2-((5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基)(甲基)氨基)乙醇(16a)的合成。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).
将2f(100mg)、N-甲基-2-羟基乙胺(24.36mg)、叔丁醇钾(77.32mg)、Pd(OAc) 2(10.02mg)、BINAP(57.21mg)加入甲苯(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到16a(50mg)。 Add 2f (100mg), N-methyl-2-hydroxyethylamine (24.36mg), potassium tert-butoxide (77.32mg), Pd(OAc) 2 (10.02mg), BINAP (57.21mg) to toluene (2mL) Under the protection of N 2 , it was heated to 120° C. and reacted for 2 hours. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 16a (50 mg).
MS(ESI):m/z 430.1[M+H] +。 MS (ESI): m/z 430.1 [M+H] + .
第二步：2-((5-叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基)(甲基)氨基)乙醇(化合物17)的合成。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.
将16a(20mg)、对甲苯磺酸(11.4mg)加入甲醇(2mL)中，室温搅拌反应12小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物17(3mg)。16a (20 mg) and p-toluenesulfonic acid (11.4 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 12 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 17 (3 mg).
MS(ESI):m/z 346.1[M+H] +。 MS (ESI): m/z 346.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.94(s,1H),7.79(s,1H),7.39(s,1H),6.79(s,1H),5.86-5.82(m,2H),4.78-4.76(m,1H),3.63-3.56(m,2H),3.55-3.34(m,2H),3.02(s,3H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.94 (s, 1H), 7.79 (s, 1H), 7.39 (s, 1H), 6.79 (s, 1H), 5.86-5.82 (m, 2H) ), 4.78-4.76 (m, 1H), 3.63-3.56 (m, 2H), 3.55-3.34 (m, 2H), 3.02 (s, 3H), 1.41 (s, 9H).
实施例17：N 5-叔丁基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物18)。 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).
Figure PCTCN2020106080-appb-000098
Figure PCTCN2020106080-appb-000098
第一步：N 5-叔丁基-N 7-(2-甲氧乙基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(17a)的合成。 The first step: N 5 -tert-butyl-N 7 -(2-methoxyethyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl ) Synthesis of thieno[3,2-b]pyridine-5,7-diamine (17a).
将2f(400mg)、2-甲氧基乙胺(345mg)、Pd 2(dba) 3(173mg)、BrettPhos(73mg)、叔丁醇钾(474mg)加入到1,4-二氧六环(18mL)中，氮气置换后加热至120℃反应4小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到17a(400mg)。 Add 2f (400mg), 2-methoxyethylamine (345mg), Pd 2 (dba) 3 (173mg), BrettPhos (73mg), potassium tert-butoxide (474mg) to 1,4-dioxane ( 18mL), after replacing with nitrogen, heating to 120°C for 4 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 17a (400 mg).
MS(ESI):m/z 430.2[M+H] +。 MS (ESI): m/z 430.2 [M+H] + .
第二步：N 5-叔丁基-N 7-(2-甲氧乙基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物18)的合成。 The second step: N 5 -tert-butyl-N 7 -(2-methoxyethyl)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridine-5,7- Synthesis of Diamine (Compound 18).
将17a(27mg)加入到无水甲醇(3mL)中，加入对甲苯磺酸(32.5mg)，室温下反应0.5小时，反应液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物18(7mg)。17a (27mg) was added to anhydrous methanol (3mL), p-toluenesulfonic acid (32.5mg) was added, and the reaction was carried out at room temperature for 0.5 hours. The reaction solution was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain the compound 18 (7mg).
MS(ESI):m/z 346.2[M+H] +。 MS (ESI): m/z 346.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.96(s,1H),7.81(s,1H),7.40(s,1H),6.78(s,1H),6.45-5.50(m,3H),3.53(t,J＝5.6Hz,2H),3.31-3.27(m,5H),1.41(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.96 (s, 1H), 7.81 (s, 1H), 7.40 (s, 1H), 6.78 (s, 1H), 6.45-5.50 (m, 3H) ), 3.53 (t, J = 5.6 Hz, 2H), 3.31-3.27 (m, 5H), 1.41 (s, 9H).
实施例18：N 7-((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)-N 5-叔丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物19)。 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).
Figure PCTCN2020106080-appb-000099
Figure PCTCN2020106080-appb-000099
第一步：(1R,5S,6s)-叔丁基6-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸酯(18a)的合成。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).
将2f(120mg)、(1R,5S,6s)-叔丁基6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸酯(163.94mg)、叔丁醇钾(92.78mg)、Pd(OAc) 2(12.38mg)、BINAP(68.65mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到18a(110mg)。 Combine 2f (120mg), (1R,5S,6s)-tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (163.94mg), potassium tert-butoxide (92.78 mg), Pd(OAc) 2 (12.38 mg), and BINAP (68.65 mg) were added to toluene (3 mL), and heated to 120°C for 2 hours under N 2 protection. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 18a (110 mg).
MS(ESI):m/z 553.3[M+H] +。 MS (ESI): m/z 553.3 [M+H] + .
第二步：N 7-((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)-N 5-叔丁基-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物19)的合成。 The second step: N 7 -((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-N 5 -tert-butyl-2-(1H-pyrazole-5- Synthesis of phenyl)thieno[3,2-b]pyridine-5,7-diamine (Compound 19).
将18a(60mg)加入到2M盐酸的二氧六环溶液(2mL)中，室温搅拌反应0.5小时。用氢氧化钠将PH调至9，减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物19(10mg)。18a (60 mg) was added to a 2M hydrochloric acid dioxane solution (2 mL), and the reaction was stirred at room temperature for 0.5 hours. The pH was adjusted to 9 with sodium hydroxide, concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 19 (10 mg).
MS(ESI):m/z 368.9[M+H] +。 MS (ESI): m/z 368.9 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.91(s,1H),7.76(s,1H),7.36(d,J＝5.3Hz,1H),6.74(s,1H),6.37(d,J＝65.1Hz,1H),5.94(d,J＝37.6Hz,1H),5.85(d,J＝8.3Hz,1H),3.71(d,J＝10.7Hz,1H),3.40(d,J＝9.0Hz,2H),3.12(d,J＝11.0Hz,1H),2.77(d,J＝10.6Hz,1H),2.18(d,J＝68.0Hz,1H),1.66(d,J＝75.1Hz,2H),1.43(s,9H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.76 (s, 1H), 7.36 (d, J = 5.3 Hz, 1H), 6.74 (s, 1H), 6.37 ( d, J = 65.1Hz, 1H), 5.94 (d, J = 37.6 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 3.71 (d, J = 10.7 Hz, 1H), 3.40 (d, J = 9.0Hz, 2H), 3.12 (d, J = 11.0 Hz, 1H), 2.77 (d, J = 10.6 Hz, 1H), 2.18 (d, J = 68.0 Hz, 1H), 1.66 (d, J = 75.1Hz, 2H), 1.43(s, 9H).
实施例19：(R)-2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-4-甲基-1-戊醇(化合物20)。Example 19: (R)-2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-4- Methyl-1-pentanol (Compound 20).
Figure PCTCN2020106080-appb-000100
Figure PCTCN2020106080-appb-000100
第一步：(2R)-2-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-4-甲基-1-戊醇(19a)的合成。The first step: (2R)-2-(5-(tert-butylamino)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[ Synthesis of 3,2-b]pyridin-7-ylamino)-4-methyl-1-pentanol (19a).
将2f(80mg)、(R)-2-氨基-4-甲基-1-戊醇(56.52mg)、Pd(OAc) 2(3.61mg)、BINAP(20.02mg)、叔丁醇钾(54.12mg)加入到甲苯(7mL)中，N 2保护，加热至120℃反应5小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到19a(40mg)。 Combine 2f (80mg), (R)-2-amino-4-methyl-1-pentanol (56.52mg), Pd(OAc) 2 (3.61mg), BINAP (20.02mg), potassium tert-butoxide (54.12 mg) was added to toluene (7mL), protected by N 2 and heated to 120°C for 5 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 19a (40 mg).
MS(ESI):m/z 472.3[M+H] +。 MS (ESI): m/z 472.3 [M+H] + .
第二步：(R)-2-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-4-甲基-1-戊醇(化合物20)的合成。The second step: (R)-2-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-4- Synthesis of methyl-1-pentanol (Compound 20).
将19a(35mg)加入到甲醇(5mL)中，于25℃下反应2小时，体系浓缩后通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物20(20mg)。19a (35 mg) was added to methanol (5 mL) and reacted at 25° C. for 2 hours. After concentration, the system was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 20 (20 mg).
MS(ESI):m/z 388.0[M+H] +。 MS (ESI): m/z 388.0 [M+H] + .
1H-NMR(DMSO-d 6，400MHz):δ12.92(s,1H),7.84-7.74(m,1H),7.35(s,1H),6.77(t,J＝2.0Hz1H),5.74(s,1H),5.68(s,1H),5.41(d,J＝8.3Hz,1H),4.71(t,J＝5.2Hz,1H),3.49-3.45(m,2H),3.35-3.33(m,1H),1.76-1.69(m,1H),1.52-1.44(m,2H),1.41(s,9H),0.93(d,J＝6.6Hz,3H),0.86(d,J＝6.5Hz,3H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ12.92(s,1H),7.84-7.74(m,1H),7.35(s,1H),6.77(t,J=2.0Hz1H), 5.74( s, 1H), 5.68 (s, 1H), 5.41 (d, J = 8.3 Hz, 1H), 4.71 (t, J = 5.2 Hz, 1H), 3.49-3.45 (m, 2H), 3.35-3.33 (m ,1H),1.76-1.69(m,1H),1.52-1.44(m,2H),1.41(s,9H),0.93(d,J=6.6Hz,3H),0.86(d,J=6.5Hz, 3H).
实施例20：(1r,4r)-4-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)环己醇(化合物21)。Example 20: (1r,4r)-4-(5-(tert-butylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino) ring Hexanol (Compound 21).
Figure PCTCN2020106080-appb-000101
Figure PCTCN2020106080-appb-000101
第一步：((1r,4r)-4-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)环己醇(20a)的合成。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).
将2f(100mg)、反式-4-氨基环己醇(79.36mg)、叔丁醇钾(77.32mg)、Pd(OAc) 2(10.31mg)、BINAP(57.21mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到20a(80mg)。 Add 2f (100mg), trans-4-aminocyclohexanol (79.36mg), potassium tert-butoxide (77.32mg), Pd(OAc) 2 (10.31mg), BINAP (57.21mg) into toluene (3mL) , Heat to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 20a (80 mg).
MS(ESI):m/z 470.3[M+H] +。 MS (ESI): m/z 470.3 [M+H] + .
第二步：(1r,4r)-4-(5-(叔丁氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)环己醇(化合物21)的合成。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).
将20a(30mg)、对甲苯磺酸(12.10mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物21(16mg)。20a (30 mg) and p-toluenesulfonic acid (12.10 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 21 (16 mg).
MS(ESI):m/z 386.0[M+H] +。 MS (ESI): m/z 386.0 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.93(s,1H),7.76(s,1H),7.35(s,1H),6.74(s,1H),5.72(d,J＝6.4Hz,2H),5.63(d,J＝7.8Hz,1H),4.60(d,J＝3.1Hz,1H),3.46-3.39(m,1H),3.26-3.16(m,1H),1.99-1.83(m,4H),1.41(s,9H),1.37-1.22(m,4H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.93 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 6.74 (s, 1H), 5.72 (d, J = 6.4 Hz, 2H), 5.63 (d, J = 7.8 Hz, 1H), 4.60 (d, J = 3.1 Hz, 1H), 3.46-3.39 (m, 1H), 3.26-3.16 (m, 1H), 1.99-1.83 (m, 4H), 1.41 (s, 9H), 1.37-1.22 (m, 4H).
实施例21：N 5-叔丁基-N 7-((3-甲基氧杂环丁烷-3-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物22)。 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).
Figure PCTCN2020106080-appb-000102
Figure PCTCN2020106080-appb-000102
第一步：N 5-叔丁基-N 7-((3-甲基氧杂环丁烷-3-基)甲基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(21a)的合成。 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).
将2f(300mg)、3-甲基-3-氨甲基-1-氧杂环丁烷(289mg)、Pd 2(dba) 3(76mg)、BrettPhos(77mg)、叔丁醇钾(232mg)加入到1,4-二氧六环(10mL)中，N 2置换后加热至120℃反应4小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)，得到21a(240mg)。 Combine 2f (300mg), 3-methyl-3-aminomethyl-1-oxetane (289mg), Pd 2 (dba) 3 (76mg), BrettPhos (77mg), potassium tert-butoxide (232mg) Add to 1,4-dioxane (10 mL), replace with N 2 and heat to 120° C. to react for 4 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and then subjected to thin layer chromatography (eluent system A) to obtain 21a (240 mg).
MS(ESI):m/z 456.2[M+H] +。 MS (ESI): m/z 456.2 [M+H] + .
第二步：N 5-叔丁基-N 7-((3-甲基氧杂环丁烷-3-基)甲基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物22)的合成。 The second step: N 5 -tert-butyl-N 7 -((3-methyloxetan-3-yl)methyl)-2-(1H-pyrazol-5-yl)thieno[3 ,2-b] Synthesis of pyridine-5,7-diamine (Compound 22).
将21a(40mg)加入到无水甲醇(3mL)中，加入对甲苯磺酸(45mg)，室温下反应0.5小时，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物22(9mg)。21a (40mg) was added to anhydrous methanol (3mL), p-toluenesulfonic acid (45mg) was added, reacted at room temperature for 0.5 hours, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 22 (9mg ).
MS(ESI):m/z 372.0[M+H] +。 MS (ESI): m/z 372.0 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ13.03(s,1H),7.83(s,1H),7.44(s,1H),6.81(s,1H),6.40-5.70(m,2H),4.48(d,J＝6.0Hz,2H),4.25(d,J＝5.6Hz,2H),3.47-3.35(m,2H),1.42(s,9H),1.34(s,3H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 13.03 (s, 1H), 7.83 (s, 1H), 7.44 (s, 1H), 6.81 (s, 1H), 6.40-5.70 (m, 2H) ), 4.48 (d, J = 6.0 Hz, 2H), 4.25 (d, J = 5.6 Hz, 2H), 3.47-3.35 (m, 2H), 1.42 (s, 9H), 1.34 (s, 3H).
实施例22：3-(5-(叔丁氨基)-2-(6-甲基吡啶-2-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物23)。Example 22: 3-(5-(tert-butylamino)-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol ( Compound 23).
Figure PCTCN2020106080-appb-000103
Figure PCTCN2020106080-appb-000103
第一步：7-溴-N-叔丁基-2-(6-甲基吡啶-2-基)噻吩并[3,2-b]吡啶-5-胺(22a)的合成。The first step: Synthesis of 7-bromo-N-tert-butyl-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-5-amine (22a).
将2e(500mg)、6-甲基吡啶-2-基硼酸(249.84mg)、PdCl 2(dppf)·CH 2Cl 2(99.32mg)、碳酸钾(322.31mg)加入到1,4-二氧六环(15mL)和水(5mL)的混合溶剂中，N 2保护下加热至80℃反应6小时。体系过滤，浓缩后经薄层层析(洗脱剂体系B)，得到22a(170mg)。 Add 2e (500mg), 6-methylpyridin-2-ylboronic acid (249.84mg), PdCl 2 (dppf) .CH 2 Cl 2 (99.32mg), potassium carbonate (322.31mg) to 1,4-dioxide In a mixed solvent of hexacyclic ring (15 mL) and water (5 mL), the mixture was heated to 80° C. for 6 hours under the protection of N 2. The system was filtered, concentrated and subjected to thin layer chromatography (eluent system B) to obtain 22a (170 mg).
MS(ESI):m/z 376.0[M+H] +。 MS (ESI): m/z 376.0 [M+H] + .
第二步：3-(5-(叔丁氨基)-2-(6-甲基吡啶-2-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物23)的合成。The second step: 3-(5-(tert-butylamino)-2-(6-methylpyridin-2-yl)thieno[3,2-b]pyridin-7-ylamino)-1-propanol( Compound 23) Synthesis.
将22a(160mg)、3-氨基丙醇(63.87mg)、Pd(OAc) 2(9.55mg)、BINAP(52.95mg)、叔丁醇钾(119.27mg)加入到甲苯(6mL)中，N 2保护，加热至120℃反应5小时。体系过滤，滤液浓缩后用少量甲醇稀释，经薄层层析(洗脱剂体系A)得到粗品，粗品通过Prep-HPLC分离纯化(洗脱条件2)，冻干得到化合物23(53mg)。 Add 22a (160mg), 3-aminopropanol (63.87mg), Pd(OAc) 2 (9.55mg), BINAP (52.95mg), potassium tert-butoxide (119.27mg) to toluene (6mL), N 2 Protect, heat to 120°C and react for 5 hours. The system was filtered, the filtrate was concentrated and diluted with a small amount of methanol, and the crude product was obtained by thin layer chromatography (eluent system A). The crude product was separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 23 (53 mg).
MS(ESI):m/z 371.0[M+H] +。 MS (ESI): m/z 371.0 [M+H] + .
1H-NMR(DMSO-d 6，400MHz):δ7.89(d,J＝7.9Hz,1H),7.75(s,1H),7.72(t,J＝7.8Hz,1H),7.16(d,J＝7.6Hz,1H),6.10(t,J＝5.4Hz,1H),5.80(s,1H),5.70(s,1H),4.54(t,J＝5.0Hz,1H),3.53(d,J＝5.5Hz,2H),3.18(d,J＝6.1Hz,2H),2.48(s,3H),1.77(t,J＝6.7Hz,2H),1.42(s,9H)。 1 H-NMR(DMSO-d 6 , 400MHz): δ7.89(d,J=7.9Hz,1H), 7.75(s,1H), 7.72(t,J=7.8Hz,1H), 7.16(d, J = 7.6Hz, 1H), 6.10 (t, J = 5.4 Hz, 1H), 5.80 (s, 1H), 5.70 (s, 1H), 4.54 (t, J = 5.0 Hz, 1H), 3.53 (d, J = 5.5 Hz, 2H), 3.18 (d, J = 6.1 Hz, 2H), 2.48 (s, 3H), 1.77 (t, J = 6.7 Hz, 2H), 1.42 (s, 9H).
实施例23：N 5-叔丁基-2-(1H-吡唑-5-基)-N 7-((四氢-2H-吡喃-4-基)甲基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物24)。 Example 23: N 5 -tert-butyl-2-(1H-pyrazol-5-yl)-N 7 -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2 -b] Pyridine-5,7-diamine (Compound 24).
Figure PCTCN2020106080-appb-000104
Figure PCTCN2020106080-appb-000104
第一步：N 5-叔丁基-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)-N 7-((四氢-2H-吡喃-4-基)甲基)噻吩并[3,2-b]吡啶-5,7-二胺(23a)的合成。 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).
将2f(70mg)、4-氨甲基四氢-2H-吡喃(21.88mg)、叔丁醇钾(54.12mg)、Pd(OAc) 2(7.22mg)、BINAP(40.04mg)加入甲苯(2mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到23a(30mg)。 Add 2f (70mg), 4-aminomethyltetrahydro-2H-pyran (21.88mg), potassium tert-butoxide (54.12mg), Pd(OAc) 2 (7.22mg), BINAP (40.04mg) into toluene ( 2mL), heated to 120°C for 2 hours under the protection of N 2. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 23a (30 mg).
MS(ESI):m/z 470.1[M+H] +。 MS (ESI): m/z 470.1 [M+H] + .
第二步：N 5-叔丁基-2-(1H-吡唑-5-基)-N 7-((四氢-2H-吡喃-4-基)甲基)噻吩并[3,2-b]吡啶-5,7-二胺(化合物24)的合成。 The second step: N 5 -tert-butyl-2-(1H-pyrazol-5-yl)-N 7 -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2 -b] Synthesis of pyridine-5,7-diamine (Compound 24).
将23a(200mg)、对甲苯磺酸(86.6mg)加入甲醇(20mL)中，室温搅拌反应12小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件2)，冻干得到化合物24(55mg)。23a (200 mg) and p-toluenesulfonic acid (86.6 mg) were added to methanol (20 mL), and the reaction was stirred at room temperature for 12 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 2), and lyophilized to obtain compound 24 (55 mg).
MS(ESI):m/z 386.1[M+H] +。 MS (ESI): m/z 386.1 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.91(s,1H),7.78(s,1H),7.36(s,1H),6.76(s,1H),6.11(s,1H),5.72-5.68(m,2H),3.89-3.84(m,2H),3.31-3.25(m,2H),3.02-2.99(m,2H),1.94-1.86(m,1H),1.68-1.64(m,2H),1.41(s,9H),1.25-1.15(m,2H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.78 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 6.11 (s, 1H), 5.72-5.68(m,2H),3.89-3.84(m,2H),3.31-3.25(m,2H),3.02-2.99(m,2H),1.94-1.86(m,1H),1.68-1.64(m ,2H),1.41(s,9H),1.25-1.15(m,2H).
实施例24：3-(5-异丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物35)。Example 24: 3-(5-isopropylamino)-2-(1H-pyrazol-5-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2-dimethyl -1-Propanol (Compound 35).
Figure PCTCN2020106080-appb-000105
Figure PCTCN2020106080-appb-000105
第一步：7-溴-2-碘-N-异丙基噻吩并[3,2-b]吡啶-5-胺(23a)的合成。The first step: Synthesis of 7-bromo-2-iodo-N-isopropylthieno[3,2-b]pyridine-5-amine (23a).
将2d(450mg)、对甲苯磺酸酐(1650mg)加入到三氟甲苯(5mL)和氯仿(5mL)中，然后滴加入异丙胺(523.06mg)，于25℃下搅拌反应2小时。体系旋干后，经快速柱层析(洗脱剂体系A)，得到23a(450mg)。2d (450 mg) and p-toluenesulfonic anhydride (1650 mg) were added to benzotrifluoride (5 mL) and chloroform (5 mL), then isopropylamine (523.06 mg) was added dropwise, and the reaction was stirred at 25° C. for 2 hours. After the system was spin-dried, it was subjected to flash column chromatography (eluent system A) to obtain 23a (450 mg).
MS(ESI):m/z 396.6[M+H] +。 MS (ESI): m/z 396.6 [M+H] + .
第二步：7-溴-N-异丙基-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-5-胺(23b)的合成。The second step: 7-bromo-N-isopropyl-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)thieno[3,2-b ] Synthesis of pyridine-5-amine (23b).
室温下，依次将碳酸钾(313.26mg)、Pd(dppf)Cl 2·CH 2Cl 2(82.92mg)加入到1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-硼酸频哪醇酯(409.80mg)和23a(450mg)的1,4-二氧六环(9mL)/水(1.5mL)溶液中，然后保持70℃搅拌反应4小时。加水淬灭反应，EA萃取，有机层干燥浓缩，经快速柱层析(洗脱剂体系A)，得到23b(400mg)。 At room temperature, potassium carbonate (313.26mg), Pd(dppf)Cl 2 ·CH 2 Cl 2 (82.92mg) were added to 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- 5-boronic acid pinacol ester (409.80mg) and 23a (450mg) in 1,4-dioxane (9mL)/water (1.5mL) solution, and then kept at 70°C and stirred for 4 hours. The reaction was quenched by adding water, extracted with EA, the organic layer was dried and concentrated, and subjected to flash column chromatography (eluent system A) to obtain 23b (400 mg).
MS(ESI):m/z 420.8[M+H] +。 MS (ESI): m/z 420.8 [M+H] + .
第三步：3-(5-(异丙氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(23c)的合成。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).
将23b(100mg)、3-氨基-2,2-二甲基-1-丙醇(73.45mg)、叔丁醇钾(79.89mg)、Pd(OAc) 2(5.33mg)、BINAP(29.56mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到23c(45mg)。 Combine 23b (100mg), 3-amino-2,2-dimethyl-1-propanol (73.45mg), potassium tert-butoxide (79.89mg), Pd(OAc) 2 (5.33mg), BINAP (29.56mg) ) Was added to toluene (3mL), heated to 120°C under N 2 protection, and reacted for 2 hours. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain 23c (45 mg).
MS(ESI):m/z 444.2[M+H] +。 MS (ESI): m/z 444.2 [M+H] + .
第四步：3-(5-(异丙氨基)-2-(1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物35)的合成。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).
将23c(45mg)、对甲苯磺酸(19.22mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物35(28mg)。23c (45 mg) and p-toluenesulfonic acid (19.22 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solvent was concentrated to dryness under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 35 (28 mg).
MS(ESI):m/z 360.2[M+H] +。 MS (ESI): m/z 360.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.93(s,1H),7.80(s,1H),7.39(s,1H),6.74(s,1H),5.88-5.76(m,2H),5.69(s,1H),4.84(t,J＝5.2Hz,1H),4.08-3.95(m,1H),3.27(d,J＝5.2Hz,2H),3.05(d,J＝5.8Hz,2H),1.13(d,J＝6.4Hz,6H),0.90(s,6H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.93 (s, 1H), 7.80 (s, 1H), 7.39 (s, 1H), 6.74 (s, 1H), 5.88-5.76 (m, 2H) ), 5.69(s,1H), 4.84(t,J=5.2Hz,1H),4.08-3.95(m,1H), 3.27(d,J=5.2Hz,2H),3.05(d,J=5.8Hz , 2H), 1.13 (d, J = 6.4 Hz, 6H), 0.90 (s, 6H).
实施例25：3-(2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物55)。Example 25: 3-(2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2 -Dimethyl-1-propanol (Compound 55).
Figure PCTCN2020106080-appb-000106
Figure PCTCN2020106080-appb-000106
第一步：7-溴-2-碘-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶(25a)的合成。The first step: Synthesis of 7-bromo-2-iodo-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridine (25a).
0℃下，将三氟甲磺酸酐(1190mg)加入到2d(500mg)的二氯甲烷(10mL)溶液中，然后缓慢滴加入四氢吡咯(699.26mg)，于25℃下搅拌反应2小时。加水淬灭，体系旋干后，经快速柱层析(洗脱剂体系A)，得到化合物25a(240mg)。At 0°C, 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).
MS(ESI):m/z 408.6[M+H] +。 MS (ESI): m/z 408.6 [M+H] + .
第二步：7-溴-5-(吡咯烷-1-基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶(25b)的合成。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).
室温下，依次将碳酸钾(162.16mg)、Pd(dppf)Cl 2·CH 2Cl 2(42.93mg)加入到1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-硼酸频哪醇酯(212.14mg)和25a(240mg)的1,4-二氧六环(6mL)/水(1mL)溶液中，然后保持70℃搅拌反应4小时。加水淬灭反应，EA萃取，有机层干燥浓缩，经快速柱层析(洗脱剂体系A)，得到化合物25b(100mg)。 At room temperature, potassium carbonate (162.16mg), Pd(dppf)Cl 2 ·CH 2 Cl 2 (42.93mg) were added to 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- 5-boronic acid pinacol ester (212.14mg) and 25a (240mg) in 1,4-dioxane (6mL)/water (1mL) solution, and then kept at 70°C and stirred for 4 hours. The reaction was quenched by adding water, extracted with EA, the organic layer was dried and concentrated, and subjected to flash column chromatography (eluent system A) to obtain compound 25b (100 mg).
MS(ESI):m/z 432.8[M+H] +。 MS (ESI): m/z 432.8 [M+H] + .
第三步：2,2-二甲基-3-(5-(吡咯烷-1-基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(25c)的合成。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).
将25b(100mg)、3-氨基-2,2-二甲基-1-丙醇(71.41mg)、叔丁醇钾(77.68mg)、Pd(OAc) 2(5.18mg)、BINAP(28.74mg)加入甲苯(3mL)中，N 2保护下加热至120℃反应2小时。旋干反应溶剂再经快速柱层析(洗脱剂体系A)，得到化合物25c(50mg)。 Combine 25b (100mg), 3-amino-2,2-dimethyl-1-propanol (71.41mg), potassium tert-butoxide (77.68mg), Pd(OAc) 2 (5.18mg), BINAP (28.74mg) ) Was added to toluene (3mL), heated to 120°C under N 2 protection, and reacted for 2 hours. The reaction solvent was spin-dried and then subjected to flash column chromatography (eluent system A) to obtain compound 25c (50 mg).
MS(ESI):m/z 456.2[M+H] +。 MS (ESI): m/z 456.2 [M+H] + .
第四步：3-(2-(1H-吡唑-5-基)-5-(吡咯烷-1-基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物55)的合成。The fourth step: 3-(2-(1H-pyrazol-5-yl)-5-(pyrrolidin-1-yl)thieno[3,2-b]pyridin-7-ylamino)-2,2 -Synthesis of dimethyl-1-propanol (Compound 55).
将25c(48mg)、对甲苯磺酸(19.96mg)加入甲醇(2mL)中，室温搅拌反应2小时。减压浓缩，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物55(25mg)。25c (48 mg) and p-toluenesulfonic acid (19.96 mg) were added to methanol (2 mL), and the reaction was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 55 (25 mg).
MS(ESI):m/z 372.2[M+H] +。 MS (ESI): m/z 372.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ12.95(s,1H),7.81(s,1H),7.43(s,1H),6.75(s,1H),5.96(t,J＝5.6Hz,1H),5.68(s,1H),4.84(t,J＝5.2Hz,1H),3.39(t,J＝6.2Hz,4H),3.26(d,J＝5.1Hz,2H),3.14(d,J＝5.9Hz,2H),1.92(t,J＝6.3Hz,4H),0.90(s,6H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.95 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 6.75 (s, 1H), 5.96 (t, J = 5.6 Hz, 1H), 5.68 (s, 1H), 4.84 (t, J = 5.2 Hz, 1H), 3.39 (t, J = 6.2 Hz, 4H), 3.26 (d, J = 5.1 Hz, 2H), 3.14 ( d, J=5.9 Hz, 2H), 1.92 (t, J=6.3 Hz, 4H), 0.90 (s, 6H).
实施例26：3-(2-(1H-吡唑-5-基)-5-(2,4,4-三甲基戊-2-基氨基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物75)。Example 26: 3-(2-(1H-pyrazol-5-yl)-5-(2,4,4-trimethylpent-2-ylamino)thieno[3,2-b]pyridine- 7-ylamino)-2,2-dimethyl-1-propanol (Compound 75).
Figure PCTCN2020106080-appb-000107
Figure PCTCN2020106080-appb-000107
第一步：7-溴-2-碘-N-(2,4,4-三甲基戊-2-基)噻吩并[3,2-b]吡啶-5-胺(26a)的合成。The first step: Synthesis of 7-bromo-2-iodo-N-(2,4,4-trimethylpent-2-yl)thieno[3,2-b]pyridin-5-amine (26a).
将2d(200mg)、对甲苯磺酸酐(733.51mg)加入到三氟甲苯(5mL)和氯仿(5mL)中，然后滴加入2,4,4-三甲基-2-戊胺(508.28mg)，于25℃下搅拌反应2小时。体系旋干后，经薄层层析(洗脱剂体系B)，得到化合物26a(232mg)。Add 2d (200mg), p-toluenesulfonic anhydride (733.51mg) to trifluorotoluene (5mL) and chloroform (5mL), and then add dropwise 2,4,4-trimethyl-2-pentylamine (508.28mg) , The reaction was stirred at 25°C for 2 hours. After the system was spin-dried, thin-layer chromatography (eluent system B) was performed to obtain compound 26a (232 mg).
该化合物无MS响应。The compound has no MS response.
第二步：7-溴-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)-N-(2,4,4-三甲基戊-2-基)噻吩并[3,2-b]吡啶-5-胺(26b)的合成。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).
将26a(280mg)、1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-硼酸频哪醇酯(250.05mg)、PdCl 2(dppf)·CH 2Cl 2(48.90mg)、碳酸钾(206.76mg)，加入到1,4-二氧六环(12mL)和水(4mL)中，N 2保护后，于70℃下搅拌反应4小时。经乙酸乙酯萃取，萃取液旋干后，经薄层层析(洗脱剂体系B)，得到化合物26b(160mg)。 26a (280mg), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (250.05mg), PdCl 2 (dppf) CH 2 Cl 2 ( 48.90 mg) and potassium carbonate (206.76 mg) were added to 1,4-dioxane (12 mL) and water (4 mL), and after N 2 protection, the reaction was stirred at 70° C. for 4 hours. After extraction with ethyl acetate, the extract was spin-dried, and then subjected to thin layer chromatography (eluent system B) to obtain compound 26b (160 mg).
MS(ESI):m/z 490.8[M+H] +。 MS (ESI): m/z 490.8 [M+H] + .
第三步：2,2-二甲基-3-(2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)-5-(2,4,4-三甲基戊-2-基氨基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(26c)的合成。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).
将26b(160mg)、3-氨基-2,2-二甲基-1-丙醇(100.75mg)、Pd(OAc) 2(7.31mg)、BINAP(40.54mg)、叔丁醇钾(91.32mg)加入到甲苯(7mL)中，N 2保护，加热至120℃反应5小时。体系经过滤，滤液浓缩后，经薄层层析(洗脱剂体系B)，得到化合物26c(85mg)。 Mix 26b (160mg), 3-amino-2,2-dimethyl-1-propanol (100.75mg), Pd(OAc) 2 (7.31mg), BINAP (40.54mg), potassium tert-butoxide (91.32mg) ) Was added to toluene (7 mL), protected by N 2 , and heated to 120° C. for reaction for 5 hours. The system was filtered, the filtrate was concentrated, and then subjected to thin layer chromatography (eluent system B) to obtain compound 26c (85 mg).
MS(ESI):m/z 514.3[M+H] +。 MS (ESI): m/z 514.3 [M+H] + .
第四步：3-(2-(1H-吡唑-5-基)-5-(2,4,4-三甲基戊-2-基氨基)噻吩并[3,2-b]吡啶-7-基氨基)-2,2-二甲基-1-丙醇(化合物75)的合成。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).
将26c(82mg)加入到甲醇(6mL)中，然后加入对甲苯磺酸(41.23mg)，于25℃下反应2小时，将反应体系旋干，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物75(30mg)。26c (82mg) was added to methanol (6mL), then p-toluenesulfonic acid (41.23mg) was added, and the reaction was carried out at 25°C for 2 hours. The reaction system was spin-dried and separated and purified by Prep-HPLC (elution condition 4) , Lyophilized to obtain compound 75 (30 mg).
MS(ESI):m/z 430.8[M+H] +。 MS (ESI): m/z 430.8 [M+H] + .
1H-NMR(DMSO-d 6，400MHz):δ12.91(s,1H),7.79(s,1H),7.35(s,1H),6.79(d,J＝2.1Hz,1H),5.73(s,1H),5.64(t,J＝5.6Hz,1H),5.62(s,1H),4.82(t,J＝5.2Hz,1H),3.28(d,J＝5.3Hz,2H),3.02(d,J＝5.8Hz,2H),1.93(s,2H),1.44(s,6H),0.93(s,9H),0.90(s,6H)。 1 H-NMR (DMSO-d 6 , 400MHz): δ 12.91 (s, 1H), 7.79 (s, 1H), 7.35 (s, 1H), 6.79 (d, J = 2.1 Hz, 1H), 5.73 ( s, 1H), 5.64 (t, J = 5.6 Hz, 1H), 5.62 (s, 1H), 4.82 (t, J = 5.2 Hz, 1H), 3.28 (d, J = 5.3 Hz, 2H), 3.02 ( d, J=5.8 Hz, 2H), 1.93 (s, 2H), 1.44 (s, 6H), 0.93 (s, 9H), 0.90 (s, 6H).
实施例27：3-(5-(叔丁氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)噻吩并[3,2-b]吡啶-7-基氨基)-1-丙醇(化合物76)。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).
Figure PCTCN2020106080-appb-000108
Figure PCTCN2020106080-appb-000108
将化合物2f(50mg)、化合物2g(11.22mg)、碳酸铯(97.07mg)的二甲基亚砜(2mL)溶液置于微波管中，升温到120℃反应5小时。加水淬灭反应，EA萃取。有机层干燥浓缩后，通过制备TLC分离纯化(洗脱剂体系A)，得到化合物76(30mg)。A solution of compound 2f (50 mg), compound 2g (11.22 mg), and cesium carbonate (97.07 mg) in dimethyl sulfoxide (2 mL) was placed in a microwave tube, and the temperature was raised to 120° C. to react for 5 hours. The reaction was quenched by adding water and extracted with EA. After the organic layer was dried and concentrated, it was separated and purified by preparative TLC (eluent system A) to obtain compound 76 (30 mg).
MS(ESI):m/z 430.2[M+H] +。 MS (ESI): m/z 430.2 [M+H] + .
1H-NMR(DMSO-d 6,400MHz):δ7.58(s,1H),7.23(s,1H),6.58(s,1H),6.11-6.10(m,1H),5.84(s,1H),5.53-5.50(m,1H),4.54-4.51(m,1H),4.00-3.97(m,1H),3.65(m,1H),3.49(m,2H),3.20-3.17(m,2H),2.43-2.32(m,2H),1.981-1.566(m,7H),1.41(s,9H)。 1 H-NMR(DMSO-d 6 ,400MHz): δ7.58(s,1H), 7.23(s,1H), 6.58(s,1H), 6.11-6.10(m,1H), 5.84(s,1H) ), 5.53-5.50 (m, 1H), 4.54-4.51 (m, 1H), 4.00-3.97 (m, 1H), 3.65 (m, 1H), 3.49 (m, 2H), 3.20-3.17 (m, 2H) ), 2.43-2.32 (m, 2H), 1.981-1.566 (m, 7H), 1.41 (s, 9H).
[活性测试][Activity Test]
实验例1：本发明的化合物对PMA诱导分化后的THP-1细胞中的IL-1β表达的激动作用。Experimental Example 1: The agonistic effect of the compound of the present invention on IL-1β expression in THP-1 cells after PMA-induced differentiation.
本实验例采用HTRF(均相时间分辨荧光)检测方法，测试本发明的化合物对NLRP3下游细胞因子IL-1β水平的影响，以评估化合物在细胞水平上对hNLRP3炎症小体或hNLRP3炎症小体通路的激动作用。In this experimental example, 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-1β, in order to evaluate the effect of the compound on the hNLRP3 inflammasome or hNLRP3 inflammasome pathway at the cellular level The excitatory effect.
试剂：RPMI 1640(Hyclone)；热灭活的FBS(胎牛血清)(Gibco)；PMA(十四烷酰佛波醇乙酸酯)(碧云天)。Reagents: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal bovine serum) (Gibco); PMA (phorbol myristyl acetate) (Biyuntian).
细胞：THP-1(南京科佰)。Cell: THP-1 (Nanjing Kebai).
试剂盒：IL-1β检测试剂盒(CISBIO)。Kit: IL-1β detection kit (CISBIO).
实验步骤：Experimental steps:
1)将处于对数生长期的THP-1细胞以5×10 5个/孔的密度接种于T75培养瓶中，置于37℃、5％CO 2的细胞培养箱中培养24小时后，用1μM PMA诱导THP-1悬浮细胞成为贴壁状态的巨噬细胞；培养基为包含10％热灭活的FBS和0.05mMβ-巯基乙醇的RPMI 1640； 1) The 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. 1μM PMA induces THP-1 suspension cells to become adherent macrophages; the medium is RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM β-mercaptoethanol;
2)细胞诱导培养24小时后，胰酶消化贴壁细胞，1000rpm离心5min，去上清液，使用包含2％热灭活的FBS的RPMI 1640培养基重悬细胞密度至2×10 6个/mL，取50μL/孔的细胞重悬液铺至96孔板，每孔细胞数目为1×10 5个； 2) After cell induction and culture for 24 hours, trypsinize adherent cells, centrifuge at 1000 rpm for 5 min, remove the supernatant, and resuspend the cell density to 2×10 6 cells in RPMI 1640 medium containing 2% heat-inactivated FBS. mL, take 50μL/well of cell resuspension and spread it on a 96-well plate, the number of cells in each well is 1×10 5 ;
3)取适量的10mM待测化合物的DMSO溶液，用含2％热灭活的FBS的RPMI 1640培养基配制成2×测试浓度；取50μL/孔稀释液加至96孔板的细胞中，充分混匀后，将板放置于37℃、5％CO 2的细胞培养箱中培养6小时；收集上清，按照IL-1β检测试剂盒说明书测量IL-1β的水平； 3) Take an appropriate amount of 10mM DMSO solution of the compound to be tested, and use RPMI 1640 medium containing 2% heat-inactivated FBS to prepare a 2× test concentration; add 50μL/well of the dilution to the cells in the 96-well plate. After mixing, place the plate in a 37°C, 5% CO 2 cell incubator for 6 hours; collect the supernatant, and measure the level of IL-1β according to the IL-1β detection kit instructions;
4)EC 50通过GraphPad软件log(agonist)vs.response-Variable slope四参数法拟合，结果见表1。 4) The EC 50 was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.
实验例2：本发明的化合物对PMA诱导分化后的NLRP3缺失的THP1细胞(THP1- defNLRP3细胞)中的IL-1β表达的激动作用。 Experimental Example 2: The agonistic effect of the compound of the present invention on IL-1β expression in NLRP3-deficient THP1 cells (THP1- def NLRP3 cells) after PMA-induced differentiation.
本实验例采用HTRF检测方法，测试本发明的化合物对THP1- defNLRP3细胞中IL-1β水平的影响，以评估化合物对hNLRP3炎症小体或hNLRP3炎症小体通路激动作用的特异性。 In this experimental example, the HTRF detection method was used to test the effect of the compound of the present invention on the level of IL-1β in THP1-def NLRP3 cells to evaluate the specificity of the compound on hNLRP3 inflammasome or hNLRP3 inflammasome pathway agonism.
试剂：与实验例1相同。Reagent: Same as Experimental Example 1.
细胞：THP1- defNLRP3(InvivoGen)。 Cell: THP1- def NLRP3 (InvivoGen).
试剂盒：与实验例1相同。Kit: Same as Experimental Example 1.
实验步骤：Experimental steps:
1)将处于对数生长期的THP1- defNLRP3细胞以5×10 5个/孔的密度接种于T75培养瓶中，置于37℃、5％CO 2的培养箱中培养24小时后，用1μM PMA诱导THP1- defNLRP3悬浮细胞成为贴壁状态的巨噬细胞；培养基为包含10％热灭活的FBS和0.05mMβ-巯基乙醇的RPMI 1640； 1) 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. 1μM PMA induces THP1- def NLRP3 suspension cells to become adherent macrophages; the medium is RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM β-mercaptoethanol;
2)细胞诱导培养24小时后，胰酶消化贴壁细胞，1000rpm离心5min，然后去上清液，使用包含2％热灭活的FBS的RPMI 1640培养基重悬细胞密度至2×10 6个/mL；取50μL/孔的细胞重悬液铺至96孔板，每孔细胞数目为1×10 5个； 2) After cell induction and culture for 24 hours, trypsinize adherent cells, centrifuge at 1000 rpm for 5 min, remove the supernatant, and resuspend the cell density to 2×10 6 cells in RPMI 1640 medium containing 2% heat-inactivated FBS /mL; Take 50μL/well of cell resuspension and spread it on a 96-well plate, the number of cells in each well is 1×10 5 ;
3)取适量的10mM待测化合物的DMSO溶液，用含2％热灭活的FBS的RPMI 1640培养基配制成2×测试浓度。取50μL/孔稀释液加至96孔板的细胞中，充分混匀后，将板放置于37℃、5％CO 2的细胞培养箱中培养6小时；收集上清，按照IL-1β检测试剂盒说明书测量IL-1β的水平； 3) Take an appropriate amount of 10 mM DMSO solution of the compound to be tested, and use RPMI 1640 medium containing 2% heat-inactivated FBS to prepare a 2× test concentration. Take 50μL/well dilution and add it to the cells in the 96-well plate. After mixing well, place the plate in a 37°C, 5% CO 2 cell incubator for 6 hours; collect the supernatant and follow the IL-1β detection reagent The box instruction measures the level of IL-1β;
4)EC 50通过GraphPad软件log(agonist)vs.response-Variable slope四参数法拟合，结果见表1。 4) The EC 50 was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.
实验例3：本发明的化合物对hTLR7的激动作用。Experimental Example 3: The agonistic effect of the compound of the present invention on hTLR7.
本实验例通过检测HEK-hTLR7-NF-κB-报告基因细胞中的荧光素酶来测试本发明的化合物对TLR7信号通路的激活作用，以评估化合物对NLRP3通路激动作用的特异性。In this experimental example, the luciferase in HEK-hTLR7-NF-κB-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.
试剂：DMEM(High glucose)；FBS(胎牛血清)(Gibco)。Reagents: DMEM (High glucose); FBS (fetal bovine serum) (Gibco).
细胞：HEK-hTLR7-NF-κB-Luciferase基因细胞(人源TLR7NF-κB-荧光素酶报告基因细胞)(南京科佰)。Cells: HEK-hTLR7-NF-κB-Luciferase gene cells (human TLR7NF-κB-luciferase reporter gene cells) (Nanjing Kebai).
试剂盒：Bright-Glo TM Luciferase检测试剂盒(Promega)。 Kit: Bright-Glo TM Luciferase detection kit (Promega).
实验步骤：Experimental steps:
1)将处于对数生长期的HEK-hTLR7-NF-κB-Luciferase基因细胞用胰酶消化，用培养基重悬至2×10 6个/mL的浓度，加入50μL/孔细胞重悬液于96孔板中，每孔细胞数为1×10 6个；取适量的10mM待测化合物的DMSO溶液，用培养基配制成2×测试浓度，加50μL/孔至96孔板的细胞中，将96孔板置于37℃、5％CO 2的培养箱中培养16小时；培养基为包含10％FBS的DMEM； 1) The HEK-hTLR7-NF-κB-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 μL/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 μL/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;
2)细胞孵育结束后，加入100μL/孔Bright-Glo TM Luciferase检测试剂，室温孵育5min，酶标仪读取相对荧光酶活性单位(Relative Luciferase Unit，RLU)； 2) After the cell incubation, add 100μL/well Bright-Glo TM Luciferase detection reagent, incubate at room temperature for 5 minutes, and read the Relative Luciferase Unit (RLU) with a microplate reader;
3)化合物对hTLR7的刺激作用EC 50通过GraphPad软件log(agonist)vs.response-Variable slope四参数法拟合，结果见表1。 3) The EC 50 of the compound's stimulating effect on hTLR7 was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.
实验例4：本发明的化合物对hTLR8的激动作用。Experimental Example 4: The agonistic effect of the compound of the present invention on hTLR8.
本实验例通过检测HEK-Blue细胞株中碱性磷酸酶的分泌量来测试本发明的化合物对TLR8信号通路的激活作用，以评估化合物对NLRP3通路激动作用的特异性。In this experimental example, 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.
试剂：DMEM(High glucose)；FBS(Gibco)；QUANTI-Blue(InvivoGen/rep-qb2)。Reagents: DMEM (High glucose); FBS (Gibco); QUANTI-Blue (InvivoGen/rep-qb2).
细胞：HEK-Blue TM hTLR8细胞(人源TLR8细胞)(InvivoGen)。 Cells: HEK-Blue ™ hTLR8 cells (human TLR8 cells) (InvivoGen).
实验步骤：Experimental steps:
1)将处于对数生长期的HEK-Blue TM hTLR8细胞用胰酶消化，用培养基重悬至2×10 6个/mL的浓度，加入50μL/孔细胞悬液于96孔板中；取适量的10mM待测化合物的DMSO溶液，用培养基配制成2×测试浓度，加50μL/孔至96孔板的细胞中；将板置于37℃、5％CO 2的培养箱中培养16小时；培养基为包含10％FBS的DMEM。 1) 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 μL/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 50μL/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.
2)细胞孵育结束后，取10μL细胞培养上清液转移至96孔板中，加入90μL/孔的QUANTI-Blue检测溶液，37℃孵育3小时，酶标仪OD 620读数； 2) After the cell incubation, transfer 10μL of cell culture supernatant to a 96-well plate, add 90μL/well of QUANTI-Blue detection solution, incubate at 37°C for 3 hours, and read OD 620 on the microplate reader;
3)化合物对hTLR8的刺激作用EC 50通过GraphPad软件log(agonist)vs.response-Variable slope四参数法拟合，结果见表1。 3) The EC 50 of the compound's stimulating effect on hTLR8 was fitted by the GraphPad software log(agonist) vs.response-Variable slope four-parameter method. The results are shown in Table 1.
表1Table 1
Figure PCTCN2020106080-appb-000109
Figure PCTCN2020106080-appb-000109
结果表明，以表1所列化合物为代表的本发明化合物对PMA诱导分化后的THP-1细胞中的IL-1β表达有明显的激动作用，而对THP-1 defNLRP3细胞中的IL-1β表达即使在最高化合物测试浓度(30μM)下也无激动作用。所测试的所有化合物在100μM下对hTLR7和hTLR8无激活作用。综上，以表1所列化合物为代表的本发明化合物对hNLRP3和/或其信号通路有明显的特异性激动活性。 The results show that the compounds of the present invention represented by the compounds listed in Table 1 have a significant agonistic effect on the expression of IL-1β in THP-1 cells after PMA-induced differentiation, but on IL-1β in THP-1 def NLRP3 cells. The expression has no agonistic effect even at the highest compound tested concentration (30 μM). All compounds tested had no activating effect on hTLR7 and hTLR8 at 100 μM. In summary, 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.
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (20)

  1. 一种具有式II结构的化合物或其药学上可接受的形式，A compound having the structure of Formula II or a pharmaceutically acceptable form thereof,
    Figure PCTCN2020106080-appb-100001
    Figure PCTCN2020106080-appb-100001
    其中，among them,
    X 1选自-C(R 6)＝和-N＝； X 1 is selected from -C(R 6 )= and -N=;
    X 2选自-C(-L-R 3)＝和-N＝；当同时存在多个L和R 3时，各个L或R 3彼此相同或不同； X 2 is selected from -C(-LR 3 )= and -N=; when there are multiple L and R 3 at the same time, each L or R 3 is the same or different from each other;
    R 1选自C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，其中所述C 1-8烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-OR 37和-SR 37； 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 Each of the heterocyclic groups is optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -OC(= O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -OR 37 and -SR 37 ;
    R 4为NR 41aR 41b；R 41a和R 41b各自独立地选自氢、C 1-6烷基、C 1-6烷氧基和C 3-8环烷基，或者R 41a和R 41b连同与其连接的N原子一起形成4-7元杂环基，其中所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-7元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、4-7元杂环基、氰基、硝基、-OR 37、-SR 37、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-C(＝O)OR 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 31R 32，且R 41a和R 41b不同时为氢； R 4 is NR 41a R 41b ; R 41a and R 41b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b together Together with the N atom to which it is attached, a 4-7 membered heterocyclic group is formed, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each any Optionally substituted by one or more substituents, each of the substituents is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 member Heterocyclic group, cyano group, nitro group, -OR 37 , -SR 37 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 ,- C(=O)OR 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 31 R 32 , and R 41a It is not hydrogen at the same time as R 41b;
    R 6选自氢、卤素、C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基，其中所述C 1-6烷基、C 1-4烷氧基、C 3-8环烷基和4-10元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、C 1-4烷氧基、C 1-4羟烷基和-NR 31R 32； 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 ;
    L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-O-、-S-、-NR 33-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-和-CR 36aR 36b-，其中所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、羟基、氰基、硝基、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基和-NR 31R 32；n、p和q各自独立地为0、1或2； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are each independently selected from C 1-8 alkylene and C 2-8 alkenylene Group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered Heteroaryl, -O-, -S-, -NR 33 -, -S(=O)-, -S(=O) 2 -, -C(=O)- and -CR 36a R 36b -, where The C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heteroalkylene group The cyclic group, C 6-12 arylene group and 5-10 membered heteroarylene group are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, hydroxyl, cyano, Nitro, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy and -NR 31 R 32 ; n, p and q are each independently 0, 1 or 2;
    R 3选自氢、卤素、氰基、硝基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40、-P(＝O)(OR 39)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-C(＝NR 38)NR 31R 32、-NR 33C(＝NR 38)NR 31R 32、-N＝NR 38、-P(R 39) 2、-P(OR 39) 2、-P(＝O)R 39R 40和-P(＝O)(OR 39)OR 30； R 3 is selected from hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aromatic Group, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C (=O)R 30 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C(=NR 38 )NR 31 R 32 , -P(R 39 ) 2 , -P(OR 39 ) 2 , -P(=O)R 39 R 40 , -P(=O)(OR 39 )OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , where The C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered aryl and heterocyclyl, 9-12-membered aryl and heteroaryl, and 9-12-membered aryl and cycloalkyl are each optionally substituted with one or more substituents, each of which is individually Independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy Group, C 1-4 hydroxyalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, -C(=O) OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 ,- OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -C(=NR 38 )NR 31 R 32 , -NR 33 C (=NR 38 )NR 31 R 32 , -N=NR 38 , -P(R 39 ) 2 , -P(OR 39 ) 2. -P(=O)R 39 R 40 and -P(=O)(OR 39 )OR 30 ;
    R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元 杂芳基)各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 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 haloalkoxy, -C(=O)O( C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)R 35 , -S(=O ) 2 R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
    R 35选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8亚烷基-C 6-12芳基和C 1-8亚烷基-(5-10元杂芳基)，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、-C(＝O)O(C 1-6烷基)、-C(＝O)NR 31R 32、-NR 31R 32、-NR 33C(＝O)R 34、-S(＝O)CH 3、-S(＝O) 2CH 3、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32； R 35 is selected from 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), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one or more substituents, each of said substituents Each is independently selected from hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, -C(=O )O(C 1-6 alkyl), -C(=O)NR 31 R 32 , -NR 31 R 32 , -NR 33 C(=O)R 34 , -S(=O)CH 3 , -S (=O) 2 CH 3 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 ;
    R 31、R 32、R 33和R 34各自独立地选自氢、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基，或者R 31和R 32连同与其连接的N原子一起形成4-8元杂环基，或者R 33和R 34连同与其对应连接的N原子和C原子一起形成4-8元杂环基，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-8元杂环基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、硝基、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基； 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 Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl;
    R 36a和R 36b各自独立地选自氢、C 1-8烷基和C 1-8烷氧基，其中所述C 1-8烷基和C 1-8烷氧基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自羟基、氰基、卤素、氨基、甲氨基和二甲氨基，或者R 36a和R 36b连同与其连接的C原子一起形成3-7元环烷基或杂环基； 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;
    R 38选自氢、羟基、氰基、硝基、-S(＝O)R 35和-S(＝O) 2R 35；并且 R 38 is selected from hydrogen, hydroxyl, cyano, nitro, -S(=O)R 35 and -S(=O) 2 R 35 ; and
    当同时存在多个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39和/或R 40时，各个R 30、R 31、R 32、R 33、R 34、R 35、R 36a、R 36b、R 37、R 38、R 39或R 40彼此相同或不同； When there are multiple 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 at the same time, each R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36a , R 36b , R 37 , R 38 , R 39 or R 40 are the same or different from each other;
    所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、共晶、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。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.
  2. 根据权利要求1所述的化合物，其为具有式IV结构的化合物，The compound of claim 1, which is a compound having the structure of formula IV,
    Figure PCTCN2020106080-appb-100002
    Figure PCTCN2020106080-appb-100002
    其中，among them,
    R 1、R 3、R 4、X 1和L如权利要求1所定义。 R 1 , R 3 , R 4 , X 1 and L are as defined in claim 1.
  3. 根据权利要求1或2所述的化合物，其为具有式IV-A结构的化合物，The compound according to claim 1 or 2, which is a compound having the structure of formula IV-A,
    Figure PCTCN2020106080-appb-100003
    Figure PCTCN2020106080-appb-100003
    其中，among them,
    R 1、R 4和R 6如权利要求1或2所定义； R 1 , R 4 and R 6 are as defined in claim 1 or 2;
    L a为-L 1a-(L 2) p-(L 3) q-，其中L 1a选自-O-、-S-和-NR 33-，并且L 2、L 3、p和q如权利要求1或2所定义； 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 right Requirement 1 or 2 as defined;
    R 3a选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32、-NR 33C(＝O)OR 30、-S(＝O)R 35、-S(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、 硝基、羟基、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O)R 35、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-S(＝O) 2NR 31R 32、-OR 37、-SR 37、-OC(＝O)R 30、-OC(＝O)NR 31R 32、-NR 33C(＝O)NR 31R 32和-NR 33C(＝O)OR 30；并且 R 3a is selected from 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, 9-12 membered aryl and heterocyclyl, 9-12 membered aryl and heteroaryl, 9-12 membered aryl and cycloalkyl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC( ＝O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 , -NR 33 C(=O)OR 30 , -S(=O)R 35 , -S(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4 -10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl and heterocyclic group, 9-12 membered aryl and heteroaryl group and 9-12 membered aryl group The cycloalkyl groups are each optionally substituted with one or more substituents, and each of the substituents is independently selected from halogen, cyano, nitro, hydroxy, C 1-4 alkyl, C 3-8 ring Alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5 -10 membered heteroaryl, 9-12 membered aryl and heterocyclic group, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O)R 35 , -S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -S(=O) 2 NR 31 R 32 , -OR 37 , -SR 37 , -OC(=O)R 30 , -OC(=O)NR 31 R 32 , -NR 33 C(=O)NR 31 R 32 and -NR 33 C(=O)OR 30 ; and
    R 30、R 31、R 32、R 33、R 34、R 35和R 37如权利要求1或2所定义。 R 30 , R 31 , R 32 , R 33 , R 34 , R 35 and R 37 are as defined in claim 1 or 2.
  4. 根据权利要求1至3中任一项所述的化合物，其为具有式V结构的化合物，The compound according to any one of claims 1 to 3, which is a compound having the structure of formula V,
    Figure PCTCN2020106080-appb-100004
    Figure PCTCN2020106080-appb-100004
    其中，among them,
    R 1、R 3、R 4、L 2、L 3、p和q如权利要求1至3中任一项所定义； R 1 , R 3 , R 4 , L 2 , L 3 , p and q are as defined in any one of claims 1 to 3;
    R 33选自氢和C 1-6烷基。 R 33 is selected from hydrogen and C 1-6 alkyl.
  5. 根据权利要求1、2和4中任一项所述的化合物，A compound according to any one of claims 1, 2 and 4,
    其中，among them,
    R 3选自氢、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基、-C(＝O)OR 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-OR 37、-SR 37、-C(＝O)R 30、-OC(＝O)R 30、-NR 33C(＝O)NR 31R 32和-S(＝O) 2NR 31R 32，其中所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、4-7元杂环基、C 6-10芳基和5-6元杂芳基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 3-6环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基、-C(＝O)OR 30、-C(＝O)R 30、-C(＝O)NR 31R 32、-NR 33C(＝O)R 34、-NR 31R 32、-S(＝O) 2R 35、-S(＝O)NR 31R 32、-OR 37、-SR 37和-NR 33C(＝O)OR 30； R 3 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocyclic group, C 6-10 aryl, 5 -6 membered heteroaryl, -C(=O)OR 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 , -S(=O) 2 R 35 , -OR 37 , -SR 37 , -C(=O)R 30 , -OC(=O)R 30 , -NR 33 C(=O)NR 31 R 32 and -S(=O) 2 NR 31 R 32 , wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group, 4-7 membered heterocyclic group, C 6-10 aryl group and 5-6 membered The heteroaryl groups are each optionally substituted by one or more substituents, and each of the substituents is independently selected from halogen, cyano, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-6 membered hetero Aryl, -C(=O)OR 30 , -C(=O)R 30 , -C(=O)NR 31 R 32 , -NR 33 C(=O)R 34 , -NR 31 R 32 ,- S(=O) 2 R 35 , -S(=O)NR 31 R 32 , -OR 37 , -SR 37 and -NR 33 C(=O)OR 30 ;
    优选地，R 3选自环丁基、羟基、氧杂环丁烷-3-基、甲氧基、甲基、吗啉-4-基、2-氧代吡咯烷-1-基、环丙基、环丙基氨基、二氟甲基、氟、异丙基、(1R,5S,6s)-1,5-二甲基-3-氮杂双环[3.1.0]己-6-基、异丁基、羟甲基和四氢-2H-吡喃-4-基。 Preferably, R 3 is selected from cyclobutyl, hydroxyl, oxetan-3-yl, methoxy, methyl, morpholin-4-yl, 2-oxopyrrolidin-1-yl, cyclopropyl Group, cyclopropylamino, difluoromethyl, fluorine, isopropyl, (1R,5S,6s)-1,5-dimethyl-3-azabicyclo[3.1.0]hex-6-yl, Isobutyl, hydroxymethyl and tetrahydro-2H-pyran-4-yl.
  6. 根据权利要求1至5中任一项所述的化合物，The compound according to any one of claims 1 to 5,
    其中，among them,
    -L-R 3或者-L a-R 3a或者-N(R 33)-(L 2) p-(L 3) q-R 3选自： -LR 3 or -L a -R 3a or -N(R 33 )-(L 2 ) p -(L 3 ) q -R 3 is selected from:
    Figure PCTCN2020106080-appb-100005
    Figure PCTCN2020106080-appb-100005
    优选地，-L-R 3或者-L a-R 3a或者-N(R 33)-(L 2) p-(L 3) q-R 3选自： Preferably, -LR 3 or -L a -R 3a or -N(R 33 )-(L 2 ) p -(L 3 ) q -R 3 is selected from:
    Figure PCTCN2020106080-appb-100006
    Figure PCTCN2020106080-appb-100006
  7. 根据权利要求1至6中任一项所述的化合物，The compound according to any one of claims 1 to 6,
    其中，among them,
    R 1为5-6元杂芳基，优选5-6元含氮杂芳基，更优选吡唑基或吡啶基，其任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自卤素优选氟、C 1-3烷基优选甲基和4-7元杂环基优选四氢-2H-吡喃-2-基； R 1 is a 5-6 membered heteroaryl group, preferably a 5-6 membered nitrogen-containing heteroaryl group, more preferably a pyrazolyl group or a pyridyl group, which is optionally substituted by one or more substituents, each of the 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;
    优选地，R 1选自吡唑基、1,3-二甲基-1H-吡唑基、甲基吡啶基和1-(四氢-2H-吡喃-2-基)-1H-吡唑基，优选1H-吡唑-5-基、1,3-二甲基-1H-吡唑-5-基、2-甲基吡啶-6-基和1-(四氢-2H-吡喃-2-基)-1H-吡唑-2-基，更优选1H-吡唑-5-基和2-甲基吡啶-6-基。 Preferably, R 1 is selected from pyrazolyl, 1,3-dimethyl-1H-pyrazolyl, picoline and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole Group, preferably 1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-5-yl, 2-picoline-6-yl and 1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-2-yl, more preferably 1H-pyrazol-5-yl and 2-methylpyridin-6-yl.
  8. 根据权利要求1至7中任一项所述的化合物，A compound according to any one of claims 1 to 7,
    其中，among them,
    R 4为-NR 41aR 41b，其中R 41a和R 41b各自独立地选自氢、C 1-4烷基和C 3-6环烷基，且R 41a和R 41b不同时为氢，或者R 41a和R 41b连同与其连接的N原子一起形成4-6元杂环基，其中所述C 1-4烷基、C 3-6环烷基和4-6元杂环基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自C 1-4烷基、C 1- 4羟烷基和羧基； R 4 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 attached form a 4-6 membered heterocyclic group, wherein the C 1-4 alkyl group, C 3-6 cycloalkyl group and 4-6 membered heterocyclic group are each optionally one or more substituents, the substituents each independently selected from C 1-4 alkyl, C 1- 4 hydroxyalkyl and carboxy;
    优选地，R 4为-NR 41aR 41b，其中R 41a和R 41b各自独立地选自氢、甲基、乙基、异丙基、叔丁基和环丙基，且R 41a和R 41b不同时为氢，或者R 41a和R 41b连同与其连接的N原子一起形成吡咯烷-1-基，其中所述甲基、乙基、异丙基、叔丁基、环丙基和吡咯烷-1-基各自任选地被一个或多个取代基取代，每一个所述取代基各自独立地选自甲基、叔丁基、羟甲基和羧基； Preferably, R 4 is -NR 41a R 41b , wherein R 41a and R 41b are each independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, and R 41a and R 41b are not It is hydrogen at the same time, or R 41a and R 41b together with the N atom to which they are attached form a pyrrolidin-1-yl group, wherein the methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and pyrrolidine-1 -Each of the groups is optionally substituted with one or more substituents, each of the substituents is independently selected from methyl, tert-butyl, hydroxymethyl and carboxy;
    更优选地，R 4选自-N(H)-C(CH 3) 3、-N(H)-CH 3、-N(H)-C 2H 5、-N(H)-异丙基、-N(H)-环丙基、-N(CH 3) 2、-N(C 2H 5) 2、-N(H)-CH 2-COOH、-N(H)-C 2H 4-OH、-N(H)-1-甲基环丙基、-N(H)-C(CH 3) 2-CH 2-C(CH 3) 3和吡咯烷-1-基，优选-N(H)-C(CH 3) 3。 More preferably, R 4 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 -N (H)-C(CH 3 ) 3 .
  9. 根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药，其中所述化合物选自：The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, polymorph, solvate, N- Oxide, isotope label, metabolite or prodrug, wherein the compound is selected from:
    Figure PCTCN2020106080-appb-100007
    Figure PCTCN2020106080-appb-100007
    Figure PCTCN2020106080-appb-100008
    Figure PCTCN2020106080-appb-100008
    Figure PCTCN2020106080-appb-100009
    Figure PCTCN2020106080-appb-100009
  10. 根据权利要求3所述的具有式IV-A结构的化合物的制备方法，其包括下列步骤：The preparation method of the compound having the structure of formula IV-A according to claim 3, which comprises the following steps:
    当式IV中的X 1为-CH＝时， When X 1 in formula IV is -CH=,
    第1步：化合物IV-1经卤代反应生成化合物IV-2；Step 1: Compound IV-1 is halogenated to produce compound IV-2;
    Figure PCTCN2020106080-appb-100010
    Figure PCTCN2020106080-appb-100010
    X代表卤素原子，选自氯和溴；X represents a halogen atom, selected from chlorine and bromine;
    第2步：化合物IV-2经碘代反应生成化合物IV-3；Step 2: Compound IV-2 is reacted by iodine to generate compound IV-3;
    Figure PCTCN2020106080-appb-100011
    Figure PCTCN2020106080-appb-100011
    第3步：化合物IV-3经氧化反应生成化合物IV-4；Step 3: Compound IV-3 is oxidized to produce compound IV-4;
    Figure PCTCN2020106080-appb-100012
    Figure PCTCN2020106080-appb-100012
    第4步：化合物IV-4与R 4H反应生成化合物IV-5，其中R 4通过氮原子与噻吩并吡啶相连； 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;
    Figure PCTCN2020106080-appb-100013
    Figure PCTCN2020106080-appb-100013
    第5步：化合物IV-5经偶联反应生成化合物IV-6；Step 5: Compound IV-5 is coupled to produce compound IV-6;
    Figure PCTCN2020106080-appb-100014
    Figure PCTCN2020106080-appb-100014
    第6-1步：化合物IV-6经取代反应生成化合物IV-A-1；Step 6-1: Compound IV-6 undergoes substitution reaction to generate compound IV-A-1;
    Figure PCTCN2020106080-appb-100015
    Figure PCTCN2020106080-appb-100015
    其中R 1、R 3a、R 4和L a如权利要求3所定义； Wherein R 1, R 3a, R 4 and L a as defined in claim 3;
    当式IV中的X 1为-CH＝且R 1为1H-吡唑-5-基时， When X 1 in formula IV is -CH= and R 1 is 1H-pyrazol-5-yl,
    第7步：化合物IV-A-1’经脱保护基反应生成化合物IV-A-2；Step 7: Compound IV-A-1' undergoes deprotection reaction to produce compound IV-A-2;
    Figure PCTCN2020106080-appb-100016
    Figure PCTCN2020106080-appb-100016
    其中R 3a、R 4和L a如权利要求3所定义；PG 1代表保护基，其选自四氢-2H-吡喃-2-基、叔丁氧羰基和苄氧羰基。 PG 1 represents a protecting group selected from tetrahydro -2H- pyran-2-yl, tert-butoxycarbonyl group and a benzyloxycarbonyl group; wherein R 3a, R 4 and L a is defined as claimed in claim 3.
  11. 根据权利要求4所述的式V化合物的制备方法，其包括下列步骤：The method for preparing the compound of formula V according to claim 4, which comprises the following steps:
    第1步：化合物IV-6经取代或偶联反应生成化合物V；Step 1: Compound IV-6 is substituted or coupled to produce compound V;
    Figure PCTCN2020106080-appb-100017
    Figure PCTCN2020106080-appb-100017
    其中R 1、R 3、R 4、R 33、L 2、L 3、p和q如权利要求4所定义。 Wherein R 1 , R 3 , R 4 , R 33 , L 2 , L 3 , p and q are as defined in claim 4.
  12. 一种药物组合物，其包含根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式，以及药学上可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.
  13. 根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物，其用作NLRP3调节剂，优选用作NLRP3激动剂。The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof or the pharmaceutical composition according to claim 12, which is used as an NLRP3 modulator, preferably as an NLRP3 agonist.
  14. 根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物在制备用于预防和/或治疗至少部分由NLRP3介导的疾病的药物中的用途。The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof or the pharmaceutical composition according to claim 12 is prepared for the prevention and/or treatment of diseases at least partly mediated by NLRP3 Use in medicines.
  15. 根据权利要求14所述的用途，其中所述的至少部分由NLRP3介导的疾病为选自癌症；优选地，所述的疾病选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、***、***癌、膀胱癌、结肠癌、直肠癌、结直肠癌、胃癌、食管癌、口腔癌、胰腺癌、肝癌、肺癌、肾癌、皮肤癌、骨癌、脑癌、神经胶质瘤和黑色素瘤。The use according to claim 14, wherein the disease at least partly mediated by NLRP3 is selected from cancer; preferably, the disease is selected from leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, cervical cancer 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, glioma and Melanoma.
  16. 一种用于预防和/或治疗至少部分由NLRP3介导的疾病的方法，其包括下列步骤：将预防和/或治疗有效量的根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物施用于对其有需求的个体。A method for preventing and/or treating a disease mediated at least in part by NLRP3, which comprises the following steps: a preventive and/or therapeutically effective amount of a compound according to any one of claims 1 to 9 or A pharmaceutically acceptable form or a pharmaceutical composition according to claim 12 is administered to individuals in need thereof.
  17. 权利要求16所述的方法，其中所述的至少部分由NLRP3介导的疾病为选自癌症；优选地，所述的疾病选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、***、***癌、膀胱癌、结肠癌、直肠癌、结直肠癌、胃癌、食管癌、口腔癌、胰腺癌、肝癌、肺癌、肾癌、皮肤癌、骨癌、脑癌、神经胶质瘤和黑色素瘤。The method of claim 16, wherein the disease at least partially mediated by NLRP3 is selected from cancer; preferably, the disease is selected from leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, and 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, glioma and melanin tumor.
  18. 一种药物联用组合物，其包含根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物，以及至少一种其他的同向NLRP3调节剂。A pharmaceutical combination composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof or the pharmaceutical composition according to claim 12, and at least one other The same direction NLRP3 modulator.
  19. 一种用于预防和/或治疗癌症的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3激动剂的根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物或者根据权利要求18所述的药物联用组合物施用于对其有需求的个体。A method for preventing and/or treating cancer, which comprises the following steps: adding a preventive and/or therapeutically effective amount of the compound according to any one of claims 1 to 9 as an NLRP3 agonist or its pharmacy The above acceptable form or the pharmaceutical composition according to claim 12 or the pharmaceutical combination composition according to claim 18 is administered to an individual in need thereof.
  20. 一种用于预防和/或治疗免疫性疾病的方法，其包括下列步骤：将预防和/或治疗有效量的且作为NLRP3拮抗剂的根据权利要求1至9中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物或者根据权利要求18所述的药物联用组合物施用于对其有需求的个体。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 compound according to any one of claims 1 to 9 as an NLRP3 antagonist or Its pharmaceutically acceptable form or the pharmaceutical composition according to claim 12 or the pharmaceutical combination composition according to claim 18 is administered to an individual in need thereof.
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