WO2023125708A1 - P38 mapk/mk2 pathway modulator, composition thereof, preparation method therefor, and use thereof - Google Patents

P38 mapk/mk2 pathway modulator, composition thereof, preparation method therefor, and use thereof Download PDF

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WO2023125708A1
WO2023125708A1 PCT/CN2022/142967 CN2022142967W WO2023125708A1 WO 2023125708 A1 WO2023125708 A1 WO 2023125708A1 CN 2022142967 W CN2022142967 W CN 2022142967W WO 2023125708 A1 WO2023125708 A1 WO 2023125708A1
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compound
alkyl
reaction
halogen
solution
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栾林波
姚元山
陈永凯
王朝东
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上海美悦生物科技发展有限公司
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Definitions

  • the disclosure belongs to the field of medicine, and in particular relates to a p38 MAPK/MK2 pathway regulator and its composition, preparation method and application.
  • Mitogen-activated protein kinase MAPK mitogen-activated protein kinase
  • MAPK mitogen-activated protein kinase
  • Stress factors include cytokines, neurotransmitters, hormones, cell stress, and cell adhesion.
  • p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thereby playing a complex biological role. effect.
  • p38 MAPK includes four members, namely p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ . Among them, p38 ⁇ is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38 ⁇ to play a role in the proliferation and survival of advanced colorectal cancer (CRC) cells.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3
  • CRC colorectal cancer
  • the main reasons for clinical failure include dose limitation to avoid toxicity, resulting in insufficient exposure of drug molecules at the target site, downregulation of anti-inflammatory pathways, redundant signaling networks, or involvement of other MAPKs Key proteins of pathway feedback regulation are inhibited, etc., and inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, resulting in increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is the main challenge facing drug development in this field.
  • p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152), 924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid the side effects caused by the overall inhibition of p38 MAPK /Primary strategy for underpowered drugs.
  • MAPK-activated protein kinase 2 (MAPK-activated protein kinase 2, MK2) is the direct downstream substrate of p38 MAPK, which can be activated by p38 ⁇ and p38 ⁇ .
  • MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus playing an important role in the regulation of multiple inflammatory diseases.
  • MK2 can increase the expression of inflammatory factors such as TNF- ⁇ , IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA.
  • MK2 inhibitors can reduce the expression of inflammatory factors MIP-1 ⁇ , TNF- ⁇ , IL-6 and IL-1 ⁇ , etc., It was also found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractility of intestinal smooth muscle was improved.
  • diseases are associated with the p38 MAPK/MK2 pathway, these diseases include (but are not limited to) autoimmune diseases and inflammatory diseases (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases, etc.
  • autoimmune diseases such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.
  • inflammatory diseases such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic
  • the present disclosure provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug:
  • W is CH or N
  • n is an integer of 0-5;
  • n is an integer of 0-3;
  • Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
  • R 1 is selected from H, halogen, CN and C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl ;
  • R 4 is selected from H, halogen and C 1-10 alkyl ;
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, unsubstituted or substituted C 1-10 alkyl and C 3-20 cycloalkyl; Ra is halogen or C 3-20 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-10 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  • W is CH or N; m is an integer of 0-5; n is an integer of 0-3;
  • Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
  • R 1 is selected from H, halogen, CN and C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl
  • R 4 is selected from H, halogen and C 1-10 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-6 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  • W is CH or N
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • Ring A is a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-12 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
  • R 1 is selected from H, halogen, CN and -C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-6 alkyl and C 3-12 cycloalkyl
  • R 4 is selected from H, halogen and C 1-6 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, C 1-6 alkyl and C 3-12 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-6 alkyl, 5-14 membered heteroaryl-C 1-6 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl and C 1-3 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-10 cycloalkyl.
  • W is CH or N
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • Ring A is a C 3-9 cycloalkyl group, a 3-9 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
  • R 1 is halogen
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is C 1-3 alkyl and C 3-6 cycloalkyl
  • R 4 is C 1-3 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen and C 1-3 alkyl
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 1-3 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl.
  • W is CH or N
  • n 0, 1, 2 or 3;
  • n 0 or 1
  • Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3] Heptyl, 2-oxaspiro[3.5]nonyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonyl, azetidinyl, tetrahydropyrrole base, thietanyl, tetrahydro-2H-thiopyranyl;
  • R 1 is Cl or Br
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is methyl or cyclopropyl
  • R 4 is methyl
  • R is selected from H, F and Cl
  • R7 is H
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl and pyridyl; each Rb is the same or different, independently selected from F, Cl and CF3 .
  • Ring A may be selected from:
  • the structure formed by R and ring A may be selected from:
  • the compound of formula I has the structure shown in formula Ia or Ib:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m, and n have the above-mentioned definitions, and the chemical bonds in bold indicate the presence of axial chirality in the compound.
  • the compound of formula I has the structure shown in formula II:
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , W, m, n and ring A independently of each other have the definitions stated above;
  • R 10 is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 from the following groups: C 1-10 alkyl, C 1-10 alkoxy, Halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkenyloxy, C 2-10 alkynyl, C 2-10 alkynyloxy ;
  • Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-10 alkyl;
  • p is an integer of 0-4.
  • R 10 is selected from the following groups H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 : C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkenyloxy, C 2-6 alkynyl, C 2-6 alkynyloxy;
  • Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • p 0, 1, 2, 3 or 4.
  • R 10 is selected from H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl; p is 0, 1 or 2;
  • Each R 11 is the same or different, independently selected from H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl.
  • R 10 is selected from H, methyl; p is 0, 1 or 2;
  • Each R 11 is the same or different and independently selected from F, Cl, CF 3 .
  • the compound of formula II has formula IIa or formula IIb:
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , A, W, m, n, and p have the above-mentioned definitions, and the chemical bonds in bold indicate the presence of compounds Axichirality.
  • the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug wherein R 2 is -OR 81 or -NHR 83 ; R 81 and R 83 are the same or different, independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl -C 1-3 alkyl, C 6-8 aryl and 5-6 membered heteroaryl; wherein, C 6-8 aryl, 5-6 membered heteroaryl are unsubstituted or optionally replaced by 1, 2, 3 , 4 or 5 substitutions independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy; the C 1-3 alkyl part is connected to O or NH.
  • the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug wherein R 2 is -OR 81 ; R 81 is C 6 aryl-C 1-3 alkyl or 6-membered heteroaryl-C 1-3 alkyl; wherein C 6 aryl or 6-membered heteroaryl Unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy; C 1 The -3 alkyl moiety is attached to O.
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein for R is selected from halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo ( O), -C(O)C 1-3 alkyl, -C(O) OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) 2 NR 93a R 93b , R 91a , R 91b , R 92 , R 93a , R 93b are the same or different, are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl.
  • the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , pharmaceutically acceptable salts or their prodrugs do not include
  • the compound of formula I has the following structure:
  • the compound shown in formula I has the following structure:
  • the present disclosure also provides a preparation method of the compound of formula I, comprising:
  • Y is Cl or Br
  • W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A are independently defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A independently of each other have the definitions stated above;
  • the reaction is carried out in the presence of an inorganic base;
  • the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
  • the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group is in the It will be removed during the reaction to obtain the deprotected OH.
  • the present disclosure also provides at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound Use in the preparation of medicines.
  • the drug may be a drug for treating and/or preventing diseases related to p38 kinase inhibitors, for example, it may be an MK2 inhibitor or a p38 MAPK/MK2 pathway modulator.
  • the present disclosure also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable At least one of the salts or prodrug compounds thereof.
  • the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the carrier includes a disintegrant, such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, carboxypropylcellulose, starch etc.; lubricants, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxyl Propyl cellulose, etc.; diluents, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants, including polysorbate 80, sodium lauryl sulfate, talc and silica.
  • Compositions of the present disclosure can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
  • the present disclosure also provides the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound, in the treatment and/or Or the use in preventing diseases mediated by p38 kinase inhibitors.
  • the present disclosure also provides a method for treating and/or preventing diseases mediated by p38 kinase inhibitors, comprising administering to a patient an effective dose of a compound represented by formula I, its racemate, stereoisomer, tautomer At least one of isomers, isotope labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof.
  • the disease may be a disease related to the p38 MAPK/MK2 pathway, such as an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related disease.
  • an autoimmune disease and an inflammatory disease such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.
  • an inflammatory disease such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease
  • the disclosed compound has a good regulating effect on the p38 MAPK/MK2 pathway and has good selectivity.
  • the compounds of the present disclosure have good properties such as pharmacokinetics.
  • the disclosed compounds are useful in the treatment of diseases associated with the mediation of p38 kinase inhibitors, and in the preparation of medicaments for such conditions or diseases.
  • the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein.
  • the numerical range “1-20” is equivalent to recording every integer value in the numerical range “1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20.
  • numbers it should be understood that both endpoints of the range, each integer within the range, and each decimal within the range are recited.
  • a number from 0 to 10 should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • halogen denotes fluorine, chlorine, bromine and iodine.
  • C 1-10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms.
  • C 1-6 alkyl means having 1, 2, 3 , straight-chain and branched-chain alkyl groups of 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined herein. Alkoxy groups containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy) are preferred, more Alkoxy having 1 to 6 carbon atoms (C 1-6 alkoxy) is preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.
  • C 2-10 alkenyl is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably “C 2-8 alkenyl”.
  • C 2-10 alkenyl is understood to mean preferably a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, For example, having 2, 3, 4, 5 or 6 carbon atoms (ie, C2-6 alkenyl), having 2 or 3 carbon atoms (ie, C2-3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl Base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • C 2-10 alkynyl is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g., having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C alkynyl ”) having 2, 3, 4, 5 or 6 carbon atoms (ie, "C 2-6 alkynyl”), having 2 or 3 carbon atoms ("C 2-3 alkynyl").
  • the alkynyl group is for example ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, Pent-3-ynyl, Pent-4-ynyl, Hex-1-ynyl, Hex-2-ynyl, Hex-3-ynyl, Hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylp
  • C 3-20 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as double ring, spiro ring, bridged ring) hydrocarbon ring or tricycloalkane, which has 3 to 20 carbon atoms, Preferable is “C 3-12 cycloalkyl", more preferably “C 3-8 cycloalkyl”.
  • C 3-12 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane, which has 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.
  • a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl
  • a bicyclic Hydrocarbon groups
  • 3-20 membered heterocyclic group refers to a saturated or unsaturated non-aromatic ring or ring system, for example, it is a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic (such as fused, spiro, bridged) or tricyclic ring systems, and contain at least one, for example 1, 2 , 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)- Or the state of -S(O) 2 -.
  • the heterocyclic group may be selected from "3-12 membered heterocyclic group".
  • the term "3-12 membered heterocyclyl” means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N.
  • the heterocyclyl group can be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom, if present.
  • the heterocyclyl may include fused or bridged rings as well as spirocyclic rings.
  • the heterocyclic group may include, but is not limited to: 3-membered rings, such as oxiranyl; 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuran base, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiane group, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl.
  • 3-membered rings such as oxiranyl
  • 4-membered rings such as azetidinyl, oxetanyl
  • 5-membered rings such as tetrahydrofuran base, dioxolyl, pyrrolidin
  • the heterocyclyl group may be benzo-fused.
  • the heterocyclic group can be bicyclic, such as but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrole And[1,2-a]pyrazin-2(1H)-yl ring.
  • a heterocyclyl group may be partially unsaturated, i.e.
  • it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzofused, such as but It is not limited to dihydroisoquinolinyl.
  • the carbon atom on the 3-12-membered heterocyclic group is connected with other groups, or it can be a 3-12-membered heterocyclic group
  • the ring heteroatoms are connected to other groups.
  • the 3- to 12-membered heterocyclic group is selected from piperazinyl
  • the nitrogen atom on piperazinyl may be connected to other groups.
  • the 3-12 membered heterocyclic group is selected from piperidinyl
  • the nitrogen atom on the piperidinyl ring and the carbon atom at its para-position may be connected to other groups.
  • spiro refers to a ring system in which two rings share 1 ring-forming atom.
  • merged ring refers to a ring system in which two rings share 2 ring-forming atoms.
  • bridged ring refers to a ring system in which two rings share more than 3 ring-forming atoms.
  • C 6-14 aryl-C 1-10 alkyl refers to a C 1-10 alkyl substituted by a C 6-14 aryl, and the connection point is at the C 1-10 alkyl.
  • 5-14 membered heteroaryl-C 1-10 alkyl refers to a C 1-10 alkyl group substituted by a 5-14 membered heteroaryl group, and the attachment point is at the C 1-10 alkyl group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described herein, wherein the ring bonded to the parent structure is an aryl ring, which is not limiting Examples include:
  • Aryl groups can be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl rings include heteroaryl fused to aryl, heterocyclyl or cycloalkyl rings as described herein, where the ring attached to the parent structure is a heteroaryl ring, without limitation Sexual examples include:
  • Heteroaryl groups can be substituted or unsubstituted.
  • alkyl alkoxy
  • cycloalkyl heterocyclyl
  • aryl and “heteroaryl” etc. herein may be substituted or unsubstituted; when substituted , which may be substituted at any available point of attachment, said substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano One or more of the same or different substituents among , amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • the pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic salts or organic salts, and if these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form bases. Addition salts; these compounds can also form internal salts if they contain both an acidic center (eg carboxyl group) and a basic center (eg amino group).
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. For example cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomers, (L)-isomers, racemic and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • the bond means unspecified configuration, Indicates the absolute configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both two configurations, Indicates the presence of axial chirality.
  • Tautomer refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam imide isomerization. All tautomeric forms of all compounds in the disclosure are within the scope of the disclosure.
  • the names of compounds named in a single way do not exclude any tautomers.
  • the present disclosure also includes some isotopically labeled compounds of the disclosure having the same structure as described herein, but wherein one or more atoms are replaced by an atom with an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
  • deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • the "therapeutically effective amount” in the present disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians look for in tissues, systems, animals, individuals or humans to cause biological or medical responses, including One or more of the following: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition.
  • Alleviating disease For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • a drug or a pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • “Pharmaceutically acceptable” in the present disclosure means that these compounds, materials, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
  • Principal in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably people.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid phase mass spectrometer were used for the determination of MS.
  • HPLC high performance liquid chromatography
  • the thin-layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm. .
  • High-performance liquid phase preparation uses Waters 2767, Waters 2545, and innovative Hengtong LC3000 preparative chromatography.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
  • the microwave reaction uses a Biotage initiator+ type microwave reactor.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
  • reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • the resolved chiral compounds can be distinguished by the sequence of retention time in the chiral chromatographic column. Therefore, the chiral compounds resolved successively according to the retention time are distinguished by the corresponding numbering suffixes P1 and P2 . That is, the suffix P1 corresponds to the chiral structure that was resolved first, and the suffix P2 corresponds to the chiral structure that was resolved later. If there is an absolute configuration of the compound listed in the reaction formula, it does not mean a one-to-one correspondence with the compounds with the numbering suffixes P1 and P2, but only indicates the two forms of absolute configuration. The absolute configuration of the compounds with the suffixes P1 and P2 is based on the absolute configuration objectively corresponding to the specific retention time.
  • a tetrahydrofuran solution (141mL, 141mmol) of bis(trimethylsilyl)amide lithium was slowly added to a solution of compound A-1 (20g, 141mmol) in tetrahydrofuran (500mL), and the reaction solution was in- After stirring at 78°C for 1 hour, acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise, and the resulting mixture was stirred at -78°C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL ⁇ 3).
  • Bistriphenylphosphine palladium dichloride (1.56 g, 2.22 mmol) was added to compound A-6 (8.4 g, 22.2 mmol) and tributyl(1-ethoxyethylene) tin (compound A-7) ( 10.21g, 24.2mmol) in 1,4-dioxane (100mL) solution, the reaction solution was heated to 130°C and stirred for 4 hours. Then the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure. The residue was dissolved by adding tetrahydrofuran (100 mL), and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour.
  • N,N-Dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to a solution of compound A-9 (1.3g, 3.1mmol) in N,N-dimethylformamide (15mL) , and the reaction mixture was stirred at 100° C. for 3 hours. After the reaction, the reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • Diphenylphosphoryl azide (23.5 g, 0.085 mol) was added to a mixture of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol/toluene (50 mL/50 mL) In solution, the reaction mixture was carried out at 110°C for 16 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (200 mL ⁇ 3).
  • methylboronic acid 530mg, 8.8mmol
  • cesium carbonate 8.96g, 27.5mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 450mg , 0.55mmol
  • N-chlorosuccinimide (330mg, 2.48mmol) and glacial acetic acid (0.2mL) were added successively to a solution of compound B-10 (910mg, 2.25mmol) in isopropanol (12mL), and the reaction mixture was heated at 60 °C and stirred for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound B-11 (1.13 g). MS m/z (ESI): 437.8 [M+1] + .
  • N,N-dimethylformamide dimethyl acetal 600mg, 5.0mmol was added to a solution of compound B-11 (1.08g, 2.5mmol) in N,N-dimethylformamide (15mL), The reaction mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • the first step the synthesis of compound 1-2
  • Acetic anhydride (51.15 mg, 0.50 mmol) was added to a solution of compound 1-3 (90 mg, 0.16 mmol) and triethylamine (67.59, 0.67 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours.
  • Compound 2 was subjected to supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mmx20mm, 5 ⁇ m; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); total flow rate: 12.5g/ min) Compound 2-P1 (19.4 mg) and Compound 2-P2 (18.6 mg) were isolated.
  • reaction solution was poured into water, extracted with ethyl acetate (50mL ⁇ 3), the combined organic phase was washed with saturated brine (50mL ⁇ 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was washed with Preparative HPLC purification (column: Xbridge-C18, 150 ⁇ 21.2mm, 5 ⁇ m; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: acetonitrile-water (0.1 % formic acid); gradient: 35-60%) to obtain compound 4 (36.6mg, yield: 31.7%).
  • reaction solution was poured into water, extracted with ethyl acetate (50mL ⁇ 3), the combined organic phase was washed with saturated brine (50mL ⁇ 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure
  • the solvent was removed, and the residue was subjected to preparative high-performance liquid chromatography (chromatographic column: Xbridge-C18, 150 ⁇ 21.2mm, 5um; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: Acetonitrile-water (0.1% formic acid); gradient: 35-60%) was purified to obtain compound 8 (52.9 mg, yield: 47.8%).
  • the fourth step the synthesis of compounds 10-P1 and 10-P2
  • the compound 10 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g /min) for chiral resolution to obtain compounds 10-P1 (15.7 mg, yield: 4.6%) and 10-P2 (17.2 mg, yield: 5.1%).
  • the fourth step the synthesis of compounds 14-G1 and 14-G2
  • Compound 16 was prepared by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80; Column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5 g/min) to obtain compounds 16-P1 (21.8 mg) and 16-P2 (22 mg).
  • the fourth step the synthesis of compound 33-P1 and compound 33-P2
  • Trifluoroacetic acid (84 mg, 0.74 mmol) was slowly added to a solution of compound 41-4 (90 mg, 0.15 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product of compound 41-5 (70 mg), which was directly used for the next reaction.
  • the fifth step the synthesis of compound 41, compound 41-P1 and compound 41-P2
  • Acetic anhydride 60 mg, 0.59 mmol was slowly added to a solution of compound 41-5 (100 mg, 0.19 mmol) and triethylamine (59 mg, 0.59 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours.
  • reaction solution was concentrated under reduced pressure, then poured into water (20mL), extracted with ethyl acetate (20mL x3), the combined organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate and filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column Temperature: 25°C; Flow rate: 14mL/min; Wavelength: 214nm; Column pressure: 80bar) to obtain compound 41 (50mg).
  • Compound 41 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm ⁇ 20mm, 5 ⁇ m; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g/min ) was purified to obtain compound 41-P1 (19 mg yield: 17.6%) and compound 41-P2 (17 mg yield: 15.7%).
  • Embodiment 14 the synthesis of compound 63, 63-P1 or 63-P2
  • the first step the synthesis of compound 63
  • Compound 63 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm ⁇ 20mm, 5 ⁇ m; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water), total flow rate: 40g/min ) was purified to obtain compound 63-P1 (25.3 mg, yield: 11.2%) and compound 63-P2 (26.7 mg, yield: 11.8%).
  • the first step the synthesis of compound 58-1
  • isobutyryl chloride 25mg, 0.23mmol was added dropwise to a solution of compound 41-5 (60mg, 0.12mmol) and triethylamine (36mg, 0.35mmol) in dichloromethane (5mL), and the reaction mixture was stirred at room temperature 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • acetic anhydride (20 mg, 0.19 mmol) was added to a solution of compound 44-5 (70 mg, 0.13 mmol) and triethylamine (27 mg, 0.26 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • the first step the synthesis of compound 69-2
  • the seventh step the synthesis of compound 76
  • Tetrahydropyran-4-carboxamidine (42 mg, 0.33 mmol) was added to compound 76-7 (80 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N, N-dimethylformamide (10 mL) In solution, the reaction mixture was stirred at 90 °C for 16 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with dichloromethane (30 mL ⁇ 3).
  • the first step the synthesis of compound 77-2
  • N,N-dimethylformamide dimethyl acetal (87mg, 0.73mmol) was added to compound 77-6 (80mg, 0.18mmol) in N,N-dimethylformamide (10mL) solution, and the reaction The mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • Tetrahydropyran-4-carboxamidine (18 mg, 0.14 mmol) was added to compound 77-7 (35 mg, 0.07 mmol) and potassium carbonate (29 mg, 0.21 mmol) in N, N-dimethylformamide (10 mL) In solution, the reaction mixture was stirred at 90 °C for 12 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with dichloromethane (30 mL ⁇ 3).
  • the first step the synthesis of compound 78-1
  • Methylamine (2.38g, 35.2mmol) was added to compound 82-1 (3g, 17.6mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.75g, 35.2 mmol), 1-hydroxybenzotriazole (4.76 g, 35.2 mmol) and triethylamine (5.34 g, 52.8 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 12 hours.
  • Compound C It is prepared according to the method of Example 1 of WO2021195475A1.
  • Test example 1 Determination of in vitro activity of p38 MAPK/MK2
  • the inhibitory effect of compounds on p38 MAPK/MK2 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10 ⁇ L reaction system was carried out in a 384-well plate (Corning, 4514), containing 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 ⁇ M Ser/Thr 4; after 1 hour of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 ⁇ L of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex.
  • Test example 2 Determination of p38 MAPK/MK5 in vitro activity
  • the inhibitory effect of compounds on p38 MAPK/MK5 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA are used as the reaction buffer to configure 2x active p38a/inactive MK5/Ser/Thr 4 mixture, the final 10 ⁇ L reaction system was carried out in a 384-well plate (Corning, 4514), containing 10 ⁇ g/mL inactive MK5 (abcam, 217826), 1ng/mL active p38a (Carna, 04-152), 2 ⁇ M Ser/Thr 4; after 4 hours of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 ⁇ L of stop buffer solution to stop the reaction, and detect with a microplate reader (Ex.
  • Test example 3 Determination of in vitro activity of p38 MAPK/ATF2
  • the inhibitory effect of compounds on p38a-catalyzed ATF2 was detected by HTRF method.
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 0.25% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 40mM Tris pH 7.5, 20mM MgCl2, 0.1mg/mL BSA, 50 ⁇ M DTT are used as the reaction buffer to configure 3.5x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5x ATP working solution, 10mM EDTA was used to stop the reaction, and the final 14 ⁇ L reaction system Carried out in 96-well plate (cisbio, 66PL96025), containing 0.29ng/ ⁇ L p38a, 0.29 ⁇ M Human ATF
  • Test example 4 Determination of in vitro activity of human PBMC cell supernatant TNF- ⁇
  • the inhibitory effect of compounds on human PBMC cell supernatant TNF- ⁇ was detected by Elisa detection kit (Beiyuntian, PI518).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 2 ⁇ M, 5-fold dilution, 6 concentrations, the cells are plated in double wells, the Elisa is detected as a single well, and the final concentration of DMSO is 0.4%.
  • the initial concentration of the compound can also be changed according to the actual situation of compound screening , ratio dilution factor, gradient concentration quantity and duplicate hole number.
  • PBMC peripheral blood mononuclear cells
  • the cocktail method was used to study the inhibition of the activity of the test compound on CYP enzyme subtypes 1A2, 2B6, 2C8, 2C19, 2C9, 2D6 and 3A4, and the IC50 values of the activity of the test compound on several CYP enzyme subtypes were measured.
  • the control compounds were: Fluvoxamine (1A2), Ketoconazole (2B6), Montelukast (2C8), Tranylcypromine (2C19), Sulfaphenazole (2C9), Quinindium (2D6) and Ketoconazole (3A4/5);
  • the CYP enzyme probe substrates used are: Phenacetin (1A2), Bupropion (2B6), Amodiaquine ( 2C8), Mephenytoin (2C19), Diclofenac (2C9), Dextromethorphan (2D6) and Testosterone (3A4/5).
  • PBS Buffer is 50mM K2HPO4 buffer.
  • the concentrations of the compounds to be tested were 50 ⁇ M, 12.5 ⁇ M, 3.125 ⁇ M, 0.781 ⁇ M, 0.195 ⁇ M, and 0.0488 ⁇ M, respectively.
  • the change of the IC50 value of the test compound on the inhibition of CYP3A4/5 subtype enzyme activity was compared under the above two conditions, and the calculated Get the corresponding IC50 shift value.
  • the control compound is: Verapamil (CYP3A4/5)
  • the probe substrate is: Testosterone (CYP3A4/5).
  • PBS Buffer is 50mM K2HPO4 buffer. The concentrations of the compounds to be tested were 50 ⁇ M, 10 ⁇ M, 2 ⁇ M, 0.4 ⁇ M, 0.08 ⁇ M, and 0.016 ⁇ M, respectively.
  • the probe substrate and PBS solution were pre-prepared into a substrate solution (1990 ⁇ L of PBS+10 ⁇ L of substrate). Add the microsomes into PBS, and pre-incubate the samples of the group without pre-reaction in a 37°C water bath for 30 minutes, then add the control compound/test compound/DMSO solution, 10mM NADPH solution and probe substrate solution to the corresponding reaction system, and place at 37°C.
  • the control compound used in this experiment was: Ketanserin, and the final concentration of microsomes in the experimental system was 0.5 mg/mL.
  • PBS Buffer is 50mM K2HPO4 buffer. The concentration of the compound to be tested was 1 ⁇ M. Add the microsomes into PBS, add the control compound/test compound to the corresponding reaction system, mix well, place in a 37°C water bath for pre-incubation for 5min, add 20mM NADPH solution, and start the reaction in a 37°C water bath (For No NADPH samples, replace 20 mM NADPH solution with an equal volume of PBS solution).
  • the disclosed compound 10-P1 and compound 63-P1 have good exposure, in vivo clearance rate and bioavailability.
  • the in vivo clearance rate CL of compound 10-P1 was 1241.95mL/hr/kg, which was significantly better than that of compound C (2313.22mL/hr/kg); in intragastric administration, The blood drug exposure of compound 10-P1 was 2120.68hr*ng/mL, double that of compound C; the in vivo clearance rate CL of compound 63-P1 was 1492.93mL/hr/kg, significantly better than Compared with the in vivo clearance rate CL of compound C (2313.22mL/hr/kg); in the intragastric administration, the blood drug exposure of compound 63-P1 is 2596.40hr*ng/mL, which is higher than the blood drug exposure of compound C doubled. Therefore, this shows that the compound of the present disclosure has good

Abstract

Disclosed in the present disclosure are a compound shown in formula (I), a racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug thereof, a composition thereof, a preparation method therefor, and a use thereof. The compound has a good modulation effect on a p38 MAPK/MK2 pathway, and has good selectivity, and good pharmacokinetic performance and the like. In addition, the compound can be used for treating diseases related to mediation of a p38 kinase inhibitor, and preparing a drug used for such disorders or diseases.

Description

一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途A p38 MAPK/MK2 pathway regulator and its composition, preparation method and application
本公开要求享有于2021年12月29日向中国国家知识产权局提交的，专利申请号为202111640112.X，名称为“一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本公开中。This disclosure claims to enjoy the patent application number 202111640112.X, which was submitted to the State Intellectual Property Office of China on December 29, 2021, and is entitled "a p38 MAPK/MK2 pathway modulator and its composition, preparation method and use" Priority of earlier application. The entirety of this prior application is incorporated by reference into this disclosure.
技术领域technical field
本公开属于医药领域，具体涉及一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途。The disclosure belongs to the field of medicine, and in particular relates to a p38 MAPK/MK2 pathway regulator and its composition, preparation method and application.
背景技术Background technique
生物信号转导涉及特异性的蛋白-蛋白相互作用和翻译后修饰、调节遗传和表观遗传过程以应对内外环境的作用。丝裂原活化蛋白激酶MAPK(mitogen-activated protein kinase)是一组能被不同的细胞内外部应激激活的丝氨酸-苏氨酸蛋白激酶，是信号从细胞表面传导到细胞核内部的重要传递者。应激因素包括细胞因子、神经递质、激素、细胞应激和细胞黏附等。Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to internal and external environments. Mitogen-activated protein kinase MAPK (mitogen-activated protein kinase) is a group of serine-threonine protein kinases that can be activated by different intracellular and external stresses, and is an important transmitter of signals from the cell surface to the interior of the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress, and cell adhesion.
作为MAPK家族的一个亚族，p38 MAPK在细胞对外界信号和炎性细胞因子的作用做出响应，p38 MAPK被激活后磷酸化并激活下游多种蛋白激酶和转录因子，从而发挥复杂的生物学作用。p38 MAPK包括四个成员，即p38α、p38β、p38γ和p38δ。其中，p38α被认为在炎症过程的信号通路中起着重要作用，而其它异构体的生物学功能尚未完全被发现，但它们具有多效性。研究表明，p38β在细胞保护机制中起着重要的作用，而丝裂原活化蛋白激酶MKK3(MAP Kinase Kinase 3)介导p38δ对晚期结直肠癌(CRC)细胞的增殖和存活有作用。作为药物开发领域一个有吸引力的靶点，p38 MAPK有多个抑制剂药物进入临床研究，截至目前还没有药物被批准上市。根据公开信息，部分候选化合物在临床研究阶段失败，临床失败的主要原因包括剂量受限制以避免毒性从到导致药物分子在作用靶点暴露量不足抗炎通路下调、信号网络冗余或参与其它MAPK通路反馈调节的关键蛋白受到抑制等，而抑制反馈机制可能上调其他促炎症途径，导致炎症增加。因此，开发一款安全有效的p38 MAPK抑制剂是目前该领域药物开发面临的主要挑战。As a subfamily of the MAPK family, p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thereby playing a complex biological role. effect. p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in the mechanism of cell protection, while mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to play a role in the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, several inhibitors of p38 MAPK have entered clinical research, but so far no drug has been approved for marketing. According to public information, some candidate compounds fail in the clinical research stage. The main reasons for clinical failure include dose limitation to avoid toxicity, resulting in insufficient exposure of drug molecules at the target site, downregulation of anti-inflammatory pathways, redundant signaling networks, or involvement of other MAPKs Key proteins of pathway feedback regulation are inhibited, etc., and inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, resulting in increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is the main challenge facing drug development in this field.
p38 MAPK可调控超过60种底物并行使不同的生理学功能[Cell 2013(152),924]，所以选择性地抑制p38 MAPK下游效应物的激活，是避免由于p38 MAPK的整体抑制而导致的副作用/药效不足的主要策略。MAPK激活蛋白激酶2(MAPK-activated protein kinase 2，MK2)是p38 MAPK下游的直接作用底物，可被p38α和p38β激活。作为第一个被发现的p38 MAPK底物，MK2可在转录和转录后水平调节炎症因子的表达，从而在多个炎症性疾病的调节中发挥重要作用。研究表明，MK2可通过稳定mRNA的AU-rich元件，从而使TNF-α、IL-6、IL-8和COX-2等炎症因子表达增加。在小鼠的术后肠梗阻模型中[The Journal of surgical research  2013(185),102]，MK2抑制剂可减少炎症因子MIP-1α、TNF-α、IL-6和IL-1β等的表达，同时发现多形核白细胞、肥大细胞、单核巨噬细胞浸润的减少和肠平滑肌收缩性能的改善。在小鼠的胶原诱发性关节炎(CIA)模型中[Journal ofimmunology 2006(177),1913]，敲除MK2基因可以减少胶原诱发性关节炎的发生，与野生型小鼠相比，MK2-/-和MK2+/-小鼠胶原诱发性关节炎的发病率减少、严重程度降低，且炎症因子TNF-α和IL-6表达也有不同程度的减少。在MK2敲除的高胆固醇血症小鼠模型中[Circ Res 2007(101),1104]，小鼠的大动脉的脂质沉积和巨噬细胞减少，而且VCAM-1和MCP-1等炎症因子表达减少。另外，有研究表明抑制MK2可以用于抗肿瘤药物的开发[Cancer cell 2007(11),175]。p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152), 924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid the side effects caused by the overall inhibition of p38 MAPK /Primary strategy for underpowered drugs. MAPK-activated protein kinase 2 (MAPK-activated protein kinase 2, MK2) is the direct downstream substrate of p38 MAPK, which can be activated by p38α and p38β. As the first discovered p38 MAPK substrate, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA. In the postoperative intestinal obstruction model in mice [The Journal of surgical research 2013(185), 102], MK2 inhibitors can reduce the expression of inflammatory factors MIP-1α, TNF-α, IL-6 and IL-1β, etc., It was also found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractility of intestinal smooth muscle was improved. In the mouse collagen-induced arthritis (CIA) model [Journal ofimmunology 2006(177), 1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis, compared with wild-type mice, MK2-/ The incidence and severity of collagen-induced arthritis in - and MK2+/- mice were reduced, and the expressions of inflammatory factors TNF-α and IL-6 were also reduced to varying degrees. In the MK2 knockout mouse model of hypercholesterolemia [Circ Res 2007(101), 1104], the lipid deposition and macrophages in the aorta of the mice were reduced, and inflammatory factors such as VCAM-1 and MCP-1 were expressed reduce. In addition, studies have shown that inhibiting MK2 can be used in the development of anti-tumor drugs [Cancer cell 2007(11), 175].
许多疾病与p38 MAPK/MK2通路相关，这些疾病包括(但不限于)自体免疫疾病和炎症性疾病(例如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、系统性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病等。选择性的抑制p38 MAPK/MK2通路减少了对p38 MAPK其它下游通路的影响，进而降低了药物开发中的潜在毒副作用和药效不充分的问题；满足与p38 MAPK/MK2通路相关疾病领域存在的未被满足的临床需求。Many diseases are associated with the p38 MAPK/MK2 pathway, these diseases include (but are not limited to) autoimmune diseases and inflammatory diseases (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases, etc. Selective inhibition of the p38 MAPK/MK2 pathway reduces the impact on other downstream pathways of p38 MAPK, thereby reducing the potential side effects and insufficient drug efficacy in drug development; meeting the existing needs in the field of diseases related to the p38 MAPK/MK2 pathway Unmet clinical needs.
发明内容Contents of the invention
本公开提供了一种如式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药：The present disclosure provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug:
Figure PCTCN2022142967-appb-000001
Figure PCTCN2022142967-appb-000001
其中，W为CH或N；Wherein, W is CH or N;
m为0-5的整数；m is an integer of 0-5;
n为0-3的整数；n is an integer of 0-3;
环A为C 3-20环烷基、3-20元的杂环基，环A中的碳原子与母核连接，所述3-20元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
R 1选自H、卤素、CN和C 1-6烷基； R 1 is selected from H, halogen, CN and C 1-6 alkyl;
R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
R 3选自H、C 1- 10烷基和C 3-20环烷基； R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl ;
R 4选自H、卤素和C 1- 10烷基； R 4 is selected from H, halogen and C 1-10 alkyl ;
R 5分别独立地选自H、卤素、-OH、-C 1-6烷基、-C 1-6烷氧基、氧代(＝O)、-C(O)C 1-6烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from H, halogen, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) 2 NR 93a R 93b ;
R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
R 7分别独立地选自H、卤素、未取代或被Ra取代的C 1-10烷基和C 3-20环烷基；Ra为卤素或C 3-20环烷基； R 7 are independently selected from H, halogen, unsubstituted or substituted C 1-10 alkyl and C 3-20 cycloalkyl; Ra is halogen or C 3-20 cycloalkyl;
R 81、R 82、R 83、R 84相同或不同，彼此独立地选自无取代或任选被1、2、3、4或5个Rb取代的C 6-14芳基-C 1-10烷基、5-14元杂芳基-C 1-10烷基、C 6-14芳基和5-14元杂芳基；每个Rb相同或不同，彼此独立地选自卤素、卤代C 1-10烷基、C 1-10烷基和C 1-10烷氧基； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-10 alkoxy;
R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-6烷基和C 3-20环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
根据本公开的实施方案，W为CH或N；m为0-5的整数；n为0-3的整数；According to an embodiment of the present disclosure, W is CH or N; m is an integer of 0-5; n is an integer of 0-3;
环A为C 3-20环烷基、3-20元的杂环基，环A中的碳原子与母核连接，所述3-20元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
R 1选自H、卤素、CN和C 1-6烷基； R 1 is selected from H, halogen, CN and C 1-6 alkyl;
R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
R 3选自H、C 1-10烷基和C 3-20环烷基； R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl;
R 4选自H、卤素和C 1-10烷基； R 4 is selected from H, halogen and C 1-10 alkyl;
R 5分别独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、氧代(＝O)、-C(O)C 1-6烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C( O )OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) NR 93a R 93b ;
R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
R 7分别独立地选自H、卤素、C 1-10烷基和C 3-20环烷基； R 7 are independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl;
R 81、R 82、R 83、R 84相同或不同，彼此独立地选自C 6-14芳基-C 1-10烷基、5-14元杂芳基-C 1-10烷基、C 6-14芳基和5-14元杂芳基；其中，C 6-14芳基、5-14元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-10烷基、C 1-10烷基和C 1-6烷氧基取代； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-6 alkoxy;
R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-6烷基和C 3-20环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
根据本公开的实施方案，According to an embodiment of the present disclosure,
W为CH或N；W is CH or N;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
n为0、1、2或3；n is 0, 1, 2 or 3;
环A为C 3-12环烷基、3-12元的杂环基，环A中的碳原子与母核连接，所述3-12元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-12 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
R 1选自H、卤素、CN和-C 1-6烷基； R 1 is selected from H, halogen, CN and -C 1-6 alkyl;
R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
R 3选自H、C 1-6烷基和C 3-12环烷基； R 3 is selected from H, C 1-6 alkyl and C 3-12 cycloalkyl;
R 4选自H、卤素和C 1-6烷基； R 4 is selected from H, halogen and C 1-6 alkyl;
R 5分别独立地选自卤素、-OH、-C 1-6烷基、-C 1-6烷氧基、氧代(＝O)、-C(O)C 1-6烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from halogen, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C ( O)OH, -C(O)NR91aR91b, -S(O)2R92 and -S ( O ) 2NR93aR93b ;
R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
R 7分别独立地选自H、卤素、C 1-6烷基和C 3-12环烷基； R 7 are independently selected from H, halogen, C 1-6 alkyl and C 3-12 cycloalkyl;
R 81、R 82、R 83、R 84相同或不同，彼此独立地选自C 6-14芳基-C 1-6烷基、5-14元杂芳基-C 1-6烷基、C 6-14芳基和5-14元杂芳基；其中，C 6-14芳基、5-14元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-6烷基、C 1-6烷基和C 1-3烷氧基取代； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-6 alkyl, 5-14 membered heteroaryl-C 1-6 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-6 alkyl, C 1-6 alkyl and C 1-3 alkoxy;
R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-3烷基和C 3-10环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-10 cycloalkyl.
根据本公开的实施方案，According to an embodiment of the present disclosure,
W为CH或N；W is CH or N;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
n为0、1、2或3；n is 0, 1, 2 or 3;
环A为C 3-9环烷基、3-9元的杂环基，环A中的碳原子与母核连接，所述3-9元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-9 cycloalkyl group, a 3-9 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
R 1为卤素； R 1 is halogen;
R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
R 3为C 1-3烷基和C 3-6环烷基； R 3 is C 1-3 alkyl and C 3-6 cycloalkyl;
R 4为C 1-3烷基； R 4 is C 1-3 alkyl;
R 5分别独立地选自卤素、-OH、-C 1-3烷基、-C 1-3烷氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=O), -C(O)C 1-3 alkyl, -C ( O)OH, -C(O)NR91aR91b, -S(O)2R92 and -S ( O ) 2NR93aR93b ;
R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
R 7分别独立地选自H、卤素和C 1-3烷基； R 7 are independently selected from H, halogen and C 1-3 alkyl;
R 81、R 82、R 83、R 84相同或不同，彼此独立地选自C 6-8芳基-C 1-3烷基、5-6元杂芳基-C 1-3烷基、C 6-14芳基和5-14元杂芳基；其中，C 6-14芳基、5-14元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-3烷基、C 1-3烷基和C 1-3烷氧基取代； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 1-3 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy;
R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-3烷基和C 3-6环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl.
根据本公开的实施方案，According to an embodiment of the present disclosure,
W为CH或N；W is CH or N;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0或1；n is 0 or 1;
环A选自哌啶基、四氢-2H-吡喃基、四氢呋喃基、氧杂环丁烷基、环丙基、环丁基、环戊基、环己基、2-氧杂螺[3.3]庚烷基、2-氧杂螺[3.5]壬烷基、2-氮杂螺[3.3]庚烷基、2-氮杂螺[3.5]壬烷基、氮杂环丁烷基、四氢吡咯基、硫杂环丁烷基、四氢-2H-噻喃基；Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3] Heptyl, 2-oxaspiro[3.5]nonyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonyl, azetidinyl, tetrahydropyrrole base, thietanyl, tetrahydro-2H-thiopyranyl;
R 1为Cl或Br； R 1 is Cl or Br;
R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
R 3为甲基或环丙基； R 3 is methyl or cyclopropyl;
R 4为甲基； R 4 is methyl;
R 5分别独立地选自F、-OH、甲基、甲氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NH 2、-C(O)NHCH 3、-S(O) 2CH 3、-S(O) 2CH 2CH 3和-S(O) 2-环丙烷； R 5 are independently selected from F, -OH, methyl, methoxy, oxo (=O), -C(O)C 1-3 alkyl, -C(O)OH, -C(O) NH 2 , -C(O)NHCH 3 , -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 and -S(O) 2 -cyclopropane;
R 6选自H、F和Cl； R is selected from H, F and Cl;
R 7为H； R7 is H;
R 81、R 82、R 83、R 84相同或不同，彼此独立地选自无取代或任选被1、2或3个Rb取代的苯基甲基、吡啶基甲基、吡啶基乙基、苯基和吡啶基；每个Rb相同或不同，彼此独立地选自F、Cl和CF 3。 R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl and pyridyl; each Rb is the same or different, independently selected from F, Cl and CF3 .
根据本公开的实施方案，环A可以选自：According to an embodiment of the present disclosure, Ring A may be selected from:
Figure PCTCN2022142967-appb-000002
Figure PCTCN2022142967-appb-000002
根据本公开的实施方案，R 5和环A形成的结构可以选自： According to an embodiment of the present disclosure, the structure formed by R and ring A may be selected from:
Figure PCTCN2022142967-appb-000003
Figure PCTCN2022142967-appb-000003
Figure PCTCN2022142967-appb-000004
Figure PCTCN2022142967-appb-000004
在一种优选的实施方案中，式Ⅰ化合物具有式Ⅰa或Ⅰb所示的结构：In a preferred embodiment, the compound of formula I has the structure shown in formula Ia or Ib:
Figure PCTCN2022142967-appb-000005
Figure PCTCN2022142967-appb-000005
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、A、W、m、n具有上文所述的定义，加粗的化学键表示化合物中存在轴手性。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m, and n have the above-mentioned definitions, and the chemical bonds in bold indicate the presence of axial chirality in the compound.
在一种优选的实施方案中，式Ⅰ化合物具有式Ⅱ所示的结构：In a preferred embodiment, the compound of formula I has the structure shown in formula II:
Figure PCTCN2022142967-appb-000006
Figure PCTCN2022142967-appb-000006
其中R 1、R 3、R 4、R 5、R 6、R 7、W、m、n和环A彼此独立地具有上文所述的定义； wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , W, m, n and ring A independently of each other have the definitions stated above;
R 10选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH 2取代的下列基团：C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 2-10烯基、C 2-10烯基氧基、C 2-10炔基、C 2-10炔基氧基； R 10 is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 from the following groups: C 1-10 alkyl, C 1-10 alkoxy, Halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkenyloxy, C 2-10 alkynyl, C 2-10 alkynyloxy ;
每个R 11相同或不同，彼此独立地选自H、卤素、C 1-6烷基、卤代C 1-10烷基； Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-10 alkyl;
p为0-4的整数。p is an integer of 0-4.
根据本公开的实施方案，R 10选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH 2取代的下列基团：C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6烯基氧基、C 2-6炔基、C 2-6炔基氧基； According to an embodiment of the present disclosure, R 10 is selected from the following groups H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 : C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkenyloxy, C 2-6 alkynyl, C 2-6 alkynyloxy;
每个R 11相同或不同，彼此独立地选自H、卤素、C 1-6烷基、卤代C 1-6烷基； Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl;
p为0、1、2、3或4。p is 0, 1, 2, 3 or 4.
根据本公开的实施方案，R 10选自H、卤素、C 1-3烷基、卤代C 1-3烷基；p为0、1或2； According to an embodiment of the present disclosure, R 10 is selected from H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl; p is 0, 1 or 2;
每个R 11相同或不同，彼此独立地选自H、卤素、C 1-3烷基、卤代C 1-3烷基。 Each R 11 is the same or different, independently selected from H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl.
根据本公开的实施方案，R 10选自H、甲基；p为0、1或2； According to an embodiment of the present disclosure, R 10 is selected from H, methyl; p is 0, 1 or 2;
每个R 11相同或不同，彼此独立地选自F、Cl、CF 3。 Each R 11 is the same or different and independently selected from F, Cl, CF 3 .
在一种更优选的实施方案中，式Ⅱ化合物具有式Ⅱa或式Ⅱb：In a more preferred embodiment, the compound of formula II has formula IIa or formula IIb:
Figure PCTCN2022142967-appb-000007
Figure PCTCN2022142967-appb-000007
其中，R 1、R 3、R 4、R 5、R 6、R 7、R 10、R 11、A、W、m、n、p具有上文所述的定义，加粗的化学键表示化合物存在轴手性。 Among them, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , A, W, m, n, and p have the above-mentioned definitions, and the chemical bonds in bold indicate the presence of compounds Axichirality.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中W为N。In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein W is N.
在一些实施方案中，式I、式Ia或式Ib所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 2为-OR 81或-NHR 83；R 81和R 83相同或不同，彼此独立地选自C 6-8芳基-C 1-3烷基、5-6元杂芳基-C 1-3烷基、C 6-8芳基和5-6元杂芳基；其中，C 6-8芳基、5-6元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-3烷基、C 1-3烷基和C 1-3烷氧基取代；C 1-3烷基部分与O或NH相连。 In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug, wherein R 2 is -OR 81 or -NHR 83 ; R 81 and R 83 are the same or different, independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl -C 1-3 alkyl, C 6-8 aryl and 5-6 membered heteroaryl; wherein, C 6-8 aryl, 5-6 membered heteroaryl are unsubstituted or optionally replaced by 1, 2, 3 , 4 or 5 substitutions independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy; the C 1-3 alkyl part is connected to O or NH.
在一些实施方案中，式I、式Ia或式Ib所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 2为-OR 81；R 81为C 6芳基-C 1-3烷基或6元杂芳基-C 1-3烷基；其中C 6芳基或6元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-3烷基、C 1-3烷基和C 1-3烷氧基取代；C 1-3烷基部分与O相连。 In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug, wherein R 2 is -OR 81 ; R 81 is C 6 aryl-C 1-3 alkyl or 6-membered heteroaryl-C 1-3 alkyl; wherein C 6 aryl or 6-membered heteroaryl Unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy; C 1 The -3 alkyl moiety is attached to O.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中
Figure PCTCN2022142967-appb-000008
为
Figure PCTCN2022142967-appb-000009
R 5选自卤素、-OH、-C 1-3烷基、-C 1-3烷氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b，R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-3烷基和C 3-6环烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein
Figure PCTCN2022142967-appb-000008
for
Figure PCTCN2022142967-appb-000009
R is selected from halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=O), -C(O)C 1-3 alkyl, -C(O) OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) 2 NR 93a R 93b , R 91a , R 91b , R 92 , R 93a , R 93b are the same or different, are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中
Figure PCTCN2022142967-appb-000010
为
Figure PCTCN2022142967-appb-000011
R 5选自F、-OH、甲基、甲氧基、-C(O)C 1-3烷基、-C(O)OH、-C(O)NH 2、-C(O)NHCH 3、-S(O) 2CH 3、-S(O) 2CH 2CH 3和-S(O) 2-环丙烷。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein
Figure PCTCN2022142967-appb-000010
for
Figure PCTCN2022142967-appb-000011
R 5 is selected from F, -OH, methyl, methoxy, -C(O)C 1-3 alkyl, -C(O)OH, -C(O)NH 2 , -C(O)NHCH 3 , -S(O) 2CH3 , -S ( O ) 2CH2CH3 and -S (O) 2 -cyclopropane.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药不包括In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , pharmaceutically acceptable salts or their prodrugs do not include
Figure PCTCN2022142967-appb-000012
Figure PCTCN2022142967-appb-000012
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 1为卤素。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein R 1 is halogen.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 3为C 1-3烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein R 3 is C 1-3 alkyl.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 4为卤素或C 1-3烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein R 4 is halogen or C 1-3 alkyl.
在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R 6为H或卤素。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein R 6 is H or halogen.
根据本公开的实施方案，式Ⅰ化合物具有以下结构：According to an embodiment of the present disclosure, the compound of formula I has the following structure:
Figure PCTCN2022142967-appb-000013
Figure PCTCN2022142967-appb-000013
Figure PCTCN2022142967-appb-000014
Figure PCTCN2022142967-appb-000014
Figure PCTCN2022142967-appb-000015
Figure PCTCN2022142967-appb-000015
Figure PCTCN2022142967-appb-000016
Figure PCTCN2022142967-appb-000016
Figure PCTCN2022142967-appb-000017
Figure PCTCN2022142967-appb-000017
Figure PCTCN2022142967-appb-000018
Figure PCTCN2022142967-appb-000018
Figure PCTCN2022142967-appb-000019
Figure PCTCN2022142967-appb-000019
Figure PCTCN2022142967-appb-000020
Figure PCTCN2022142967-appb-000020
Figure PCTCN2022142967-appb-000021
Figure PCTCN2022142967-appb-000021
Figure PCTCN2022142967-appb-000022
Figure PCTCN2022142967-appb-000022
Figure PCTCN2022142967-appb-000023
Figure PCTCN2022142967-appb-000023
其中化合物10和63结构式中的*表示该处存在顺反结构，且*处为顺式或反式的一种。The * in the structural formulas of compounds 10 and 63 indicates that there is a cis-trans structure, and the * is either cis or trans.
根据本公开的实施方案，式I所示化合物具有以下结构：According to an embodiment of the present disclosure, the compound shown in formula I has the following structure:
Figure PCTCN2022142967-appb-000024
Figure PCTCN2022142967-appb-000024
Figure PCTCN2022142967-appb-000025
Figure PCTCN2022142967-appb-000025
其中化合物10-P1或10-P2和63-P1或63-P2结构式中的*表示该处存在顺反结构，且*处为顺 式或反式的一种。The * in the structural formulas of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates that there is a cis-trans structure, and the * is a cis or trans structure.
本公开还提供一种式Ⅰ化合物的制备方法，包括：The present disclosure also provides a preparation method of the compound of formula I, comprising:
方案一：化合物a1与化合物a2发生偶联反应得到式Ⅰ化合物。Scheme 1: compound a1 and compound a2 undergo a coupling reaction to obtain a compound of formula I.
反应式如下：The reaction formula is as follows:
Figure PCTCN2022142967-appb-000026
Figure PCTCN2022142967-appb-000026
其中，Y为Cl或Br；W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n和环A彼此独立地具有上文所述定义。 Wherein, Y is Cl or Br; W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A are independently defined above.
方案二：当W为N，R 7为H时，化合物b1与化合物b2反应得到式I化合物； Scheme 2: When W is N and R 7 is H, compound b1 reacts with compound b2 to obtain a compound of formula I;
反应式如下：The reaction formula is as follows:
Figure PCTCN2022142967-appb-000027
Figure PCTCN2022142967-appb-000027
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n和环A彼此独立地具有上文所述的定义； wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A independently of each other have the definitions stated above;
根据本公开的实施方案，所述反应在无机碱的存在下进行；所述无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化钾中的一种。According to an embodiment of the present disclosure, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
根据本公开的实施方案，当R 5为OH时，化合物b2中的OH可以被硅保护基保护，所述硅保护基可以为叔丁基二苯基硅基；所述硅保护基在所述反应中会脱除，得到脱保护的OH。 According to an embodiment of the present disclosure, when R 5 is OH, the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group is in the It will be removed during the reaction to obtain the deprotected OH.
本公开还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种在制备药物中的用途。The present disclosure also provides at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound Use in the preparation of medicines.
根据本公开的实施方案，所述药物可以为治疗和/或预防与p38激酶抑制剂有关的疾病的药物，例如可以为MK2抑制剂或p38 MAPK/MK2通路调节剂。According to an embodiment of the present disclosure, the drug may be a drug for treating and/or preventing diseases related to p38 kinase inhibitors, for example, it may be an MK2 inhibitor or a p38 MAPK/MK2 pathway modulator.
本公开还提供一种药物组合物，其包含治疗有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少 一种。The present disclosure also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable At least one of the salts or prodrug compounds thereof.
根据本公开的实施方案，所述药物组合物还包括至少一种药学上可接受的载体。According to an embodiment of the present disclosure, the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.
根据本公开的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to embodiments of the present disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents.
所述的载体包括崩解剂，例如甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、聚乙烯基吡咯烷酮、羧丙基纤维素、淀粉等；润滑剂，包括硬脂酸钙、硬脂酸锌、硬脂酸镁、硬脂酰醇富马酸钠等；粘合剂，包括明胶、聚乙二醇、糖、树胶、淀粉、羟丙基纤维素等；稀释剂，包括甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇和淀粉；表面活性剂，包括聚山梨酯80、十二烷基硫酸钠、滑石粉和二氧化硅。可通过使用本领域中已知的方法配制本公开组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。The carrier includes a disintegrant, such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, carboxypropylcellulose, starch etc.; lubricants, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxyl Propyl cellulose, etc.; diluents, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants, including polysorbate 80, sodium lauryl sulfate, talc and silica. Compositions of the present disclosure can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
本公开还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物，在治疗和/或预防与p38激酶抑制剂介导有关的疾病中的用途。The present disclosure also provides the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound, in the treatment and/or Or the use in preventing diseases mediated by p38 kinase inhibitors.
本公开还提供治疗和/或预防与p38激酶抑制剂介导有关的疾病的方法，包括给予患者治疗或预防有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种。The present disclosure also provides a method for treating and/or preventing diseases mediated by p38 kinase inhibitors, comprising administering to a patient an effective dose of a compound represented by formula I, its racemate, stereoisomer, tautomer At least one of isomers, isotope labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof.
根据本公开的实施方案，所述疾病可以为与p38 MAPK/MK2通路相关的疾病，例如可以为自体免疫疾病和炎症性疾病(如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、系统性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病。According to an embodiment of the present disclosure, the disease may be a disease related to the p38 MAPK/MK2 pathway, such as an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related disease.
有益效果Beneficial effect
本公开的化合物对p38 MAPK/MK2通路具有良好的调节作用，并具有良好的选择性。另外，本公开的化合物药代动力学等性能良好。还有，本公开的化合物可用于治疗与p38激酶抑制剂介导有关的疾病，以及制备用于此类病症或疾病的药物。The disclosed compound has a good regulating effect on the p38 MAPK/MK2 pathway and has good selectivity. In addition, the compounds of the present disclosure have good properties such as pharmacokinetics. Also, the disclosed compounds are useful in the treatment of diseases associated with the mediation of p38 kinase inhibitors, and in the preparation of medicaments for such conditions or diseases.
术语定义与说明Definition and Explanation of Terms
除非另有说明，本公开说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本公开说明书和/或权利要求书记载的范围内。Unless otherwise stated, the definitions of groups and terms described in the specification and claims of this disclosure include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should be understood as falling within the scope of the present disclosure and/or claims.
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-20”相当于记载了数值范围“1-20”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。此外，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9 和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。Unless otherwise stated, the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording every integer value in the numerical range "1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20. Additionally, when certain numerical ranges are defined as "numbers," it should be understood that both endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
应当理解，本文在描述一个、两个或更多个中，“更多个”应当是指大于2，例如大于等于3的整数，例如3、4、5、6、7、8、9或10。It should be understood that in describing one, two or more herein, "more" shall refer to an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .
术语“卤素”表示氟、氯、溴和碘。The term "halogen" denotes fluorine, chlorine, bromine and iodine.
术语“C 1-10烷基”应理解为表示具有1～10个碳原子的直链或支链饱和一价烃基。例如，表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基，“C 1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。 The term "C 1-10 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, means straight chain and branched chain alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-6 alkyl" means having 1, 2, 3 , straight-chain and branched-chain alkyl groups of 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如本文中所述。优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷氧基(C 1-12烷氧基)，更优选含有1至6个碳原子的烷氧基(C 1-6烷氧基)。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是取代的或未取代的。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Alkoxy groups containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy) are preferred, more Alkoxy having 1 to 6 carbon atoms (C 1-6 alkoxy) is preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.
术语“C 2-10烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，更优选“C 2-8烯基”。“C 2-10烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7或8个碳原子，例如，具有2、3、4、5或6个碳原子(即，C 2-6烯基)，具有2或3个碳原子(即，C 2-3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。 The term "C 2-10 alkenyl" is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 alkenyl". "C 2-10 alkenyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, For example, having 2, 3, 4, 5 or 6 carbon atoms (ie, C2-6 alkenyl), having 2 or 3 carbon atoms (ie, C2-3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl Base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl , 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, ( Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methyl But-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2- Alkenyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E )-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methyl 1-butylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
术语“C 2-10炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子，例如，具有2、3、4、5、6、7或8个碳原子(即，“C 2-8炔基”)，具有2、3、4、5或6个碳原子(即，“C 2-6炔基”)，具有2或3个碳原子(“C 2-3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1- 乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。 The term "C 2-10 alkynyl" is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g., having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C alkynyl ") having 2, 3, 4, 5 or 6 carbon atoms (ie, "C 2-6 alkynyl"), having 2 or 3 carbon atoms ("C 2-3 alkynyl"). The alkynyl group is for example ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, Pent-3-ynyl, Pent-4-ynyl, Hex-1-ynyl, Hex-2-ynyl, Hex-3-ynyl, Hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut- 2-alkynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbutanyl -3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
术语“C 3-20环烷基”应理解为表示饱和的一价单环、二环(如并环、螺环、桥环)烃环或三环烷烃，其具有3～20个碳原子，优选“C 3-12环烷基”，更优选优选“C 3-8环烷基”。术语“C 3-12环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C 3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。 The term "C 3-20 cycloalkyl" should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as double ring, spiro ring, bridged ring) hydrocarbon ring or tricycloalkane, which has 3 to 20 carbon atoms, Preferable is "C 3-12 cycloalkyl", more preferably "C 3-8 cycloalkyl". The term "C 3-12 cycloalkyl" should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane, which has 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms. The C 3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2. 1] Heptenyl, 6,6-Dimethylbicyclo[3.1.1]heptyl, 2,6,6-Trimethylbicyclo[3.1.1]heptyl, Bicyclo[2.2.2]octyl 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.
术语“3-20元杂环基”是指饱和的或不饱和的非芳族的环或环系，例如，其是4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-、12-、13-或14-元的二环(如并环、螺环、桥环)或者三环环系，并且含有至少一个，例如1、2、3、4、5个或更多个选自O、S和N的杂原子，其中N和S还可以任选被氧化成各种氧化状态，以形成氮氧化物、-S(O)-或-S(O) 2-的状态。优选地，所述杂环基可以选自“3-12元杂环基”。术语“3-12元杂环基”意指饱和的或不饱和的非芳族的环或环系，并且含有至少一个选自O、S和N的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地，所述杂环基可以包括但不限于：3元环，如环氧乙烷基；4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、1,2,3,5-四氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。所述3-12元杂环基与其它基团相连构成本公开的化合物时，可以为3-12元杂环基上的碳原子与其它基团相连，也可以为3-12元杂环基环上杂环原子与其它基团相连。例如当3-12元杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与其它基团相连。或当3-12元杂环基选自哌啶基时，可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。 The term "3-20 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, it is a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic (such as fused, spiro, bridged) or tricyclic ring systems, and contain at least one, for example 1, 2 , 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)- Or the state of -S(O) 2 -. Preferably, the heterocyclic group may be selected from "3-12 membered heterocyclic group". The term "3-12 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl group can be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl may include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to: 3-membered rings, such as oxiranyl; 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuran base, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiane group, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclic group can be bicyclic, such as but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrole And[1,2-a]pyrazin-2(1H)-yl ring. A heterocyclyl group may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzofused, such as but It is not limited to dihydroisoquinolinyl. When the 3-12-membered heterocyclic group is connected with other groups to form the compound of the present disclosure, it can be that the carbon atom on the 3-12-membered heterocyclic group is connected with other groups, or it can be a 3-12-membered heterocyclic group The ring heteroatoms are connected to other groups. For example, when the 3- to 12-membered heterocyclic group is selected from piperazinyl, the nitrogen atom on piperazinyl may be connected to other groups. Or when the 3-12 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at its para-position may be connected to other groups.
术语“螺环”是指两个环共用1个成环原子的环系。The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.
术语“并环”是指两个环共用2个成环原子的环系。The term "merged ring" refers to a ring system in which two rings share 2 ring-forming atoms.
术语“桥环”是指两个环共用3个以上成环原子的环系。The term "bridged ring" refers to a ring system in which two rings share more than 3 ring-forming atoms.
术语“C 6-14芳基-C 1-10烷基”指被C 6-14芳基取代的C 1-10烷基，连接位点在C 1-10烷基。 The term "C 6-14 aryl-C 1-10 alkyl" refers to a C 1-10 alkyl substituted by a C 6-14 aryl, and the connection point is at the C 1-10 alkyl.
术语“5-14元杂芳基-C 1-10烷基”指被5-14元杂芳基取代的C 1-10烷基，连接位点在C 1-10烷基。 The term "5-14 membered heteroaryl-C 1-10 alkyl" refers to a C 1-10 alkyl group substituted by a 5-14 membered heteroaryl group, and the attachment point is at the C 1-10 alkyl group.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如本文中所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described herein, wherein the ring bonded to the parent structure is an aryl ring, which is not limiting Examples include:
Figure PCTCN2022142967-appb-000028
Figure PCTCN2022142967-appb-000029
芳基可以是取代的或未取代的。
Figure PCTCN2022142967-appb-000028
Figure PCTCN2022142967-appb-000029
Aryl groups can be substituted or unsubstituted.
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如本文中所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl rings include heteroaryl fused to aryl, heterocyclyl or cycloalkyl rings as described herein, where the ring attached to the parent structure is a heteroaryl ring, without limitation Sexual examples include:
Figure PCTCN2022142967-appb-000030
Figure PCTCN2022142967-appb-000031
杂芳基可以是取代的或未取代的。
Figure PCTCN2022142967-appb-000030
Figure PCTCN2022142967-appb-000031
Heteroaryl groups can be substituted or unsubstituted.
本文中的术语“烷基”、“烷氧基”、“环烷基”、“杂环基”、“芳基”和“杂芳基”等可以是取代的或未取代的；当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基。The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" etc. herein may be substituted or unsubstituted; when substituted , which may be substituted at any available point of attachment, said substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano One or more of the same or different substituents among , amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
本公开中所述化合物的药学上可接受的盐可为无机盐或有机盐，如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。The pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic salts or organic salts, and if these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form bases. Addition salts; these compounds can also form internal salts if they contain both an acidic center (eg carboxyl group) and a basic center (eg amino group).
本公开化合物可以存在特定的几何或立体异构体形式。例如顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，外消旋混合物和其他混合物，以及对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. For example cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomers, (L)-isomers, racemic and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
本公开所述化合物的化学结构中，键
Figure PCTCN2022142967-appb-000032
表示未指定构型，
Figure PCTCN2022142967-appb-000033
表示绝对构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022142967-appb-000034
可以为
Figure PCTCN2022142967-appb-000035
或者同时包含
Figure PCTCN2022142967-appb-000036
两种构型，
Figure PCTCN2022142967-appb-000037
表示存在轴手性。 In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022142967-appb-000032
means unspecified configuration,
Figure PCTCN2022142967-appb-000033
Indicates the absolute configuration, i.e. if chiral isomers exist in the chemical structure, the bond
Figure PCTCN2022142967-appb-000034
can be
Figure PCTCN2022142967-appb-000035
or both
Figure PCTCN2022142967-appb-000036
two configurations,
Figure PCTCN2022142967-appb-000037
Indicates the presence of axial chirality.
键
Figure PCTCN2022142967-appb-000038
表示未指定构型，包括顺式(E)或反式(Z)构型。 key
Figure PCTCN2022142967-appb-000038
Denotes unassigned configuration, including cis (E) or trans (Z) configuration.
另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。“互变异构体”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇异构化、亚胺-烯胺异构化和内酰胺-内酰亚胺异构化。本公开中的所有化合物的所有的互变异构形式均在本公开的范围内。用单一方式命名的化合物的名称不排除任何互变异构体。In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam imide isomerization. All tautomeric forms of all compounds in the disclosure are within the scope of the disclosure. The names of compounds named in a single way do not exclude any tautomers.
本公开还包括一些与本文中记载的结构相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。 The present disclosure also includes some isotopically labeled compounds of the disclosure having the same structure as described herein, but wherein one or more atoms are replaced by an atom with an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
本公开的“治疗有效量”是指研究人员、兽医、医师或其它临床医师等在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。针对药物或药理学活性剂而言，“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The "therapeutically effective amount" in the present disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians look for in tissues, systems, animals, individuals or humans to cause biological or medical responses, including One or more of the following: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition. For a drug or a pharmacologically active agent, "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
本公开“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。"Pharmaceutically acceptable" in the present disclosure means that these compounds, materials, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
本公开的“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。"Patient" in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably people.
具体实施方式Detailed ways
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开 上述内容所实现的技术均涵盖在本公开旨在保护的范围内。The technical solution of the present disclosure will be further described in detail in conjunction with specific embodiments below. It should be understood that the following examples are only for illustrating and explaining the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above contents of the present disclosure are covered within the scope of protection intended by the present disclosure.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker ASCEND TM-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use Bruker ASCEND ™ -400 nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is Tetramethylsilane (TMS).
MS的测定用Agilent 6110，Agilent 1100，Agilent 6120，AgilentG6125B液相质谱联用仪。Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid phase mass spectrometer were used for the determination of MS.
HPLC的测定使用岛津HPLC-2010C高效液相色谱仪(XBRIDGE 2.1*50mm,3.5um色谱柱)。The determination of HPLC uses Shimadzu HPLC-2010C high performance liquid chromatography (XBRIDGE 2.1*50mm, 3.5um chromatographic column).
手性HPLC分析测定使用THARSFC X5。Chiral HPLC analysis was performed using THARSFC X5.
薄层层析硅胶板使用烟台青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm. .
柱层析一般使用青岛海洋硅胶200～300目硅胶为载体。Column chromatography generally uses Qingdao Ocean Silica gel 200-300 mesh silica gel as the carrier.
高效液相制备使用Waters 2767、Waters 2545、和创新恒通LC3000制备型色谱仪。High-performance liquid phase preparation uses Waters 2767, Waters 2545, and innovative Hengtong LC3000 preparative chromatography.
手性制备柱层析使用，Shimadzu LC-20AP、THARSFC PREP 80。For chiral preparative column chromatography, Shimadzu LC-20AP and THARSFC PREP 80 were used.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
加压氢化反应使用北京佳维科创科技GCD-500G型氢气发生器。The pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
微波反应使用Biotage initiator+型微波反应器。The microwave reaction uses a Biotage initiator+ type microwave reactor.
实验例中如无特殊说明，反应均在氩气氛或者氮气氛下进行。In the experimental examples, unless otherwise specified, the reactions were all carried out under an argon or nitrogen atmosphere.
氩气氛或者氮气氛是指反应瓶连接一个约1升容积的氩气或者氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.
氢气氛是指反应瓶连接一个约1升容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
实验例中如无特殊说明，反应温度均为室温，温度范围是20℃-30℃。In the experimental example, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20°C-30°C.
反应路线中化学结构式中的星号(*)表示特定环结构位置存在顺反异构(本领域技术人员能够理解取代环烷烃结构中存在顺反异构现象)，示例性顺反异构现象如下：The asterisk (*) in the chemical structural formula in the reaction scheme indicates that there is cis-trans isomerism at a specific ring structure position (those skilled in the art can understand the existence of cis-trans isomerism in the substituted cycloalkane structure), and the exemplary cis-trans isomerism is as follows :
Figure PCTCN2022142967-appb-000039
*处为顺式或反式中的一种。
Figure PCTCN2022142967-appb-000039
* is one of cis or trans.
本领域技术人员应当理解，拆分的手性化合物可以通过在手性色谱柱中的保留时间的先后进行区分，因此，针对保留时间先后拆分出来的手性化合物以编号后缀P1、P2对应区分。即后缀P1对应先拆分出来的手性结构，后缀P2对应后拆分出来的手性结构。反应式中若有列出化合物的绝对构型，则其不意味着与编号后缀P1、P2的化合物一一对应，仅是示意绝对构型的两种存在形式。编号后缀P1、P2的化合物的绝对构型以特定保留时间客观对应的绝对构型为准。Those skilled in the art should understand that the resolved chiral compounds can be distinguished by the sequence of retention time in the chiral chromatographic column. Therefore, the chiral compounds resolved successively according to the retention time are distinguished by the corresponding numbering suffixes P1 and P2 . That is, the suffix P1 corresponds to the chiral structure that was resolved first, and the suffix P2 corresponds to the chiral structure that was resolved later. If there is an absolute configuration of the compound listed in the reaction formula, it does not mean a one-to-one correspondence with the compounds with the numbering suffixes P1 and P2, but only indicates the two forms of absolute configuration. The absolute configuration of the compounds with the suffixes P1 and P2 is based on the absolute configuration objectively corresponding to the specific retention time.
中间体化合物A-5的合成Synthesis of intermediate compound A-5
Figure PCTCN2022142967-appb-000040
Figure PCTCN2022142967-appb-000040
第一步：化合物A-5b的合成The first step: the synthesis of compound A-5b
将氯化亚砜(22.43g,188.5mmol)缓慢滴加到化合物A-5a(20g，125mol)的乙醇(60mL)溶液中，反应混合物在60℃下进行3小时。反应结束后，反应液直接减压浓缩除去溶剂后得到化合物A-5b(20g)粗品，该粗品直接用于下一步反应。MS m/z(ESI):187.9[M+1] +。 Thionyl chloride (22.43 g, 188.5 mmol) was slowly added dropwise to a solution of compound A-5a (20 g, 125 mol) in ethanol (60 mL), and the reaction mixture was carried out at 60° C. for 3 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude product of compound A-5b (20 g), which was directly used for the next reaction. MS m/z (ESI): 187.9 [M+1] + .
第二步：化合物A-5c的合成The second step: the synthesis of compound A-5c
将化合物A-5b(16g，85.6mmol)溶于乙醇(60mL)中，再将硼氢化钠(6.48g，171.2mmol)在0℃分批缓慢加入溶液中。将所得混合物在室温下搅拌3小时。反应结束后，减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/5)纯化得到化合物A-5c(16g，收率：73.5％)。MS m/z(ESI):146.1[M+1] +。 Compound A-5b (16 g, 85.6 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (6.48 g, 171.2 mmol) was slowly added to the solution in batches at 0°C. The resulting mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to obtain compound A-5c (16 g, yield: 73.5%). MS m/z (ESI): 146.1 [M+1] + .
第三步:化合物A-5的合成The third step: the synthesis of compound A-5
在室温下，将氯化亚砜(1.77g，0.015mol)缓慢加入到化合物A-5c(1.8g，0.0124mol)和N,N-二甲基甲酰胺(5滴)的二氯甲烷(50mL)溶液中，反应混合物在室温下进行1小时。反应结束后，向反应液中加入氯化铵溶液(100mL,4M)调节pH值至中性，然后加入水(20mL)并用二氯甲烷(10mL×3)萃取，合并的有机相用无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物经柱层析(石油醚/乙酸乙酯＝1/0～5/1)纯化得到化合物A-5(1.8g，收率：84.68％)。 1H NMR(400MHz,CDCl 3)δ8.35(d,J＝2.4Hz,1H),7.26(ddd,J＝9.1,8.0,2.6Hz,1H),4.72(d,J＝2.1Hz,2H). Thionyl chloride (1.77 g, 0.015 mol) was slowly added to compound A-5c (1.8 g, 0.0124 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL ) solution, the reaction mixture was carried out at room temperature for 1 hour. After the reaction was over, ammonium chloride solution (100mL, 4M) was added to the reaction solution to adjust the pH to neutral, then water (20mL) was added and extracted with dichloromethane (10mL×3), and the combined organic phase was washed with anhydrous sulfuric acid Sodium was dried and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=1/0～5/1) to obtain compound A-5 (1.8g, yield: 84.68 %). 1 H NMR (400MHz, CDCl 3 ) δ8.35 (d, J = 2.4Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6Hz, 1H), 4.72 (d, J = 2.1Hz, 2H) .
中间体化合物A的合成：Synthesis of Intermediate Compound A:
Figure PCTCN2022142967-appb-000041
Figure PCTCN2022142967-appb-000041
第一步：化合物A-2的合成The first step: the synthesis of compound A-2
在-78℃，将双(三甲基硅基)胺基锂的四氢呋喃溶液(141mL,141mmol)慢慢加入到化合物A-1(20g,141mmol)的四氢呋喃(500mL)溶液中，反应液在-78℃搅拌1小时后再慢慢滴加乙酰氯(6.6g,844mmol)，得到的混合物在-78℃继续搅拌1小时。反应结束后，反 应液缓慢倒入饱和氯化铵水溶液中(500mL),用乙酸乙酯萃取(300mL×3)。合并的有机相用饱和食盐水洗涤(300mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物用柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物A-2(6.6g，收率：30％)。MS m/z(ESI):185.1[M+1] +。 At -78°C, a tetrahydrofuran solution (141mL, 141mmol) of bis(trimethylsilyl)amide lithium was slowly added to a solution of compound A-1 (20g, 141mmol) in tetrahydrofuran (500mL), and the reaction solution was in- After stirring at 78°C for 1 hour, acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise, and the resulting mixture was stirred at -78°C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with saturated brine (300mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain Compound A-2 (6.6 g, yield: 30%). MS m/z (ESI): 185.1 [M+1] + .
第二步：化合物A-4的合成The second step: the synthesis of compound A-4
将化合物A-2(8.98g,48.7mmol)和化合物A-3(4.63g,32.5mmol)的1,4-二氧六环(150mL)溶液加热至90℃并搅拌3.5小时。反应液自然冷却至室温后，加入甲磺酸(3.12g,32.5mmol)，然后反应加热至50℃继续搅拌3小时。反应结束后，反应混合液自然冷却到室温并过滤，滤饼收集后干燥得到化合物A-4(5.6g，收率：69％)。MS m/z(ESI):251.0[M+1] +。 A solution of compound A-2 (8.98 g, 48.7 mmol) and compound A-3 (4.63 g, 32.5 mmol) in 1,4-dioxane (150 mL) was heated to 90° C. and stirred for 3.5 hours. After the reaction solution was naturally cooled to room temperature, methanesulfonic acid (3.12 g, 32.5 mmol) was added, and then the reaction was heated to 50° C. and stirred for 3 hours. After the reaction, the reaction mixture was naturally cooled to room temperature and filtered, and the filter cake was collected and dried to obtain compound A-4 (5.6 g, yield: 69%). MS m/z (ESI): 251.0 [M+1] + .
第三步：化合物A-6的合成The third step: the synthesis of compound A-6
将化合物A-5(4.01g，24.6mmol)加到化合物A-4(5.6g，22.3mmol)，碳酸钾(7.69g，55.7mmol)和18-冠-6(1.18g，4.4mmol)的N,N-二甲基甲酰胺(80mL)混合液中，反应在室温搅拌16小时。反应结束后，反应液倒入水中(100mL),用乙酸乙酯萃取(80mL×3)。合并的有机相用食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物A-6(8.4g，收率80％)粗品，该粗品直接用于下一步反应。MS m/z(ESI):378.0[M+1] +。 Compound A-5 (4.01g, 24.6mmol) was added to the N of compound A-4 (5.6g, 22.3mmol), potassium carbonate (7.69g, 55.7mmol) and 18-crown-6 (1.18g, 4.4mmol). , N-dimethylformamide (80 mL) mixture, the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was poured into water (100 mL), and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound A-6 (8.4 g, yield 80%), which was directly used in the next step reaction. MS m/z (ESI): 378.0 [M+1] + .
第四步：化合物A-8的合成The fourth step: the synthesis of compound A-8
将双三苯基膦二氯化钯(1.56g,2.22mmol)加到化合物A-6(8.4g,22.2mmol)和三丁基(1-乙氧基乙烯)锡(化合物A-7)(10.21g,24.2mmol)的1,4-二氧六环(100mL)溶液中，反应液加热到130℃并搅拌4小时。然后反应液过滤，滤液直接减压浓缩，残余物中加入四氢呋喃(100mL)溶解，再滴入5mL浓盐酸并搅拌1小时。反应结束后，反应液减压浓缩，所得残余物经柱层析(乙酸乙酯)纯化得到化合物A-8(5g，收率：60％)。MS m/z(ESI):386.0[M+1] +。 Bistriphenylphosphine palladium dichloride (1.56 g, 2.22 mmol) was added to compound A-6 (8.4 g, 22.2 mmol) and tributyl(1-ethoxyethylene) tin (compound A-7) ( 10.21g, 24.2mmol) in 1,4-dioxane (100mL) solution, the reaction solution was heated to 130°C and stirred for 4 hours. Then the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure. The residue was dissolved by adding tetrahydrofuran (100 mL), and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction, the reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate) to obtain compound A-8 (5 g, yield: 60%). MS m/z (ESI): 386.0 [M+1] + .
第五步：化合物A-9的合成The fifth step: the synthesis of compound A-9
将醋酸(2mL)滴加到化合物A-8(5g，13mmol)和N-氯代丁二酰亚胺(1.9g，14.3mmol)的异丙醇(100mL)溶液中，反应在60℃条件下搅拌16小时。反应结束后，反应液减压浓缩，所得残余物用柱层析(乙酸乙酯)纯化得到化合物A-9(3.6g，收率：70％)。MS m/z(ESI):420.0[M+1] +。 Acetic acid (2mL) was added dropwise to a solution of compound A-8 (5g, 13mmol) and N-chlorosuccinimide (1.9g, 14.3mmol) in isopropanol (100mL), reacted at 60°C Stir for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate) to obtain compound A-9 (3.6 g, yield: 70%). MS m/z (ESI): 420.0 [M+1] + .
第六步：化合物A的合成Step 6: Synthesis of Compound A
将N，N-二甲基甲酰胺二甲基缩醛(0.85g,7.2mmol)加入到化合物A-9(1.3g,3.1mmol)的N，N-二甲基甲酰胺(15mL)溶液中，反应混合物在100℃条件下搅拌3小时。反应结束后，反应混合液倒入水中(50mL),用乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物用柱层析(二氯甲烷/甲醇＝50/1)纯化得到化合物A(900mg，收率：78％)。MS m/z(ESI):474.9[M+H] +。 N,N-Dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to a solution of compound A-9 (1.3g, 3.1mmol) in N,N-dimethylformamide (15mL) , and the reaction mixture was stirred at 100° C. for 3 hours. After the reaction, the reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol=50/1) to obtain the compound A (900 mg, yield: 78%). MS m/z (ESI): 474.9 [M+H] + .
中间体化合物B的合成：Synthesis of Intermediate Compound B:
Figure PCTCN2022142967-appb-000042
Figure PCTCN2022142967-appb-000042
第一步：化合物B-2的合成The first step: the synthesis of compound B-2
将叠氮磷酸二苯酯(23.5g，0.085mol)加入到化合物B-1(10g，0.057mol)和三乙胺(17.3g，0.17mol)的叔丁醇/甲苯(50mL/50mL)的混合溶液中，反应混合物在110℃进行16小时。反应结束后，将反应液倒入水中，用二氯甲烷(200mL×3)萃取。合并的有机相用水(30mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物B-2(3.6g，收率：25％)。MS m/z(ESI):247.0[M+1] +。 Diphenylphosphoryl azide (23.5 g, 0.085 mol) was added to a mixture of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol/toluene (50 mL/50 mL) In solution, the reaction mixture was carried out at 110°C for 16 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (200 mL×3). The combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound B -2 (3.6 g, yield: 25%). MS m/z (ESI): 247.0 [M+1] + .
第二步：化合物B-3的合成The second step: the synthesis of compound B-3
将化合物B-2(3.6g，14.5mol)加入到三氟乙酸/二氯甲烷(15mL/30mL)的混合溶液中，反应混合物在室温下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到化合物B-3粗品(3.1g)。MS m/z(ESI):147.0[M+1] +。 Compound B-2 (3.6 g, 14.5 mol) was added to a mixed solution of trifluoroacetic acid/dichloromethane (15 mL/30 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain a crude compound B-3 (3.1 g). MS m/z (ESI): 147.0 [M+1] + .
第三步：化合物B-4的合成The third step: the synthesis of compound B-4
将硫酸银(6.61g，0.02mol)和碘(5.38g，0.02mol)加入到化合物B-3(3.1g，0.02mol)的乙醇(50mL)溶液中，反应在50℃条件下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，得到的残余物通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物B-4(4.9g，收率：65％)。MS m/z(ESI):272.7[M+1] +。 Silver sulfate (6.61 g, 0.02 mol) and iodine (5.38 g, 0.02 mol) were added to a solution of compound B-3 (3.1 g, 0.02 mol) in ethanol (50 mL), and the reaction was stirred at 50° C. for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound B-4 (4.9 g, yield: 65%). MS m/z (ESI): 272.7 [M+1] + .
第四步：化合物B-6的合成The fourth step: the synthesis of compound B-6
在氮气保护下，将甲基硼酸(530mg，8.8mmol)，碳酸铯(8.96g，27.5mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(450mg，0.55mmol)依次加入到化合物B-4(1.5g，5.5mmol)的1，4-二氧六环(30mL)溶液中，反应混合物在100℃进行1.5小时。反应结束后，向反应液中加入碳酸氢钠水溶液进行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水洗一次，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(石油醚/乙酸乙酯＝2/3)纯化得到化合物B-6(0.43g，收率：48％)。MS m/z(ESI):161.0 [M+1] +。 Under nitrogen protection, methylboronic acid (530mg, 8.8mmol), cesium carbonate (8.96g, 27.5mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (450mg , 0.55mmol) were successively added to a solution of compound B-4 (1.5g, 5.5mmol) in 1,4-dioxane (30mL), and the reaction mixture was carried out at 100°C for 1.5 hours. After the reaction, add aqueous sodium bicarbonate solution to the reaction solution for dilution, extract with ethyl acetate (50mL×3), wash the combined organic phase once with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure The solvent was removed, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/3) to obtain compound B-6 (0.43 g, yield: 48%). MS m/z (ESI): 161.0 [M+1] + .
第五步：化合物B-7的合成The fifth step: the synthesis of compound B-7
将化合物B-6(1.2g，6.88mmol)加入到化合物A-5(850mg，5.29mmol)的无水1，4-二氧六环(8mL)溶液中，反应混合物加热到110℃并在该温度下搅拌1小时。反应液自然降温至50℃后，加入甲基磺酸(285mg，2.96mmol)，然后反应在50℃继续进行1小时。反应结束后，向反应液中加入水(50mL)进行稀释，用乙酸乙酯萃取(100mL×3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓缩除去溶剂，所得残余物通过硅胶柱层析(二氯甲烷)纯化得到化合物B-7(530mg，收率：66％)。MS m/z(ESI):269.0[M+1] +。 Compound B-6 (1.2g, 6.88mmol) was added to compound A-5 (850mg, 5.29mmol) in anhydrous 1,4-dioxane (8mL) solution, the reaction mixture was heated to 110°C and the Stir at temperature for 1 hour. After the reaction solution was naturally cooled to 50°C, methanesulfonic acid (285mg, 2.96mmol) was added, and the reaction was continued at 50°C for 1 hour. After the reaction, water (50 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain compound B-7 (530 mg, harvested rate: 66%). MS m/z (ESI): 269.0 [M+1] + .
第六步：化合物B-8的合成Step 6: Synthesis of Compound B-8
将碳酸钾(1.14g，8.28mmol)，18-冠-6(175mg，0.66mmol)加入到化合物A-5(702mg，4.30mmol)和化合物B-7(890mg，3.31mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物加热到40℃并在该温度下搅拌16小时。反应结束后，反应液冷却至室温，加入水(50mL)进行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓缩得到化合物B-8(1.5g，纯度：84％，收率：96％)粗品，该粗品直接用于下一步反应。MS m/z(ESI):395.8[M+1] +。 Potassium carbonate (1.14g, 8.28mmol), 18-crown-6 (175mg, 0.66mmol) was added to the N,N- In dimethylformamide (15 mL), the reaction mixture was heated to 40° C. and stirred at this temperature for 16 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude compound B-8 (1.5 g, purity: 84%, yield: 96%), which was directly used in the next reaction. MS m/z (ESI): 395.8 [M+1] + .
第七步:化合物B-9的合成The seventh step: the synthesis of compound B-9
将化合物A-7(2.01g，5.55mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(257mg，0.37mmol)加入到化合物B-8(1.45g，3.70mmol)的1，4-二氧六环(20mL)溶液中，反应混合物在130℃搅拌1.5小时。反应结束后，反应液直接减压浓缩得到化合物B-9(3.9g)粗品，该粗品直接用于下一步。MS m/z(ESI):431.9[M+1] +。 Compound A-7 (2.01g, 5.55mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257mg, 0.37mmol) was added to compound B-8 (1.45g , 3.70 mmol) in 1,4-dioxane (20 mL), the reaction mixture was stirred at 130° C. for 1.5 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product of compound B-9 (3.9 g), which was directly used in the next step. MS m/z (ESI): 431.9 [M+1] + .
第八步:化合物B-10的合成The eighth step: the synthesis of compound B-10
将化合物B-9(1.45g，3.40mmol)加入到四氢呋喃(15mL)和浓盐酸(0.5mL)溶液中，反应混合物在室温搅拌1小时。反应结束后，将反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝3/2)纯化得到B-10(910mg，收率：66％)。MS m/z(ESI):403.9[M+1] +。 Compound B-9 (1.45 g, 3.40 mmol) was added to a solution of tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/2) to obtain B-10 (910 mg, yield: 66%). MS m/z (ESI): 403.9 [M+1] + .
第九步：化合物B-11的合成Step 9: Synthesis of compound B-11
将N-氯代丁二酰亚胺(330mg，2.48mmol)和冰醋酸(0.2mL)依次加入到化合物B-10(910mg，2.25mmol)的异丙醇(12mL)溶液中，反应混合物在60℃搅拌3小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(乙酸乙酯)纯化得到化合物B-11(1.13g)。MS m/z(ESI):437.8[M+1] +。 N-chlorosuccinimide (330mg, 2.48mmol) and glacial acetic acid (0.2mL) were added successively to a solution of compound B-10 (910mg, 2.25mmol) in isopropanol (12mL), and the reaction mixture was heated at 60 °C and stirred for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound B-11 (1.13 g). MS m/z (ESI): 437.8 [M+1] + .
第十步：化合物B的合成Step 10: Synthesis of Compound B
将N,N-二甲基甲酰胺二甲基缩醛(600mg，5.0mmol)加入到化合物B-11(1.08g，2.5mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物在100℃条件下搅拌3小时。反应结束后，反应液自然冷却至室温，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，得到的残余物 通过硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物B(900mg，收率：72％)。MS m/z(ESI):492.7[M+1] +。 N,N-dimethylformamide dimethyl acetal (600mg, 5.0mmol) was added to a solution of compound B-11 (1.08g, 2.5mmol) in N,N-dimethylformamide (15mL), The reaction mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the compound B (900 mg, yield: 72%). MS m/z (ESI): 492.7 [M+1] + .
实施例1化合物1的合成The synthesis of embodiment 1 compound 1
Figure PCTCN2022142967-appb-000043
Figure PCTCN2022142967-appb-000043
第一步：化合物1-2的合成The first step: the synthesis of compound 1-2
将化合物A(200mg，0.42mmol)加入到化合物1-1(191.5mg，0.84mmol)和碳酸钾(232.9mg，1.684mmol)的N,N-二甲基甲酰胺(2mL)溶液中。反应混合物加热至60℃并在该温度下搅拌18小时。反应结束后，将反应液自然冷却至室温，加入乙酸乙酯(40mL)稀释，然后用饱和食盐水(20mL×5)洗涤。有机相用无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析(甲醇/二氯甲烷＝1/10)纯化得到化合物1-2(200mg，收率：71％)。MS m/z(ESI)：661.0[M+23] +。 Compound A (200 mg, 0.42 mmol) was added to a solution of compound 1-1 (191.5 mg, 0.84 mmol) and potassium carbonate (232.9 mg, 1.684 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 60°C and stirred at this temperature for 18 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with saturated brine (20 mL×5). The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (methanol/dichloromethane=1/10) to obtain compound 1-2 (200 mg, yield: 71%) . MS m/z (ESI): 661.0 [M+23] + .
第二步：化合物1-3的合成The second step: the synthesis of compound 1-3
将化合物1-2(280mg)加入到三氟乙酸/二氯甲烷(3mL/6mL)混合溶液中，反应混合物在室温下搅拌16小时。反应结束后，将反应混合物减压浓缩除去溶剂，所得残余物经柱层析(甲醇/二氯甲烷＝1:10)纯化得到化合物1-3(220mg，收率：84％)。MS m/z(ESI):538.7[M+1] +。 Compound 1-2 (280 mg) was added to a trifluoroacetic acid/dichloromethane (3 mL/6 mL) mixed solution, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (methanol/dichloromethane=1:10) to obtain compound 1-3 (220 mg, yield: 84%). MS m/z (ESI): 538.7 [M+1] + .
第三步：化合物1的合成The third step: the synthesis of compound 1
将多聚甲醛(55mg)和冰醋酸(0.1mL)加入到化合物1-3(110mg)的甲醇(5mL)溶液中，反应在室温下搅拌0.5小时候，加入氰基硼氢化钠(39mg)并室温下继续反应16小时。反应结束后，将反应液减压浓缩除去溶剂，所得残余物通过高效液相制备色谱(色谱柱：Xbridge-C18；150×21.2mm，5μm；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动相：乙腈-水(0.1％甲酸)；梯度：15-40％)纯化得到化合物1(25.5mg，收率：22％)。MS m/z(ESI):553.0[M+1] +。 1H NMR(400MHz,CD 3OD)：δ8.90(d,J＝5.2Hz,1H),8.85(s,1H),8.49(d,J＝2.3Hz,1H),8.38(s,1H),8.31(d,J＝5.2Hz,1H),7.80-7.72(m,1H),6.86(s,1H),5.54(d,J＝1.6Hz,2H),3.42-3.33(m,2H),3.22-3.10(m,1H),2.84(t,J＝11.2Hz,2H),2.70 (s,3H),2.32-2.22(m,3H),2.20(s,3H),2.19-2.12(m,1H),2.08(s,3H)。 Paraformaldehyde (55 mg) and glacial acetic acid (0.1 mL) were added to a solution of compound 1-3 (110 mg) in methanol (5 mL), the reaction was stirred at room temperature for 0.5 hours, sodium cyanoborohydride (39 mg) was added and heated at room temperature The reaction was continued for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was subjected to preparative high performance liquid chromatography (chromatographic column: Xbridge-C18; 150×21.2mm, 5 μm; column temperature: 25°C; flow rate: 20mL/min; wavelength : 214nm; column pressure: 80bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15-40%) was purified to obtain compound 1 (25.5 mg, yield: 22%). MS m/z (ESI): 553.0 [M+1] + . 1 H NMR (400MHz, CD 3 OD): δ8.90(d, J=5.2Hz, 1H), 8.85(s, 1H), 8.49(d, J=2.3Hz, 1H), 8.38(s, 1H) ,8.31(d,J=5.2Hz,1H),7.80-7.72(m,1H),6.86(s,1H),5.54(d,J=1.6Hz,2H),3.42-3.33(m,2H), 3.22-3.10(m,1H),2.84(t,J＝11.2Hz,2H),2.70(s,3H),2.32-2.22(m,3H),2.20(s,3H),2.19-2.12(m, 1H), 2.08(s, 3H).
实施例2化合物2、2-P1和2-P2的合成The synthesis of embodiment 2 compound 2, 2-P1 and 2-P2
Figure PCTCN2022142967-appb-000044
Figure PCTCN2022142967-appb-000044
将醋酸酐(51.15mg,0.50mmol)加入到化合物1-3(90mg，0.16mmol)和三乙胺(67.59,0.67mmol)的二氯甲烷(8mL)溶液中，反应在室温搅拌12小时。反应完成后，反应液减压浓缩，加入水(20mL)稀释，用乙酸乙酯萃取(20mL×3)，合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析(二氯甲烷/甲醇＝10/1)和制备HPLC(色谱柱:Xbridge-Gemini-C18，150×21.2mm，5μm；流动相:乙腈-水(0.1％甲酸)梯度:30-60％)纯化得到化合物2(43.8mg，收率：43.77％)。MS m/z(ESI):580.8[M+H] +。 1H NMR(400MHz,CD 3OD)：δ8.88(d,J＝5.3Hz,1H),8.83(s,1H),8.49(d,J＝2.3Hz,1H),8.42(s,1H),8.29(dd,J＝5.3,2.3Hz,1H),7.81-7.72(m,1H),6.84(s,1H),5.53(d,J＝1.8Hz,2H),4.69-4.57(m,1H),4.06(d,J＝11.8Hz,1H),3.31-3.16(m,2H),2.84(t,J＝12.7Hz,1H),2.19(s,3H),2.17-2.05(m,8H),2.04-1.83(m,2H)。 Acetic anhydride (51.15 mg, 0.50 mmol) was added to a solution of compound 1-3 (90 mg, 0.16 mmol) and triethylamine (67.59, 0.67 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered , the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (dichloromethane/methanol=10/1) and preparative HPLC (chromatographic column: Xbridge-Gemini-C18, 150×21.2mm, 5 μm; mobile phase: acetonitrile- Water (0.1% formic acid) gradient: 30-60%) was purified to obtain compound 2 (43.8 mg, yield: 43.77%). MS m/z (ESI): 580.8 [M+H] + . 1 H NMR (400MHz, CD 3 OD): δ8.88(d, J=5.3Hz, 1H), 8.83(s, 1H), 8.49(d, J=2.3Hz, 1H), 8.42(s, 1H) ,8.29(dd,J=5.3,2.3Hz,1H),7.81-7.72(m,1H),6.84(s,1H),5.53(d,J=1.8Hz,2H),4.69-4.57(m,1H ), 4.06(d, J=11.8Hz, 1H), 3.31-3.16(m, 2H), 2.84(t, J=12.7Hz, 1H), 2.19(s, 3H), 2.17-2.05(m, 8H) ,2.04-1.83(m,2H).
化合物2经过超临界流体制备色谱(设备：SFC Thar prep 80；柱子：CHIRALPAK AD-H，250mmx20mm，5μm；流动相：40％甲醇(甲醇/二氧化碳，0.2％的氨水)；总流速：12.5g/min)分离得到化合物2-P1(19.4mg)和化合物2-P2(18.6mg)。Compound 2 was subjected to supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mmx20mm, 5 μm; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); total flow rate: 12.5g/ min) Compound 2-P1 (19.4 mg) and Compound 2-P2 (18.6 mg) were isolated.
化合物2-P1：Compound 2-P1:
MS m/z(ESI):581.1[M+H] +；SFC：保留时间＝4.08min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.83(d,J＝5.2Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.37(d,J＝1.6Hz,1H),8.25(dd,J＝5.3,2.3Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.80(s,1H),5.49(d,J＝1.9Hz,2H),4.64-4.50(m,1H),4.06-3.97(m,1H),3.21(ddd,J＝15.4,11.1,7.8Hz,2H),2.80(t,J＝12.8Hz,1H),2.15(s,3H),2.11-2.05(m,5H),2.04(s,3H),2.01-1.86(m,2H)。 MS m/z (ESI): 581.1[M+H] + ; SFC: retention time = 4.08min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.83 (d, J = 5.2Hz, 1H ),8.79(s,1H),8.44(d,J=2.4Hz,1H),8.37(d,J=1.6Hz,1H),8.25(dd,J=5.3,2.3Hz,1H),7.71(ddd ,J=9.6,8.6,2.4Hz,1H),6.80(s,1H),5.49(d,J=1.9Hz,2H),4.64-4.50(m,1H),4.06-3.97(m,1H), 3.21(ddd, J＝15.4, 11.1, 7.8Hz, 2H), 2.80(t, J＝12.8Hz, 1H), 2.15(s, 3H), 2.11-2.05(m, 5H), 2.04(s, 3H) ,2.01-1.86(m,2H).
化合物2-P2：Compound 2-P2:
MS m/z(ESI):581.1[M+H] +；SFC：保留时间＝5.51min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.83(dd,J＝5.3,0.6Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.36(s,1H),8.25(dd,J＝5.3,2.2Hz,1H),7.76–7.66(m,1H),6.81(s,1H),5.49(d,J＝2.0Hz,2H),4.58(ddd,J＝13.0,5.4,3.2Hz,1H),4.00(dd,J＝18.6,12.5Hz,1H),3.26-3.15(m,2H),2.87-2.74(m,1H),2.15(s,3H),2.10(m,5H),2.04(m,3H),1.99-1.84(m,2H)。 MS m/z (ESI): 581.1[M+H] + ; SFC: retention time = 5.51min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.83 (dd, J = 5.3, 0.6Hz ,1H),8.79(s,1H),8.44(d,J=2.4Hz,1H),8.36(s,1H),8.25(dd,J=5.3,2.2Hz,1H),7.76–7.66(m, 1H),6.81(s,1H),5.49(d,J=2.0Hz,2H),4.58(ddd,J=13.0,5.4,3.2Hz,1H),4.00(dd,J=18.6,12.5Hz,1H ), 3.26-3.15(m,2H), 2.87-2.74(m,1H), 2.15(s,3H), 2.10(m,5H), 2.04(m,3H), 1.99-1.84(m,2H).
实施例3化合物3及3-P1和3-P2的合成The synthesis of embodiment 3 compound 3 and 3-P1 and 3-P2
Figure PCTCN2022142967-appb-000045
Figure PCTCN2022142967-appb-000045
将化合物3-1(134mg，1.05mmol)和碳酸钾(218mg，1.57mmol)加入到化合物A(250mg，0.52mmol)的N,N-二甲基甲酰胺(5mL)溶液中。反应液加热到60℃并在该温度下搅拌16小时。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(50mL×3)。合并的有机相用饱和食盐水洗(50mL×3)，无水硫酸钠干燥并过滤，过滤液通过减压浓缩除去溶剂，残余物经高效液相制备色谱(色谱柱：Xbridge-C18，150×21.2mm，5μm；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动相：乙腈-水(0.1％甲酸)；梯度：30-60％)纯化得到化合物3(121.2mg，收率：47％)。MS m/z(ESI)：540.2[M+1] +； 1H NMR(400MHz,DMSO-d6)：δ8.90(d,J＝5.2Hz,1H),8.83(s,1H),8.58(d,J＝2.4Hz,1H),8.34(s,1H),8.17(d,J＝5.2Hz,1H),8.11-8.04(m,1H),6.79(s,1H),5.45(d,J＝1.5Hz,2H),3.96-3.87(m,2H),3.43(td,J＝11.6,2.4Hz,2H),3.15-3.04(m,1H),2.05(s,3H),1.93(s,3H),1.91-1.79(m,4H)。 Compound 3-1 (134 mg, 1.05 mmol) and potassium carbonate (218 mg, 1.57 mmol) were added to a solution of compound A (250 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL). The reaction was heated to 60°C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (50mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was subjected to preparative high performance liquid chromatography (chromatographic column: Xbridge-C18, 150×21.2 mm, 5 μm; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%) was purified to obtain compound 3 (121.2 mg, yield: 47%). MS m/z (ESI): 540.2[M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.90(d, J=5.2Hz, 1H), 8.83(s, 1H), 8.58( d,J=2.4Hz,1H),8.34(s,1H),8.17(d,J=5.2Hz,1H),8.11-8.04(m,1H),6.79(s,1H),5.45(d,J =1.5Hz,2H),3.96-3.87(m,2H),3.43(td,J=11.6,2.4Hz,2H),3.15-3.04(m,1H),2.05(s,3H),1.93(s, 3H), 1.91-1.79 (m, 4H).
将化合物3通过超临界流体制备色谱(设备：SFC Thar prep 80；色谱柱：chiralpak-AD；流动相：40％异丙醇(异丙醇/二氧化碳，0.2％氨水)，流速：12.5g/min)拆分得到化合物3-P1(62.1mg,收率21％)和化合物3-P2(59.1mg，收率20％)。Compound 3 was preparatively chromatographed by supercritical fluid (equipment: SFC Thar prep 80; Chromatographic column: chiralpak-AD; Mobile phase: 40% isopropanol (isopropanol/carbon dioxide, 0.2% ammoniacal liquor), flow rate: 12.5g/min ) to obtain compound 3-P1 (62.1mg, yield 21%) and compound 3-P2 (59.1mg, yield 20%).
化合物3-P1：Compound 3-P1:
MS m/z(ESI):540.2[M+1] +；SFC：保留时间＝3.42min,UV＝214nm； 1H NMR(400MHz,CD 3OD)：δ8.88(d,J＝5.2Hz,1H),8.84(s,1H),8.49(d,J＝2.2Hz,1H),8.41(s,1H),8.29(d,J＝5.3Hz,1H),7.80-7.71(m,1H),6.86(s,1H),5.54(d,J＝1.4Hz,2H),4.08(d,J＝11.1Hz,2H),3.62(dd,J＝17.9,6.7Hz,2H),3.28-3.17(m,1H),2.20(s,3H),2.13-1.91(m,7H)。 MS m/z (ESI): 540.2[M+1] + ; SFC: retention time = 3.42min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD): δ8.88 (d, J = 5.2Hz, 1H),8.84(s,1H),8.49(d,J=2.2Hz,1H),8.41(s,1H),8.29(d,J=5.3Hz,1H),7.80-7.71(m,1H), 6.86(s,1H),5.54(d,J=1.4Hz,2H),4.08(d,J=11.1Hz,2H),3.62(dd,J=17.9,6.7Hz,2H),3.28-3.17(m ,1H), 2.20(s,3H), 2.13-1.91(m,7H).
化合物3-P2：Compound 3-P2:
MS m/z(ESI):540.2[M+1] +；SFC：保留时间＝4.64min,UV＝214nm； 1H NMR(400MHz,CD 3OD)：δ8.88(d,J＝5.3Hz,1H),8.84(s,1H),8.49(d,J＝2.3Hz,1H),8.41(s,1H),8.29(d,J＝5.3Hz,1H),7.80-7.71(m,1H),6.85(s,1H),5.54(d,J＝1.8Hz,2H),4.12-4.03(m,2H),3.62(dt,J＝13.0,6.7Hz,2H),3.27-3.17(m,1H),2.20(s,3H),2.12-1.95(m,7H)。 MS m/z (ESI): 540.2[M+1] + ; SFC: retention time = 4.64min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD): δ8.88 (d, J = 5.3Hz, 1H),8.84(s,1H),8.49(d,J=2.3Hz,1H),8.41(s,1H),8.29(d,J=5.3Hz,1H),7.80-7.71(m,1H), 6.85(s,1H),5.54(d,J=1.8Hz,2H),4.12-4.03(m,2H),3.62(dt,J=13.0,6.7Hz,2H),3.27-3.17(m,1H) ,2.20(s,3H),2.12-1.95(m,7H).
实施例4化合物4的合成The synthesis of embodiment 4 compound 4
Figure PCTCN2022142967-appb-000046
Figure PCTCN2022142967-appb-000046
将碳酸钾(87.32mg，0.63mmol)和化合物4-1(63.44mg，0.42mmol)加入到化合物A的(100mg，0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在80℃下搅拌12小时。反应结束后，将反应液倒入水中，乙酸乙酯萃取(50mL×3)，合并的有机相用饱和食盐水洗(50mL×3)，无水硫酸钠干燥，减压浓缩除去溶剂，残余物经高效液相制备色谱纯化(色谱柱：Xbridge-C18，150×21.2mm，5μm；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动相：乙腈-水(0.1％甲酸)；梯度：35-60％)得到化合物4(36.6mg，收率：31.7％)。MS m/z(ESI)：525.8[M+1] +。 1H NMR(400MHz,CD 3OD):δ8.83(dd,J＝5.2,0.9Hz,1H),8.80(s,1H),8.44(d,J＝2.4Hz,1H),8.37(d,J＝1.5Hz,1H),8.26(dd,J＝5.2,0.9Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝1.9Hz,2H),4.23-4.14(m,1H),4.133.99(m,2H),3.94-3.86(m,1H),3.85-3.76(m,1H),2.39(ddd,J＝13.5,6.7,1.4Hz,2H),2.15(s,3H),2.04(d,J＝0.7Hz,3H)。 Potassium carbonate (87.32mg, 0.63mmol) and compound 4-1 (63.44mg, 0.42mmol) were added to compound A (100mg, 0.21mmol) in N,N-dimethylformamide (10mL) solution, and the reaction The mixture was stirred at 80°C for 12 hours. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate (50mL×3), the combined organic phase was washed with saturated brine (50mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was washed with Preparative HPLC purification (column: Xbridge-C18, 150×21.2mm, 5μm; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: acetonitrile-water (0.1 % formic acid); gradient: 35-60%) to obtain compound 4 (36.6mg, yield: 31.7%). MS m/z (ESI): 525.8 [M+1] + . 1 H NMR (400MHz, CD 3 OD): δ8.83(dd, J=5.2, 0.9Hz, 1H), 8.80(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.37(d, J＝1.5Hz, 1H), 8.26(dd, J＝5.2, 0.9Hz, 1H), 7.71(ddd, J＝9.6, 8.6, 2.4Hz, 1H), 6.81(d, J＝0.5Hz, 1H), 5.49(d,J=1.9Hz,2H),4.23-4.14(m,1H),4.133.99(m,2H),3.94-3.86(m,1H),3.85-3.76(m,1H),2.39( ddd, J=13.5, 6.7, 1.4Hz, 2H), 2.15(s, 3H), 2.04(d, J=0.7Hz, 3H).
实施例5化合物6的合成The synthesis of embodiment 5 compound 6
Figure PCTCN2022142967-appb-000047
Figure PCTCN2022142967-appb-000047
将碳酸钾(116mg，0.84mmol)和化合物6-1(62mg，0.42mmol)加入到化合物A(100mg，0.21mmol)的N,N-二甲基甲酰胺(3mL)溶液中，反应混合物加热到60℃并在该温度下搅拌16小时。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(50mL×3)，合并的有机相用饱和食盐水洗(50mL×3)，无水硫酸钠干燥并过滤，过滤液通过减压浓缩除去溶剂，残余物经高效液相制备色谱(色谱柱：Xbridge-C18，150×21.2mm，5μm；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动相：乙腈-水(0.1％甲酸)；梯度：50-70％)纯化得到化合物6(35.3mg，收率：32％)。MS m/z(ESI)：524.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)：δ8.90(d,J＝5.2Hz,1H),8.86(s,1H),8.61(d,J＝2.4Hz,1H),8.31(s,1H),8.17(d,J＝5.2Hz,1H),8.14-8.07(m,1H),6.83(s,1H),5.49(s,2H),3.40-3.33(m,1H),2.10(s,3H),2.08-2.00(m,2H),1.96(s,3H),1.94-1.86(m,2H),1.83-1.72(m,2H),1.71-1.59(m,2H)。 Potassium carbonate (116mg, 0.84mmol) and compound 6-1 (62mg, 0.42mmol) were added to compound A (100mg, 0.21mmol) in N,N-dimethylformamide (3mL) solution, and the reaction mixture was heated to 60°C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate (50mL×3), the combined organic phase was washed with saturated brine (50mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The solvent was removed, and the residue was subjected to preparative high-performance liquid chromatography (chromatographic column: Xbridge-C18, 150×21.2mm, 5 μm; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: Acetonitrile-water (0.1% formic acid); gradient: 50-70%) was purified to obtain compound 6 (35.3 mg, yield: 32%). MS m/z (ESI): 524.0 [M+1] + . 1 H NMR (400MHz, DMSO-d 6 ): δ8.90(d, J=5.2Hz, 1H), 8.86(s, 1H), 8.61(d, J=2.4Hz, 1H), 8.31(s, 1H ),8.17(d,J＝5.2Hz,1H),8.14-8.07(m,1H),6.83(s,1H),5.49(s,2H),3.40-3.33(m,1H),2.10(s, 3H), 2.08-2.00(m,2H), 1.96(s,3H), 1.94-1.86(m,2H), 1.83-1.72(m,2H), 1.71-1.59(m,2H).
实施例6化合物7的合成The synthesis of embodiment 6 compound 7
Figure PCTCN2022142967-appb-000048
Figure PCTCN2022142967-appb-000048
将碳酸钾(186.25mg，1.35mmol)和化合物7-1(81.2mg，0.67mmol)加入到化合物A (160mg，0.34mmol)的N,N-二甲基甲酰胺(2mL)溶液中，反应混合物加热至60℃并在该温度下搅拌18小时。反应结束后，反应液中加入乙酸乙酯(30mL)稀释，用饱和食盐水洗(30mL×5)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物通过高效液相制备色谱(Gemini-C18，150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)＝45-60％，UV:214nm)纯化得到化合物7(43mg，收率：25.2％)。MS m/z(ESI)：496.0[M+1] +。 1H NMR(400MHz,CD 3OD)δ8.85(s,1H),8.80(d,J＝5.2Hz,1H),8.61(d,J＝2.4Hz,1H),8.32(s,1H),8.14-8.08(m,2H),6.83(s,1H),5.50(s,2H),2.33-2.24(m,1H),2.09(s,3H),1.96(s,3H),1.18-1.15(m,1H),1.12-1.06(m,3H)。 Potassium carbonate (186.25mg, 1.35mmol) and compound 7-1 (81.2mg, 0.67mmol) were added to compound A (160mg, 0.34mmol) in N,N-dimethylformamide (2mL) solution, the reaction mixture Heat to 60°C and stir at this temperature for 18 hours. After the reaction was completed, ethyl acetate (30 mL) was added to the reaction solution for dilution, washed with saturated brine (30 mL×5), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative high performance liquid chromatography ( Gemini-C18, 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid) = 45-60%, UV: 214nm) was purified to obtain compound 7 (43mg, yield: 25.2%). MS m/z (ESI): 496.0 [M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.85(s, 1H), 8.80(d, J=5.2Hz, 1H), 8.61(d, J=2.4Hz, 1H), 8.32(s, 1H), 8.14-8.08(m,2H),6.83(s,1H),5.50(s,2H),2.33-2.24(m,1H),2.09(s,3H),1.96(s,3H),1.18-1.15( m,1H), 1.12-1.06(m,3H).
实施例7化合物8的合成The synthesis of embodiment 7 compound 8
Figure PCTCN2022142967-appb-000049
Figure PCTCN2022142967-appb-000049
将碳酸钾(87.32mg，0.63mmol)和化合物8-1(56.7mg，0.42mmol)加入到化合物A(100mg，0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应液加热到80℃并在该温度下搅拌12小时。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(50mL×3)，合并的有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，残余物经高效液相制备色谱(色谱柱：Xbridge-C18，150×21.2mm，5um；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动相：乙腈-水(0.1％甲酸)；梯度：35-60％)纯化得到化合物8(52.9mg，收率：47.8％)。MS m/z(ESI)：509.8[M+1] +。 1H NMR(400MHz,CD 3OD)δ8.83-8.78(m,2H),8.44(d,J＝2.4Hz,1H),8.38(s,1H),8.22(d,J＝5.3Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.80(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),3.91-3.79(m,1H),2.57-2.44(m,2H),2.41-2.31(m,2H),2.15(s,3H),2.13-2.06(m,1H),2.06-2.03(m,3H),1.99-1.89(m,1H)。 Potassium carbonate (87.32mg, 0.63mmol) and compound 8-1 (56.7mg, 0.42mmol) were added to compound A (100mg, 0.21mmol) in N,N-dimethylformamide (10mL) solution, the reaction solution Heat to 80°C and stir at this temperature for 12 hours. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate (50mL×3), the combined organic phase was washed with saturated brine (50mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure The solvent was removed, and the residue was subjected to preparative high-performance liquid chromatography (chromatographic column: Xbridge-C18, 150×21.2mm, 5um; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; mobile phase: Acetonitrile-water (0.1% formic acid); gradient: 35-60%) was purified to obtain compound 8 (52.9 mg, yield: 47.8%). MS m/z (ESI): 509.8 [M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.83-8.78(m, 2H), 8.44(d, J=2.4Hz, 1H), 8.38(s, 1H), 8.22(d, J=5.3Hz, 1H ),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.80(d,J=0.5Hz,1H),5.49(d,J=2.0Hz,2H),3.91-3.79(m,1H) ,2.57-2.44(m,2H),2.41-2.31(m,2H),2.15(s,3H),2.13-2.06(m,1H),2.06-2.03(m,3H),1.99-1.89(m, 1H).
实施例8化合物9的合成The synthesis of embodiment 8 compound 9
Figure PCTCN2022142967-appb-000050
Figure PCTCN2022142967-appb-000050
第一步：化合物9-2的合成The first step: the synthesis of compound 9-2
冰浴下，将硼氢化钠(200mg，5mmol)缓慢加入到化合物9-1(1g，10mmol)的甲醇(15mL)溶液中。反应在室温下搅拌3小时。反应结束后，反应混合物减压浓缩，所得残余物经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物9-2(560mg，收率：57％)。 1H NMR(400MHz,CDCl 3)：δ4.28-4.18(m,1H),2.79-2.69(m,2H),2.62-2.51(m,1H),2.37-2.26(m,2H)。 Under ice-cooling, sodium borohydride (200 mg, 5 mmol) was slowly added to a solution of compound 9-1 (1 g, 10 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 9-2 (560 mg, yield: 57%). 1 H NMR (400 MHz, CDCl 3 ): δ 4.28-4.18 (m, 1H), 2.79-2.69 (m, 2H), 2.62-2.51 (m, 1H), 2.37-2.26 (m, 2H).
第二步：化合物9-4的合成The second step: the synthesis of compound 9-4
将化合物9-3(1.56g，5.68mmol)加到化合物9-2(460mg，4.74mmol)和咪唑(644mg，9.47mmol)的二氯甲烷(15mL)溶液中，反应液在室温下搅拌16小时。反应结束后，反应液倒入水(30mL)中稀释，用二氯甲烷萃取(20mL×3)，合并的有机相用水(20mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析法(石油醚/乙酸乙酯＝10/1)纯化得到化合物9-4(1.2g，收率：80％)。MS m/z(ESI):358.0[M+23] +。 Compound 9-3 (1.56g, 5.68mmol) was added to compound 9-2 (460mg, 4.74mmol) and imidazole (644mg, 9.47mmol) in dichloromethane (15mL) solution, and the reaction solution was stirred at room temperature for 16 hours . After the reaction, the reaction solution was poured into water (30 mL) for dilution, extracted with dichloromethane (20 mL×3), the combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 9-4 (1.2 g, yield: 80%). MS m/z (ESI): 358.0 [M+23] + .
第三步：化合物9-5的合成The third step: the synthesis of compound 9-5
将盐酸乙醚溶液(2.0M,5mL)滴加到化合物9-4(100mg，0.29mmol)的甲醇(27mg，0.89mmol)溶液中，反应混合物在室温下搅拌16小时后，反应液减压浓缩，加入氨甲醇溶液(7.0M,5mL)，反应在室温下继续进行3小时。反应结束后，反应液直接减压浓缩得到化合物9-5(41mg，收率39％)粗品，该粗品直接用于下一步。MS m/z(ESI):353.0[M+1] +。 Hydrochloric acid ether solution (2.0M, 5mL) was added dropwise to compound 9-4 (100mg, 0.29mmol) in methanol (27mg, 0.89mmol) solution, the reaction mixture was stirred at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, Ammonia in methanol (7.0 M, 5 mL) was added and the reaction was continued at room temperature for 3 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 9-5 (41 mg, yield 39%), which was directly used in the next step. MS m/z (ESI): 353.0 [M+1] + .
第四步：化合物9的合成The fourth step: the synthesis of compound 9
将碳酸钾(30mg，0.221mmol)和化合物9-5(39mg,0.110mmol)加入到化合物A(35mg，0.073mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应加热至100℃并在该温度下搅拌16小时。反应结束后，反应混合物倒入水中(20mL)，用乙酸乙酯萃取(20mL×3)，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经薄板层析(二氯甲烷/甲醇＝10/1)纯化得到化合物9(8.7mg，收率：15％)。MS m/z(ESI):525.7[M+1] +； 1H NMR(400MHz,CD 3OD)：δ8.82-8.77(m,2H),8.46-8.41(m,2H),8.24(d,J＝5.2Hz,1H),7.74-7.67(m,1H),6.82(s,1H),5.49(d,J＝1.9Hz,2H),4.25-4.21(m,1H),3.26-3.24(m,1H),2.75-2.62(m,2H),2.51-2.31(m,2H),2.16(s,3H),2.05(s,3H)。 Potassium carbonate (30mg, 0.221mmol) and compound 9-5 (39mg, 0.110mmol) were added to compound A (35mg, 0.073mmol) in N,N-dimethylformamide (5mL) solution, and the reaction was heated to 100 °C and stirred at this temperature for 16 hours. After the reaction, the reaction mixture was poured into water (20mL), extracted with ethyl acetate (20mL×3), the combined organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was reduced to Concentrated under reduced pressure, and the resulting residue was purified by thin-plate chromatography (dichloromethane/methanol=10/1) to obtain compound 9 (8.7 mg, yield: 15%). MS m/z (ESI): 525.7[M+1] + ; 1 H NMR (400MHz, CD 3 OD): δ8.82-8.77(m, 2H), 8.46-8.41(m, 2H), 8.24(d ,J=5.2Hz,1H),7.74-7.67(m,1H),6.82(s,1H),5.49(d,J=1.9Hz,2H),4.25-4.21(m,1H),3.26-3.24( m,1H), 2.75-2.62(m,2H), 2.51-2.31(m,2H), 2.16(s,3H), 2.05(s,3H).
实施例9化合物10、10-P1&化合物10-P2的合成The synthesis of embodiment 9 compound 10, 10-P1 & compound 10-P2
Figure PCTCN2022142967-appb-000051
第一步：化合物10-2的合成
Figure PCTCN2022142967-appb-000051
The first step: the synthesis of compound 10-2
在-5℃下，将四氯化钛(6.3mL，6.3mmol)和甲基锂氯化锂络合物(2.0M，3.2mL，6.3mmol)缓慢滴加到化合物10-1(500mg，5.2mmol)的甲苯(15mL)溶液中，反应体系自然升温到室温并在室温下搅拌3小时。反应结束后，反应混合物倒入饱和氯化铵水溶液中(30mL)淬灭，用乙酸乙酯(20mL×3)萃取。合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物10-2(230mg)粗品，该粗品直接用于下一步反应。At -5°C, titanium tetrachloride (6.3mL, 6.3mmol) and methyl lithium lithium chloride complex (2.0M, 3.2mL, 6.3mmol) were slowly added dropwise to compound 10-1 (500mg, 5.2 mmol) in toluene (15 mL), the reaction system was naturally warmed to room temperature and stirred at room temperature for 3 hours. After the reaction, the reaction mixture was quenched by pouring into saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 10-2 (230 mg), which was directly used in the next reaction.
第二步：化合物10-3的合成The second step: the synthesis of compound 10-3
将羟胺水溶液(50％,2mL)加入到化合物10-2(160mg，1.44mmol)的乙醇(5mL)溶液中，反应加热至75℃并在该温度下搅拌12小时，反应结束后，反应液直接减压浓缩得到化合物10-3(300mg)粗品，该粗品将直接用于下一步反应。MS m/z(ESI):145.1[M+H] +。 Aqueous hydroxylamine solution (50%, 2mL) was added to compound 10-2 (160mg, 1.44mmol) in ethanol (5mL) solution, the reaction was heated to 75 ° C and stirred at this temperature for 12 hours, after the reaction, the reaction solution was directly Concentration under reduced pressure gave the crude compound 10-3 (300 mg), which was directly used in the next reaction. MS m/z (ESI): 145.1 [M+H] + .
第三步：化合物10-4的合成The third step: the synthesis of compound 10-4
在室温和氮气保护下，将雷尼镍(400mg)加入到化合物10-3(200mg，1.39mmol)的甲醇(8mL)溶液中。室温下，反应在氢气氛围下常压反应12小时。反应结束后，反应液直接过滤，过滤液减压浓缩得到化合物10-4(160mg)粗品，该粗品直接用于下一步反应。MS m/z(ESI):129.1[M+H] +。 At room temperature under the protection of nitrogen, Raney nickel (400 mg) was added to a solution of compound 10-3 (200 mg, 1.39 mmol) in methanol (8 mL). At room temperature, the reaction was carried out at atmospheric pressure under a hydrogen atmosphere for 12 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 10-4 (160 mg), which was directly used in the next reaction. MS m/z (ESI): 129.1 [M+H] + .
第四步：化合物10-P1和10-P2的合成The fourth step: the synthesis of compounds 10-P1 and 10-P2
将化合物10-4(160mg，1.11mmol)和碳酸钾(262mg，1.89mmol)加入到化合物A(300mg，0.63mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应加热至90℃并在该温度下搅拌12小时。反应结束后，反应混合物倒入水中(30mL)，用二氯甲烷萃取(20mL×3)，合并的有机相用水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物用高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：35-55％，柱温:25℃；流速:14mL/min；波长:214nm；柱压:80bar)纯化得到化合物10(70mg)。Compound 10-4 (160mg, 1.11mmol) and potassium carbonate (262mg, 1.89mmol) were added to compound A (300mg, 0.63mmol) in N,N-dimethylformamide (15mL) solution, and the reaction was heated to 90 °C and stirred at this temperature for 12 hours. After the reaction, the reaction mixture was poured into water (30 mL), extracted with dichloromethane (20 mL×3), the combined organic phases were washed with water (20 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was preparatively chromatographed by high performance liquid phase (chromatographic column: Gemini-C18, 150 × 21.2mm, 5 μ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-55%, column temperature: 25 ℃; flow rate : 14mL/min; wavelength: 214nm; column pressure: 80bar) was purified to obtain compound 10 (70mg).
该化合物10通过超临界流体制备色谱(设备：SFC Thar prep 80；柱子：CHIRALPAK AD-H 250mm*20mm，5μm；流动相：40％乙醇(乙醇/二氧化碳，0.2％的氨水)； 流速：12.5g/min)进行手性拆分得到化合物10-P1(15.7mg，收率：4.6％)和10-P2(17.2mg，收率：5.1％)。The compound 10 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm*20mm, 5 μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g /min) for chiral resolution to obtain compounds 10-P1 (15.7 mg, yield: 4.6%) and 10-P2 (17.2 mg, yield: 5.1%).
化合物10-P1：Compound 10-P1:
MS m/z(ESI):539.8[M+1] +；SFC：保留时间＝2.66min,UV＝214nm； 1H NMR(400MHz,CD 3OD)：δ8.79(d,J＝5.1Hz,2H),8.48–8.42(m,2H),8.23(d,J＝5.3Hz,1H),7.75–7.67(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),3.41–3.30(m,1H),2.63–2.50(m,2H),2.39-2.44(m,2H),2.15(s,3H),2.05(s,3H),1.44(s,3H)。 MS m/z (ESI): 539.8[M+1] + ; SFC: retention time = 2.66min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD): δ8.79 (d, J = 5.1Hz, 2H),8.48–8.42(m,2H),8.23(d,J＝5.3Hz,1H),7.75–7.67(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H ), 3.41–3.30(m,1H), 2.63–2.50(m,2H), 2.39–2.44(m,2H), 2.15(s,3H), 2.05(s,3H), 1.44(s,3H).
化合物10-P2：Compound 10-P2:
MS m/z(ESI):539.8[M+1] +；SFC：保留时间＝3.22min,UV＝214nm； 1H NMR(400MHz,CD 3OD)：δ8.79(d,J＝5.2Hz,2H),8.49–8.42(m,2H),8.23(d,J＝5.3Hz,1H),7.68-7.72(m,1H),6.82(d,J＝0.6Hz,1H),5.49(d,J＝1.9Hz,2H),3.38–3.31(m,1H),2.55(dd,J＝10.7,9.7Hz,2H),2.47–2.36(m,2H),2.15(s,3H),2.05(s,3H),1.44(s,3H)。 MS m/z (ESI): 539.8[M+1] + ; SFC: retention time = 3.22min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD): δ8.79 (d, J = 5.2Hz, 2H),8.49–8.42(m,2H),8.23(d,J＝5.3Hz,1H),7.68-7.72(m,1H),6.82(d,J＝0.6Hz,1H),5.49(d,J =1.9Hz,2H),3.38–3.31(m,1H),2.55(dd,J＝10.7,9.7Hz,2H),2.47–2.36(m,2H),2.15(s,3H),2.05(s, 3H), 1.44(s, 3H).
实施例10化合物14、14-G1和14-G2的合成The synthesis of embodiment 10 compound 14, 14-G1 and 14-G2
Figure PCTCN2022142967-appb-000052
Figure PCTCN2022142967-appb-000052
第一步：化合物14-2的合成The first step: the synthesis of compound 14-2
在-5℃下，将四氯化钛(19.4mL，19.40mmol，1M)和甲基锂(9.7mL，19.40mmol，2M)缓慢滴加到化合物14-1(2.0g,16.20mmol)的甲苯(50mL)溶液中，滴加完后反应自然升温到室温并在室温下搅拌3小时。反应结束后，向反应液中加入饱和氯化铵溶液(20mL)淬灭反应，用乙酸乙酯萃取(50mL x3)萃取，合并的有机相用饱和食盐水洗涤(50mL)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析法(乙酸乙酯/石油醚＝1/2)纯化得到化合物14-2(1.0g，收率：40％)。 1H NMR(400MHz,CDCl 3)δ2.87–2.33(m,1H),2.05–1.80(m,2H),1.79–1.53(m,3H),1.39(m,3H),1.28–1.19(m,3H)。 At -5°C, titanium tetrachloride (19.4mL, 19.40mmol, 1M) and methyllithium (9.7mL, 19.40mmol, 2M) were slowly added dropwise to compound 14-1 (2.0g, 16.20mmol) in toluene (50 mL) solution, after the dropwise addition, the reaction was naturally warmed to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate And filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate/petroleum ether=1/2) to obtain compound 14-2 (1.0 g, yield: 40%). 1 H NMR (400MHz, CDCl 3 ) δ2.87–2.33(m,1H),2.05–1.80(m,2H),1.79–1.53(m,3H),1.39(m,3H),1.28–1.19(m ,3H).
第二步:化合物14-3的合成The second step: the synthesis of compound 14-3
将羟胺水溶液(50％,0.5mL)加入到化合物14-2(200mg，1.4mmol)的乙醇(5mL)溶液中，反应加热至75℃并在该温度下搅拌16小时，反应结束后，反应液直接减压浓缩得到粗品化合物14-3(300mg)，该粗品直接用于下一步反应。MS m/z(ESI):173.1[M+H] +。 Aqueous hydroxylamine solution (50%, 0.5mL) was added to compound 14-2 (200mg, 1.4mmol) in ethanol (5mL) solution, the reaction was heated to 75 ° C and stirred at this temperature for 16 hours, after the reaction, the reaction solution Directly concentrated under reduced pressure to obtain crude compound 14-3 (300 mg), which was directly used in the next reaction. MS m/z (ESI): 173.1 [M+H] + .
第三步：化合物14-4的合成The third step: the synthesis of compound 14-4
在氮气保护下，将雷尼镍(40mg)加入到化合物14-3(300mg，1.70mmol)的甲醇(10mL)溶液中，反应在室温和常压氢气氛围下进行16小时。反应完成后，将反应液过滤，滤液直接减压浓缩得到化合物14-4(300mg)粗品，该粗品直接用于下一步。MS m/z(ESI):157.1[M+H] +。 Under the protection of nitrogen, Raney nickel (40 mg) was added to a solution of compound 14-3 (300 mg, 1.70 mmol) in methanol (10 mL), and the reaction was carried out at room temperature under hydrogen atmosphere at normal pressure for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain a crude compound 14-4 (300 mg), which was directly used in the next step. MS m/z (ESI): 157.1 [M+H] + .
第四步：化合物14-G1和14-G2的合成The fourth step: the synthesis of compounds 14-G1 and 14-G2
将化合物14-4(200mg,1.2mmol)和碳酸钾(34mg,2.50mmol)加入到化合物A(304mg,0.64mmol)的N，N-二甲基甲酰胺(10mL)溶液，反应加热至90℃并在该温度下搅拌12小时。反应结束后，反应混合液倒入水中(50mL)，用二氯甲烷萃取(30mL x3)，合并的有机相用水洗涤(20mL x2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物通过高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5um；流动相：乙腈-水(0.1％的三氟乙酸)；梯度：35-45％，柱温:25℃；流速:14mL/min；波长:214nm；柱压:80bar)纯化得到两组化合物14-G1(10mg，收率：1.20％)和化合物14-G2(20mg，收率：2.34％)。。Compound 14-4 (200mg, 1.2mmol) and potassium carbonate (34mg, 2.50mmol) were added to compound A (304mg, 0.64mmol) in N,N-dimethylformamide (10mL) solution, and the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction, the reaction mixture was poured into water (50mL), extracted with dichloromethane (30mL x3), the combined organic phase was washed with water (20mL x2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain The residue was subjected to preparative high-performance liquid chromatography (chromatographic column: Gemini-C18, 150 × 21.2mm, 5um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 35-45%, column temperature: 25°C ; Flow rate: 14mL/min; Wavelength: 214nm; Column pressure: 80bar) purified to obtain two groups of compound 14-G1 (10mg, yield: 1.20%) and compound 14-G2 (20mg, yield: 2.34%). .
化合物14-G1：Compound 14-G1:
MS m/z(ESI):568.7[M+H] +；HPLC：保留时间＝5.00min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.92–8.81(m,2H),8.49(d,J＝2.3Hz,1H),8.41(s,1H),8.30(d,J＝5.3Hz,1H),7.81–7.70(m,1H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.02–2.93(m,1H),2.20(s,3H),2.11–2.01(m,5H),1.94–1.78(m,4H),1.67(dd,J＝12.6,3.9Hz,2H),1.31(s,3H)。 MS m/z (ESI): 568.7[M+H] + ; HPLC: retention time = 5.00min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.92–8.81 (m, 2H), 8.49 (d,J=2.3Hz,1H),8.41(s,1H),8.30(d,J=5.3Hz,1H),7.81–7.70(m,1H),6.85(s,1H),5.53(d, J＝1.8Hz, 2H), 3.02–2.93(m, 1H), 2.20(s, 3H), 2.11–2.01(m, 5H), 1.94–1.78(m, 4H), 1.67(dd, J＝12.6, 3.9Hz, 2H), 1.31(s, 3H).
化合物14-G2：Compound 14-G2:
MS m/z(ESI):568.1[M+H] +；HPLC：保留时间＝5.31min,UV＝214nm； 1H NMR(400MHz,CD 3OD)：δ8.91–8.82(m,2H),8.52–8.44(m,2H),8.33(d,J＝5.4Hz,1H),7.81–7.70(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),2.92(ddd,J＝12.6,7.8,3.3Hz,1H),2.23–2.04(m,8H),1.83(t,J＝13.6Hz,4H),1.63–1.52(m,2H),1.26(s,3H)。 MS m/z (ESI): 568.1[M+H] + ; HPLC: retention time = 5.31min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD): δ8.91–8.82 (m, 2H), 8.52–8.44(m,2H),8.33(d,J=5.4Hz,1H),7.81–7.70(m,1H),6.86(s,1H),5.54(d,J=1.8Hz,2H),2.92 (ddd,J=12.6,7.8,3.3Hz,1H),2.23–2.04(m,8H),1.83(t,J=13.6Hz,4H),1.63–1.52(m,2H),1.26(s,3H ).
实施例11化合物16、16-P1和16-P2的合成The synthesis of embodiment 11 compound 16, 16-P1 and 16-P2
Figure PCTCN2022142967-appb-000053
Figure PCTCN2022142967-appb-000053
第一步：化合物16-2的合成The first step: the synthesis of compound 16-2
在冰浴下，依次将三甲基氰硅烷(11.89g，119.8mmol)和碘化锌(0.82g，2.56mmol)缓慢加入到化合物16-1(6g，85.6mmol)的四氢呋喃(100mL)溶液中。反应自然升温到室温并在室温下搅拌40小时。反应结束后，反应液直接减压浓缩，所得残余物经柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物16-2(5.2g，收率：59.5％)。 1H NMR(400MHz,CDCl 3)δ3.55(s,1H),2.71-2.57(m,2H),2.42-2.28(m,2H),2.05-1.88(m,2H)。 In an ice bath, trimethylsilyl cyanide (11.89 g, 119.8 mmol) and zinc iodide (0.82 g, 2.56 mmol) were slowly added to a solution of compound 16-1 (6 g, 85.6 mmol) in tetrahydrofuran (100 mL) successively. . The reaction was allowed to warm to room temperature and stirred at room temperature for 40 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain compound 16-2 (5.2 g, yield: 59.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.55 (s, 1H), 2.71-2.57 (m, 2H), 2.42-2.28 (m, 2H), 2.05-1.88 (m, 2H).
第二步：化合物16-3的合成The second step: the synthesis of compound 16-3
将化合物16-2(5.2g，53.5mmol)加入到盐酸乙醇溶液(4M，25mL)中，反应在室温搅拌12小时。反应结束后，反应液直接减压浓缩，所得残余物用乙醚(20mL)打浆、过滤，滤饼收集并干燥得到化合物16-3(2.8g，收率：32.9％)。MS m/z(ESI):144.0[M+1] +1。 1H NMR(400MHz,DMSO-d 6)：δ11.13(d,J＝111.0Hz,2H),4.54(q,J＝7.0Hz,2H),2.43-2.20(m,2H),1.98-1.65(m,2H),1.49-1.31(m,3H)。 Compound 16-2 (5.2 g, 53.5 mmol) was added to hydrochloric acid ethanol solution (4M, 25 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was slurried with ether (20 mL), filtered, and the filter cake was collected and dried to obtain compound 16-3 (2.8 g, yield: 32.9%). MS m/z (ESI): 144.0 [M+1] +1 . 1 H NMR (400MHz, DMSO-d 6 ): δ11.13 (d, J = 111.0Hz, 2H), 4.54 (q, J = 7.0Hz, 2H), 2.43-2.20 (m, 2H), 1.98-1.65 (m,2H), 1.49-1.31(m,3H).
第三步：化合物16-4的合成The third step: the synthesis of compound 16-4
将化合物16-3(2.8g，19.6mmol)加入到氨的乙醇溶液(2M，30mL)中，反应在室温搅拌12小时。反应结束后，反应液过滤，滤液减压浓缩，所得残余物用乙醚(15mL)打浆，过滤，滤饼收集并干燥得到化合物16-4(1.4g，收率：56.1％)。MS m/z(ESI):115.1[M+1] +。 Compound 16-3 (2.8 g, 19.6 mmol) was added to ammonia in ethanol solution (2M, 30 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was slurried with diethyl ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 16-4 (1.4 g, yield: 56.1%). MS m/z (ESI): 115.1 [M+1] + .
第四步：化合物16的合成The fourth step: the synthesis of compound 16
将化合物16-4(144.21mg,1.26mmol)和碳酸钾(261.92mg，1.895mmol)加入到化合物A(300mg，0.63mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应在微波(90℃)条件下搅拌2小时。反应结束后，反应液倒入水中(20mL)，用乙酸乙酯萃取(20mL×3)，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化和高效液相色谱(色谱柱:Gemini-C18，150×21.2mm，5um；流动相:乙腈-水(0.1％甲酸)，梯度:40-60％)进一步纯化得到化合物16(60mg)。MS m/z(ESI):525.8[M+1] +。 1H NMR(400MHz,CD 3OD)：δ8.92(d,J＝5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J＝2.3Hz,1H),8.28(d,J＝5.2Hz,1H),7.76-7.67(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),2.77-2.66(m,2H),2.37(dd,J＝10.5,9.1Hz,2H),2.16(s,3H),2.04(d,J＝5.9Hz,3H),2.02-1.94(m,2H)。 Compound 16-4 (144.21mg, 1.26mmol) and potassium carbonate (261.92mg, 1.895mmol) were added to compound A (300mg, 0.63mmol) in N,N-dimethylformamide (5mL) solution, reacted in Stir under microwave (90°C) conditions for 2 hours. After the reaction, the reaction solution was poured into water (20mL), extracted with ethyl acetate (20mL×3), the combined organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was reduced to Concentrate under reduced pressure, the resulting residue is purified by column chromatography (dichloromethane/methanol=10/1) and high performance liquid chromatography (chromatographic column: Gemini-C18, 150 * 21.2mm, 5um; Mobile phase: acetonitrile-water (0.1 % formic acid), gradient: 40-60%) was further purified to obtain compound 16 (60 mg). MS m/z (ESI): 525.8 [M+1] + . 1 H NMR (400MHz, CD 3 OD): δ8.92(d, J=5.2Hz, 1H), 8.80(s, 1H), 8.51(s, 1H), 8.44(d, J=2.3Hz, 1H) ,8.28(d,J=5.2Hz,1H),7.76-7.67(m,1H),6.81(s,1H),5.49(d,J=1.9Hz,2H),2.77-2.66(m,2H), 2.37 (dd, J = 10.5, 9.1 Hz, 2H), 2.16 (s, 3H), 2.04 (d, J = 5.9 Hz, 3H), 2.02-1.94 (m, 2H).
化合物16通过超临界流体手性制备色谱(设备：SFC Thar prep 80；Column：CHIRALPAK AD-H 250mm*20mm，5μm；流动相：40％乙醇(乙醇/二氧化碳，0.2％的氨水)；流速：12.5g/min)纯化得到化合物16-P1(21.8mg)和16-P2(22mg)。Compound 16 was prepared by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80; Column: CHIRALPAK AD-H 250mm*20mm, 5 μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5 g/min) to obtain compounds 16-P1 (21.8 mg) and 16-P2 (22 mg).
化合物16-P1：Compound 16-P1:
MS m/z(ESI):525.8[M+1] +1。手性HPLC：保留时间＝6.36min,UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.92(d,J＝5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J＝2.4Hz,1H),8.28(d,J＝5.2Hz,1H),7.71(ddd,J＝9.7,8.6,2.4Hz,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),2.77–2.67(m,2H),2.38(dt,J＝11.8,8.8Hz,2H),2.16(s,3H),2.05(d,J＝0.5Hz,3H),2.03–1.94(m,2H). MS m/z (ESI): 525.8 [M+1] +1 . Chiral HPLC: retention time = 6.36min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.92(d, J=5.2Hz, 1H), 8.80(s, 1H), 8.51(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.28(d, J=5.2Hz, 1H), 7.71(ddd, J=9.7, 8.6, 2.4Hz, 1H), 6.81(d, J=0.6Hz, 1H), 5.49(d, J=2.0Hz, 2H ),2.77–2.67(m,2H),2.38(dt,J＝11.8,8.8Hz,2H),2.16(s,3H),2.05(d,J＝0.5Hz,3H),2.03–1.94(m, 2H).
化合物16-P2：Compound 16-P2:
MS m/z(ESI):525.8[M+1] +1。手性HPLC：保留时间＝16.05min,UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.92(d,J＝5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J＝2.4Hz,1H),8.28(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),2.71(ddd,J＝9.8,7.2,5.1Hz,2H),2.38(dd,J＝9.3,3.4Hz,2H),2.16(s,3H),2.05(d,J＝0.5Hz,3H),2.03–1.94(m,2H). MS m/z (ESI): 525.8 [M+1] +1 . Chiral HPLC: retention time = 16.05min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.92(d, J=5.2Hz, 1H), 8.80(s, 1H), 8.51(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.28(d, J=5.2Hz, 1H), 7.71(ddd, J=9.6, 8.6, 2.4Hz, 1H), 6.81(d, J=0.5Hz, 1H), 5.49(d, J=2.0Hz, 2H ),2.71(ddd,J=9.8,7.2,5.1Hz,2H),2.38(dd,J=9.3,3.4Hz,2H),2.16(s,3H),2.05(d,J=0.5Hz,3H) ,2.03–1.94(m,2H).
实施例12化合物33、33-P1或33-P2的合成The synthesis of embodiment 12 compound 33, 33-P1 or 33-P2
Figure PCTCN2022142967-appb-000054
Figure PCTCN2022142967-appb-000054
第一步：化合物33-2的合成The first step: the synthesis of compound 33-2
冰浴下，将三甲基腈硅烷(3.31g，33.3mmol)和碘化锌(0.23g，0.71mmol)依次加入到化合物33-1(2.0g，23.8mmol)的四氢呋喃(25mL)溶液中。反应自然升温到室温并在室温条件下搅拌24小时。反应结束后，反应液减压浓缩，将所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物33-2(1.5g，收率：32.7％)。 1H NMR(400MHz,CDCl 3)：δ2.11-2.05(m,2H),2.04–1.96(m,2H),1.89–1.73(m,4H),0.25–0.22(m,9H). Under ice-cooling, trimethylnitrile silane (3.31 g, 33.3 mmol) and zinc iodide (0.23 g, 0.71 mmol) were sequentially added to a solution of compound 33-1 (2.0 g, 23.8 mmol) in tetrahydrofuran (25 mL). The reaction was allowed to warm to room temperature and stirred at room temperature for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 33-2 (1.5 g, yield: 32.7%). 1 H NMR (400MHz, CDCl 3 ): δ2.11-2.05(m, 2H), 2.04-1.96(m, 2H), 1.89-1.73(m, 4H), 0.25-0.22(m, 9H).
第二步：化合物33-3的合成The second step: the synthesis of compound 33-3
将化合物33-2(1.5g，8.2mmol)加入到盐酸乙醇溶液(4M，15mL)中，反应在室温搅拌12小时。反应结束后，反应液减压浓缩，所得残余物用乙醚(15mL)打浆，过滤，滤饼收集并干燥得到化合物33-3(0.8g，收率：58.5％)。MS m/z(ESI):158.1[M+H] +。 Compound 33-2 (1.5 g, 8.2 mmol) was added to hydrochloric acid ethanol solution (4M, 15 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction liquid was concentrated under reduced pressure, the resulting residue was slurried with ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-3 (0.8 g, yield: 58.5%). MS m/z (ESI): 158.1 [M+H] + .
第三步：化合物33-4的合成The third step: the synthesis of compound 33-4
将化合物33-3(0.5g，3.2mmol)加入到氨的乙醇溶液(2M，15mL)中，反应在室温搅拌12小时。反应结束后，反应液减压浓缩，所得残余物用乙醚(15mL)打浆，过滤，滤饼收集并干燥得到化合物33-4(0.23g，收率：50.8％)。MS m/z(ESI):129.1[M+H] +。 Compound 33-3 (0.5 g, 3.2 mmol) was added to ammonia in ethanol solution (2M, 15 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the obtained residue was slurried with ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-4 (0.23 g, yield: 50.8%). MS m/z (ESI): 129.1 [M+H] + .
第四步:化合物33-P1和化合物33-P2的合成The fourth step: the synthesis of compound 33-P1 and compound 33-P2
将化合物33-4(162mg,1.26mmol)和碳酸钾(262mg，1.9mmol)加入到化合物A(300mg，0.63mmol)，的N,N-二甲基甲酰胺(15mL)溶液中，反应加热至90℃并在该温度下搅拌12小时。反应结束后，将反应液倒入水中(20mL)，用乙酸乙酯萃取(20mL x3)，合并的 有机相用饱和食盐水(20mL x3)洗涤，无水硫酸钠干燥并过滤，滤液减压浓缩，将所得残余物通过柱层析(二氯甲烷/甲醇＝10/1)纯化和高效液相制备色谱(色谱柱:Gemini-C18 150×21.2mm，5um；流动相：乙腈-水(0.1％甲酸)；梯度:40-60％)纯化得到化合物33。Compound 33-4 (162mg, 1.26mmol) and potassium carbonate (262mg, 1.9mmol) were added to compound A (300mg, 0.63mmol), in N,N-dimethylformamide (15mL) solution, and the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction, the reaction solution was poured into water (20mL), extracted with ethyl acetate (20mL x3), the combined organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure , the resulting residue was purified by column chromatography (dichloromethane/methanol=10/1) and preparative high performance liquid chromatography (chromatographic column: Gemini-C18 150 × 21.2mm, 5um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 33.
化合物33经过超临界流体制备色谱(设备：SFC Thar prep 80；柱子：CHIRALPAK AD-H，250mm×20mm，5μm；流动相：40％异丙醇(异丙醇/二氧化碳，0.2％的氨水)；流速：15g/min)拆分得到化合物33-P1(11.3mg)和化合物33-P2(14.2mg)。Compound 33 was subjected to supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mm×20mm, 5 μm; mobile phase: 40% isopropanol (isopropanol/carbon dioxide, 0.2% ammonia water); Flow rate: 15 g/min) to obtain compound 33-P1 (11.3 mg) and compound 33-P2 (14.2 mg).
化合物33-P1：Compound 33-P1:
MS m/z(ESI):539.8[M+H] +；SFC：保留时间＝6.67min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.92(d,J＝5.2Hz,1H),8.84(s,1H),8.56(s,1H),8.48(d,J＝2.4Hz,1H),8.30(d,J＝5.2Hz,1H),7.81–7.71(m,1H),6.86(s,1H),5.53(d,J＝1.9Hz,2H),2.42–2.26(m,2H),2.20(s,3H),2.10(s,3H),2.06–1.83(m,6H). MS m/z (ESI): 539.8[M+H] + ; SFC: retention time = 6.67min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.92 (d, J = 5.2Hz, 1H ),8.84(s,1H),8.56(s,1H),8.48(d,J=2.4Hz,1H),8.30(d,J=5.2Hz,1H),7.81–7.71(m,1H),6.86 (s,1H),5.53(d,J=1.9Hz,2H),2.42–2.26(m,2H),2.20(s,3H),2.10(s,3H),2.06–1.83(m,6H).
化合物33-P2：Compound 33-P2:
MS m/z(ESI):539.8[M+H] +；SFC：保留时间＝11.99min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.80(d,J＝5.2Hz,1H),8.72(s,1H),8.44(s,1H),8.36(d,J＝2.3Hz,1H),8.17(d,J＝5.2Hz,1H),7.64–7.61(m,1H),6.74(s,1H),5.41(d,J＝1.9Hz,2H),2.42–2.23(m,2H),2.08(s,3H),1.98(s,3H),1.93–1.72(m,6H)。 MS m/z (ESI): 539.8[M+H] + ; SFC: retention time = 11.99min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.80 (d, J = 5.2Hz, 1H ),8.72(s,1H),8.44(s,1H),8.36(d,J=2.3Hz,1H),8.17(d,J=5.2Hz,1H),7.64–7.61(m,1H),6.74 (s, 1H), 5.41 (d, J=1.9Hz, 2H), 2.42–2.23 (m, 2H), 2.08 (s, 3H), 1.98 (s, 3H), 1.93–1.72 (m, 6H).
实施例13化合物41、41-P1和化合物41-P2的合成The synthesis of embodiment 13 compound 41, 41-P1 and compound 41-P2
Figure PCTCN2022142967-appb-000055
Figure PCTCN2022142967-appb-000055
第一步：化合物41-2的合成The first step: the synthesis of compound 41-2
将羟胺水溶液(50％,5mL)加入到41-1(5.0g，1.4mmol)的乙醇(5mL)溶液中，反 应加热至75℃并在该温度下搅拌12小时，反应结束后，反应液直接减压浓缩得到粗品化合物41-2(5.8g)，该粗品将直接用于下一步反应。MS m/z(ESI):160.1[M+H] +。 Aqueous hydroxylamine solution (50%, 5mL) was added to 41-1 (5.0g, 1.4mmol) in ethanol (5mL) solution, the reaction was heated to 75°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was directly Concentration under reduced pressure gave crude compound 41-2 (5.8 g), which was directly used in the next reaction. MS m/z (ESI): 160.1 [M+H] + .
第二步：化合物41-3的合成The second step: the synthesis of compound 41-3
在氮气保护下，将雷尼镍(3.0g)加入到化合物41-2(5.8g，27.9mmol)的甲醇(50mL)溶液中，反应在室温和常压氢气氛围下进行12小时。反应完成后，将反应液过滤，滤液直接减压浓缩得到化合物41-3(5.2g)粗品，该粗品直接用于下一步反应。MS m/z(ESI):200.1[M+H] +。 Under the protection of nitrogen, Raney nickel (3.0 g) was added to a solution of compound 41-2 (5.8 g, 27.9 mmol) in methanol (50 mL), and the reaction was carried out at room temperature under hydrogen atmosphere at normal pressure for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain a crude compound 41-3 (5.2 g), which was directly used in the next reaction. MS m/z (ESI): 200.1 [M+H] + .
第三步：化合物41-4的合成The third step: the synthesis of compound 41-4
将化合物41-3(193mg,0.96mmol)和碳酸钾(201mg，1.45mmol)加入到化合物A(230mg，0.48mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应加热至90℃并在该温度下搅拌12小时。反应结束后，将反应液倒入水中(50mL)，用乙酸乙酯萃取(50mL x3)，合并的有机相用饱和食盐水洗涤(20mL x3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，将所得残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物41-4(90mg，收率：28％)。MS m/z(ESI):510.8[M-Boc] +。 Compound 41-3 (193mg, 0.96mmol) and potassium carbonate (201mg, 1.45mmol) were added to compound A (230mg, 0.48mmol) in N,N-dimethylformamide (10mL) solution, and the reaction was heated to 90 °C and stirred at this temperature for 12 hours. After the reaction, the reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL x3), the combined organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed After concentration, the resulting residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain compound 41-4 (90 mg, yield: 28%). MS m/z (ESI): 510.8 [M-Boc] + .
第四步：化合物41-5的合成The fourth step: the synthesis of compound 41-5
将三氟乙酸(84mg,0.74mmol)缓慢加入到化合物41-4(90mg,0.15mmol)的二氯甲烷溶液(10mL)中,反应在室温进行12小时。反应结束后，反应液直接减压浓缩得到化合物41-5(70mg)粗品，该粗品直接用于下一步反应。MS m/z(ESI):510.8[M+H] +。 Trifluoroacetic acid (84 mg, 0.74 mmol) was slowly added to a solution of compound 41-4 (90 mg, 0.15 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude product of compound 41-5 (70 mg), which was directly used for the next reaction. MS m/z (ESI): 510.8 [M+H] + .
第五步：化合物41、化合物41-P1和化合物41-P2的合成The fifth step: the synthesis of compound 41, compound 41-P1 and compound 41-P2
将醋酸酐(60mg,0.59mmol)缓慢加入到化合物41-5(100mg,0.19mmol)和三乙胺(59mg，0.59mmol)的二氯甲烷(8mL)溶液中，反应在室温搅拌12小时。反应结束后，反应液减压浓缩，然后倒入水中(20mL)，用乙酸乙酯萃取(20mL x3)，合并的有机相用饱和食盐水(20mL x3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经过高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相:乙腈-水(0.1％甲酸)；梯度:30-60％；柱温:25℃；流速:14mL/min；波长:214nm；柱压:80bar)得到化合物41(50mg)。Acetic anhydride (60 mg, 0.59 mmol) was slowly added to a solution of compound 41-5 (100 mg, 0.19 mmol) and triethylamine (59 mg, 0.59 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, then poured into water (20mL), extracted with ethyl acetate (20mL x3), the combined organic phase was washed with saturated brine (20mL x3), dried over anhydrous sodium sulfate and filtered, The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150 × 21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column Temperature: 25°C; Flow rate: 14mL/min; Wavelength: 214nm; Column pressure: 80bar) to obtain compound 41 (50mg).
化合物41通过超临界流体制备色谱(设备：SFC Thar prep 80；柱子：CHIRALPAK AD-H 250mm×20mm，5μm；流动相：40％甲醇(甲醇/二氧化碳，0.2％氨水)；流速：12.5g/min)纯化得到化合物41-P1(19mg收率：17.6％)和化合物41-P2(17mg收率：15.7％)。Compound 41 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g/min ) was purified to obtain compound 41-P1 (19 mg yield: 17.6%) and compound 41-P2 (17 mg yield: 15.7%).
化合物41-P1Compound 41-P1
MS m/z(ESI):552.8[M+H] +；SFC：保留时间＝6.33min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.90(dd,J＝5.2,4.3Hz,1H),8.81(s,1H),8.44(d,J＝2.4Hz,1H),8.39(d,J＝2.3Hz,1H),8.30(dd,J＝5.3,1.1Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.80(s,1H),5.48(d,J＝1.9Hz,2H),4.57(ddd,J＝14.7,8.7,4.3Hz,2H),4.40–4.30(m,2H),4.16(ddd,J＝8.8,5.9,2.8Hz,1H),2.15(s,3H),2.03(s,3H),1.87(s,3H)。 MS m/z (ESI): 552.8[M+H] + ; SFC: retention time = 6.33min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.90 (dd, J = 5.2, 4.3Hz ,1H),8.81(s,1H),8.44(d,J=2.4Hz,1H),8.39(d,J=2.3Hz,1H),8.30(dd,J=5.3,1.1Hz,1H),7.71 (ddd, J=9.6,8.6,2.4Hz,1H),6.80(s,1H),5.48(d,J=1.9Hz,2H),4.57(ddd,J=14.7,8.7,4.3Hz,2H), 4.40–4.30 (m, 2H), 4.16 (ddd, J=8.8, 5.9, 2.8Hz, 1H), 2.15 (s, 3H), 2.03 (s, 3H), 1.87 (s, 3H).
化合物41-P2Compound 41-P2
MS m/z(ESI):552.8[M+H] +；SFC：保留时间＝13.32min,UV＝214nm； 1H NMR(400MHz,CD 3OD)δ8.90(dd,J＝5.2,4.4Hz,1H),8.81(s,1H),8.44(d,J＝2.4Hz,1H),8.38(s,1H),8.31(dd,J＝5.2,1.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.57(ddd,J＝14.7,8.8,4.1Hz,2H),4.40–4.30(m,2H),4.17(ddd,J＝8.9,5.9,2.9Hz,1H),2.15(s,3H),2.04(s,3H),1.87(s,3H)。 MS m/z (ESI): 552.8[M+H] + ; SFC: retention time = 13.32min, UV = 214nm; 1 H NMR (400MHz, CD 3 OD) δ8.90 (dd, J = 5.2, 4.4Hz ,1H),8.81(s,1H),8.44(d,J=2.4Hz,1H),8.38(s,1H),8.31(dd,J=5.2,1.2Hz,1H),7.71(ddd,J= 9.6,8.6,2.4Hz,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.57(ddd,J＝14.7,8.8,4.1Hz,2H),4.40–4.30(m , 2H), 4.17 (ddd, J = 8.9, 5.9, 2.9 Hz, 1H), 2.15 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H).
实施例14：化合物63、63-P1或63-P2的合成Embodiment 14: the synthesis of compound 63, 63-P1 or 63-P2
Figure PCTCN2022142967-appb-000056
Figure PCTCN2022142967-appb-000056
第一步：化合物63的合成The first step: the synthesis of compound 63
将化合物10-4(104mg，0.81mmol)和碳酸钾(168mg，1.2mmol)加入到化合物B(200mg，0.41mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应加热至90℃并在该温度下搅拌12小时。反应结束后，反应混合液倒入水中(30mL)，用乙酸乙酯萃取(20mL x3)萃取。合并的有机相用饱和食盐水洗涤(20mL x2)，无水硫酸钠干燥并过滤，滤液减压浓缩，所得残余物用高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5um；流动相：乙腈-水(0.1％甲酸)；梯度：35-65％，柱温:25℃；流速:14mL/min；波长:214nm；柱压:80bar)纯化得到化合物63(65mg)。Compound 10-4 (104mg, 0.81mmol) and potassium carbonate (168mg, 1.2mmol) were added to compound B (200mg, 0.41mmol) in N,N-dimethylformamide (15mL) solution, and the reaction was heated to 90 °C and stirred at this temperature for 12 hours. After the reaction, the reaction mixture was poured into water (30mL), and extracted with ethyl acetate (20mL x 3). The combined organic phases were washed with saturated brine (20mL x2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18, 150×21.2mm, 5um ; Mobile phase: acetonitrile-water (0.1% formic acid); Gradient: 35-65%, column temperature: 25°C; Flow rate: 14mL/min; Wavelength: 214nm; Column pressure: 80bar) purified to obtain compound 63 (65mg).
化合物63通过超临界流体制备色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm；流动相：40％乙醇(乙醇/二氧化碳，0.2％氨水),总流速：40g/min)纯化得到化合物63-P1(25.3mg，收率：11.2％)和化合物63-P2(26.7mg，收率：11.8％)。Compound 63 was prepared by supercritical fluid chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water), total flow rate: 40g/min ) was purified to obtain compound 63-P1 (25.3 mg, yield: 11.2%) and compound 63-P2 (26.7 mg, yield: 11.8%).
化合物63-P1：Compound 63-P1:
MS m/z(ESI):557.8[M+1] +；SFC：保留时间＝2.90min,UV＝220nm； 1H NMR(400MHz,CD 3OD)δ8.89(d,J＝5.3Hz,1H),8.73(d,J＝0.5Hz,1H),8.48(d,J＝2.3Hz,1H),7.98(d,J＝4.8Hz,1H),7.75(ddd,J＝9.6,8.6,2.4Hz,1H),6.91(s,1H),5.55(d,J＝1.9Hz,2H),3.42(dd,J＝17.0, 8.6Hz,1H),2.59(dd,J＝15.0,5.7Hz,2H),2.53–2.44(m,2H),2.25(s,3H),2.16(s,3H),1.48(s,3H). MS m/z (ESI): 557.8[M+1] + ; SFC: retention time = 2.90min, UV = 220nm; 1 H NMR (400MHz, CD 3 OD) δ8.89 (d, J = 5.3Hz, 1H ), 8.73(d, J=0.5Hz, 1H), 8.48(d, J=2.3Hz, 1H), 7.98(d, J=4.8Hz, 1H), 7.75(ddd, J=9.6, 8.6, 2.4Hz ,1H),6.91(s,1H),5.55(d,J=1.9Hz,2H),3.42(dd,J=17.0,8.6Hz,1H),2.59(dd,J=15.0,5.7Hz,2H) ,2.53–2.44(m,2H),2.25(s,3H),2.16(s,3H),1.48(s,3H).
化合物63-P2：Compound 63-P2:
MS m/z(ESI):557.8[M+1] +；SFC：保留时间＝5.56min,UV＝220nm； 1H NMR(400MHz,CD 3OD)δ8.77(d,J＝5.3Hz,1H),8.61(d,J＝0.6Hz,1H),8.36(d,J＝2.4Hz,1H),7.86(d,J＝4.8Hz,1H),7.63(ddd,J＝9.6,8.6,2.4Hz,1H),6.78(d,J＝0.6Hz,1H),5.42(d,J＝1.9Hz,2H),3.31(t,J＝8.3Hz,1H),2.53–2.42(m,2H),2.41–2.32(m,2H),2.13(s,3H),2.04(s,3H),1.36(s,3H). MS m/z (ESI): 557.8[M+1] + ; SFC: retention time = 5.56min, UV = 220nm; 1 H NMR (400MHz, CD 3 OD) δ8.77 (d, J = 5.3Hz, 1H ), 8.61(d, J=0.6Hz, 1H), 8.36(d, J=2.4Hz, 1H), 7.86(d, J=4.8Hz, 1H), 7.63(ddd, J=9.6, 8.6, 2.4Hz ,1H),6.78(d,J=0.6Hz,1H),5.42(d,J=1.9Hz,2H),3.31(t,J=8.3Hz,1H),2.53–2.42(m,2H),2.41 –2.32(m,2H),2.13(s,3H),2.04(s,3H),1.36(s,3H).
实施例15化合物58的合成The synthesis of embodiment 15 compound 58
Figure PCTCN2022142967-appb-000057
Figure PCTCN2022142967-appb-000057
第一步：化合物58-1的合成The first step: the synthesis of compound 58-1
将三氟甲磺酸酐(2.37g，8.4mmol)缓慢加入到化合物A-4(1.2g，4.2mmol)和三乙胺(1.27g，12.6mmol)的二氯甲烷(20mL)溶液中。反应在室温下搅拌12小时。反应结束后，减压浓缩除去溶剂，所得残余物经柱层析(石油醚/乙酸乙酯＝1/5)纯化得到化合物58-1(0.35g，收率：64％)。MS m/z(ESI):416.9[M+1] +。 Trifluoromethanesulfonic anhydride (2.37 g, 8.4 mmol) was slowly added to a solution of compound A-4 (1.2 g, 4.2 mmol) and triethylamine (1.27 g, 12.6 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 12 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=1/5) to obtain compound 58-1 (0.35 g, yield: 64%). MS m/z (ESI): 416.9 [M+1] + .
第二步：化合物58-4的合成The second step: the synthesis of compound 58-4
将化合物58-2(205mg，1.45mmol)加入到化合物58-1(500mg，1.2mmol)的1,4-二氧六环(10mL)溶液中，反应加热到90℃并在该温度下搅拌12小时。反应结束后，减压浓缩除去溶剂，所得残余物经柱层析(石油醚/乙酸乙酯＝2/3)纯化得到化合物58-3(1.3g，收率：71.4％)。MS m/z(ESI):409.9[M+1] +。 Compound 58-2 (205 mg, 1.45 mmol) was added to a solution of compound 58-1 (500 mg, 1.2 mmol) in 1,4-dioxane (10 mL), and the reaction was heated to 90° C. and stirred at this temperature for 12 Hour. After the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=2/3) to obtain compound 58-3 (1.3 g, yield: 71.4%). MS m/z (ESI): 409.9 [M+1] + .
第三步:化合物58-4的合成The third step: the synthesis of compound 58-4
将双三苯基膦二氯化钯(68mg，0.1mmol)加入到化合物58-3(200mg，0.48mmol)和化合物A-7(704mg，1.95mmol)的1，4-二氧六环/水(10mL/1mL)溶液中，反应加热到110℃并在该温度下搅拌3小时。反应结束后，反应液过滤，滤液减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷/甲醇＝5/1)纯化得到化合物58-4(0.11g，收率：48％)。MS m/z(ESI):446.1[M+1] +。 Bistriphenylphosphine palladium dichloride (68 mg, 0.1 mmol) was added to compound 58-3 (200 mg, 0.48 mmol) and compound A-7 (704 mg, 1.95 mmol) in 1,4-dioxane/water (10 mL/1 mL) solution, the reaction was heated to 110 °C and stirred at this temperature for 3 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue obtained was purified by column chromatography (dichloromethane/methanol=5/1) to obtain compound 58-4 (0.11 g, yield: 48%). MS m/z (ESI): 446.1 [M+1] + .
第四步：化合物58-5的合成The fourth step: the synthesis of compound 58-5
将化合物58-4(120mg，0.67mmol)溶于四氢呋喃/盐酸(5mL/1mL)溶液中，反应在室温下搅拌反应3小时。反应结束后，减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物58-5(0.1g，收率：80.4％)。MS m/z(ESI):418.1[M+1] +。 Compound 58-4 (120 mg, 0.67 mmol) was dissolved in tetrahydrofuran/hydrochloric acid (5 mL/1 mL) solution, and the reaction was stirred at room temperature for 3 hours. After the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain compound 58-5 (0.1 g, yield: 80.4%). MS m/z (ESI): 418.1 [M+1] + .
第五步：化合物58-6的合成The fifth step: the synthesis of compound 58-6
将化合物58-5(100mg，0.24mmol)加入N,N-二甲基甲酰胺二甲基缩醛(42mg，0.36mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应加热到100℃并在该温度下搅拌2小时。反应结束后，减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物58-6(0.1g，收率：80％)。MS m/z(ESI):472.8[M+1] +。 Compound 58-5 (100mg, 0.24mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (42mg, 0.36mmol) in N,N-dimethylformamide (10mL), and the reaction was heated to 100°C and stirred at this temperature for 2 hours. After the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain compound 58-6 (0.1 g, yield: 80%). MS m/z (ESI): 472.8 [M+1] + .
第六步：化合物71的合成Step 6: Synthesis of Compound 71
将化合物58-7(108mg，0.84mmol)和碳酸钾(58mg，0.42mmol)加入到化合物58-6(100mg，0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应加热到90℃并在该温度下搅拌16小时。反应结束后，减压浓缩除去溶剂，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5um；流动相:乙腈-水(0.1％甲酸)；梯度:35-70％)纯化得到化合物71(9.1mg，收率：7.9％)。MS m/z(ESI):538.1[M+1] +； 1H NMR(400MHz,CD 3OD)：δ8.86(d,J＝5.3Hz,1H),8.80(s,1H),8.34(s,1H),8.27(d,J＝5.3Hz,1H),7.48-7.39(m,1H),7.07-6.98(m,2H),6.23(s,1H),4.67(s,2H),4.11-4.04(m,2H),3.66-3.57(m,2H),3.25-3.14(m,1H),2.19(s,3H),2.10-1.96(m,4H),1.94(s,3H)。 Compound 58-7 (108mg, 0.84mmol) and potassium carbonate (58mg, 0.42mmol) were added to compound 58-6 (100mg, 0.21mmol) in N,N-dimethylformamide (10mL) solution, and the reaction was heated to 90°C and stirred at this temperature for 16 hours. After the reaction was finished, the solvent was removed by concentration under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18, 150×21.2mm, 5um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35- 70%) was purified to obtain compound 71 (9.1 mg, yield: 7.9%). MS m/z (ESI): 538.1[M+1] + ; 1 H NMR (400MHz, CD 3 OD): δ8.86(d, J=5.3Hz, 1H), 8.80(s, 1H), 8.34( s,1H),8.27(d,J=5.3Hz,1H),7.48-7.39(m,1H),7.07-6.98(m,2H),6.23(s,1H),4.67(s,2H),4.11 -4.04 (m, 2H), 3.66-3.57 (m, 2H), 3.25-3.14 (m, 1H), 2.19 (s, 3H), 2.10-1.96 (m, 4H), 1.94 (s, 3H).
实施例16化合物12的合成The synthesis of embodiment 16 compound 12
Figure PCTCN2022142967-appb-000058
Figure PCTCN2022142967-appb-000058
第一步：化合物12-2的合成The first step: the synthesis of compound 12-2
将羟胺水溶液(1mL)加入到化合物12-1(234mg，2.0mmol)的乙醇(5mL)溶液中，反应混合物加热至75℃并在该温度下搅拌16小时，反应结束后，反应液减压浓缩得化合物12-2(260mg,粗品)。MS m/z(ESI):151.0[M+1] +。 Hydroxylamine aqueous solution (1 mL) was added to compound 12-1 (234 mg, 2.0 mmol) in ethanol (5 mL) solution, the reaction mixture was heated to 75 ° C and stirred at this temperature for 16 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure Compound 12-2 (260 mg, crude product) was obtained. MS m/z (ESI): 151.0 [M+1] + .
第二步：化合物12-3的合成The second step: the synthesis of compound 12-3
将雷尼镍(508mg)加入到化合物12-2(260mg，1.73mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下常压搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩得化合物12-3(180mg，粗品).MS m/z(ESI):135.1[M+H] +。 Raney nickel (508 mg) was added to a solution of compound 12-2 (260 mg, 1.73 mmol) in methanol (10 mL), and the reaction mixture was stirred under a hydrogen atmosphere at normal pressure for 12 hours. After the reaction, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-3 (180 mg, crude product). MS m/z (ESI): 135.1 [M+H] + .
第三步：化合物12的合成The third step: the synthesis of compound 12
将碳酸钾(104mg，0.75mmol)加入到化合物A(120mg，0.25mmol)和化合物12-3(68 mg，0.50mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物加热至90℃并搅拌12小时。反应结束后，反应液加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并的有机相经饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-50％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物12(17.1mg，收率12.4％)。MS m/z(ESI):545.8[M+1] +。 1H NMR(400MHz,CD 3OD)δ8.86(d,J＝5.3Hz,1H),8.80(s,1H),8.44(d,J＝2.4Hz,1H),8.38(s,1H),8.27(d,J＝5.3Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.80(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),3.70–3.59(m,1H),3.08–2.91(m,4H),2.15(s,3H),2.04(d,J＝0.5Hz,3H)。 Potassium carbonate (104mg, 0.75mmol) was added to compound A (120mg, 0.25mmol) and compound 12-3 (68 mg, 0.50mmol) in N,N-dimethylformamide (5mL) solution, and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2mm , 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-50%; column temperature: 25 ° C; flow rate: 20mL/min; wavelength: 214nm; , yield 12.4%). MS m/z (ESI): 545.8 [M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.86(d, J=5.3Hz, 1H), 8.80(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.38(s, 1H), 8.27(d, J=5.3Hz, 1H), 7.71(ddd, J=9.6, 8.6, 2.4Hz, 1H), 6.80(d, J=0.5Hz, 1H), 5.49(d, J=2.0Hz, 2H ), 3.70–3.59 (m, 1H), 3.08–2.91 (m, 4H), 2.15 (s, 3H), 2.04 (d, J=0.5Hz, 3H).
实施例17化合物37的合成The synthesis of embodiment 17 compound 37
Figure PCTCN2022142967-appb-000059
Figure PCTCN2022142967-appb-000059
将碳酸钾(252mg，1.82mmol)加入到中间体B(300mg，0.61mmol)和中间体16-4(139mg,1.2mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物在微波条件下加热至90℃搅拌2小时。反应结束后，反应液倒入水中(20mL)，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1：0～10：1)纯化得到粗品，该粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-60％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物37(17.7mg，收率：5.1％)。MS m/z(ESI):543.7[M+1] +。 1H NMR(400MHz,CD 3OD)δ8.96(d,J＝5.2Hz,1H),8.70(s,1H),8.44(d,J＝2.4Hz,1H),8.06(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.87(s,1H),5.50(d,J＝1.9Hz,2H),2.75–2.66(m,2H),2.46–2.35(m,2H),2.21(s,3H),2.12(s,3H),2.03-1.90(m,2H)。 Potassium carbonate (252mg, 1.82mmol) was added to Intermediate B (300mg, 0.61mmol) and Intermediate 16-4 (139mg, 1.2mmol) in N,N-dimethylformamide (15mL) solution, the reaction mixture Heat to 90°C under microwave conditions and stir for 2 hours. After the reaction, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0～10:1 ) was purified to obtain a crude product, which was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150 × 21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25° C.; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 37 (17.7 mg, yield: 5.1%). MS m/z (ESI): 543.7 [M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.96(d, J=5.2Hz, 1H), 8.70(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.06(d, J=5.2 Hz, 1H), 7.71(ddd, J=9.6, 8.6, 2.4Hz, 1H), 6.87(s, 1H), 5.50(d, J=1.9Hz, 2H), 2.75–2.66(m, 2H), 2.46 –2.35(m,2H),2.21(s,3H),2.12(s,3H),2.03-1.90(m,2H).
实施例18化合物38的合成The synthesis of embodiment 18 compound 38
Figure PCTCN2022142967-appb-000060
Figure PCTCN2022142967-appb-000060
将碳酸钾(405mg 3mmol)加入到化合物B(200mg，0.4mmol)和化合物33-4(400mg  3mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物加热至90℃搅拌12小时。反应结束后，反应液倒入水中(20mL)，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1：0-10：1)纯化得到粗品，粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-60％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物38(22mg,收率15％)。MS m/z(ESI):558.1[M+1] +。 1H NMR(400MHz,CD 3OD)δ8.98(d,J＝5.3Hz,1H),8.75(s,1H),8.49(d,J＝2.4Hz,1H),8.13(d,J＝5.3Hz,1H),7.76(ddd,J＝9.6,8.6,2.4Hz,1H),6.91(s,1H),5.55(d,J＝1.9Hz,2H),2.41–2.30(m,2H),2.26(s,3H),2.16(s,3H),2.04–1.89(m,6H)。 Potassium carbonate (405mg 3mmol) was added to compound B (200mg, 0.4mmol) and compound 33-4 (400mg 3mmol) in N,N-dimethylformamide (15mL) solution, and the reaction mixture was heated to 90°C and stirred for 12 Hour. After the reaction, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0-10:1 ) was purified to obtain the crude product, and the crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150 × 21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25 ℃; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 38 (22mg, yield 15%). MS m/z (ESI): 558.1 [M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.98(d, J=5.3Hz, 1H), 8.75(s, 1H), 8.49(d, J=2.4Hz, 1H), 8.13(d, J=5.3 Hz, 1H), 7.76(ddd, J=9.6, 8.6, 2.4Hz, 1H), 6.91(s, 1H), 5.55(d, J=1.9Hz, 2H), 2.41–2.30(m, 2H), 2.26 (s,3H), 2.16(s,3H), 2.04–1.89(m,6H).
实施例19化合物42的合成The synthesis of embodiment 19 compound 42
Figure PCTCN2022142967-appb-000061
Figure PCTCN2022142967-appb-000061
0℃下，将丙酰氯(13mg,0.14mmol)滴加到化合物41-5(35mg，0.068mmol)和三乙胺(21mg,0.21mmol)的二氯甲烷(5mL)溶液，反应混合物室温搅拌12小时。反应结束后，反应液减压浓缩去除溶剂，残余物加水(20mL)稀释，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，滤液减压浓缩，残余物经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：35-36％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物42(16.7mg，收率：42％)。MS m/z(ESI):556.8[M+H] +。 1H NMR(400MHz,CD 3OD)δ9.01–8.89(m,1H),8.85(s,1H),8.49(d,J＝2.4Hz,1H),8.43(d,J＝1.7Hz,1H),8.35(dd,J＝5.2,1.4Hz,1H),7.80–7.72(m,1H),6.84(d,J＝1.9Hz,1H),5.53(d,J＝1.8Hz,2H),4.60(dt,J＝14.4,8.7Hz,2H),4.46–4.32(m,2H),4.26–4.14(m,1H),2.26–2.12(m,5H),2.07(d,J＝1.7Hz,3H),1.10(dt,J＝9.2,7.6Hz,3H)。 At 0°C, propionyl chloride (13 mg, 0.14 mmol) was added dropwise to a solution of compound 41-5 (35 mg, 0.068 mmol) and triethylamine (21 mg, 0.21 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 12 Hour. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2mm, 5 μm Mobile phase: acetonitrile-water (0.1% formic acid); Gradient: 35-36%; Column temperature: 25 ℃; Flow rate: 14mL/min; Wavelength: 214nm; rate: 42%). MS m/z (ESI): 556.8 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ9.01–8.89 (m, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.4Hz, 1H), 8.43 (d, J = 1.7Hz, 1H ),8.35(dd,J=5.2,1.4Hz,1H),7.80–7.72(m,1H),6.84(d,J=1.9Hz,1H),5.53(d,J=1.8Hz,2H),4.60 (dt,J=14.4,8.7Hz,2H),4.46–4.32(m,2H),4.26–4.14(m,1H),2.26–2.12(m,5H),2.07(d,J=1.7Hz,3H ), 1.10 (dt, J=9.2, 7.6Hz, 3H).
实施例20化合物43的合成The synthesis of embodiment 20 compound 43
Figure PCTCN2022142967-appb-000062
Figure PCTCN2022142967-appb-000062
0℃下，异丁酰氯(25mg,0.23mmol)滴加到化合物41-5(60mg，0.12mmol)和三乙胺(36mg,0.35mmol)的二氯甲烷(5mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液减压浓缩，残余物加水稀释(20mL)，乙酸乙酯萃取(20mL×3)。合并的有机 相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：25-70％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物43(16.7mg，收率：12.5％)。MS m/z(ESI):580.8[M+H] +。 1H NMR(400MHz,CD3OD)δ8.94(dd,J＝6.7,5.3Hz,1H),8.85(s,1H),8.49(d,J＝2.2Hz,1H),8.41(d,J＝4.1Hz,1H),8.35(d,J＝5.2Hz,1H),7.81–7.72(m,1H),6.85(d,J＝2.6Hz,1H),5.53(s,2H),4.68(t,J＝8.6Hz,1H),4.60(dd,J＝8.6,5.8Hz,1H),4.41(t,J＝9.5Hz,1H),4.36–4.27(m,1H),4.25–4.13(m,1H),2.60(dd,J＝13.6,6.8Hz,1H),2.20(d,J＝1.8Hz,3H),2.07(d,J＝2.0Hz,3H),1.11(dd,J＝6.8,3.2Hz,3H),1.05(dd,J＝14.0,6.8 3.2Hz,3H)。 At 0°C, isobutyryl chloride (25mg, 0.23mmol) was added dropwise to a solution of compound 41-5 (60mg, 0.12mmol) and triethylamine (36mg, 0.35mmol) in dichloromethane (5mL), and the reaction mixture was stirred at room temperature 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 ° C; flow rate: 14mL/min; wavelength: 214nm; Yield: 12.5%). MS m/z (ESI): 580.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.94(dd, J=6.7, 5.3Hz, 1H), 8.85(s, 1H), 8.49(d, J=2.2Hz, 1H), 8.41(d, J=4.1 Hz,1H),8.35(d,J=5.2Hz,1H),7.81–7.72(m,1H),6.85(d,J=2.6Hz,1H),5.53(s,2H),4.68(t,J ＝8.6Hz, 1H), 4.60(dd, J＝8.6, 5.8Hz, 1H), 4.41(t, J＝9.5Hz, 1H), 4.36–4.27(m, 1H), 4.25–4.13(m, 1H) ,2.60(dd,J=13.6,6.8Hz,1H),2.20(d,J=1.8Hz,3H),2.07(d,J=2.0Hz,3H),1.11(dd,J=6.8,3.2Hz, 3H), 1.05 (dd, J = 14.0, 6.8 3.2Hz, 3H).
实施例21化合物44的合成The synthesis of embodiment 21 compound 44
Figure PCTCN2022142967-appb-000063
Figure PCTCN2022142967-appb-000063
第一步：化合物44-2的合成The first step: the synthesis of compound 44-2
将羟胺水溶液(0.5mL)加入到化合物44-1(200mg，1.0mmol)的乙醇溶液中，反应混合物加热至80℃搅拌12小时。反应结束后，反应液减压浓缩得化合物44-2(300mg，粗品)。MS m/z(ESI):230.1[M+H] +。 Aqueous hydroxylamine solution (0.5 mL) was added to a solution of compound 44-1 (200 mg, 1.0 mmol) in ethanol, and the reaction mixture was heated to 80° C. and stirred for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 44-2 (300 mg, crude product). MS m/z (ESI): 230.1 [M+H] + .
第二步：化合物44-3的合成The second step: the synthesis of compound 44-3
将雷尼镍(30mg)加入到化合物44-2(300mg，1.3mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下常压搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩得化合物44-3(300mg，粗品)。MS m/z(ESI):214.1[M+H] +。 Raney nickel (30 mg) was added to a solution of compound 44-2 (300 mg, 1.3 mmol) in methanol (10 mL), and the reaction mixture was stirred under a hydrogen atmosphere at normal pressure for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44-3 (300 mg, crude product). MS m/z (ESI): 214.1 [M+H] + .
第三步：化合物44-4的合成The third step: the synthesis of compound 44-4
将碳酸钾(260mg，1.9mmol)加入到化合物44-3(200mg，0.93mmol)和化合物A(356mg,0.75mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物加热至90℃并搅拌12小时。反应结束后，反应液加水(50mL)稀释，乙酸乙酯萃取(50mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到化合物44-4(90mg，收率：13％)。MS m/z(ESI):525.0[M-100] +。 Potassium carbonate (260mg, 1.9mmol) was added to compound 44-3 (200mg, 0.93mmol) and compound A (356mg, 0.75mmol) in N,N-dimethylformamide (10mL) solution, and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0～10: 1) Purification to obtain compound 44-4 (90 mg, yield: 13%). MS m/z (ESI): 525.0 [M-100] + .
第四步：化合物44-5的合成The fourth step: the synthesis of compound 44-5
常温下，将氯化氢的1,4-二氧六环溶液(4M,2mL)加入到化合物44-4(70mg,0.11mmol)的二氯甲烷(10mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液减压浓缩得到化合物44-5(100mg，粗品)。MS m/z(ESI):525.2[M+H] +。 Hydrogen chloride in 1,4-dioxane (4M, 2 mL) was added to compound 44-4 (70 mg, 0.11 mmol) in dichloromethane (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 44-5 (100 mg, crude product). MS m/z (ESI): 525.2 [M+H] + .
第五步：化合物44的合成The fifth step: the synthesis of compound 44
常温下，将醋酸酐(20mg,0.19mmol)加入到化合物44-5(70mg，0.13mmol)和三乙胺(27mg,0.26mmol)的二氯甲烷(5mL)溶液中，反应混合物室温搅拌2小时。反应完成后，反应液减压浓缩，残余物加水(20mL)稀释，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％三氟乙酸)；梯度：15-50％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)得到化合物44(10mg，收率：12.6％)。MS m/z(ESI):[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.91(d,J＝5.2Hz,1H),8.85(s,1H),8.49(dd,J＝2.2,1.1Hz,1H),8.43–8.30(m,2H),7.80–7.71(m,1H),6.85(s,1H),5.54(s,2H),4.14–3.63(m,5H),2.56–2.30(m,2H),2.20(s,3H),2.08(dd,J＝11.2,5.0Hz,6H)。 At room temperature, acetic anhydride (20 mg, 0.19 mmol) was added to a solution of compound 44-5 (70 mg, 0.13 mmol) and triethylamine (27 mg, 0.26 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2mm , 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 15-50%; column temperature: 25 ° C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 44 (10mg , yield: 12.6%). MS m/z (ESI): [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.91(d, J=5.2Hz, 1H), 8.85(s, 1H), 8.49(dd, J=2.2, 1.1Hz, 1H), 8.43–8.30(m ,2H),7.80–7.71(m,1H),6.85(s,1H),5.54(s,2H),4.14–3.63(m,5H),2.56–2.30(m,2H),2.20(s,3H ), 2.08 (dd, J=11.2, 5.0Hz, 6H).
实施例22化合物66、66-P1、66-P2、66-P3和66-P4的合成Synthesis of Example 22 Compounds 66, 66-P1, 66-P2, 66-P3 and 66-P4
Figure PCTCN2022142967-appb-000064
Figure PCTCN2022142967-appb-000064
第一步：化合物66-2的合成The first step: the synthesis of compound 66-2
将化合物66-1(3g,23mmol)加入到氨的乙醇(150mL)溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液减压浓缩得到化合物66-2(3g，收率：90％)。MS m/z(ESI):130.3[M+1] +。 Compound 66-1 (3 g, 23 mmol) was added to a solution of ammonia in ethanol (150 mL), and the reaction mixture was stirred at 90° C. for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 66-2 (3 g, yield: 90%). MS m/z (ESI): 130.3 [M+1] + .
第二步：化合物66-3的合成The second step: the synthesis of compound 66-3
将对甲苯磺酰氯(5.3g,27.8mmol)加入到化合物66-2(3g,23.2mmol)和三乙胺(4.7g,46mmol)的二氯甲烷(20mL)溶液中，反应混合物室温搅拌5小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到化合物66-3(5.2g，收率：71％)。MS m/z(ESI):284.0[M+1] +。 p-Toluenesulfonyl chloride (5.3g, 27.8mmol) was added to a solution of compound 66-2 (3g, 23.2mmol) and triethylamine (4.7g, 46mmol) in dichloromethane (20mL), and the reaction mixture was stirred at room temperature for 5 hours . After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0~10:1) to obtain compound 66-3 (5.2 g, yield: 71%). MS m/z (ESI): 284.0 [M+1] + .
第三步：化合物66-4的合成The third step: the synthesis of compound 66-4
将化合物66-3(5.78g,20.4mmol)和氰化钠(2g,40.8mmol)的二甲基亚砜(40mL)溶液加热至110℃并在该温度下搅拌16小时。反应结束后，反应液加水(150mL)淬灭，用乙酸乙酯萃取(100mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，经硅胶柱层析(二氯甲烷：甲醇＝1:0～10:1)纯化得到化合物66-4(400mg，收率：13％)。 1H NMR(400MHz,CD 3OD)δ3.30–3.21(m,2H),2.68(s,3H),2.64–2.51(m,2H),2.50–2.42(m,2H)。 A solution of compound 66-3 (5.78 g, 20.4 mmol) and sodium cyanide (2 g, 40.8 mmol) in dimethyl sulfoxide (40 mL) was heated to 110° C. and stirred at this temperature for 16 hours. After the reaction, the reaction solution was quenched with water (150 mL), extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography (2 Chloromethane:methanol=1:0～10:1) was purified to obtain compound 66-4 (400 mg, yield: 13%). 1 H NMR (400 MHz, CD 3 OD) δ 3.30-3.21 (m, 2H), 2.68 (s, 3H), 2.64-2.51 (m, 2H), 2.50-2.42 (m, 2H).
第四步：化合物66-5的合成The fourth step: the synthesis of compound 66-5
将羟胺水溶液(1mL)加入到化合物66-4(400mg,2.89mmol)的乙醇(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物66-5(350mg，收率：56％)。MS m/z(ESI):172.1[M+1] +。 Hydroxylamine aqueous solution (1 mL) was added to a solution of compound 66-4 (400 mg, 2.89 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75° C. for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 66-5 (350 mg, yield: 56%). MS m/z (ESI): 172.1 [M+1] + .
第五步：化合物66-6的合成The fifth step: the synthesis of compound 66-6
将雷尼镍(1.2g,20mmol)加入到化合物66-5(350mg,2mmol)和乙酸(122mg,2mmol)的甲醇(15mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物66-6(300mg，收率：89％)。MS m/z(ESI):156.2[M+1] +。 Raney nickel (1.2 g, 20 mmol) was added to a solution of compound 66-5 (350 mg, 2 mmol) and acetic acid (122 mg, 2 mmol) in methanol (15 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 66-6 (300 mg, yield: 89%). MS m/z (ESI): 156.2 [M+1] + .
第六步：化合物66的合成Step 6: Synthesis of Compound 66
将碳酸钾(232mg,1.68mmol)加入到化合物66-6(196mg,1.26mmol)和化合物A(200mg,0.42mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到粗品化合物，粗品经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO 2(NH 4OH 0.2％)，总流速：40g/min)拆分得到化合物66-P1(16.3mg，收率6.8％)，化合物66-P2(7.4mg，收率3.1％)，化合物66-P3(14.7mg，收率6.1％)和化合物66-P4(8.2mg，收率3.4％)。 Potassium carbonate (232mg, 1.68mmol) was added to compound 66-6 (196mg, 1.26mmol) and compound A (200mg, 0.42mmol) in N,N-dimethylformamide (10mL) solution, and the reaction mixture was heated at 90 Stir at °C for 16 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0～10:1) to obtain the crude product compound, which was subjected to supercritical fluid chiral chromatography ( Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) to obtain compound 66-P1 (16.3mg, yield 6.8%), compound 66-P2 (7.4mg, yield 3.1%), compound 66-P3 (14.7mg, yield 6.1%) and compound 66-P4 (8.2mg, yield 3.4%) ).
化合物66-P1：Compound 66-P1:
MS m/z(ESI):566.8[M+1] +。超临界流体色谱SFC：保留时间＝7.2min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.73(d,J＝5.3Hz,2H),8.40–8.34(m,2H),8.17(d,J＝5.3Hz,1H),7.68–7.59(m,1H),6.74(s,1H),5.42(d,J＝1.8Hz,2H),3.69–3.59(m,1H),3.01(ddd,J＝17.8,9.6,8.3Hz,1H),2.67–2.54(m,7H),2.08(s,3H),1.98(s,3H)。 MS m/z (ESI): 566.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 7.2min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.73(d, J=5.3Hz, 2H), 8.40–8.34(m, 2H), 8.17(d, J=5.3Hz, 1H), 7.68–7.59(m ,1H),6.74(s,1H),5.42(d,J=1.8Hz,2H),3.69–3.59(m,1H),3.01(ddd,J=17.8,9.6,8.3Hz,1H),2.67– 2.54(m,7H),2.08(s,3H),1.98(s,3H).
化合物66-P2：Compound 66-P2:
MS m/z(ESI):566.8[M+1] +。超临界流体色谱SFC：保留时间＝7.9min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.88(d,J＝5.3Hz,1H),8.85(s,1H),8.49(d,J＝2.3Hz,1H),8.43(s,1H),8.29(d,J＝5.3Hz,1H),7.81–7.72(m,1H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.91(dt,J＝14.8,7.2Hz,1H),3.31–3.24(m,1H),2.75–2.58(m,7H),2.20(s,3H),2.09(s,3H)。 MS m/z (ESI): 566.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 7.9 min, UV = 214 nm. 1 H NMR (400MHz, CD 3 OD) δ8.88(d, J=5.3Hz, 1H), 8.85(s, 1H), 8.49(d, J=2.3Hz, 1H), 8.43(s, 1H), 8.29(d, J=5.3Hz, 1H), 7.81–7.72(m, 1H), 6.85(s, 1H), 5.53(d, J=1.8Hz, 2H), 3.91(dt, J=14.8, 7.2Hz ,1H), 3.31–3.24(m,1H), 2.75–2.58(m,7H), 2.20(s,3H), 2.09(s,3H).
化合物66-P3：Compound 66-P3:
MS m/z(ESI):566.8[M+1] +。超临界流体色谱SFC：保留时间＝8.56min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.85(d,J＝5.3Hz,2H),8.49(d,J＝2.4Hz,1H),8.47(s,1H),8.29(d,J＝5.3Hz,1H),7.78–7.72(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),3.82–3.72(m,1H),3.18–3.09(m,1H),2.73–2.58(m,7H),2.20(s,3H),2.10(s,3H)。 MS m/z (ESI): 566.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 8.56min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.85(d, J=5.3Hz, 2H), 8.49(d, J=2.4Hz, 1H), 8.47(s, 1H), 8.29(d, J=5.3 Hz,1H),7.78–7.72(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),3.82–3.72(m,1H),3.18–3.09(m,1H) ,2.73–2.58(m,7H),2.20(s,3H),2.10(s,3H).
化合物66-P4：Compound 66-P4:
MS m/z(ESI):566.8[M+1] +。超临界流体色谱SFC：保留时间＝9.8min，UV＝214nm。1H NMR(400MHz,CD 3OD)δ8.76(d,J＝5.2Hz,1H),8.73(s,1H),8.37(d,J＝2.4Hz,1H),8.31(s,1H),8.17(d,J＝5.3Hz,1H),7.68–7.60(m,1H),6.73(s,1H),5.41(d,J＝1.8Hz,2H),3.86–3.73(m,1H),3.18–3.10(m,1H),2.65–2.55(m,7H),2.08(s,3H),1.97(s,3H)。 MS m/z (ESI): 566.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 9.8 min, UV = 214 nm. 1H NMR (400MHz, CD 3 OD) δ8.76(d, J=5.2Hz, 1H), 8.73(s, 1H), 8.37(d, J=2.4Hz, 1H), 8.31(s, 1H), 8.17 (d,J=5.3Hz,1H),7.68–7.60(m,1H),6.73(s,1H),5.41(d,J=1.8Hz,2H),3.86–3.73(m,1H),3.18– 3.10 (m, 1H), 2.65–2.55 (m, 7H), 2.08 (s, 3H), 1.97 (s, 3H).
实施例23化合物69的合成The synthesis of embodiment 23 compound 69
Figure PCTCN2022142967-appb-000065
Figure PCTCN2022142967-appb-000065
第一步：化合物69-2的合成The first step: the synthesis of compound 69-2
将羟胺水溶液(1mL)加入到化合物69-1(500mg,3.93mmol)的乙醇(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物69-2(610mg，收率：82.3％)。MS m/z(ESI):161.1[M+1] +。 Aqueous hydroxylamine solution (1 mL) was added to a solution of compound 69-1 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75° C. for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 69-2 (610 mg, yield: 82.3%). MS m/z (ESI): 161.1 [M+1] + .
第二步：化合物69-3的合成The second step: the synthesis of compound 69-3
将雷尼镍(670mg，11.42mmol)加入到化合物69-2(610mg,3.81mmol)的甲醇和乙酸(15mL/1mL)混合溶液中，反应混合物在室温下搅拌16小时。反应结束后，反应液减压浓缩得到化合物69-3(500mg,粗品)。MS m/z(ESI):145.1.[M+1] +。 Raney nickel (670 mg, 11.42 mmol) was added to a mixed solution of compound 69-2 (610 mg, 3.81 mmol) in methanol and acetic acid (15 mL/1 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 69-3 (500 mg, crude product). MS m/z (ESI): 145.1.[M+1] + .
第三步：化合物69-4的合成The third step: the synthesis of compound 69-4
将碳酸钾(174mg,1.26mmol)加入到化合物69-3(182mg,1.26mmol)和化合物A(150mg,0.32mmol)的乙腈(5mL)溶液中，反应混合物在75℃下搅拌12小时。反应结束后，反应液加水(30mL)稀释，乙酸乙酯萃取(30mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩后，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物69-4(100mg，收率：54％)。MS m/z(ESI):555.7.[M+1] +。 Potassium carbonate (174 mg, 1.26 mmol) was added to a solution of compound 69-3 (182 mg, 1.26 mmol) and compound A (150 mg, 0.32 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 75° C. for 12 hours. After the reaction, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol=1/0～10/1) was purified to obtain compound 69-4 (100 mg, yield: 54%). MS m/z (ESI): 555.7.[M+1] + .
第四步：化合物69的合成The fourth step: the synthesis of compound 69
将过硫酸氢钾(331.6mg,0.54mmol)加入到化合物69-4(100mg,0.18mmol)的甲醇(5mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液减压浓缩，残余物加水(20mL)稀释，用乙醚萃取(20mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压 浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到粗品化合物69，该粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-60％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物69(40mg，收率：35.9％)。MS m/z(ESI):587.7[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(d,J＝5.2Hz,1H),8.83(s,1H),8.57(d,J＝2.4Hz,1H),8.29(s,1H),8.19(d,J＝5.2Hz,1H),8.07(ddd,J＝10.0,9.0,2.4Hz,1H),6.79(s,1H),5.46(d,J＝1.7Hz,2H),3.35–3.32(m,1H),3.27(ddd,J＝9.5,3.8,1.7Hz,2H),3.09(dt,J＝6.9,6.2Hz,2H),2.45–2.34(m,2H),2.32–2.20(m,2H),2.06(s,3H),1.93(s,3H)。 Potassium persulfate (331.6 mg, 0.54 mmol) was added to a solution of compound 69-4 (100 mg, 0.18 mmol) in methanol (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with ether (20 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (petroleum ether/ethyl acetate=1/0～1/2) was purified to obtain crude compound 69, which was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150×21.2mm, 5 μm; mobile phase : acetonitrile-water (0.1% formic acid); Gradient: 40-60%; Column temperature: 25°C; Flow rate: 20mL/min; Wavelength: 214nm; ). MS m/z (ESI): 587.7 [M+1] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(d, J=5.2Hz, 1H), 8.83(s, 1H), 8.57(d, J=2.4Hz, 1H), 8.29(s, 1H) ,8.19(d,J=5.2Hz,1H),8.07(ddd,J=10.0,9.0,2.4Hz,1H),6.79(s,1H),5.46(d,J=1.7Hz,2H),3.35– 3.32(m,1H),3.27(ddd,J＝9.5,3.8,1.7Hz,2H),3.09(dt,J＝6.9,6.2Hz,2H),2.45–2.34(m,2H),2.32–2.20( m,2H), 2.06(s,3H), 1.93(s,3H).
实施例24化合物70、70-P1、70-P2、70-P3和70-P4的合成Synthesis of Example 24 Compound 70, 70-P1, 70-P2, 70-P3 and 70-P4
Figure PCTCN2022142967-appb-000066
Figure PCTCN2022142967-appb-000066
第一步：化合物70-2的合成The first step: the synthesis of compound 70-2
将硼氢化钠(1.53g,40.4mmol)加入到化合物70-1(3.5g,36.8mmol)的甲醇(150mL)溶液中，反应混合物在0℃下搅拌1小时。反应结束后，反应液加水(100mL)淬灭，用乙酸乙酯(100mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物70-2(3.4g，收率：76％)。Sodium borohydride (1.53 g, 40.4 mmol) was added to a solution of compound 70-1 (3.5 g, 36.8 mmol) in methanol (150 mL), and the reaction mixture was stirred at 0° C. for 1 hour. After the reaction, the reaction solution was quenched with water (100mL), extracted with ethyl acetate (100mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-2 (3.4g , yield: 76%).
第二步：化合物70-3的合成The second step: the synthesis of compound 70-3
0℃下，将对甲苯磺酰氯(7.34g,38.5mmol)滴加到化合物70-2(3.4g,35mmol)、4-二甲氨基吡啶(0.86g,7mmol)和三乙胺(4.25g,42mmol)的二氯甲烷(50mL)溶液中，反应混合物室温搅拌2小时。反应结束后，反应液用盐酸(1M)淬灭，二氯甲烷萃取(30mL ×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～10/1)纯化得到化合物70-3(5g，收率：54％)。 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.3Hz,2H),7.37(d,J＝8.0Hz,2H),4.81–4.69(m,1H),2.74–2.59(m,3H),2.59–2.48(m,2H),2.46(s,3H)。 At 0°C, p-toluenesulfonyl chloride (7.34g, 38.5mmol) was added dropwise to compound 70-2 (3.4g, 35mmol), 4-dimethylaminopyridine (0.86g, 7mmol) and triethylamine (4.25g, 42 mmol) in dichloromethane (50 mL), the reaction mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was quenched with hydrochloric acid (1M), extracted with dichloromethane (30mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. (Petroleum ether/ethyl acetate=1/0～10/1) was purified to obtain compound 70-3 (5 g, yield: 54%). 1 H NMR (400MHz, CDCl 3 ) δ7.77(d, J=8.3Hz, 2H), 7.37(d, J=8.0Hz, 2H), 4.81–4.69(m,1H), 2.74–2.59(m, 3H), 2.59–2.48(m, 2H), 2.46(s, 3H).
第三步：化合物70-4的合成The third step: the synthesis of compound 70-4
将硫代乙酸钾(3.64g,31.8mmol)加入到化合物70-3(4g,15.91mmol)N,N-二甲基甲酰胺(40mL)溶液中，反应混合物在80℃下搅拌2小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～3/1)纯化得到化合物70-4(2g，收率：72％)。 1H NMR(400MHz,CDCl 3)δ4.31–4.18(m,1H),3.29–3.25(m,1H),2.93–2.86(m,2H),2.50–2.42(m,2H),2.31(s,3H)。 Potassium thioacetate (3.64 g, 31.8 mmol) was added to compound 70-3 (4 g, 15.91 mmol) N,N-dimethylformamide (40 mL) solution, and the reaction mixture was stirred at 80° C. for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0-3/1) to obtain compound 70-4 (2 g, yield: 72%). 1 H NMR (400MHz, CDCl 3 ) δ4.31–4.18(m,1H),3.29–3.25(m,1H),2.93–2.86(m,2H),2.50–2.42(m,2H),2.31(s ,3H).
第四步：化合物70-5的合成The fourth step: the synthesis of compound 70-5
将碳酸钾(890mg,6.44mmol)加入到化合物70-4(500mg,3.22mmol)的甲醇(10mL)溶液中，反应混合物在50℃下搅拌3小时。反应结束后，反应液加水(10mL)稀释，用1N盐酸调pH＝4，乙酸乙酯萃取(15mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～3/1)纯化得到化合物70-5(600mg，收率：74％)。 1H NMR(400MHz,CDCl 3)δ3.81–3.73(m,2H),3.31–3.11(m,2H),2.83–2.62(m,4H),2.55–2.35(m,4H)。 Potassium carbonate (890 mg, 6.44 mmol) was added to a solution of compound 70-4 (500 mg, 3.22 mmol) in methanol (10 mL), and the reaction mixture was stirred at 50° C. for 3 hours. After the reaction, the reaction liquid was diluted with water (10 mL), adjusted to pH = 4 with 1N hydrochloric acid, extracted with ethyl acetate (15 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue The compound was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0～3/1) to obtain compound 70-5 (600 mg, yield: 74%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.81–3.73 (m, 2H), 3.31–3.11 (m, 2H), 2.83–2.62 (m, 4H), 2.55–2.35 (m, 4H).
第五步：化合物70-6的合成The fifth step: the synthesis of compound 70-6
将盐酸(31.2mL,2M)加入到化合物70-5(700mg,3.12mmol)的四氢呋喃(15mL)溶液中，搅拌下加入锌粉(2.04g,3.12mmol)，反应混合物在45℃下搅拌1小时。反应结束后，反应液减压浓缩，残余物加水(10mL)稀释，乙酸乙酯萃取(15mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，得到化合物70-6(320mg，收率：81％)。 1H NMR(400MHz,CDCl 3)δ3.80–3.74(m,1H),3.22–3.30(m,1H),2.95–2.79(m,2H),2.45–2.30(m,2H),1.90(d,J＝7.2Hz,1H)。 Hydrochloric acid (31.2mL, 2M) was added to a solution of compound 70-5 (700mg, 3.12mmol) in tetrahydrofuran (15mL), zinc powder (2.04g, 3.12mmol) was added under stirring, and the reaction mixture was stirred at 45°C for 1 hour . After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), extracted with ethyl acetate (15 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70 -6 (320 mg, yield: 81%). 1 H NMR (400MHz, CDCl 3 ) δ3.80–3.74(m,1H),3.22–3.30(m,1H),2.95–2.79(m,2H),2.45–2.30(m,2H),1.90(d , J=7.2Hz, 1H).
第六步：化合物70-7的合成Step 6: Synthesis of Compound 70-7
将碘甲烷(1.2g,8.5mmol)加入到化合物70-7(320mg,2.83mmol)和碳酸钾(781mg,5.6mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液加水(10mL)稀释，乙酸乙酯萃取(15mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～4/1)纯化得到化合物70-7(350mg，收率：87％)。 1H NMR(400MHz,CDCl 3)δ3.67–3.56(m,1H),3.36–3.24(m,1H),2.81–2.69(m,2H),2.40–2.29(m,2H),2.07(s,3H)。 Iodomethane (1.2g, 8.5mmol) was added to compound 70-7 (320mg, 2.83mmol) and potassium carbonate (781mg, 5.6mmol) in N,N-dimethylformamide (15mL) solution, and the reaction mixture was Stir for 12 hours. After the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum Ether/ethyl acetate=1/0～4/1) was purified to obtain compound 70-7 (350 mg, yield: 87%). 1 H NMR (400MHz, CDCl 3 ) δ3.67–3.56(m,1H),3.36–3.24(m,1H),2.81–2.69(m,2H),2.40–2.29(m,2H),2.07(s ,3H).
第七步：化合物70-8的合成The seventh step: the synthesis of compound 70-8
将羟胺(649mg,19.65mmol)加入到化合物70-7(500mg,3.93mmol)的乙醇(10mL)溶液中，反应混合物在70℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物70-8(600mg，收率：66％)。MS m/z(ESI):161.2[M+1] +。 Hydroxylamine (649 mg, 19.65 mmol) was added to a solution of compound 70-7 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 70° C. for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 70-8 (600 mg, yield: 66%). MS m/z (ESI): 161.2 [M+1] + .
第八步：化合物70-9的合成The eighth step: the synthesis of compound 70-9
将铝镍合金(2.650g,31.2mmol)加入到化合物70-8(500mg,3.12mmol)和乙酸(2mL)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩得到化合物70-9(500mg，收率：77％)。MS m/z(ESI):145.2[M+1] +。 Al-nickel alloy (2.650 g, 31.2 mmol) was added to compound 70-8 (500 mg, 3.12 mmol) and acetic acid (2 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-9 (500 mg, yield: 77%). MS m/z (ESI): 145.2 [M+1] + .
第九步：化合物70-10的合成Step 9: Synthesis of Compound 70-10
将化合物70-9(455mg,3.15mmol)加入到化合物A(500mg,1.05mmol)和碳酸钾(436mg,3.15mmol)的于N,N-二甲基甲酰胺(15mL)溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～5/4)纯化得到化合物70-10(350mg，收率：50％)。MS m/z(ESI):555.8[M+1] +。 Compound 70-9 (455mg, 3.15mmol) was added to a solution of Compound A (500mg, 1.05mmol) and potassium carbonate (436mg, 3.15mmol) in N,N-dimethylformamide (15mL), and the reaction mixture was Stir at 90°C for 12 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0～5/4) to obtain compound 70-10 (350 mg, yield: 50 %). MS m/z (ESI): 555.8 [M+1] + .
第十步：化合物70的合成Step 10: Synthesis of Compound 70
将过硫酸氢钾(1127mg,1.83mmol)加入到化合物70-10(340mg,0.61mmol)的甲醇(20mL)溶液中，反应混合物室温搅拌12小时，反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物70，化合物70经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO 2(NH 4OH 0.2％)，总流速：40g/min)拆分得到化合物70-P1(16.5mg，收率4.6％)，化合物70-P2(6.3mg，收率1.7％)，化合物70-P3(23.0mg，收率6.4％)和化合物70-P4(6.9mg，收率1.9％)。 Potassium persulfate (1127mg, 1.83mmol) was added to a solution of compound 70-10 (340mg, 0.61mmol) in methanol (20mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was depressurized. Concentration, the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0～10/1) to obtain compound 70, compound 70 was subjected to supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD -H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) resolved to obtain compound 70-P1 (16.5mg, yield 4.6%), compound 70-P2 (6.3 mg, yield 1.7%), compound 70-P3 (23.0 mg, yield 6.4%) and compound 70-P4 (6.9 mg, yield 1.9%).
化合物70-P1：Compound 70-P1:
MS m/z(ESI):587.7[M+1] +。超临界流体色谱SFC：保留时间＝7.59min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.87–8.79(m,2H),8.44(s,2H),8.25(d,J＝5.3Hz,1H),7.73–7.67(m,1H),6.81(s,1H),5.49(s,2H),4.09–3.98(m,1H),3.90–3.79(m,1H),2.99(dt,J＝12.6,9.4Hz,1H),2.92–2.81(m,4H),2.78–2.66(m,2H),2.15(s,3H),2.06(d,J＝0.4Hz,3H)。 MS m/z (ESI): 587.7 [M+1] + . Supercritical fluid chromatography SFC: retention time = 7.59 min, UV = 214 nm. 1 H NMR (400MHz, CD 3 OD) δ8.87–8.79 (m, 2H), 8.44 (s, 2H), 8.25 (d, J=5.3Hz, 1H), 7.73–7.67 (m, 1H), 6.81 (s,1H),5.49(s,2H),4.09–3.98(m,1H),3.90–3.79(m,1H),2.99(dt,J＝12.6,9.4Hz,1H),2.92–2.81(m , 4H), 2.78–2.66 (m, 2H), 2.15 (s, 3H), 2.06 (d, J=0.4Hz, 3H).
化合物70-P2：Compound 70-P2:
MS m/z(ESI):587.7[M+1] +。超临界流体色谱SFC：保留时间＝7.96min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.90–8.78(m,2H),8.47–8.39(m,2H),8.27(d,J＝5.3Hz,1H),7.73–7.67(m,1H),6.80(s,1H),5.49(d,J＝1.9Hz,2H),4.13–3.91(m,2H),2.96–2.88(m,5H),2.88–2.78(m,2H),2.15(s,3H),2.05(s,3H)。 MS m/z (ESI): 587.7 [M+1] + . Supercritical fluid chromatography SFC: retention time = 7.96min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.90–8.78(m,2H),8.47–8.39(m,2H),8.27(d,J＝5.3Hz,1H),7.73–7.67(m,1H) ,6.80(s,1H),5.49(d,J＝1.9Hz,2H),4.13–3.91(m,2H),2.96–2.88(m,5H),2.88–2.78(m,2H),2.15(s ,3H), 2.05(s,3H).
化合物70-P3：Compound 70-P3:
MS m/z(ESI):587.7[M+1] +。超临界流体色谱SFC：保留时间＝9.71min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.87–8.77(m,2H),8.44(d,J＝2.7Hz,2H),8.25(d,J＝5.3Hz,1H),7.73–7.67(m,1H),6.80(d,J＝0.7Hz,1H),5.49(d,J＝1.9Hz,2H),4.07–3.95(m,1H),3.89–3.80(m,1H),3.03–2.96(m,1H),2.92–2.82(m,4H),2.77–2.66(m,2H),2.15(s,3H),2.05(d,J＝0.5Hz,3H)。 MS m/z (ESI): 587.7 [M+1] + . Supercritical fluid chromatography SFC: retention time = 9.71 min, UV = 214 nm. 1 H NMR (400MHz, CD 3 OD) δ8.87–8.77(m, 2H), 8.44(d, J=2.7Hz, 2H), 8.25(d, J=5.3Hz, 1H), 7.73–7.67(m ,1H),6.80(d,J=0.7Hz,1H),5.49(d,J=1.9Hz,2H),4.07–3.95(m,1H),3.89–3.80(m,1H),3.03–2.96( m, 1H), 2.92–2.82 (m, 4H), 2.77–2.66 (m, 2H), 2.15 (s, 3H), 2.05 (d, J=0.5Hz, 3H).
化合物70-P4：Compound 70-P4:
MS m/z(ESI):587.7[M+1] +。超临界流体色谱SFC：保留时间＝10.98min，UV＝214nm。1H NMR(400MHz,CD 3OD)δ8.86(d,J＝5.3Hz,1H),8.80(s,1H),8.48–8.38(m,2H),8.27(d,J＝5.3Hz,1H),7.73–7.67(m,1H),6.80(s,1H),5.49(d,J＝1.8Hz,2H),4.12–3.90(m,2H),2.99–2.78(m,7H),2.15(s,3H),2.04(s,3H)。 MS m/z (ESI): 587.7 [M+1] + . Supercritical fluid chromatography SFC: retention time = 10.98 min, UV = 214 nm. 1H NMR (400MHz, CD 3 OD) δ8.86 (d, J = 5.3Hz, 1H), 8.80 (s, 1H), 8.48–8.38 (m, 2H), 8.27 (d, J = 5.3Hz, 1H) ,7.73–7.67(m,1H),6.80(s,1H),5.49(d,J＝1.8Hz,2H),4.12–3.90(m,2H),2.99–2.78(m,7H),2.15(s ,3H), 2.04(s,3H).
实施例25化合物76的合成The synthesis of embodiment 25 compound 76
Figure PCTCN2022142967-appb-000067
Figure PCTCN2022142967-appb-000067
第一步：化合物76-2的合成The first step: the synthesis of compound 76-2
将氯化亚砜(813g,6.8mmol)加入到化合物76-1(800mg,4.6mmol)的乙醇(20mL)溶液中，反应混合物在60℃下搅拌3小时。反应结束后，反应液冷却至室温，加入饱和碳酸氢钠溶液(10mL)淬灭，减压浓缩除去乙醇，残余物加入水(20mL)，乙酸乙酯(20mL×2)萃取，合并的有机相减压浓缩得到化合物76-2(900mg，粗品)。MS m/z(ESI):204.1[M+H] +。 Thionyl chloride (813 g, 6.8 mmol) was added to a solution of compound 76-1 (800 mg, 4.6 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 60° C. for 3 hours. After the reaction, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (10mL), concentrated under reduced pressure to remove ethanol, the residue was added with water (20mL), extracted with ethyl acetate (20mL×2), and the combined organic phase Concentration under reduced pressure gave compound 76-2 (900 mg, crude product). MS m/z (ESI): 204.1 [M+H] + .
第二步：化合物76-3的合成The second step: the synthesis of compound 76-3
将硼氢化钠(334mg，8.8mmol)加到化合物76-2(900mg，4.4mmol)的乙醇(20mL)溶液中，反应混合物在25℃下搅拌12小时。反应结束后，反应液加入饱和氯化铵溶液(5mL)淬灭，减压浓缩除去乙醇，残余物加入(20mL)水稀释，乙酸乙酯(30mL×3)萃取，合并的有机相减压浓缩得到化合物76-3(600mg，粗品)。MS m/z(ESI):162.1[M+H] +。 Sodium borohydride (334 mg, 8.8 mmol) was added to a solution of compound 76-2 (900 mg, 4.4 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 25° C. for 12 hours. After the reaction, the reaction solution was quenched by adding saturated ammonium chloride solution (5 mL), concentrated under reduced pressure to remove ethanol, the residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phase was concentrated under reduced pressure Compound 76-3 (600 mg, crude product) was obtained. MS m/z (ESI): 162.1 [M+H] + .
第三步：化合物76-4的合成The third step: the synthesis of compound 76-4
向化合物76-3(100mg，0.62mmol)的二氯甲烷(10mL)溶液中滴入2滴的N，N-二甲基甲酰胺后，再加入0.1mL的氯化亚砜溶液，反应混合物室温搅拌2小时。反应结束后，反应液减压浓缩得到化合物76-4(100mg，粗品)。Add 2 drops of N,N-dimethylformamide to a solution of compound 76-3 (100mg, 0.62mmol) in dichloromethane (10mL), then add 0.1mL of thionyl chloride solution, and the reaction mixture at room temperature Stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 76-4 (100 mg, crude product).
第四步：化合物76-5的合成The fourth step: the synthesis of compound 76-5
将化合物A-4(143mg，0.55mmol)加入到化合物76-4(100mg，0.55mmol)和碳酸钾(154mg，1.11mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在65℃下搅拌3小时。反应结束后，反应液加水(50mL)稀释,乙酸乙酯萃取(30mL×3)。合并的有机相经饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～2/1)纯化得到化合物76-5(100mg，收率：45％)。MS m/z(ESI):402.0[M+H] +。 Compound A-4 (143 mg, 0.55 mmol) was added to compound 76-4 (100 mg, 0.55 mmol) and potassium carbonate (154 mg, 1.11 mmol) in N,N-dimethylformamide (5 mL) solution, and the reaction mixture Stir at 65°C for 3 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=1/0～2/1 ) was purified to obtain compound 76-5 (100 mg, yield: 45%). MS m/z (ESI): 402.0 [M+H] + .
第五步：化合物76-6的合成The fifth step: the synthesis of compound 76-6
将N-氯代丁二酰亚胺(50mg，0.37mmol)加入到化合物76-5(100mg，0.25mmol)的异丙醇(10mL)溶液中，反应液在60℃下搅拌16小时。反应结束后，反应液减压浓缩，残 余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～5/1)纯化得到化合物76-6(100mg，收率：92％)。MS m/z(ESI):435.9[M+H] +。 N-chlorosuccinimide (50 mg, 0.37 mmol) was added to a solution of compound 76-5 (100 mg, 0.25 mmol) in isopropanol (10 mL), and the reaction solution was stirred at 60° C. for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0-5/1) to obtain compound 76-6 (100 mg, yield: 92%). MS m/z (ESI): 435.9 [M+H] + .
第六步：化合物76-7的合成Step 6: Synthesis of Compound 76-7
将N，N-二甲基甲酰胺二甲基缩醛(55mg,0.46mmol)加入到化合物76-6(100mg,0.23mmol)的N，N-二甲基甲酰胺(10mL)溶液中，反应混合物在100℃下搅拌16小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～5/1)纯化得到化合物76-7(80mg，收率：71％)。MS m/z(ESI):491.0[M+H] +。 N,N-dimethylformamide dimethyl acetal (55mg, 0.46mmol) was added to compound 76-6 (100mg, 0.23mmol) in N,N-dimethylformamide (10mL) solution, and the reaction The mixture was stirred at 100°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0-5/1) to obtain compound 76-7 (80 mg, yield: 71%). MS m/z (ESI): 491.0 [M+H] + .
第七步：化合物76的合成The seventh step: the synthesis of compound 76
将四氢吡喃-4-甲脒(42mg,0.33mmol)加入到化合物76-7(80mg,0.16mmol)和碳酸钾(68mg,0.49mmol)的N，N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌16小时。反应结束后，反应液加水(50mL)稀释，二氯甲烷萃取(30mL×3)。合并的有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经高压液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5um；流动项：乙腈-水(0.1％甲酸)；梯度：40-70％，柱温：25℃；流速:14mL/min；波长:214nm；柱压：80bar)纯化得到化合物76(13.4mg，收率：14.7％)。MS m/z(ESI):556.1 558.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.82(d,J＝3.9Hz,1H),8.74(s,1H),8.48(d,J＝1.5Hz,1H),8.31(s,1H),8.21(d,J＝3.5Hz,1H),7.59(dd,J＝8.8,1.8Hz,1H),6.42(s,1H),5.43(s,2H),4.11(dd,J＝12.5,6.0Hz,2H),3.58(t,J＝10.8Hz,2H),3.19(t,J＝10.6Hz,1H),2.20(s,3H),2.13-2.07(m,2H),2.01-1.96(m,5H)。 Tetrahydropyran-4-carboxamidine (42 mg, 0.33 mmol) was added to compound 76-7 (80 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N, N-dimethylformamide (10 mL) In solution, the reaction mixture was stirred at 90 °C for 16 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-pressure liquid chromatography (column: Gemini-C18, 150×21.2 mm, 5um; flow item: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25°C; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 76 (13.4mg, Yield: 14.7%). MS m/z (ESI): 556.1 558.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.82(d, J=3.9Hz, 1H), 8.74(s, 1H), 8.48(d, J=1.5Hz, 1H), 8.31(s, 1H), 8.21 (d,J=3.5Hz,1H),7.59(dd,J=8.8,1.8Hz,1H),6.42(s,1H),5.43(s,2H),4.11(dd,J=12.5,6.0Hz, 2H), 3.58(t, J=10.8Hz, 2H), 3.19(t, J=10.6Hz, 1H), 2.20(s, 3H), 2.13-2.07(m, 2H), 2.01-1.96(m, 5H ).
实施例26化合物77的合成The synthesis of embodiment 26 compound 77
Figure PCTCN2022142967-appb-000068
Figure PCTCN2022142967-appb-000068
第一步：化合物77-2的合成The first step: the synthesis of compound 77-2
将二氯亚砜(813mg，6.83mmol)缓慢滴入化合物77-1(800mg，4.56mmol)的乙醇(15mL)溶液中，反应混合物在60℃下搅拌3小时。反应结束后，反应液减压浓缩得到化合物77-2(910mg，粗品)。MS m/z(ESI):203.9[M+H] +。 Thionyl chloride (813 mg, 6.83 mmol) was slowly dropped into a solution of compound 77-1 (800 mg, 4.56 mmol) in ethanol (15 mL), and the reaction mixture was stirred at 60° C. for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 77-2 (910 mg, crude product). MS m/z (ESI): 203.9 [M+H] + .
第二步：化合物77-3的合成The second step: the synthesis of compound 77-3
将硼氢化钠(353.07mg，9.3mmol)分批加入化合物77-2(910mg，4.6mmol)的乙醇(15mL)溶液中，反应混合物在室温下搅拌16小时。反应结束后，反应液减压浓缩，残余物加水 (50mL)稀释，乙酸乙酯萃取(80mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物77-3(700mg，粗品)。MS m/z(ESI):162.0[M+H] +。 Sodium borohydride (353.07 mg, 9.3 mmol) was added in portions to a solution of compound 77-2 (910 mg, 4.6 mmol) in ethanol (15 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (50 mL), and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 77-3 (700 mg, crude product). MS m/z (ESI): 162.0 [M+H] + .
第三步：化合物77-4的合成The third step: the synthesis of compound 77-4
向化合物77-3(120mg，0.74mmol)的二氯甲烷(5mL)溶液中滴入2滴N，N-二甲基甲酰胺后，再加入0.5mL的氯化亚砜溶液，反应混合物室温搅拌2小时。反应结束后，反应液减压浓缩得到化合物77-4(60mg，粗品)。MS m/z(ESI):180.7[M+H] +。 Add 2 drops of N, N-dimethylformamide to a solution of compound 77-3 (120 mg, 0.74 mmol) in dichloromethane (5 mL), then add 0.5 mL of thionyl chloride solution, and stir the reaction mixture at room temperature 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 77-4 (60 mg, crude product). MS m/z (ESI): 180.7 [M+H] + .
第四步：化合物77-5的合成The fourth step: the synthesis of compound 77-5
将化合物A-4(110mg，0.42mmol)加入到化合物77-4(76mg，0.42mmol)和碳酸钾(117mg，0.85mmol)的N,N-二甲基甲酰胺(20mL)溶液中，反应混合物在60℃下搅拌3小时。反应结束后，反应液加水(100mL)稀释，乙酸乙酯萃取(80mL×3)。合并的有机相用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物77-5(80mg，收率42％)。MS m/z(ESI):401.9[M+H] +。 Compound A-4 (110mg, 0.42mmol) was added to compound 77-4 (76mg, 0.42mmol) and potassium carbonate (117mg, 0.85mmol) in N,N-dimethylformamide (20mL) solution, the reaction mixture Stir at 60°C for 3 hours. After the reaction, the reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 77-5 (80 mg, yield 42%). MS m/z (ESI): 401.9 [M+H] + .
第五步：化合物77-6的合成The fifth step: the synthesis of compound 77-6
将N-氯代丁二酰亚胺(26mg，0.19mmol)加入到化合物77-5(80mg，0.91mmol)的异丙醇(15mL)溶液中，反应液混合物在60℃下搅拌3小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(乙酸乙酯/石油醚＝0/1～1/0)纯化得到化合物77-6(80mg，收率：73％)。MS m/z(ESI):437.0[M+H] +。 N-chlorosuccinimide (26 mg, 0.19 mmol) was added to a solution of compound 77-5 (80 mg, 0.91 mmol) in isopropanol (15 mL), and the reaction mixture was stirred at 60° C. for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0/1-1/0) to obtain compound 77-6 (80 mg, yield: 73%). MS m/z (ESI): 437.0 [M+H] + .
第六步：化合物77-7的合成Step 6: Synthesis of compound 77-7
将N，N-二甲基甲酰胺二甲基缩醛(87mg,0.73mmol)加入到化合物77-6(80mg,0.18mmol)的N，N-二甲基甲酰胺(10mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束后，反应液加水(50mL)稀释，乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～50/1)纯化得到化合物77-7(35mg，收率：34％)。MS m/z(ESI):491.0[M+H] +。 N,N-dimethylformamide dimethyl acetal (87mg, 0.73mmol) was added to compound 77-6 (80mg, 0.18mmol) in N,N-dimethylformamide (10mL) solution, and the reaction The mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=1/0～50/1 ) was purified to obtain compound 77-7 (35 mg, yield: 34%). MS m/z (ESI): 491.0 [M+H] + .
第七步：化合物77的合成Step 7: Synthesis of Compound 77
将四氢吡喃-4-甲脒(18mg,0.14mmol)加入到化合物77-7(35mg,0.07mmol)和碳酸钾(29mg,0.21mmol)的N，N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液加水(50mL)稀释，二氯甲烷萃取(30mL×3)。合并的有机相经饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5um；流动项：乙腈-水(0.1％甲酸)；梯度：40-70％，柱温：25℃；流速:14mL/min；波长：214nm；柱压：80bar)纯化得到化合物77(6.6mg，收率：14.2％)。MS m/z(ESI):556.0 558.0[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.88(d,J＝5.3Hz,1H),8.84(s,1H),8.55(d,J＝2.5Hz,1H),8.41(s,1H),8.29(d,J＝5.3Hz,1H),7.97(dd,J＝8.2,2.5Hz,1H),6.81(s,1H),5.58(s,2H),4.12–4.03(m,2H),3.62(dd,J＝17.8,6.6Hz,2H),3.27–3.14(m,1H),2.20(s,3H),2.09–1.96(m,7H)。 Tetrahydropyran-4-carboxamidine (18 mg, 0.14 mmol) was added to compound 77-7 (35 mg, 0.07 mmol) and potassium carbonate (29 mg, 0.21 mmol) in N, N-dimethylformamide (10 mL) In solution, the reaction mixture was stirred at 90 °C for 12 hours. After the reaction, the reaction solution was diluted with water (50 mL), and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18, 150×21.2mm, 5um; flow item: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25°C; flow rate: 14mL/min; wavelength: 214nm; Yield: 14.2%). MS m/z (ESI): 556.0 558.0 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.88(d, J=5.3Hz, 1H), 8.84(s, 1H), 8.55(d, J=2.5Hz, 1H), 8.41(s, 1H), 8.29(d, J=5.3Hz, 1H), 7.97(dd, J=8.2, 2.5Hz, 1H), 6.81(s, 1H), 5.58(s, 2H), 4.12–4.03(m, 2H), 3.62 (dd, J=17.8, 6.6Hz, 2H), 3.27–3.14(m, 1H), 2.20(s, 3H), 2.09–1.96(m, 7H).
实施例27化合物78、78-P1和78-P2的合成Synthesis of Example 27 Compound 78, 78-P1 and 78-P2
Figure PCTCN2022142967-appb-000069
Figure PCTCN2022142967-appb-000069
第一步：化合物78-1的合成The first step: the synthesis of compound 78-1
将化合物69-3(878mg,6.09mmol)加入到化合物B(500mg,1.01mmol)和碳酸钾(981mg,7.10mmol)的乙腈(10mL)溶液中，反应混合物在75℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物78-1(100mg，收率：16％)。MS m/z(ESI):574.0[M+1] +。 Compound 69-3 (878 mg, 6.09 mmol) was added to a solution of compound B (500 mg, 1.01 mmol) and potassium carbonate (981 mg, 7.10 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75° C. for 12 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0～20/1) to obtain compound 78-1 (100mg, yield: 16% ). MS m/z (ESI): 574.0 [M+1] + .
第二步：化合物78的合成The second step: the synthesis of compound 78
将过硫酸氢钾(546mg,0.89mmol)加入到化合物78-1(170mg,0.30mmol)的甲醇(10mL)溶液中，反应混合物室温搅拌16小时，反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物78，化合物78经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO 2(NH 4OH 0.2％)，总流速：40g/min)拆分得到化合物78-P1(15.6mg，收率8.26％)和化合物78-P2(19.0mg，收率10％)。 Potassium persulfate (546mg, 0.89mmol) was added to a solution of compound 78-1 (170mg, 0.30mmol) in methanol (10mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was depressurized. Concentration, the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0～10/1) to obtain compound 78, compound 78 was subjected to supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD -H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) resolved to obtain compound 78-P1 (15.6mg, yield 8.26%) and compound 78-P2 (19.0 mg, yield 10%).
化合物78-P1：Compound 78-P1:
MS m/z(ESI):606.0[M+1] +。超临界流体色谱SFC：保留时间＝4.58min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.89–8.84(m,1H),8.66–8.59(m,1H),8.41(d,J＝2.4Hz,1H),7.95(d,J＝5.2Hz,1H),7.54–7.52(m,1H),6.58(d,J＝0.6Hz,1H),5.41(d,J＝2.0Hz,2H),3.30–3.19(m,1H),3.15–3.04(m,4H),2.41(dd,J＝12.0,5.9Hz,4H),2.15(d,J＝0.4Hz,3H),1.99(s,3H)。 MS m/z (ESI): 606.0 [M+1] + . Supercritical fluid chromatography SFC: retention time = 4.58min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.89–8.84(m,1H),8.66–8.59(m,1H),8.41(d,J=2.4Hz,1H),7.95(d,J=5.2Hz ,1H),7.54–7.52(m,1H),6.58(d,J＝0.6Hz,1H),5.41(d,J＝2.0Hz,2H),3.30–3.19(m,1H),3.15–3.04( m, 4H), 2.41 (dd, J = 12.0, 5.9 Hz, 4H), 2.15 (d, J = 0.4 Hz, 3H), 1.99 (s, 3H).
化合物78-P2：Compound 78-P2:
MS m/z(ESI):606.0[M+1] +。超临界流体色谱SFC：保留时间＝6.39min，UV＝214nm。 1H NMR(400MHz,CD 3OD)δ8.86(d,J＝5.2Hz,1H),8.62(s,1H),8.41(d,J＝2.4Hz,1H),7.95(d,J＝5.2Hz,1H),7.54–7.52(m,1H),6.58(d,J＝0.5Hz,1H),5.41(d,J＝2.0Hz,2H),3.30–3.20(m,1H),3.16–3.04(m,4H),2.41(dd,J＝12.0,5.9Hz,4H),2.15(s,3H),1.99(s,3H)。 MS m/z (ESI): 606.0 [M+1] + . Supercritical fluid chromatography SFC: retention time = 6.39min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.86(d, J=5.2Hz, 1H), 8.62(s, 1H), 8.41(d, J=2.4Hz, 1H), 7.95(d, J=5.2 Hz,1H),7.54–7.52(m,1H),6.58(d,J=0.5Hz,1H),5.41(d,J=2.0Hz,2H),3.30–3.20(m,1H),3.16–3.04 (m, 4H), 2.41 (dd, J = 12.0, 5.9 Hz, 4H), 2.15 (s, 3H), 1.99 (s, 3H).
实施例28化合物82、82-P1和82-P2的合成Synthesis of Example 28 Compound 82, 82-P1 and 82-P2
Figure PCTCN2022142967-appb-000070
Figure PCTCN2022142967-appb-000070
第一步：化合物82-2的合成The first step: the synthesis of compound 82-2
将甲胺(2.38g,35.2mmol)加入到化合物82-1(3g,17.6mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(6.75g,35.2mmol)、1-羟基苯并三唑(4.76g,35.2mmol)和三乙胺(5.34g,52.8mmol)的二氯甲烷(50mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液加水(150mL)稀释，用二氯甲烷萃取(100mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～5/2)纯化得到化合物82-2(1.1g，收率：30％)。MS m/z(ESI):184.1[M+1] +。 Methylamine (2.38g, 35.2mmol) was added to compound 82-1 (3g, 17.6mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.75g, 35.2 mmol), 1-hydroxybenzotriazole (4.76 g, 35.2 mmol) and triethylamine (5.34 g, 52.8 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was diluted with water (150 mL), extracted with dichloromethane (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate=1/0～5/2) was purified to obtain compound 82-2 (1.1 g, yield: 30%). MS m/z (ESI): 184.1 [M+1] + .
第二步：化合物82-3的合成The second step: the synthesis of compound 82-3
将化合物82-2(1.1g,6mmol)加入到氨的乙醇溶液(8.6mL,60mmol)中，反应混合物置于封管内，加热至90℃并在该温度下搅拌12小时。反应结束后，反应液减压浓缩得到化合物82-3(1g，收率：90％)。MS m/z(ESI):168.9[M+1] +。 Compound 82-2 (1.1 g, 6 mmol) was added to ammonia ethanol solution (8.6 mL, 60 mmol), and the reaction mixture was placed in a sealed tube, heated to 90° C. and stirred at this temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 82-3 (1 g, yield: 90%). MS m/z (ESI): 168.9 [M+1] + .
第三步：化合物82-4的合成The third step: the synthesis of compound 82-4
将三氟乙酸酐(1.86g,8.8mmol)加入到化合物82-3(1g,5.9mmol)和三乙胺(3g,29.5mmol)的二氯甲烷(20mL)溶液中，反应混合物室温搅拌2小时。反应结束后，反应液加水(50mL)稀释，用二氯甲烷萃取(50mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物82-4(280mg，收率：28％)。MS m/z(ESI):150.9[M+1] +。 Trifluoroacetic anhydride (1.86g, 8.8mmol) was added to a solution of compound 82-3 (1g, 5.9mmol) and triethylamine (3g, 29.5mmol) in dichloromethane (20mL), and the reaction mixture was stirred at room temperature for 2 hours . After the reaction, the reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol=1/0～10/1) was purified to obtain compound 82-4 (280 mg, yield: 28%). MS m/z (ESI): 150.9 [M+1] + .
第四步：化合物82-5的合成The fourth step: the synthesis of compound 82-5
将羟胺的水溶液(2mL,3.73mmol)加入到化合物82-4(280mg,1.86mmol)的乙醇(10mL)溶液中，反应混合物在75℃下搅拌12小时。反应结束后，反应液减压浓缩得到化合物82-5(300mg，收率：79％)。MS m/z(ESI):184.0[M+1] +。 An aqueous solution of hydroxylamine (2 mL, 3.73 mmol) was added to a solution of compound 82-4 (280 mg, 1.86 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75° C. for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 82-5 (300 mg, yield: 79%). MS m/z (ESI): 184.0 [M+1] + .
第五步：化合物82-6的合成The fifth step: the synthesis of compound 82-6
将雷尼镍(14mg,0.24mmol)加入到化合物82-5(300mg,1.6mmol)和乙酸(1mL)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌12小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物82-6(300mg，收率：98％)。MS m/z(ESI):168.2[M+1] +。 Raney nickel (14 mg, 0.24 mmol) was added to a solution of compound 82-5 (300 mg, 1.6 mmol) and acetic acid (1 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 82-6 (300 mg, yield: 98%). MS m/z (ESI): 168.2 [M+1] + .
第六步：化合物82的合成Step 6: Synthesis of Compound 82
将化合物82-6(300mg,0.6mmol)加入到化合物A(211mg,1.2mmol)和碳酸钾(175mg,1.2mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌12小时，反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物82，化合物82再经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO 2(NH 4OH 0.2％)，总流速：40g/min)拆分得到化合物82-P1(35.2mg，收率9.61％)和化合物82-P2(36.6mg，收率10.61％)。 Compound 82-6 (300mg, 0.6mmol) was added to compound A (211mg, 1.2mmol) and potassium carbonate (175mg, 1.2mmol) in N,N-dimethylformamide (10mL) solution, and the reaction mixture was heated at 90 Stirring at ℃ for 12 hours, after the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0～10/1) to obtain compound 82, and compound 82 was further After supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min ) to obtain compound 82-P1 (35.2 mg, yield 9.61%) and compound 82-P2 (36.6 mg, yield 10.61%).
化合物82-P1：Compound 82-P1:
MS m/z(ESI):578.8[M+1] +。超临界流体色谱SFC：保留时间＝2.37min，UV＝254nm。 1H NMR(400MHz,CD 3OD)δ8.89–8.83(m,2H),8.49(d,J＝2.3Hz,1H),8.39–8.31(m,2H),7.79–7.71(m,1H),6.85(s,1H),5.54(d,J＝1.8Hz,2H),2.77(s,3H),2.43(d,J＝12.0Hz,6H),2.19(s,3H),2.08(s,3H)。 MS m/z (ESI): 578.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 2.37min, UV = 254nm. 1 H NMR (400MHz, CD 3 OD) δ8.89–8.83(m,2H),8.49(d,J=2.3Hz,1H),8.39–8.31(m,2H),7.79–7.71(m,1H) ,6.85(s,1H),5.54(d,J=1.8Hz,2H),2.77(s,3H),2.43(d,J=12.0Hz,6H),2.19(s,3H),2.08(s, 3H).
化合物82-P2：Compound 82-P2:
MS m/z(ESI):578.8[M+1] +。超临界流体色谱SFC：保留时间＝7.9min，UV＝254nm。 1H NMR(400MHz,CD 3OD)δ8.88–8.84(m,2H),8.49(d,J＝2.3Hz,1H),8.38–8.32(m,2H),7.79–7.71(m,1H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),2.77(s,3H),2.45(s,6H),2.19(s,3H),2.08(s,3H)。 MS m/z (ESI): 578.8 [M+1] + . Supercritical fluid chromatography SFC: retention time = 7.9 min, UV = 254 nm. 1 H NMR (400MHz, CD 3 OD) δ8.88–8.84(m,2H),8.49(d,J＝2.3Hz,1H),8.38–8.32(m,2H),7.79–7.71(m,1H) , 6.85(s, 1H), 5.53(d, J=1.8Hz, 2H), 2.77(s, 3H), 2.45(s, 6H), 2.19(s, 3H), 2.08(s, 3H).
根据上述实施例1-28的方法，制备如下化合物：According to the method of above-mentioned embodiment 1-28, prepare following compound:
Figure PCTCN2022142967-appb-000071
Figure PCTCN2022142967-appb-000071
Figure PCTCN2022142967-appb-000072
Figure PCTCN2022142967-appb-000072
Figure PCTCN2022142967-appb-000073
Figure PCTCN2022142967-appb-000073
Figure PCTCN2022142967-appb-000074
Figure PCTCN2022142967-appb-000074
Figure PCTCN2022142967-appb-000075
Figure PCTCN2022142967-appb-000075
Figure PCTCN2022142967-appb-000076
Figure PCTCN2022142967-appb-000076
Figure PCTCN2022142967-appb-000077
Figure PCTCN2022142967-appb-000077
Figure PCTCN2022142967-appb-000078
Figure PCTCN2022142967-appb-000078
Figure PCTCN2022142967-appb-000079
Figure PCTCN2022142967-appb-000079
化合物C：
Figure PCTCN2022142967-appb-000080
参照WO2021195475A1实施例1的方法制备得到。 Compound C:
Figure PCTCN2022142967-appb-000080
It is prepared according to the method of Example 1 of WO2021195475A1.
生物学评价biological evaluation
测试例1.p38 MAPK/MK2体外活性的测定Test example 1. Determination of in vitro activity of p38 MAPK/MK2
化合物对p38 MAPK/MK2的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl 2,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK2/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有500ng/mL inactive MK2(abcam,79910),8ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应1小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测(Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC 50。结果如表1所示。 The inhibitory effect of compounds on p38 MAPK/MK2 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 μM Ser/Thr 4; after 1 hour of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 μL of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex. 400nm, Em.445nm; Ex.400nm, Em.520nm). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC 50 . The results are shown in Table 1.
表1Table 1
化合物compound p38 MAPK/MK2 IC 50(nM) p38 MAPK/MK2 IC 50 (nM)
化合物2Compound 2 6.146.14
化合物2-P1Compound 2-P1 0.60.6
化合物3Compound 3 2.342.34
化合物3-P1Compound 3-P1 2.922.92
化合物4Compound 4 3.563.56
化合物6Compound 6 7.557.55
化合物7Compound 7 35.5335.53
化合物8Compound 8 1.861.86
化合物9Compound 9 4.524.52
化合物10Compound 10 6.676.67
化合物10-P1Compound 10-P1 1.591.59
化合物14-G1Compound 14-G1 12.9212.92
化合物14-G2Compound 14-G2 10.510.5
化合物16Compound 16 1.461.46
化合物16-P1Compound 16-P1 0.120.12
化合物33-P1Compound 33-P1 1.821.82
化合物37Compound 37 1.111.11
化合物38Compound 38 0.180.18
化合物41Compound 41 11.0311.03
化合物41-P1Compound 41-P1 15.1515.15
化合物42Compound 42 46.046.0
化合物44Compound 44 13.5713.57
化合物58Compound 58 4.814.81
化合物63-P1Compound 63-P1 0.450.45
化合物12Compound 12 3.293.29
化合物43Compound 43 135.2135.2
化合物66-P2Compound 66-P2 1.881.88
化合物69Compound 69 28.2228.22
化合物70-P2Compound 70-P2 0.320.32
化合物76Compound 76 8.938.93
化合物78-P1Compound 78-P1 0.350.35
化合物82-P2Compound 82-P2 0.650.65
从表1可知，本公开的化合物对p38 MAPK/MK2具有良好的抑制活性。It can be seen from Table 1 that the compounds of the present disclosure have good inhibitory activity on p38 MAPK/MK2.
测试例2.p38 MAPK/MK5体外活性测定Test example 2. Determination of p38 MAPK/MK5 in vitro activity
化合物对p38 MAPK/MK5的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM， 1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl 2,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK5/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有10μg/mL inactive MK5(abcam,217826),1ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应4小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测(Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC 50。结果如表2所示。 The inhibitory effect of compounds on p38 MAPK/MK5 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA are used as the reaction buffer to configure 2x active p38a/inactive MK5/Ser/Thr 4 mixture, the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 10 μg/mL inactive MK5 (abcam, 217826), 1ng/mL active p38a (Carna, 04-152), 2 μM Ser/Thr 4; after 4 hours of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 μL of stop buffer solution to stop the reaction, and detect with a microplate reader (Ex. 400nm, Em.445nm; Ex.400nm, Em.520nm). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC 50 . The results are shown in Table 2.
表2Table 2
化合物compound p38 MAPK/MK5 IC 50(nM) p38 MAPK/MK5 IC 50 (nM)
化合物3Compound 3 93539353
化合物3-P1Compound 3-P1 31553155
化合物4Compound 4 57295729
化合物6Compound 6 39333933
化合物7Compound 7 93219321
化合物8Compound 8 46214621
化合物9Compound 9 864864
化合物10Compound 10 28942894
化合物10-P1Compound 10-P1 19801980
化合物14-G1Compound 14-G1 773.2773.2
化合物14-G2Compound 14-G2 26742674
化合物16-P1Compound 16-P1 89408940
化合物33-P1Compound 33-P1 679.5679.5
化合物42Compound 42 20912091
化合物58Compound 58 873.7873.7
化合物63-P1Compound 63-P1 54495449
从表2可知，本公开的化合物对p38 MAPK/MK5抑制活性均大于0.6μM。这进一步说明本公开的化合物对p38 MAPK/MK2具有良好的选择性。It can be seen from Table 2 that the inhibitory activity of the compounds of the present disclosure on p38 MAPK/MK5 is greater than 0.6 μM. This further shows that the compound of the present disclosure has good selectivity to p38 MAPK/MK2.
测试例3.p38 MAPK/ATF2体外活性的测定Test example 3. Determination of in vitro activity of p38 MAPK/ATF2
化合物对p38a催化ATF2的抑制作用采用HTRF方法进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，0.25％DMSO,5倍倍比稀释，8个浓度，双复孔；40mM Tris pH 7.5,20mM MgCl2,0.1mg/mL BSA,50μM DTT作为反应缓冲液用来配置3.5x p38a(MAPK14,Carna Biosciences,04-152)蛋白工作液、3.5x Human ATF2 Protein(Sino Biological,11599-H20B)工作液和3.5x ATP工作液，10mM的EDTA用来终止反 应，最终14μL的反应体系在96孔板(cisbio，66PL96025)中进行，含有0.29ng/μL p38a,0.29μM Human ATF2 Protein；25μM ATP。20℃反应35min后，每孔加入预先配置好的抗体溶液(cibio,63ADK015PEG,Phospho-ATF2 Eu Cryptate antibody,Phospho-ATF2 d2 antibody,用Detection buffer稀释40倍)室温孵育过夜，酶标仪检测(HTRF compatible reader)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC 50。结果如表3所示。 The inhibitory effect of compounds on p38a-catalyzed ATF2 was detected by HTRF method. The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 0.25% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 40mM Tris pH 7.5, 20mM MgCl2, 0.1mg/mL BSA, 50μM DTT are used as the reaction buffer to configure 3.5x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5x ATP working solution, 10mM EDTA was used to stop the reaction, and the final 14μL reaction system Carried out in 96-well plate (cisbio, 66PL96025), containing 0.29ng/μL p38a, 0.29μM Human ATF2 Protein; 25μM ATP. After reacting at 20°C for 35 minutes, add a pre-configured antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2 antibody, diluted 40 times with Detection buffer) to each well and incubate overnight at room temperature, and detect with a microplate reader (HTRF compatible reader). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC 50 . The results are shown in Table 3.
表3table 3
化合物compound p38 MAPK/ATF2 IC 50(nM) p38 MAPK/ATF2 IC 50 (nM)
化合物2-P1Compound 2-P1 902.7902.7
化合物3-P1Compound 3-P1 47154715
化合物4Compound 4 2802128021
化合物6Compound 6 854.7854.7
化合物7Compound 7 53895389
化合物8Compound 8 14501450
化合物9Compound 9 69766976
化合物10Compound 10 46574657
化合物10-P1Compound 10-P1 11731173
化合物14-G1Compound 14-G1 1591515915
化合物14-G2Compound 14-G2 82628262
化合物16-P1Compound 16-P1 86348634
化合物33-P1Compound 33-P1 >20000>20000
化合物41Compound 41 >20000>20000
化合物63-P1Compound 63-P1 12501250
从表3可知，本公开的化合物对p38 MAPK/ATF2抑制活性均大于0.8μM。这进一步说明本公开的化合物对p38 MAPK/MK2具有良好的选择性。It can be seen from Table 3 that the inhibitory activity of the compounds of the present disclosure on p38 MAPK/ATF2 is greater than 0.8 μM. This further shows that the compound of the present disclosure has good selectivity to p38 MAPK/MK2.
测试例4.对人PBMC细胞上清TNF-α体外活性测定Test example 4. Determination of in vitro activity of human PBMC cell supernatant TNF-α
化合物对人PBMC细胞上清TNF-α的抑制作用实验方案用Elisa检测试剂盒(碧云天，PI518)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为2μM，5倍倍比稀释，6个浓度，细胞铺板双复孔，Elisa检测为单孔，DMSO终浓度为0.4％，也可根据化合物筛选的实际情况，变更化合物起始浓度、倍比稀释倍数、梯度浓度数量和复孔数。The inhibitory effect of compounds on human PBMC cell supernatant TNF-α was detected by Elisa detection kit (Beiyuntian, PI518). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 2 μM, 5-fold dilution, 6 concentrations, the cells are plated in double wells, the Elisa is detected as a single well, and the final concentration of DMSO is 0.4%. The initial concentration of the compound can also be changed according to the actual situation of compound screening , ratio dilution factor, gradient concentration quantity and duplicate hole number.
新鲜人外周血单个核细胞(PBMC)(赛笠生物)以2*10^5的数量铺在96孔板(Corning,3599)中，每孔含有100μL的RPMI-1640(Gibco#A1049101)+10％FBS(Gibco,10099141C),37℃，5％CO 2过夜培养；待测化合物已25μL/孔的体积加入96孔培养板中，1h后，加入5μL的LPS，使 其终浓度为100ng/mL，阴性对照孔不加LPS及化合物，阳性对照孔中不加化合物，37℃，5％CO 2继续培养24h后，500rcf离心8min收集细胞培养上清，按照Elisaa试剂盒中操作手册进行操作，检测TNF-α的浓度。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC 50。结果如表4所示。 Fresh human peripheral blood mononuclear cells (PBMC) (Sai Li Biological) were plated in 96-well plates (Corning, 3599) in a quantity of 2*10^5, and each well contained 100 μL of RPMI-1640 (Gibco#A1049101)+10 %FBS (Gibco, 10099141C), culture overnight at 37°C, 5% CO 2 ; the compound to be tested was added to a 96-well culture plate in a volume of 25 μL/well, and after 1 hour, 5 μL of LPS was added to make the final concentration 100 ng/mL , no LPS and compounds were added to the negative control wells, no compound was added to the positive control wells, after 37°C, 5% CO 2 continued to culture for 24 hours, the cell culture supernatant was collected by centrifugation at 500rcf for 8 minutes, and the operation was carried out according to the operation manual in the Elisaa kit, and the detection Concentration of TNF-α. The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC 50 . The results are shown in Table 4.
表4Table 4
化合物compound TNF-αIC50(nM)TNF-αIC50(nM)
化合物2Compound 2 45.3845.38
化合物2-P1Compound 2-P1 10.3910.39
化合物3Compound 3 41.4041.40
化合物3-P1Compound 3-P1 6.396.39
化合物6Compound 6 14.9614.96
化合物7Compound 7 41.4841.48
化合物9Compound 9 37.9137.91
化合物10Compound 10 17.6817.68
化合物10-P1Compound 10-P1 7.587.58
化合物14-G1Compound 14-G1 7.967.96
化合物14-G2Compound 14-G2 4.844.84
化合物16Compound 16 29.1529.15
化合物16-P1Compound 16-P1 9.279.27
化合物33-P1Compound 33-P1 22.7922.79
化合物37Compound 37 0.610.61
化合物38Compound 38 0.210.21
化合物41Compound 41 98.8498.84
化合物63-P1Compound 63-P1 1.731.73
化合物66-P2Compound 66-P2 24.6224.62
化合物70-P2Compound 70-P2 9.929.92
化合物82-P2Compound 82-P2 17.2717.27
从表4可知，本公开的化合物对人PBMC细胞的TNF-α具有良好的抑制作用。It can be known from Table 4 that the compounds of the present disclosure have good inhibitory effect on TNF-α of human PBMC cells.
测试例5.体外CYP酶抑制评价Test Example 5. In vitro CYP Enzyme Inhibition Evaluation
本实验采用鸡尾酒法进行待测化合物对CYP酶的1A2，2B6,2C8，2C19,2C9,2D6和3A4亚型酶活性抑制研究，测得待测化合物对几种CYP酶亚型活性的IC50值。对照化合物为：氟伏沙明Fluvoxamine(1A2),酮康唑Ketoconazole(2B6),孟鲁司特钠Montelukast(2C8),反苯环丙胺Tranylcypromine(2C19),磺胺苯吡唑Sulfaphenazole(2C9),奎尼丁Quinindium(2D6)和酮康唑 Ketoconazole(3A4/5)；所用CYP酶探针底物为：非那西丁Phenacetin(1A2)，安非他酮Bupropion(2B6)，阿莫地奎Amodiaquine(2C8)，美芬诺酮Mephenytoin(2C19)，双氯芬酸钠Diclofenac(2C9)，右美沙芬Dextromethorphan(2D6)和睾酮Testosterone(3A4/5)。PBS Buffer为50mM的K2HPO4缓冲液。待测化合物浓度分别为50μM，12.5μM，3.125μM，0.781μM，0.195μM，0.0488μM。将相应探针底物和微粒体加入PBS中，混合均匀，随后分别在对应反应体系中加入对照化合物/待测化合物/DMSO溶液，37℃水浴预孵育5min，加入10mM NADPH溶液，置于37℃水浴反应10min，加入内标乙腈溶液终止反应。4000rpm离心，取上清溶液加入等体积的纯水混合均匀，LC-MS/MS(AB Triple Quard 5500)分别分析各探针底物反应生成物的量，并利用测得的产物生成量用GraphPad Prism 5进行IC50的计算。结果见表5：In this experiment, the cocktail method was used to study the inhibition of the activity of the test compound on CYP enzyme subtypes 1A2, 2B6, 2C8, 2C19, 2C9, 2D6 and 3A4, and the IC50 values of the activity of the test compound on several CYP enzyme subtypes were measured. The control compounds were: Fluvoxamine (1A2), Ketoconazole (2B6), Montelukast (2C8), Tranylcypromine (2C19), Sulfaphenazole (2C9), Quinindium (2D6) and Ketoconazole (3A4/5); the CYP enzyme probe substrates used are: Phenacetin (1A2), Bupropion (2B6), Amodiaquine ( 2C8), Mephenytoin (2C19), Diclofenac (2C9), Dextromethorphan (2D6) and Testosterone (3A4/5). PBS Buffer is 50mM K2HPO4 buffer. The concentrations of the compounds to be tested were 50 μM, 12.5 μM, 3.125 μM, 0.781 μM, 0.195 μM, and 0.0488 μM, respectively. Add the corresponding probe substrate and microsomes into PBS, mix well, then add the control compound/test compound/DMSO solution to the corresponding reaction system, pre-incubate in a water bath at 37°C for 5min, add 10mM NADPH solution, and place at 37°C The reaction was carried out in a water bath for 10 min, and the internal standard acetonitrile solution was added to terminate the reaction. Centrifuge at 4000rpm, take the supernatant solution and add an equal volume of pure water to mix evenly, analyze the amount of each probe substrate reaction product by LC-MS/MS (AB Triple Quard 5500), and use the measured product generation amount to use GraphPad Prism 5 for IC50 calculations. The results are shown in Table 5:
表5table 5
Figure PCTCN2022142967-appb-000081
Figure PCTCN2022142967-appb-000081
从表5可知，本公开化合物10-P1和63-P1对体外CYP酶无抑制作用。It can be seen from Table 5 that compounds 10-P1 and 63-P1 of the present disclosure have no inhibitory effect on CYP enzymes in vitro.
测试例6.体外时间依赖性CYP3A4酶抑制评价Test Example 6. In vitro time-dependent CYP3A4 enzyme inhibition evaluation
本实验通过待测化合物与微粒体反应体系预反应和没有预反应的实验条件下，比较在上述两个条件下，待测化合物对CYP3A4/5亚型酶活性抑制的IC50值变化情况，并计算出相应的IC50 shift值。对照化合物为：Verapamil(CYP3A4/5)，探针底物为：睾酮Testosterone(CYP3A4/5)。PBS Buffer为50mM的K2HPO4缓冲液。待测化合物浓度分别为50μM，10μM，2μM，0.4μM，0.08μM，0.016μM。探针底物与PBS溶液预先配制成底物溶液(1990μL的PBS+10μL底物)。将微粒体加入PBS中，没有预反应组样品在37℃水浴预孵育30min后，在相应反应体系中加入对照化合物/待测化合物/DMSO溶液、10mM NADPH溶液和探针底物溶液，置于37℃水浴反应10min，加入内标乙腈溶液终止反应；预反应组样品相应体系中加入对照化合物/待测化合物/DMSO溶液、10mM NADPH溶液，混合均匀，置于37℃水浴反应30min，接着加入探针底物溶液，置于37℃水浴反应10min，加入内标乙腈溶液终止反应。4000rpm离心后，取上清溶液加入等体积的纯水混合均匀，LC-MS/MS(AB Triple Quard 5500)分别分析各探针底物反应生成物的量，并利用测得的产物生成量用GraphPad Prism 5进行IC50的计算。结果见表6：In this experiment, under the experimental conditions of pre-reaction and no pre-reaction between the test compound and the microsomal reaction system, the change of the IC50 value of the test compound on the inhibition of CYP3A4/5 subtype enzyme activity was compared under the above two conditions, and the calculated Get the corresponding IC50 shift value. The control compound is: Verapamil (CYP3A4/5), and the probe substrate is: Testosterone (CYP3A4/5). PBS Buffer is 50mM K2HPO4 buffer. The concentrations of the compounds to be tested were 50 μM, 10 μM, 2 μM, 0.4 μM, 0.08 μM, and 0.016 μM, respectively. The probe substrate and PBS solution were pre-prepared into a substrate solution (1990 μL of PBS+10 μL of substrate). Add the microsomes into PBS, and pre-incubate the samples of the group without pre-reaction in a 37°C water bath for 30 minutes, then add the control compound/test compound/DMSO solution, 10mM NADPH solution and probe substrate solution to the corresponding reaction system, and place at 37°C. ℃ water bath reaction for 10 minutes, adding internal standard acetonitrile solution to terminate the reaction; adding control compound/test compound/DMSO solution and 10mM NADPH solution to the corresponding system of pre-reaction group samples, mixed evenly, placed in 37 ℃ water bath for 30 minutes, and then added probe The substrate solution was placed in a water bath at 37°C for 10 min, and an internal standard acetonitrile solution was added to terminate the reaction. After centrifugation at 4000rpm, take the supernatant solution and add an equal volume of pure water to mix evenly. LC-MS/MS (AB Triple Quard 5500) analyzes the amount of each probe substrate reaction product respectively, and uses the measured product generation amount to use GraphPad Prism 5 for IC50 calculations. The results are shown in Table 6:
表6Table 6
Figure PCTCN2022142967-appb-000082
Figure PCTCN2022142967-appb-000082
Figure PCTCN2022142967-appb-000083
Figure PCTCN2022142967-appb-000083
从表6可知，本公开化合物10-P1和63-P1没有时间依赖性CYP3A4酶抑制作用。It can be seen from Table 6 that compounds 10-P1 and 63-P1 of the present disclosure have no time-dependent inhibitory effect on CYP3A4 enzymes.
测试例7.体外肝微粒体稳定性评价Test Example 7. In vitro stability evaluation of liver microsomes
本实验所用对照化合物为：Ketanserin，微粒体在实验体系中的终浓度为0.5mg/mL。PBS Buffer为50mM的K2HPO4缓冲液。待测化合物浓度为1μM。将微粒体加入PBS中，分别在对应的反应体系中加入对照化合物/待测化合物，混合均匀后，置于37℃水浴预孵育5min，加入20mM的NADPH溶液，在37℃水浴条件下，启动反应(对于No NADPH样品，用同等体积PBS溶液替代20mM的NADPH溶液)。分别在反应时间点0min，10min，30min，60min和90min时，每个反应体系各取出30μL的反应样品(对于No NADPH样品，在反应时间点0min，90min分别取样)，立刻加入300μL的内标乙腈溶液终止反应。4000rpm离心后，取上清溶液加入等体积的纯水混合均匀，LC-MS/MS(AB Triple Quard 5500)分别检测每个时间点样品中化合物量并计算出T 1/2。结果见表7： The control compound used in this experiment was: Ketanserin, and the final concentration of microsomes in the experimental system was 0.5 mg/mL. PBS Buffer is 50mM K2HPO4 buffer. The concentration of the compound to be tested was 1 μM. Add the microsomes into PBS, add the control compound/test compound to the corresponding reaction system, mix well, place in a 37°C water bath for pre-incubation for 5min, add 20mM NADPH solution, and start the reaction in a 37°C water bath (For No NADPH samples, replace 20 mM NADPH solution with an equal volume of PBS solution). At the reaction time points of 0min, 10min, 30min, 60min and 90min, 30μL of reaction samples were taken from each reaction system (for No NADPH samples, samples were taken at the reaction time points of 0min and 90min), and 300μL of internal standard acetonitrile was added immediately solution to terminate the reaction. After centrifugation at 4000rpm, the supernatant solution was added to an equal volume of pure water and mixed evenly. LC-MS/MS (AB Triple Quard 5500) was used to detect the amount of compounds in the samples at each time point and calculate T 1/2 . The results are shown in Table 7:
表7Table 7
Figure PCTCN2022142967-appb-000084
Figure PCTCN2022142967-appb-000084
从表7可知，本公开化合物10-P1具有良好的体外肝微粒体稳定性(人/小鼠/大鼠)。It can be seen from Table 7 that the disclosed compound 10-P1 has good in vitro liver microsomal stability (human/mouse/rat).
测试例8.小鼠体内药代动力学评价Test Example 8. In vivo pharmacokinetic evaluation in mice
称取化合物溶于DMAC：Solutol：PBS＝1:1:8的混合溶剂中，小鼠静脉/灌胃后，于0.083、0.25、0.5、1、2、4、7和24小时采集全血30μL，使用EDTA-K2抗凝后，立即在4℃下，4000rpm离心5min，取上清，样品冻存于-80℃冰箱。血浆样品的处理：经含内标的CH3CN沉淀剂沉淀后，12700rpm离心10min，取上清进LC-MS/MS(AB Triple Quard 5500)进行分析，获得血药浓度，并通过Winnolin 8.1版本的非房室模型进行参数计算。结果见表8：Weigh the compound and dissolve it in a mixed solvent of DMAC: Solutol: PBS = 1:1:8, collect 30 μL of whole blood at 0.083, 0.25, 0.5, 1, 2, 4, 7 and 24 hours after intravenous/gastric administration of mice After anticoagulation with EDTA-K2, immediately centrifuge at 4000rpm for 5min at 4°C, take the supernatant, and freeze the samples in a -80°C refrigerator. Plasma sample processing: After precipitation by CH3CN precipitant containing internal standard, centrifuge at 12700rpm for 10min, take the supernatant into LC-MS/MS (AB Triple Quard 5500) for analysis, obtain blood drug concentration, and pass Winnolin 8.1 version non-household The parameters of the chamber model are calculated. The results are shown in Table 8:
表8Table 8
Figure PCTCN2022142967-appb-000085
Figure PCTCN2022142967-appb-000085
Figure PCTCN2022142967-appb-000086
Figure PCTCN2022142967-appb-000086
从表8可知，在所给药的浓度剂量和检测时间范围内，本公开化合物10-P1和化合物63-P1均具有良好的暴露量、体内清除率和生物利用度。在静脉注射给药中，化合物10-P1的体内清除率CL为1241.95mL/hr/kg，显著优于化合物C的体内清除率CL(2313.22mL/hr/kg)；在灌胃给药中，化合物10-P1的血药暴露量为2120.68hr*ng/mL，比化合物C的血药暴露量提高了一倍；化合物63-P1的体内清除率CL为1492.93mL/hr/kg，显著优于比化合物C的体内清除率CL(2313.22mL/hr/kg)；在灌胃给药中，化合物63-P1的血药暴露量为2596.40hr*ng/mL，比化合物C的血药暴露量提高了一倍。因此，这表明本公开化合物具有良好的体内药代动力学性质，并显著优于对照化合物C。It can be seen from Table 8 that within the range of the administered concentration, dosage and detection time, the disclosed compound 10-P1 and compound 63-P1 have good exposure, in vivo clearance rate and bioavailability. In intravenous administration, the in vivo clearance rate CL of compound 10-P1 was 1241.95mL/hr/kg, which was significantly better than that of compound C (2313.22mL/hr/kg); in intragastric administration, The blood drug exposure of compound 10-P1 was 2120.68hr*ng/mL, double that of compound C; the in vivo clearance rate CL of compound 63-P1 was 1492.93mL/hr/kg, significantly better than Compared with the in vivo clearance rate CL of compound C (2313.22mL/hr/kg); in the intragastric administration, the blood drug exposure of compound 63-P1 is 2596.40hr*ng/mL, which is higher than the blood drug exposure of compound C doubled. Therefore, this shows that the compound of the present disclosure has good pharmacokinetic properties in vivo, which is significantly better than that of the control compound C.
以上，对本公开的实施方式进行了说明。但是，本公开不限定于上述实施方式。凡在本公开的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。The embodiments of the present disclosure have been described above. However, the present disclosure is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present disclosure shall be included within the protection scope of the present disclosure.

Claims (11)

  1. 一种如式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药：A compound as shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug:
    Figure PCTCN2022142967-appb-100001
    Figure PCTCN2022142967-appb-100001
    其中，W为CH或N；Wherein, W is CH or N;
    m为0-5的整数；m is an integer of 0-5;
    n为0-3的整数；n is an integer of 0-3;
    环A为C 3-20环烷基、3-20元的杂环基，环A中的碳原子与母核连接，所述3-20元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
    R 1选自H、卤素、CN和C 1-6烷基； R 1 is selected from H, halogen, CN and C 1-6 alkyl;
    R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
    R 3选自H、C 1-10烷基和C 3-20环烷基； R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl;
    R 4选自H、卤素和C 1-10烷基； R 4 is selected from H, halogen and C 1-10 alkyl;
    R 5分别独立地选自H、卤素、-OH、-C 1-6烷基、-C 1-6烷氧基、氧代(＝O)、-C(O)C 1-6烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from H, halogen, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) 2 NR 93a R 93b ;
    R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
    R 7分别独立地选自H、卤素、未取代或被Ra取代的C 1-10烷基和C 3-20环烷基；Ra选自卤素、C 3-20环烷基； R 7 are independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl unsubstituted or substituted by Ra; Ra is selected from halogen, C 3-20 cycloalkyl;
    R 81、R 82、R 83、R 84相同或不同，彼此独立地选自无取代或任选被1、2、3、4或5个Rb取代的C 6-14芳基-C 1-10烷基、5-14元杂芳基-C 1-10烷基、C 6-14芳基和5-14元杂芳基；每个Rb相同或不同，彼此独立地选自卤素、卤代C 1-10烷基、C 1-10烷基和C 1-10烷氧基； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-10 alkoxy;
    R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-6烷基和C 3-20环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  2. 根据权利要求1所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, is characterized in that,
    W为CH或N；W is CH or N;
    m为0-5的整数；m is an integer of 0-5;
    n为0-3的整数；n is an integer of 0-3;
    环A为C 3-20环烷基、3-20元的杂环基，环A中的碳原子与母核连接，所述3-20元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-20 cycloalkyl group, a 3-20 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
    R 1选自H、卤素、CN和C 1-6烷基； R 1 is selected from H, halogen, CN and C 1-6 alkyl;
    R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
    R 3选自H、C 1-10烷基和C 3-20环烷基； R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl;
    R 4选自H、卤素和C 1-10烷基； R 4 is selected from H, halogen and C 1-10 alkyl;
    R 5分别独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、氧代(＝O)、-C(O)C 1-6烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C( O )OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) NR 93a R 93b ;
    R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
    R 7分别独立地选自H、卤素、C 1-10烷基和C 3-20环烷基； R 7 are independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl;
    R 81、R 82、R 83、R 84相同或不同，彼此独立地选自C 6-14芳基-C 1-10烷基、5-14元杂芳基-C 1-10烷基、C 6-14芳基和5-14元杂芳基；其中，C 6-14芳基、5-14元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-10烷基、C 1-10烷基和C 1-6烷氧基取代； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-6 alkoxy;
    R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-6烷基和C 3-20环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  3. 根据权利要求1或2所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, is characterized in that,
    W为CH或N；W is CH or N;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    n为0、1、2、3；n is 0, 1, 2, 3;
    环A为C 3-9环烷基、3-9元的杂环基，环A中的碳原子与母核连接，所述3-9元杂环基中含有1个、2个或更多个O、N或S原子； Ring A is a C 3-9 cycloalkyl group, a 3-9 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains 1, 2 or more O, N or S atoms;
    R 1为卤素； R 1 is halogen;
    R 2选自-OR 81、-NH-C(O)R 82、-NHR 83和-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
    R 3为C 1-3烷基或C 3-6环烷基； R 3 is C 1-3 alkyl or C 3-6 cycloalkyl;
    R 4为C 1-3烷基； R 4 is C 1-3 alkyl;
    R 5分别独立地选自卤素、-OH、-C 1-3烷基、-C 1-3烷氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b； R 5 are independently selected from halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=O), -C(O)C 1-3 alkyl, -C ( O)OH, -C(O)NR91aR91b, -S(O)2R92 and -S ( O ) 2NR93aR93b ;
    R 6选自H、卤素和甲基； R is selected from H, halogen and methyl;
    R 7分别独立地选自H、卤素和C 1-3烷基； R 7 are independently selected from H, halogen and C 1-3 alkyl;
    R 81、R 82、R 83、R 84相同或不同，彼此独立地选自C 6-8芳基-C 1-3烷基、5-6元杂芳基-C 1-3烷基、C 6-14芳基和5-14元杂芳基；其中，C 6-14芳基、5-14元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C 1-3烷基、C 1-3烷基和C 1-3烷氧基取代； R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 1-3 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein, C 6-14 aryl, 5-14 membered heteroaryl are unsubstituted or optionally selected from 1, 2, 3, 4 or 5 independently of each other Substituted from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy;
    R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-3烷基和C 3-6环烷基。 R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl.
  4. 根据权利要求1-3任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位 素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，The compound according to any one of claims 1-3, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein is that
    W为CH或N；W is CH or N;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0或1；n is 0 or 1;
    环A选自哌啶基、四氢-2H-吡喃基、四氢呋喃基、氧杂环丁烷基、环丙基、环丁基、环戊基、环己基、2-氧杂螺[3.3]庚烷基、2-氧杂螺[3.5]壬烷基、2-氮杂螺[3.3]庚烷基、2-氮杂螺[3.5]壬烷基、氮杂环丁烷基、四氢吡咯基、硫杂环丁烷基、四氢-2H-噻喃基；Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3] Heptyl, 2-oxaspiro[3.5]nonyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonyl, azetidinyl, tetrahydropyrrole base, thietanyl, tetrahydro-2H-thiopyranyl;
    R 1选自Cl、Br； R 1 is selected from Cl, Br;
    R 2选自-OR 81、-NH-C(O)R 82、-NHR 83、-C(O)NHR 84； R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 , -C(O)NHR 84 ;
    R 3选自甲基、环丙基； R 3 is selected from methyl, cyclopropyl;
    R 4选自甲基； R 4 is selected from methyl;
    R 5分别独立地选自F、-OH、甲基、甲氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NH 2、-C(O)NHCH 3、-S(O) 2CH 3、-S(O) 2CH 2CH 3、-S(O) 2-环丙烷； R 5 are independently selected from F, -OH, methyl, methoxy, oxo (=O), -C(O)C 1-3 alkyl, -C(O)OH, -C(O) NH 2 , -C(O)NHCH 3 , -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 , -S(O) 2 -cyclopropane;
    R 6选自H、F、Cl； R 6 is selected from H, F, Cl;
    R 7选自H； R7 is selected from H;
    R 81、R 82、R 83、R 84相同或不同，彼此独立地选自无取代或任选被1、2或3个Rb取代的苯基甲基、吡啶基甲基、吡啶基乙基、苯基、吡啶基；每个Rb相同或不同，彼此独立地选自F、Cl、CF 3。 R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl, pyridyl; each Rb is the same or different, independently selected from F, Cl, CF 3 .
  5. 根据权利要求1-4任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，所述环A选自以下结构：The compound according to any one of claims 1-4, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in In that, the ring A is selected from the following structures:
    Figure PCTCN2022142967-appb-100002
    Figure PCTCN2022142967-appb-100002
    优选地，R 5和环A形成的结构选自： Preferably, the structure formed by R and ring A is selected from:
    Figure PCTCN2022142967-appb-100003
    Figure PCTCN2022142967-appb-100003
    优选地，式Ⅰ所示化合物具有式Ⅰa或Ⅰb所示的结构：Preferably, the compound shown in formula I has the structure shown in formula Ia or Ib:
    Figure PCTCN2022142967-appb-100004
    Figure PCTCN2022142967-appb-100004
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、A、W、m、n具有权利要求1-4任一项所述的定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m, and n have the definitions described in any one of claims 1-4.
  6. 根据权利要求1-5任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，式I具有式Ⅱ所示的结构：The compound according to any one of claims 1-5, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein In that, formula I has the structure shown in formula II:
    Figure PCTCN2022142967-appb-100005
    Figure PCTCN2022142967-appb-100005
    其中R 1、R 3、R 4、R 5、R 6、R 7、W、m、n和环A彼此独立地具有权利要求1-5任一项所述的定义； Wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , W, m, n and ring A independently have the definition described in any one of claims 1-5;
    R 10选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH 2取代的下列基团：C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 2-10烯基、C 2-10烯基氧基、C 2-10炔基、C 2-10炔基氧基； R 10 is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 from the following groups: C 1-10 alkyl, C 1-10 alkoxy, Halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkenyloxy, C 2-10 alkynyl, C 2-10 alkynyloxy ;
    每个R 11相同或不同，彼此独立地选自H、卤素、C 1-6烷基、卤代C 1-10烷基； Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-10 alkyl;
    p为0-4的整数；p is an integer of 0-4;
    优选地，R 10选自H、甲基；p为0、1或2； Preferably, R 10 is selected from H, methyl; p is 0, 1 or 2;
    每个R 11相同或不同，彼此独立地选自F、Cl、CF 3； Each R 11 is the same or different, independently selected from F, Cl, CF 3 ;
    优选地，式ⅠI所示化合物具有式ⅠIa或ⅠIb所示的结构：Preferably, the compound shown in formula II has the structure shown in formula IIa or IIb:
    Figure PCTCN2022142967-appb-100006
    Figure PCTCN2022142967-appb-100006
    其中，R 1、R 3、R 4、R 5、R 6、R 7、R 10、R 11、A、W、m、n、p具有上述或权利要求1-5任一项所述的定义。 Wherein, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , A, W, m, n, p have the definitions mentioned above or any one of claims 1-5 .
  7. 根据权利要求1或6所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中
    Figure PCTCN2022142967-appb-100007
    为
    Figure PCTCN2022142967-appb-100008
    R 5选自卤素、-OH、-C 1-3烷基、-C 1-3烷氧基、氧代(＝O)、-C(O)C 1-3烷基、-C(O)OH、-C(O)NR 91aR 91b、-S(O) 2R 92和-S(O) 2NR 93aR 93b，R 91a、R 91b、R 92、R 93a、R 93b相同或不同，彼此独立地选自H、C 1-3烷基和C 3-6环烷基；优选地，R 5选自F、-OH、甲基、甲氧基、-C(O)C 1-3烷基、-C(O)OH、-C(O)NH 2、-C(O)NHCH 3、-S(O) 2CH 3、-S(O) 2CH 2CH 3和-S(O) 2-环丙烷。     The compound according to claim 1 or 6, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, wherein
    Figure PCTCN2022142967-appb-100007
    for
    Figure PCTCN2022142967-appb-100008
    R is selected from halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=O), -C(O)C 1-3 alkyl, -C(O) OH, -C(O)NR 91a R 91b , -S(O) 2 R 92 and -S(O) 2 NR 93a R 93b , R 91a , R 91b , R 92 , R 93a , R 93b are the same or different, are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl; preferably, R is selected from F, -OH, methyl, methoxy, -C(O)C 1-3 Alkyl, -C(O)OH, -C(O)NH 2 , -C(O)NHCH 3 , -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 and -S(O) ) 2 -cyclopropane.
  8. 根据权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，所述化合物具有以下结构：The compound according to any one of claims 1-7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein In that, the compound has the following structure:
    Figure PCTCN2022142967-appb-100009
    Figure PCTCN2022142967-appb-100009
    Figure PCTCN2022142967-appb-100010
    Figure PCTCN2022142967-appb-100010
    Figure PCTCN2022142967-appb-100011
    Figure PCTCN2022142967-appb-100011
    Figure PCTCN2022142967-appb-100012
    Figure PCTCN2022142967-appb-100012
    Figure PCTCN2022142967-appb-100013
    Figure PCTCN2022142967-appb-100013
    Figure PCTCN2022142967-appb-100014
    Figure PCTCN2022142967-appb-100014
    Figure PCTCN2022142967-appb-100015
    Figure PCTCN2022142967-appb-100015
    Figure PCTCN2022142967-appb-100016
    Figure PCTCN2022142967-appb-100016
    Figure PCTCN2022142967-appb-100017
    Figure PCTCN2022142967-appb-100017
    Figure PCTCN2022142967-appb-100018
    Figure PCTCN2022142967-appb-100018
    Figure PCTCN2022142967-appb-100019
    Figure PCTCN2022142967-appb-100019
    其中化合物10和63结构式中的*表示该处存在顺反结构，且*处为顺式或反式的一种；The * in the structural formulas of compounds 10 and 63 means that there is a cis-trans structure, and the * is either cis or trans;
    优选地，式I所示化合物具有以下结构：Preferably, the compound shown in formula I has the following structure:
    Figure PCTCN2022142967-appb-100020
    Figure PCTCN2022142967-appb-100020
    Figure PCTCN2022142967-appb-100021
    Figure PCTCN2022142967-appb-100021
    其中化合物10-P1或10-P2和63-P1或63-P2结构式中的*表示该处存在顺反结构，且* 处为顺式或反式的一种。The * in the structural formulas of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates that there is a cis-trans structure, and the * is either cis or trans.
  9. 权利要求1-8任一项所述化合物的制备方法，其特征在于，包括以下步骤：The preparation method of the compound described in any one of claims 1-8, is characterized in that, comprises the following steps:
    方案一：化合物a1与化合物a2发生偶联反应得到式Ⅰ化合物Scheme 1: Compound a1 and compound a2 undergo a coupling reaction to obtain a compound of formula I
    反应式如下：The reaction formula is as follows:
    Figure PCTCN2022142967-appb-100022
    Figure PCTCN2022142967-appb-100022
    其中，Y为Cl或Br；W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n和环A彼此独立地具有上文所述定义。 Wherein, Y is Cl or Br; W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A are independently defined above.
    方案二：当W为N，R 7为H时，化合物b1与化合物b2反应得到式I化合物 Scheme 2: When W is N and R 7 is H, compound b1 reacts with compound b2 to obtain the compound of formula I
    反应式如下：The reaction formula is as follows:
    Figure PCTCN2022142967-appb-100023
    Figure PCTCN2022142967-appb-100023
    其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、p和环A彼此独立地具有权利要求1-7任一项所述的定义； Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, p and ring A independently have the definition described in any one of claims 1-7;
    优选地，所述反应在无机碱的存在下进行；所述无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化钾中的一种；Preferably, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide;
    优选地，当R 5为OH时，化合物b2中的OH可以被硅保护基保护，所述硅保护基可以为叔丁基二苯基硅基；所述硅保护基在所述反应中会脱除，得到脱保护的OH。 Preferably, when R 5 is OH, the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group will be removed in the reaction In addition, the deprotected OH is obtained.
  10. 一种药物组合物，其包含治疗有效量的权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种，以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically At least one of acceptable salts or prodrug compounds thereof, and one or more pharmaceutically acceptable carriers.
  11. 权利要求1-8任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种或权利要求10中所述的药 物组合物在制备药物中的用途；At least one of the compound of any one of claims 1-8, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound One or the purposes of the pharmaceutical composition described in claim 10 in the preparation of medicine;
    优选地，所述药物为治疗和/或预防与p38激酶抑制剂有关的疾病的药物，例如可以为MK2抑制剂或p38 MAPK/MK2通路调节剂；Preferably, the drug is a drug for treating and/or preventing diseases related to p38 kinase inhibitors, such as MK2 inhibitors or p38 MAPK/MK2 pathway regulators;
    优选地，所述疾病为与p38 MAPK/MK2通路相关的疾病，例如可以为自体免疫疾病和炎症性疾病(如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、系统性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病。Preferably, the disease is a disease related to the p38 MAPK/MK2 pathway, for example, it can be an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.
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