WO2021008173A1 - 一种螺(3,3'-异丙基吡咯烷氧化吲哚)类肝x受体调节剂及其制备方法和应用 - Google Patents

一种螺(3,3'-异丙基吡咯烷氧化吲哚)类肝x受体调节剂及其制备方法和应用 Download PDF

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WO2021008173A1
WO2021008173A1 PCT/CN2020/083073 CN2020083073W WO2021008173A1 WO 2021008173 A1 WO2021008173 A1 WO 2021008173A1 CN 2020083073 W CN2020083073 W CN 2020083073W WO 2021008173 A1 WO2021008173 A1 WO 2021008173A1
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alkyl
cooh
halogenated
alkoxy
independently
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French (fr)
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陈子扬
顾琼
陈浩
徐峻
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深圳市三启药物开发有限公司
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Priority to EP20841629.7A priority Critical patent/EP3992195B1/en
Priority to JP2022503560A priority patent/JP7432704B2/ja
Publication of WO2021008173A1 publication Critical patent/WO2021008173A1/zh
Priority to US17/577,018 priority patent/US20220135579A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of biomedicine. Specifically, the present invention relates to a spiro (3,3'-isopropylpyrrolidine oxyindole) liver X receptor modulator and its preparation method and application.
  • Liver X receptor is a ligand-dependent transcription factor that often forms a heterodimer form with retinol X receptor (RXR): LXR/RXR, under the premise of ligand activation, can interact with The LXR response element (LXRE) on the target gene is combined to regulate the transcription process of the target gene.
  • LXR includes two subtypes, LXR ⁇ and LXR ⁇ . LXR ⁇ is distributed in the liver, small intestine, fat and immune function macrophages, while LXR ⁇ is widely distributed throughout the body.
  • LXR is a nuclear receptor activated by oxidized sterols. It plays an important role in fat, cholesterol, sugar metabolism and inflammation.
  • LXR synthetic agonists include GW3965 and TO901317.
  • the development of LXR agonists can be used as lead compounds for the treatment of diseases such as atherosclerosis, cancer, Alzheimer's disease, and atopic dermatitis.
  • LXR antagonists or inverse agonists are rarely found, mainly including SR9243, SR9238, PP2P, fenofibrate, morin, and foxglove.
  • LXR antagonists or inverse agonists have strong anti-fatty liver activity.
  • the mechanism of LXR antagonists or inverse agonists for lowering lipids is: down-regulation of LXR target genes sterol regulatory element binding protein (SREBP-1c), acetyl-coenzyme A carboxylase (ACC), fat synthase (FAS), hard Acyl-CoA desaturase-1 (SCD-1) reduces triglyceride synthesis.
  • SREBP-1c sterol regulatory element binding protein
  • ACC acetyl-coenzyme A carboxylase
  • FAS fat synthase
  • SCD-1 hard Acyl-CoA desaturase-1
  • SR9243 can also produce broad-spectrum anti-tumor effects by inhibiting glycolysis and lipogenesis in tumor cells.
  • LXR antagonists or inverse agonists can be used as lead compounds for the treatment of hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome and targeted tumor energy metabolism.
  • liver X receptor modulator Through a large number of experimental studies, the inventor proposed a new liver X receptor modulator, and was surprisingly surprised to find that it has significant liver X receptor modulating activity and can not only be effectively used to treat or prevent hyperlipidemia, fat Liver, obesity, diabetes, metabolic syndrome, or used to target tumor energy metabolism, and for cancer such as glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson’s, Alzheimer’s disease, Multiple sclerosis, atopic dermatitis, rheumatoid arthritis and osteoporosis have significant curative effects, and their application prospects are very broad.
  • cancer such as glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson’s, Alzheimer’s disease, Multiple sclerosis, atopic dermatitis, rheumatoid arthritis and osteoporosis have significant curative effects, and their application prospects are very broad.
  • the present invention provides a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (I) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • X 1 and X 2 are independently C(R 7a ) 2 , O, S or NR 8 ;
  • R 3 is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, oxo or C 1-6 alkyl;
  • Each R 4 , R 5 , and R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH or C 1-6 alkyl;
  • Each R 7a , R 7b , R 7c , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-6 alkyl or halogenated C 1-6 alkyl;
  • n1, m2, and n1 are independently 0, 1, 2, 3, or 4.
  • the aforementioned compound may further include at least one of the following additional technical features:
  • each R 4 , R 5 , and R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH or C 1 -4 alkyl;
  • Each R 7a , R 7b , R 7c , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-4 alkyl or halogenated C 1-4 alkyl.
  • each R 4 , R 5 , R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, methyl , Ethyl, n-propyl, isopropyl, tert-butyl or n-butyl;
  • Each R 7a , R 7b , R 7c , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl or 3,3,3- Trifluoropropyl.
  • the present invention is a compound represented by formula (II-1) or (II-2), or a stereoisomer of a compound represented by formula (II-1) and (II-2), geometric isomer Forms, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the present invention is a compound represented by formula (II-1-A), (II-1-B) or (II-1-C), or formula (II-1-A), (II- 1-B), (II-1-C) stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable Salt or prodrug,
  • R 13a is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl , C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 12c is H, D, F, Cl, Br, I, -CN,- NO 2 , -OH, -NH 2 , -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, halogenated C 1-6 alkyl , Hydroxy-substituted C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy
  • the compound represented by formula (II-1-C) can effectively stimulate liver X receptors, effectively treat or prevent glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Drugs for Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, osteoporosis, or a combination thereof.
  • R 13a is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • R 12c is H, D, F, Cl, Br, I, -CN,- NO 2 , -OH, -NH 2 , -COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogenated C 1-4 alkyl , Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy or halo C 1-4 alkoxy
  • R 13a is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, 1-chloroethyl, difluoromethyl, 2- Fluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, 1-hydroxyethyl, dihydroxymethyl, 2-hydroxyethyl or 3,3,3-trihydroxypropyl;
  • R 12c is H, D, F, Cl, Br, I, -CN,- NO 2 , -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, 1-chloroethyl, difluoromethyl , 2-fluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, 1-hydroxyethyl, dihydroxymethyl, 2-hydroxyethyl, 3,
  • the present invention it is of formula (II-1-Aa), (II-1-Ab), (II-1-Ba), (II-1-Bb), (II-1-Ca) or (II-1-Cb) compound, or formula (II-1-Aa), (II-1-Ab), (II-1-Ba), (II-1-Bb), (II-1- Ca), (II-1-Cb) stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or Prodrug,
  • the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate of a compound having one of the following structures , Metabolite, pharmaceutically acceptable salt or its prodrug:
  • the present invention proposes a pharmaceutical composition comprising the aforementioned compound.
  • the aforementioned pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or any combination thereof.
  • the pharmaceutical composition further includes an additional therapeutic agent.
  • the additional therapeutic agent is a drug for the treatment of hyperlipidemia, fatty liver, obesity, diabetes, or metabolic syndrome, or a combination thereof.
  • the additional therapeutic agent is the treatment of glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's, Alzheimer's disease, multiple sclerosis, atopic dermatitis , Rheumatoid arthritis or osteoporosis drugs or their combination.
  • the drugs for treating hyperlipidemia, fatty liver, obesity, diabetes or metabolic syndrome are atorvastatin, gemfibrozil, amoxicillin, doeikang pills, metformin, Glimepiride, repaglinide, empagliflozin, etc. or any combination thereof.
  • the treatment of glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid joints The drugs for inflammation or osteoporosis are temozolomide, formustine, statins, fibrates, trihexyphenidyl, aspirin, non-steroidal anti-inflammatory drugs, or any combination thereof.
  • the statin is lovastatin or simvastatin
  • the fibrate is clofibrate, rifibrate or bezafibrate
  • the non-steroidal anti-inflammatory drug is diclofenac , Nabumetone or Meloxicam.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine or a kit for regulating liver X receptors in order to For scientific research.
  • the medicament or kit is used to inversely agonize liver X receptors or used to stimulate liver X receptors.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of medicines for the treatment or prevention of hyperlipidemia, fatty liver, obesity, Diabetes or metabolic syndrome, or used to target tumor energy metabolism; or the drug is used to treat or prevent glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's disease, Alzheimer's disease , Multiple sclerosis, atopic dermatitis, rheumatoid arthritis, osteoporosis drugs or their combination.
  • Figure 1 is a schematic diagram of the lipid-lowering activity of compound 2a-1 in HepG2 cells and its mechanism of action according to an embodiment of the present invention
  • Figure 2 is a schematic diagram of the lipid-lowering activity of compound 2a-1 in 3T3L1 cells and its mechanism of action according to an embodiment of the present invention
  • Figure 3 shows the lipid-lowering activity of compound 2a-1 according to an embodiment of the present invention in hyperlipidemia mice induced by Triton WR-1339.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot be superimposed but are mirror images of each other.
  • Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention can be used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • a class of compounds can be understood that the term “optionally substituted” and the term “substituted or unsubstituted” can be used interchangeably. Generally speaking, the term “optionally” whether or not preceded by the term “substituted” means that one or more hydrogen atoms in a given structure may be substituted or unsubstituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position
  • alkyl as used in the present invention includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, wherein the alkyl groups can be independently optionally substituted with one or more substituents described in the present invention.
  • the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, and in other embodiments, the alkyl group contains 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
  • haloalkyl refers to the case where the alkyl group may be substituted by one or more identical or different halogen atoms, the halogen atom being F, Cl, Br or I. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl, 3,3,3 -Trifluoropropyl, etc.
  • hydroxy-substituted alkyl group refers to the case where the alkyl group may be substituted by one or more hydroxy groups. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, dihydroxymethyl, 2-hydroxyethyl, 3,3,3- Trihydroxypropyl, etc.
  • amino refers to -NH 2 .
  • alkoxy refers to an alkyl group, as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • alkyl group as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • examples include, but are not limited to, methoxy, ethoxy, propoxy and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • the bicyclic or tricyclic ring system may include fused rings, bridged rings, and spiro rings.
  • the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in this invention.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, at least one of which is aromatic of.
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl means a monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is aromatic, And at least one ring contains one or more heteroatoms.
  • the heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring”, “aromatic heterocycle” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • the ring system formed by the substituent R'connected to the central ring by a bond represents that the substituent R'can be substituted at any substitutable or any reasonable position on the ring.
  • formula a represents that any position on the B'ring that may be substituted can be substituted by R', as shown in formula b, formula c and formula d.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • “Hydrate” in the present invention refers to the compound or its salt provided by the present invention, which also includes water bound by non-covalent intermolecular forces in chemical or non-chemical quantities. It can also be said that solvent molecules are formed by water. Associate.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • esters in the present invention means that the compound represented by formula (I) to formula (IV) containing a hydroxyl group can form an ester that is hydrolyzable in vivo.
  • esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol.
  • the groups of hydrolyzable esters in the compound represented by formula (I)-(IV) containing hydroxyl include, but are not limited to, phosphoric acid group, acetoxymethoxy group, 2,2-dimethylpropionyloxy group Methoxy, alkanoyl, benzoyl, benzylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.
  • N-oxide in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride .
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) to formula (IV) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically-labeled compounds, which are equivalent to the compounds described in formula (I)-formula (II), but one or more of the atoms has an atomic mass or mass number different from the common atomic mass or mass number in nature. Replaced.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention containing the above isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention.
  • the isotope-labeled compounds represented by formula (I)-formula (II) of the present invention and their prodrugs can generally be prepared in this way.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • compositions can be prepared by the active ingredient and a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citric acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or obtained by other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate , Laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectinate, persul
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.
  • alkaline earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc.
  • One of the objectives of the present invention is to provide new compounds with significant liver X receptor modulating activity.
  • the second objective of the present invention is to provide new compounds that can significantly treat hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome, and target tumor energy metabolism.
  • the third objective of the present invention is to provide a method for preparing the liver X receptor modulator.
  • the fourth object of the present invention is to provide the application of the compound in the treatment of hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome and targeted tumor energy metabolism.
  • the present invention provides a method for preparing the spiro (3,3'-isopropylpyrrolidine oxyindole) liver X receptor modulator, which comprises the following steps: dissolving tryptamine and isobutyraldehyde in dichloromethane, Pictet-Spengler reaction occurs in the environment to obtain intermediate 1a; 1a is dissolved in tetrahydrofuran and rearranged under the action of N-bromosuccinimide to obtain intermediate 1b; 1b is dissolved in dichloromethane, and triethylamine is added , React with di-tert-butyl dicarbonate to obtain intermediate 1c; 1c is dissolved in toluene, add cuprous iodide, N,N-dimethylethylenediamine, potassium carbonate, and react with m-chloroiodobenzene to obtain intermediate 1d; 1d is dissolved in 2,4,-dioxane, added bis(dibenzyliden
  • the compound provided by the present invention has significant liver X receptor regulating activity and lipid-lowering activity, and can be used as a lead compound for the treatment of hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome and targeted tumor energy metabolism.
  • the compound provided by the present invention is used to screen out liver X receptor modulators on HEK293T cells using reporter gene method, and the lipid-lowering activity of the compounds in hepatocytes and adipocytes is tested on HepG2 cells and 3T3-L1 cells. It was found that compound 2a-1 had the best liver X receptor regulating activity and lipid-lowering activity, and the lipid-lowering mechanism was studied. The results showed that the compound can down-regulate liver X receptor downstream genes SREBP-1c, ACC, FAS, SCD -1 Play a lipid-lowering effect. At the same time, in the hyperlipidemia model induced by Triton WR-1339 in mice, compound 2a-1 also has lipid-lowering activity.
  • the present invention has the following beneficial effects:
  • the compound provided by the present invention is easy to obtain raw materials, simple to prepare, and has significant liver X receptor regulating activity and lipid-lowering activity.
  • the spiro (3,3'-isopropylpyrrolidine oxyindole) liver X receptor Body regulators exert their lipid-lowering effects by down-regulating the downstream genes of liver X receptors SREBP-1c, ACC, FAS, and SCD-1, and are used in the preparation and treatment of hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome and tumors. Have great application prospects.
  • the spiro (3,3'-isopropylpyrrolidine oxyindole) compound is obtained through six or seven steps of reaction.
  • the reaction route is as follows:
  • reaction solution is washed with saturated ammonium chloride and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude intermediate 1e, which is purified by silica gel column chromatography to obtain the pure product.
  • Example 2 Liver X receptor activity test of the compound obtained in Example 1
  • HEK293T cells human embryonic kidney cells
  • DMEM high glucose
  • fetal bovine serum 10% fetal bovine serum and 1% double antibody at 37°C and 5% CO 2 .
  • HEK293T cells were seeded in 96-well plates with a cell density of 2 ⁇ 10 4 cells/well. After 24 hours, transfection was performed according to Lipofectamine TM 3000 reagent instructions. The specific transfection steps are as follows:
  • the results were analyzed using Renilla luciferase activity to correct the firefly luciferase activity.
  • the liver X receptor inverse agonistic activity of the compounds is shown in Table 1. Analysis of Table 1 shows that compounds 2a, 2a-1, 2a-2, 2b, 2c, 2d, etc. can inversely agonize liver X receptors, among which compound 2a-1 has the best inverse agonistic activity, so its lipid-lowering activity And mechanism research. In addition, the liver X receptor agonistic activity of the compounds is shown in Table 2. From Table 2, it can be seen that compounds 3a, 3b, and 3c can agonize liver X receptors.
  • Table 1 The liver X receptor inverse agonistic activity of the compounds
  • NA means that no activity is shown in the test range, and NT means not detected.
  • Example 3 Study on lipid-lowering activity of compound 2a-1 obtained in Example 1 in HepG2 cells and 3T3-L1 cells
  • HepG2 cells human liver cancer cells
  • 3T3L1 cells mouse pre-adipocytes
  • DMEM high glucose
  • HepG2 cells were seeded on a 12-well plate and starved with DMEM (low sugar) medium for 12 hours. When the cells grow to 70% density, change to DMEM (high sugar) medium and add drugs for 24 hours.
  • DMEM low sugar
  • Cells were seeded in a 48-well plate, cultured in complete medium to complete contact (day 0), and the medium was changed to differentiated medium I (the complete medium was supplemented with 2 ⁇ g/mL insulin, 100ng/mL dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine and 10ng/mL biotin) were cultured for 3 days.
  • the blank control group was still cultured with complete medium.
  • change to differentiation medium II (2 ⁇ g/mL insulin added to complete medium) and continue to culture for 3 days.
  • the cells were harvested for subsequent analysis.
  • Triglyceride test harvest the treated cells, wash them twice with ice PBS (0.2M NaCl, 10mM Na 2 HPO4, 3mM KCl, 2mM KH 2 PO4, pH 7.4), ultrasonically disrupt the cells and use triglyceride detection reagent Box (built in Nanjing), the absorbance is detected at 510nm.
  • Example 4 Study on lipid-lowering activity of compound 2a-1 obtained in Example 1 in HepG2 cells and 3T3-L1 cells
  • HepG2 cells were seeded in a 6-well plate with a cell density of 8 ⁇ 10 5 cells/well and incubated for 24 hours. The cells were harvested 24 hours after adding the test compound. The 3T3-L1 cells were harvested on the 6th day of differentiation. The cells were washed twice with PBS, total RNA was extracted with RNAiso plus reagent, 1 ⁇ g of total RNA was reverse transcribed into cDNA using ReverTra Ace qPCR RT Master Mix, and then PCR amplification was performed using SYBR Green Realtime PCR Master Mix.
  • 2a-1 decreased the mRNA content of SREBP-1c, ACC, FAS and SCD-1 in a concentration-dependent manner. In HepG2 cells, 2a-1 can also significantly reduce the mRNA content of these four genes. The above results prove that in 3T3-L1 cells and HepG2 cells, 2a-1 can inhibit the expression of SREBP-1c, ACC, FAS and SCD-1, thereby inhibiting fat synthesis.
  • Example 5 Study on lipid-lowering activity of compound 2a-1 obtained in Example 1 in hyperlipidemia mice induced by Triton WR-1339
  • mice SPF female C57BL/6J mice aged 6 weeks were purchased from the Experimental Animal Center of Sun Yat-sen University. The mice were randomly divided into 4 groups, 6 in each group, which were the normal control group, the model group, the fenofibrate group (100mg/kg), and the B1 group (100mg/kg). The mice were given intragastrically for 8 days. Twenty-four hours before the last dose, the normal control group was injected with saline intramuscularly, and the other groups were injected with Triton WR-1339 (1500 mg/kg). One hour after the last administration, the eyeballs were removed to collect blood, the cervical vertebrae were dislocated, and the liver was collected.
  • Triton WR-1339 Triton WR-1339
  • the plasma was allowed to stand for 1 hour, and the supernatant was collected by centrifugation at 4°C and 3000 rpm. Weigh 100 mg of liver, add 3 times volume of methanol, and homogenize thoroughly. Add 6 times the volume of chloroform and vortex. Centrifuge at 3000 rpm for 10 minutes, remove the lower chloroform layer, and evaporate naturally overnight in a fume hood. Add 150 ⁇ L of 1% Triton ethanol and heat at 65°C to fully dissolve it. Finally, detect triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in serum and liver samples.
  • TG total cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • the positive drugs Fenofibrate and compound 2a-1 can significantly inhibit the increase in the levels of TG, TC, LDL-C and HDL-C induced by Triton WR-1339.
  • Neither fenofibrate nor compound 2a-1 had a significant effect on HDL-C/TC, but 2a-1 could slightly increase HDL-C/LDL-C.
  • the above results indicate that 2a-1 can significantly reduce the blood lipid levels of hyperlipidemia mice induced by Triton WR-1339.
  • 2a-1 can reduce the triglyceride content in the liver of mice. There were no significant differences in liver cholesterol levels between groups.
  • the above results indicate that 2a-1 can significantly reduce triglyceride accumulation in the liver of hyperlipidemia mice induced by Triton WR-1339.
  • 2a-1 also has significant lipid-lowering activity in mice.
  • the compound of the present invention has significant liver X receptor inverse agonistic activity, and can reduce lipids by inhibiting liver X receptor target genes SREBP-1c, ACC, FAS and SCD-1. It can be used as a lead compound for the treatment of hyperlipidemia, fatty liver, obesity, diabetes, metabolic syndrome and targeted tumor energy metabolism.

Abstract

本发明涉及一种螺(3,3'-异丙基吡咯烷氧化吲哚)类肝X受体调节剂及其制备方法和应用，具体提出了化合物，其为式(I)所示化合物，或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药。

Description

一种螺(3,3’-异丙基吡咯烷氧化吲哚)类肝X受体调节剂及其制备方法和应用 技术领域
本发明涉及生物医药领域，具体地，本发明涉及一种螺(3,3’-异丙基吡咯烷氧化吲哚)类肝X受体调节剂及其制备方法和应用。
背景技术
肝X受体(LXR)是一种配体依赖的转录因子，常与视黄醇X受体(RXR)形成异源二聚体形式：LXR/RXR，在配体激活的前提下，能够与靶基因上的LXR反应元件(LXRE)相结合，进而调节靶基因转录过程。LXR包括LXRα和LXRβ两种亚型，LXRα分布于机体肝、小肠、脂肪以及具有免疫功能的巨噬细胞，而LXRβ在全身广泛分布。
LXR是一种氧化甾醇激活的核受体，在脂肪、胆固醇、糖的代谢以及炎症中发挥着不可忽视的作用，以LXR为靶标研发新药具有广阔的发展前景。LXR人工合成的激动剂包括GW3965与TO901317等。开发LXR激动剂，可以作为治疗动脉粥样硬化、癌症、阿尔兹海默症、特应性皮炎等疾病的先导化合物。
目前，LXR拮抗剂或反向激动剂的发现较少，主要包括SR9243、SR9238、PP2P、非诺贝特、桑色素、毛地黄黄酮等。多篇文章指出，LXR拮抗剂或反向激动剂具有较强的抗脂肪肝活性。其中，LXR拮抗剂或反向激动剂降脂的作用机制为：下调LXR靶基因甾醇调节元件结合蛋白(SREBP-1c)、乙酰辅酶A羧化酶(ACC)、脂肪合成酶(FAS)，硬脂酰辅酶A去饱和酶-1(SCD-1)，降低甘油三酯合成。此外，SR9243还能通过抑制肿瘤细胞糖酵解和脂肪生成，产生广谱抗肿瘤作用。开发LXR拮抗剂或反向激动剂，可以作为治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及靶向肿瘤能量代谢的先导化合物。
发明内容
本申请是基于发明人对以下事实和问题的发现和认识作出的：
发明人通过大量的实验研究，提出了一种新的肝X受体调节剂，惊喜地发现，其具有显著的肝X受体调节活性，不仅可以有效用于治疗或预防高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征，或用于靶向肿瘤能量代谢，而且对胶质母细胞瘤等癌症、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎和骨质疏松具有显著疗效，应用前景十分广阔。
在本发明的第一方面，本发明提出了一种化合物，其为式(I)所示化合物，或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代 谢产物，药学上可接受的盐或前药，
Figure PCTCN2020083073-appb-000001
其中：
X 1、X 2独立地为C(R 7a) 2、O、S或NR 8；
R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-12个原子组成的杂芳基，其中，所述C 6-10芳基、5-12个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-；
R 2为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝O)NR 8aR 8b、-C(＝S)NR 8aR 8b、-NR 8C(＝O)R 7c、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7c或R 7cS(＝O) 2-；
R 3为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、氧代或C 1-6烷基；
各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH或C 1-6烷基；
各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基或卤代C 1-6烷基；
m1、m2和n1独立地为0，1，2，3或4。
根据本发明的实施例，上述化合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、 R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-10个原子组成的杂芳基，其中，所述C 6-10芳基、5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
根据本发明的实施例，R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-10个原子组成的杂芳基，其中，所述C 6-10芳基、5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
根据本发明的实施例，各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH或C 1-4烷基；
各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基或卤代C 1-4烷基。
根据本发明的实施例，各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基或正丁基；
各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基或3,3,3-三氟丙基。
根据本发明的实施例，其为式(II-1)或(II-2)所示化合物，或式(II-1)、(II-2)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
Figure PCTCN2020083073-appb-000002
其中：
R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
根据本发明的实施例，R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
根据本发明的实施例，R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
根据本发明的实施例，其为式(II-1-A)、(II-1-B)或(II-1-C)所示化合物，或式(II-1-A)、(II-1-B)、(II-1-C)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
Figure PCTCN2020083073-appb-000003
其中：
R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
发明人发现，式(II-1-A)或(II-1-B)所示化合物能够有效反向激动肝X受体，有效治疗或预防高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征，或用于靶向肿瘤能量代谢。 另外，发明人发现，式(II-1-C)所示化合物能够有效激动肝X受体，有效治疗或预防胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎、骨质疏松的药物或它们的组合。
根据本发明的实施例，R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基；
R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
根据本发明的实施例，R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基或3,3,3-三羟基丙基；
R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
根据本发明的实施例，其为式(II-1-A-a)、(II-1-A-b)、(II-1-B-a)、(II-1-B-b)、(II-1-C-a) 或(II-1-C-b)所示化合物，或式(II-1-A-a)、(II-1-A-b)、(II-1-B-a)、(II-1-B-b)、(II-1-C-a)、(II-1-C-b)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
Figure PCTCN2020083073-appb-000004
根据本发明的实施例，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它的前药：
Figure PCTCN2020083073-appb-000005
Figure PCTCN2020083073-appb-000006
在本发明的第二方面，本发明提出了一种药物组合物，其包含前面所描述的化合物。
根据本发明的实施例，上述药物组合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物组合物其进一步包括药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的任意组合。
根据本发明的实施例，所述药物组合物进一步包括附加治疗剂。在一些实施例中，所述附加治疗剂为治疗高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征的药物或它们的组合。在另一些实施例中，所述附加治疗剂为治疗胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎或骨质疏松的药物或它们的组合。
根据本发明的实施例，所述治疗高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征的药物为阿托伐他汀、吉非贝齐、阿莫西司、多烯康丸、二甲双胍、格列美脲、瑞格列奈、恩格列净等或它们的任意组合。
根据本发明的实施例，所述治疗胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎或骨质疏松的药物为替莫唑胺、福莫司汀、他汀类药物、贝特类药物、苯海索、阿司匹林、非甾类抗炎药或它们的任意组合。在一些实施例中，所述他汀类药物为洛伐他汀或辛伐他汀，所述贝特类药物为氯贝特、利贝特或苯扎贝特，所述非甾类抗炎药为双氯芬酸、萘丁美酮或美洛昔康。
在本发明的第三方面，本发明提出了前面所描述的化合物或前面所描述的药物组合物在制备药物或试剂盒中的用途，所述药物或试剂盒用于调节肝X受体，以便用于科学研究。根据本发明的实施例，所述药物或试剂盒用于反向激动肝X受体或用于激动肝X受体。
在本发明的第四方面，本发明提出了前面所描述的化合物或前面所描述的药物组合物在制备药物中的用途，所述药物用于治疗或预防高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征，或用于靶向肿瘤能量代谢；或者所述药物用于治疗或预防胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎、骨质疏松的药物或它们的组合。
附图说明
图1为根据本发明实施例的化合物2a-1在HepG2细胞中的降脂活性及其作用机制示意图；
图2为根据本发明实施例的化合物2a-1在3T3L1细胞中的降脂活性及其作用机制示意；
图3为根据本发明实施例的化合物2a-1在Triton WR-1339诱发的高脂血症小鼠中的降脂活性。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed. Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基所取代或不取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团 含有1-10个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子，另外一些实施例是，烷基基团含有2-6个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3) ，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。
术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况，卤原子为F、Cl、Br或I。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，1-氯乙基，二氟甲基，2-氟乙基，3,3,3-三氟丙基，等。
术语“羟基取代的烷基”表示烷基可以被一个或多个羟基所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于羟甲基，1-羟基乙基，二羟基甲基，2-羟基乙基，3,3,3-三羟基丙基，等。
术语“氨基”是指-NH 2。
本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。这样的实施例包括，但并不限于，甲氧基，乙氧基，丙氧基等等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环或三环体系可以包括稠环、桥环和螺环。在一实施方案中，环烷基包含3-10个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环 和三环的碳环体系，其中至少有一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳基”可以和术语“芳环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少有一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”，“芳杂环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。
如本发明所描述，取代基R’由一个键连接到中心的环上形成的环体系代表取代基R’可以在该环上任何可取代或任何合理的位置进行取代。例如，式a代表B’环上任何可能被取代的位置均可被R’取代，如式b，式c和式d所示。
Figure PCTCN2020083073-appb-000007
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理 解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，式(I)中，m1个R 4中，每个R 4的具体选项可以相同，也可以不同；又例如，式(I)中，各个R 4、R 5或R 6的具体选项可以相同，也可以不同，且R 4、R 5和R 6相互之间所表达的具体项也可以一样或不一样。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。
本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
本发明的“酯”是指含有羟基的式(I)-式(IV)所示化合物可形成体内可水解的酯。这样的酯是例如在人或动物体内水解产生母体醇的药学上可接受的酯。含有羟基的式(I)-式(IV)所示化合物体内可水解的酯的基团包括，但不限于，磷酸基，乙酰氧基甲氧基，2,2-二甲基丙酰氧基甲氧基，烷酰基，苯甲酰基，苯甲乙酰基，烷氧基羰基，二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基等。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间氯过氧苯甲酸(MCPBA)反应。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)-式(IV)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。本发明包括同位素标记的化合物，它们等同于式(I)-式(II)所述的化合物，但其中一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。同位素标记的本发明式(I)-式(II)所示化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择 也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
本发明所使用的任何氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、 公认的缩写为准，或参照IUPAC-IUBCommission on Biochemical Nomenclature(参见Biochem.1972，11：942-944)。
本发明的目的之一在于提供新的具有显著肝X受体调节活性的化合物。
本发明的目的之二在于提供新的具有显著治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及靶向肿瘤能量代谢的化合物。
本发明的目的之三在于提供所述肝X受体调节剂的制备方法。
本发明的目的之四在于提供所述化合物在治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及靶向肿瘤能量代谢的应用。
本发明提供所述的螺(3,3’-异丙基吡咯烷氧化吲哚)类肝X受体调节剂的制备方法，包括如下步骤：将色胺与异丁醛溶于二氯甲烷，在酸性环境中发生Pictet-Spengler反应，得到中间体1a；1a溶于四氢呋喃，在N-溴代琥珀酰亚胺作用下，发生重排，得到中间体1b；1b溶于二氯甲烷，加入三乙胺，与二碳酸二叔丁酯反应得到中间体1c；1c溶于甲苯，加入碘化亚铜，N，N-二甲基乙二胺，碳酸钾，与间氯碘苯反应得到中间体1d；1d溶于2,4,-二氧六环，加入双(二亚芐基丙酮)钯，双联频哪醇硼酸酯，乙酸钾在氮气环境中反应，得到中间体1e；1e与溴代R1片段发生suzuki偶联反应，得到中间体1f；1f在酸性条件下脱去保护基，与含有R2的酸酐、酰氯反应得到所述的螺(3,3’-异丙基吡咯烷氧化吲哚)类肝X受体调节剂。
本发明提供的化合物具有显著的肝X受体调节活性与降脂活性，可作为治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及靶向肿瘤能量代谢的先导化合物。
进一步地，本发明提供的化合物通过在HEK293T细胞上，用报告基因方法筛选出肝X受体调节剂，在HepG2细胞、3T3-L1细胞上分别测试化合物在肝细胞、脂肪细胞中的降脂活性，发现化合物2a-1的肝X受体调节活性和降脂活性最好，并对其进行降脂机制研究，结果表明该化合物通过下调肝X受体下游基因SREBP-1c、ACC、FAS、SCD-1发挥降脂作用。同时，在小鼠Triton WR-1339诱导的高脂血症模型中，化合物2a-1也具有降脂活性。
与现有技术相比，本发明具备如下有益效果：
本发明提供的化合物原料易得，制备简单，且具备显著的肝X受体调节活性和降脂活性，所述的螺(3,3’-异丙基吡咯烷氧化吲哚)类肝X受体调节剂通过下调肝X受体下游基因SREBP-1c、ACC、FAS，SCD-1发挥降脂效果，在制备预防及治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及肿瘤中具备极大的应用前景。
下面结合具体实施例和附图进一步说明本发明的内容，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的简单修改或替换， 均属于本发明的范围；若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1化合物的合成
以色胺为起始原料，经六或七步反应得到螺(3,3’-异丙基吡咯烷氧化吲哚)类化合物。反应路线如下所示：
Figure PCTCN2020083073-appb-000008
具体步骤如下：
1、将色胺(20mmol)溶于50mL二氯甲烷，加入异丁醛(20mmol，1eq.)后，缓缓加入三氟乙酸(40mmol，2eq.)，反应搅拌过夜。反应液加入石油醚，过滤得到白色固体，得到中间体1a。
2、将中间体1a(18mmol)溶于四氢呋喃/水溶液，0℃下加入N-溴代琥珀酰亚胺(18mmol，1eq.)反应4小时，乙酸乙酯萃取反应液，加入饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到中间体1b粗品。
3、中间体1b溶于50mL二氯甲烷，加入三乙胺(20mmol，1.1eq.)，缓缓加入二碳酸 二叔丁酯，反应2小时，二氯甲烷稀释反应液，加入饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到中间体1c粗品，加入30mL石油醚/乙酸乙酯(v/v：5/1)重结晶，得到中间体1c。
4、中间体1c(15mmol)溶于甲苯，加入碳酸钾(15mmol，1eq.)，间氯碘苯(15mmol，1eq.)，N，N-二甲基乙二胺(0.15mmol，0.01eq.)，碘化亚铜(0.75mmol，0.05eq.)，氮气保护下，85℃反应10小时。反应液用二氯甲烷稀释，加入饱和氯化铵、氯化钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到中间体1d粗品，加入30mL石油醚/乙酸乙酯(v/v：5/1)重结晶，得到中间体1d。
5、中间体1d(10mmol)溶于2,4-二氧六环，加入乙酸钾(10mmol，1eq.)，双联频哪醇硼酸酯(11mmol，1.1eq.)，双(二亚芐基丙酮)钯(0.5mmol，0.05eq.)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(0.5mmol，0.05eq.)，氮气保护下，85℃反应10小时。反应液加入饱和氯化铵、氯化钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到中间体1e粗品，硅胶柱层析色谱纯化得到纯品。
6、将中间体1e(8mmol)溶于2,4-二氧六环，加入碳酸钠(9.6mmol，1.2eq.)，溴代R a衍生物(9.6mmol，1.2eq.)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.4mmol，0.05eq.)，氮气保护下，85℃反应10小时。反应液用二氯甲烷稀释，加入饱和氯化铵、氯化钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到粗品，硅胶柱层析色谱纯化得到化合物2a、3a、4a。
7、化合物2a、3a或者4a溶于二氯甲烷，加入三氟乙酸(5eq.)反应1小时，反应液减压旋干，直接进行下一步反应。将中间体粗品溶于二氯甲烷/吡啶(v/v：5/1)，加入含有R b的酸酐或者酰氯反应过夜。反应液用二氯甲烷稀释，加入饱和碳酸氢钠、氯化钠水溶液洗涤，无水硫酸钠干燥，旋干溶剂，得到粗品，硅胶柱层析色谱纯化得到目标化合物2b-2e、3b-3f、4b-4c。
终产物1a-4e的结构、外观和核磁共振谱图数据如以下所示。
Figure PCTCN2020083073-appb-000009
1a:白色固体(92％)。 1H NMR(400MHz,Methanol-d 4)δ7.48(dd,J＝7.95,1.04Hz,1H),7.37(dt,J＝8.21,0.93Hz,1H),7.16(ddd,J＝8.23,7.04,1.18Hz,1H),7.06(ddd,J＝8.01,7.05,1.01Hz,1H),4.67(dd,J＝4.02,2.06Hz,1H),3.75(ddd,J＝12.51,5.50,3.28Hz,1H),3.45(ddd,J＝12.70,9.70,5.71Hz,1H),3.18–3.00(m,2H),2.64(pd,J＝7.10,4.00Hz,1H),1.25(d,J＝7.06Hz,3H),0.97(d,J＝7.07Hz,3H).m/z(ESI-MS):215.3[M+H] +.
Figure PCTCN2020083073-appb-000010
1c:白色固体(81％)。 1H NMR(400MHz,Methanol-d 4)δ9.45(s,1H),7.24–7.18(m,1H),7.15(td,J＝7.73,1.16Hz,1H),6.93(td,J＝7.61,1.05Hz,1H),6.86(d,J＝7.72Hz,1H),4.00(dt,J＝11.02,7.85Hz,1H),3.91(d,J＝6.05Hz,1H),3.43(ddd,J＝11.13,7.42,5.83Hz,1H),2.20–2.10(m,2H),2.00–1.86(m,1H),1.42(s,9H),0.94(d,J＝6.78Hz,3H),0.62(d,J＝6.68Hz,3H).m/z(ESI-MS):231.2[M+H] +
Figure PCTCN2020083073-appb-000011
1d:白色固体(58％)。 1H NMR(400MHz,Chloroform-d)δ7.37–7.32(m,2H),7.32–7.28(m,1H),7.23(m,2H),7.14(td,J＝7.74,1.16Hz,1H),7.00(t,J＝7.53Hz,1H),6.75(d,J＝7.86Hz,1H),3.98(m,2H),3.46(dt,J＝11.18,6.74Hz,1H),2.21(dd,J＝8.41,5.45Hz,2H),2.00(h,J＝6.66Hz,1H),1.39(s,9H),0.94(d,J＝6.78Hz,3H),0.63(d,J＝6.68Hz,3H).m/z(ESI-MS):441.3[M+H] +
Figure PCTCN2020083073-appb-000012
1e:白色固体(63％)。 1H NMR(400MHz,Chloroform-d)δ7.76(d,J＝7.22Hz,1H),7.72(d, J＝2.00Hz,1H),7.44(t,J＝7.56Hz,1H),7.38(d,J＝8.44Hz,1H),7.30(d,J＝7.42Hz,1H),7.13(t,J＝7.71Hz,1H),6.99(t,J＝7.50Hz,1H),6.69(d,J＝7.88Hz,1H),4.08–3.95(m,2H),3.48(dt,J＝11.24,6.71Hz,1H),2.23(m,2H),2.02(q,J＝6.66Hz,1H),1.40(s,9H),1.26(s,12H),0.96(d,J＝6.81Hz,3H),0.66(d,J＝6.65Hz,3H).
Figure PCTCN2020083073-appb-000013
2a:白色固体(58％)。 1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝1.94Hz,1H),7.74(dd,J＝7.92,1.96Hz,1H),7.59(d,J＝7.97Hz,1H),7.57–7.47(m,3H),7.34(t,J＝6.53Hz,2H),7.16(t,J＝7.72Hz,1H),7.02(t,J＝7.53Hz,1H),6.77(d,J＝7.92Hz,1H),4.90(d,J＝6.03Hz,2H),4.11–3.86(m,2H),3.63(t,J＝6.34Hz,1H),3.48(dt,J＝11.17,6.69Hz,1H),3.09(s,3H),2.39–2.20(m,2H),2.04(q,J＝6.62Hz,1H),1.37(s,10H),0.97(d,J＝6.78Hz,3H),0.68(d,J＝6.67Hz,3H). 13C NMR(101MHz,CDCl 3)δ177.63,155.20,142.50,139.39,139.36,138.68,137.77,134.10,131.45,130.71,129.36,127.49,127.35,127.15,125.75,125.43,124.33,124.30,121.89,108.43,78.74,66.99,61.10,55.24,44.82,43.96,34.42,29.76,27.43,20.74.17.91.ESI-HRMS[M+H] +m/z＝591.2520,calcd for C 33H 38N 2O 6S,591.2523.
Figure PCTCN2020083073-appb-000014
2b:白色固体(70％)。 1H NMR(500MHz,Chloroform-d)δ8.17(d,J＝3.11Hz,1H),7.78(d, J＝6.34Hz,1H),7.58(m,4H),7.36(d,J＝7.56Hz,2H),7.25–7.20(m,1H),7.08(d,J＝6.54Hz,1H),6.81(d,J＝7.07Hz,1H),4.91(d,J＝7.16Hz,1H),4.42(t,J＝4.50Hz,1H),4.23(q,J＝9.36Hz,1H),3.88–3.79(m,1H),3.63(t,J＝5.63Hz,1H),3.13(d,J＝3.15Hz,3H),3.12–3.05(m,2H),2.49(dd,J＝8.73,3.47Hz,1H),2.44(dd,J＝8.65,4.13Hz,1H),2.18(q,J＝7.37,6.89Hz,1H),0.99(d,J＝5.84Hz,3H),0.75(d,J＝6.63Hz,3H). 13C NMR(126MHz,Chloroform-d)δ178.00,157.75(q),143.80,140.77,140.49,139.41,139.13,134.78,132.68,132.19,130.51,129.18,128.49,127.08,126.71,126.51,125.41,125.31,123.19,116.55(q),109.85,68.44,62.65,54.50,45.17,45.04,34.38,30.35,22.02,18.58.ESI-HRMS[M+H] +m/z＝587.1819,calcd for C 30H 29F 3N 2O 5S,587.1822.
Figure PCTCN2020083073-appb-000015
2c:白色固体(84％)。 1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝1.84Hz,1H),7.75(dd,J＝7.90,1.90Hz,1H),7.56(dd,J＝13.86,5.20Hz,5H),7.39–7.27(m,2H),7.24–7.11(m,1H),7.04(t,J＝7.55Hz,1H),6.78(d,J＝7.87Hz,1H),4.91(s,2H),4.42(d,J＝6.03Hz,1H),4.03(q,J＝8.81Hz,1H),3.66(td,J＝9.58,3.28Hz,1H),3.39(d,J＝12.98Hz,1H),3.12(s,3H),2.45(dt,J＝13.30,8.69Hz,1H),2.40–2.32(m,1H),2.19(d,J＝14.27Hz,1H),2.08(q,J＝6.63Hz,1H),1.02(s,8H),0.97(d,J＝6.88Hz,3H),0.72(d,J＝6.63Hz,3H). 13C NMR(101MHz,CDCl 3)δ177.50,171.70,142.77,139.65,139.37,138.51,137.97,134.06,131.58,131.09,131.00,129.34,127.66,127.58,127.46,127.32,126.64,125.81,125.54,124.45,124.25,121.82,108.49,65.36,61.42,53.97,45.75,45.43,44.09,33.34,30.36,29.68,29.09,21.35,18.06.ESI-HRMS[M+H] +m/z＝589.2734,calcd for C 34H 40N 2O 5S,589.2731.
Figure PCTCN2020083073-appb-000016
2d:白色固体(78％)。 1H NMR(500MHz,Chloroform-d)δ8.15(d,J＝1.84Hz,1H),7.75(dd,J＝7.86,1.86Hz,1H),7.58(d,J＝7.87Hz,1H),7.57–7.49(m,3H),7.35(dd,J＝7.61,3.15Hz,2H),7.23–7.14(m,1H),7.04(t,J＝7.54Hz,1H),6.76(d,J＝7.86Hz,1H),4.90(s,2H),4.56(d,J＝6.76Hz,1H),4.23(dt,J＝10.47,7.49Hz,1H),3.77(dt,J＝10.44,7.05Hz,1H),3.40(s,1H),3.12(s,3H),2.40(t,J＝7.20Hz,2H),2.07(h,J＝6.79Hz,1H),1.26(s,9H),0.90(d,J＝6.81Hz,3H),0.65(d,J＝6.59Hz,3H). 13C NMR(126MHz,CDCl 3)δ177.67,177.11,142.79,139.65,139.39,138.47,137.93,134.13,131.59,131.00,129.40,127.57,127.32,127.12,125.86,125.70,124.54,124.14,121.74,108.46,67.08,61.42,53.33,45.32,44.07,38.44,34.42,29.30,27.00,20.88,17.68.ESI-HRMS[M+H] +m/z＝575.2541,calcd for C 33H 38N 2O 5S,575.2574.
Figure PCTCN2020083073-appb-000017
2e:白色固体(63％)。 1H NMR(400MHz,Chloroform-d)δ7.67–7.55(m,5H),7.47(d,J＝7.79Hz,2H),7.43(d,J＝7.61Hz,1H),7.40(dd,J＝7.46,1.73Hz,1H),7.26(d,J＝7.84Hz,1H),7.12(t,J＝7.54Hz,1H),6.92(d,J＝7.91Hz,1H),4.77(s,2H),4.13(d,J＝7.06Hz,2H),3.60(dt,J＝12.04,6.78Hz,1H),2.38(td,J＝19.24,16.22,9.53Hz,2H),2.14(h,J＝6.62Hz, 1H),1.51(d,J＝1.52Hz,9H),1.07(dd,J＝6.92,1.48Hz,3H),0.76(d,J＝6.64Hz,3H). 13C NMR(101MHz,CDCl 3)δ178.51,156.16,143.79,142.50,140.49,139.48,134.89,130.00,128.79,128.37,127.48,127.39,126.71,125.45,125.24,122.66,109.52,79.79,64.99,56.23,46.06,35.76,30.80,29.70,28.48,21.49,19.00.ESI-HRMS[M+H] +m/z＝513.2724,calcd for C 32H 36N 2O 4,513.2748.
Figure PCTCN2020083073-appb-000018
3a:白色固体(76％)。 1H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.61–7.56(m,3H),7.54(d,J＝8.00Hz,1H),7.41(t,J＝6.97Hz,2H),7.36(d,J＝7.91Hz,1H),7.24(t,J＝7.80Hz,1H),7.09(t,J＝7.55Hz,1H),6.87(d,J＝7.92Hz,1H),4.09(q,J＝7.12Hz,2H),3.56(dt,J＝12.24,6.81Hz,1H),3.14(s,3H),2.90(s,3H),2.40–2.26(m,2H),2.10(q,J＝6.67Hz,1H),1.47(s,9H),1.04(d,J＝6.75Hz,3H),0.74(d,J＝6.62Hz,3H). 13C NMR(101MHz,CDCl 3)δ178.51,168.16,156.11,143.51,142.24,140.67,135.45,135.11,130.86,130.24,128.55,128.45,128.27,128.14,126.63,126.20,126.07,125.35,125.30,122.84,109.41,79.62,74.81,68.13,60.33,56.23,45.92,38.11,34.68,30.77,28.47,21.62.ESI-HRMS[M+H] +m/z＝588.2617,calcd for C 34H 38ClN 3O 4,588.2624.
Figure PCTCN2020083073-appb-000019
3b:白色固体(77％)。 1H NMR(500MHz,Chloroform-d)δ7.64–7.57(m,1H),7.55(d,J＝1.59Hz,1H),7.51(t,J＝6.62Hz,2H),7.47(dd,J＝7.87,1.60Hz,1H),7.39(td,J＝7.72,2.71Hz,1H),7.34(dd,J＝7.02,2.26Hz,2H),7.30(d,J＝7.90Hz,1H),7.22–7.15(m,1H),7.04(t,J＝7.53Hz,1H),4.57(d,J＝6.78Hz,1H),4.23(dt,J＝10.47,7.41Hz,1H),3.77(dt,J＝10.45,6.99Hz,1H),3.09(s,3H),2.85(s,3H),2.38(t,J＝7.21Hz,2H),2.07(h,J＝6.80Hz,1H),1.28(s,9H),0.91(d,J＝6.80Hz,3H),0.64(d,J＝6.60Hz,3H). 13C NMR(126MHz,CDCl 3)δ177.57,177.00,167.22,142.81,141.25,139.76,134.38,134.04,129.27,127.53,127.51,127.23,127.21,127.19,125.76,125.50,125.11,124.49,124.13,121.66,108.43,67.10,53.33,45.32,38.44,37.14,34.45,33.69,29.30,27.01,20.82,17.68.ESI-HRMS[M+H] +m/z＝572.2659,calcd for C 34H 38ClN 3O 3,572.2674.
Figure PCTCN2020083073-appb-000020
3c:白色固体(49％)。 1H NMR(400MHz,Chloroform-d)δ7.64(m,3H),7.58–7.53(m,1H),7.45(s,1H),7.40(d,J＝2.49Hz,1H),7.38(t,J＝3.51Hz,1H),7.29(d,J＝2.83Hz,1H),7.28–7.23(m,1H),7.12(d,J＝7.39Hz,1H),6.91(d,J＝8.02Hz,1H),4.80(d,J＝7.01Hz, 1H),4.33(q,J＝8.46Hz,1H),3.41-3.37(m,1H),3.75(td,J＝9.55,3.82Hz,1H),3.17(s,3H),2.93(s,3H),2.56–2.47(m,1H),2.39–2.27(m,1H),2.05(brs,3H),1.58(s,6H),0.83(d,J＝6.66Hz,3H),0.60(d,J＝6.52Hz,3H). 13C NMR(101MHz,CDCl 3)δ179.80,176.78,167.20,142.65,141.58,139.71,134.45,133.95,131.22,129.87,129.23,127.77,127.26,127.17,126.61,125.70,125.06,124.33,124.03,122.08,108.53,73.91,68.21,55.48,54.79,53.15,47.12,44.25,40.02,37.12,33.69,28.26.ESI-HRMS[M+H] +m/z＝604.2557,calcd for C 34H 39ClN 4O 2S,604.2555.
Figure PCTCN2020083073-appb-000021
3d:白色固体(43％)。 1H NMR(400MHz,Chloroform-d)δ7.68–7.61(m,3H),7.59(d,J＝2.13Hz,1H),7.56(dd,J＝7.86,1.63Hz,1H),7.44(t,J＝7.62Hz,2H),7.40(d,J＝7.92Hz,1H),7.32(t,J＝7.75Hz,1H),7.16(t,J＝7.51Hz,1H),6.96(d,J＝7.92Hz,1H),4.45(dd,J＝11.03,8.60Hz,1H),4.10(d,J＝8.34Hz,1H),3.36(td,J＝11.63,5.60Hz,1H),3.18(s,3H),2.94(s,3H),2.47(td,J＝11.99,8.65Hz,1H),2.03–1.93(m,2H),1.97(d,J＝7.21Hz,1H),1.92(s,6H),1.09(d,J＝6.70Hz,3H),0.60(d,J＝6.76Hz,3H). 13C NMR(101MHz,CDCl 3)δ176.48,168.18,142.56,142.21,140.89,135.56,135.13,130.94,130.42,130.37,128.40,128.32,128.20,126.90,126.09,125.97,125.14,125.06,122.97,109.84,84.38,75.11,56.94,40.96,40.42,38.14,34.72,31.56,28.36,27.67,22.09,19.02.ESI-HRMS[M+H] +m/z＝594.2178,calcd for C 32H 36ClN 3O 4S,594.2188.
Figure PCTCN2020083073-appb-000022
3e:白色固体(75％)。 1H NMR(400MHz,Chloroform-d)δ7.62(d,J＝1.72Hz,1H),7.58(dq,J＝4.12,2.68,1.96Hz,3H),7.54(dd,J＝7.92,1.74Hz,1H),7.41(ddd,J＝7.02,3.24,1.68Hz,2H),7.37(d,J＝7.92Hz,1H),7.29–7.22(m,1H),7.11(td,J＝7.58,1.09Hz,1H),6.87(d,J＝7.86Hz,1H),4.48(d,J＝6.05Hz,1H),4.10(dt,J＝10.05,8.30Hz,1H),3.72(td,J＝9.49,3.36Hz,1H),3.16(s,3H),2.91(s,3H),2.51(dt,J＝13.15,8.72Hz,1H),2.41-2.36(m,1H),2.37(d,J＝14.32Hz,1H),2.28(d,J＝14.28Hz,1H),2.15(h,J＝6.88Hz,1H),1.11(s,9H),1.04(d,J＝6.83Hz,3H),0.78(d,J＝6.65Hz,3H). 13C NMR(101MHz,CDCl 3)δ177.42,171.59,167.22,142.78,141.23,139.73,134.39,133.93,129.85,129.21,127.60,127.23,127.19,126.69,125.70,125.31,125.09,124.40,124.23,121.74,108.46,65.33,53.94,45.72,45.39,37.13,33.69,33.32,30.34,29.68,29.08,21.31,18.05.ESI-HRMS[M+H] +m/z＝586.2834,calcd for C 35H 40ClN 3O 3,586.2831.
Figure PCTCN2020083073-appb-000023
3f:白色固体(61％)。 1H NMR(400MHz,Chloroform-d)δ7.58–7.49(m,4H),7.48(s,1H),7.44(dd,J＝8.00,1.78Hz,1H),7.33(td,J＝6.08,3.36Hz,2H),7.184(t,J＝6.85Hz 1H),7.03 (t,J＝6.76Hz 1H),6.81(d,J＝7.92Hz,1H),4.75(s,2H),4.03(d,J＝6.58Hz,2H),3.50(dt,J＝11.50,7.22Hz,1H),2.37–2.14(m,1H),2.05(dt,J＝13.26,6.87Hz,2H),1.41(d,J＝3.89Hz,9H),0.98(d,J＝6.77Hz,3H),0.68(d,J＝6.63Hz,3H). 13C NMR(101MHz,CDCl 3)δ177.50,155.15,142.61,140.09,139.85,136.58,133.96,132.09,129.13,128.04,127.61,127.39,126.86,125.62,124.94,124.75,124.26,124.20,121.73,108.43,78.72,61.51,56.40,49.84,44.96,34.60,29.78,27.45,20.55,17.95.ESI-HRMS[M+H] +m/z＝545.2554,calcd for C 33H 37ClN 2O 3,545.2565.
Figure PCTCN2020083073-appb-000024
4a:白色固体(75％)。 1H NMR(400MHz,Chloroform-d)δ7.73(td,J＝8.43,7.83,3.14Hz,3H),7.62(t,J＝7.79Hz,1H),7.57(s,1H),7.45(d,J＝7.58Hz,1H),7.43–7.40(m,1H),7.38(dd,J＝7.85,1.77Hz,1H),7.32–7.19(m,1H),7.18–7.05(m,2H),6.95(d,J＝7.91Hz,1H),6.54(d,J＝3.05Hz,1H),4.17(d,J＝5.78Hz,2H),3.87(s,3H),3.62(ddd,J＝11.26,7.78,5.71Hz,1H),2.39(overlapped,2H),2.17(q,J＝6.66Hz,1H),1.53(s,9H),1.10(d,J＝6.76Hz,3H),0.80(d,J＝6.67Hz,3H). 13C NMR(101MHz,CDCl 3)δ177.49,155.15,143.23,142.95,136.15,133.72,132.93,128.84,128.77,127.73,127.34,127.14,126.11,124.51,124.16,123.70,121.53,120.12,118.15,108.59,106.89,99.83,78.63,67.16,55.44,45.04,34.71,31.91,29.78,27.47,20.49,17.98.ESI-HRMS[M+H] +m/z＝536.2912,calcd for C 34H 37N 3O 4,536.2908.
Figure PCTCN2020083073-appb-000025
4b:白色固体(82％)。 1H NMR(500MHz,Chloroform-d)δ7.63(d,J＝9.08Hz,2H),7.59(d,J＝6.69Hz,1H),7.50(t,J＝7.82Hz,1H),7.46(s,1H),7.34(d,J＝7.52Hz,1H),7.30(dd,J＝8.31,1.43Hz,1H),7.25(d,J＝7.57Hz,1H),7.16(d,J＝7.73Hz,1H),7.06–6.96(m,2H),6.81(d,J＝7.89Hz,1H),6.43(d,J＝3.04Hz,1H),4.59(d,J＝6.79Hz,1H),4.25(dt,J＝10.33,7.36Hz,1H),3.78(overlapped,4H),2.44–2.35(m,2H),2.08(h,J＝6.83Hz,1H),1.29(s,9H),0.91(d,J＝6.83Hz,3H),0.66(d,J＝6.61Hz,3H). 13C NMR(126MHz,CDCl 3)δ177.56,161.42,143.26,136.14,133.66,132.95,128.90,128.75,127.43,127.33,127.10,126.25,124.63,124.00,123.98,121.39,120.10,118.17,108.63,106.97,99.81,67.17,53.37,45.41,38.46,34.60,31.97,29.33,27.03,20.76,17.71.ESI-HRMS[M+H] +m/z＝520.2945,calcd for C 34H 37N 3O 2,520.2959.
Figure PCTCN2020083073-appb-000026
4c:白色固体(80％)。 1H NMR(500MHz,Chloroform-d)δ7.66–7.60(m,2H),7.59(dd,J＝4.48,2.71Hz,1H),7.50(t,J＝7.84Hz,1H),7.47(s,1H),7.33(d,J＝7.56Hz,1H),7.30(dd,J＝8.26,1.41Hz,1H),7.25(d,J＝8.13Hz,1H),7.17(d,J＝7.77Hz,1H),7.06–6.92(m,2H),6.82(d,J＝7.90Hz,1H),6.43(d,J＝3.02Hz,1H),4.44(d,J＝6.06Hz,1H),3.78(s,3H),3.67 (dd,J＝9.61,3.51Hz,1H),3.63(brs,1H),2.44(dt,J＝13.25,8.66Hz,1H),2.38-2.30(m,2H),2.29(d,J＝14.34Hz,1H),2.23(d,J＝14.31Hz,1H),2.10(h,J＝6.75Hz,1H),1.05(s,9H),0.98(d,J＝6.79Hz,3H),0.73(d,J＝6.67Hz,3H). 13C NMR(126MHz,CDCl 3)δ177.42,170.14,143.23,136.14,133.57,132.91,128.85,128.76,127.52,127.11,126.79,126.20,124.54,124.11,123.85,121.47,120.10,118.16,108.65,106.96,99.80,65.36,53.96,45.74,45.44,33.45,31.97,30.34,29.70,21.28,20.03,18.07.ESI-HRMS[M+H] +m/z＝534.3109,calcd for C 35H 39N 3O 2,534.3115.
实施例2实施例1所得的化合物的肝X受体活性测试
(1)细胞培养。HEK293T细胞(人胚胎肾细胞)使用含有10％胎牛血清、1％双抗的DMEM(高糖)培养基，在37℃，5％CO 2条件下培养。
(2)转染。HEK293T细胞接种于96孔板中，细胞密度为2×10 4个/孔。24小时后，按照Lipofectamine TM3000试剂说明书进行转染。具体转染步骤如下：
①将15μL L3000试剂加到500μL DMEM(高糖)培养基中，涡旋震荡2秒。
②将6.5μg pGL3/(DR-4)-c-fos-FF-luc质粒、0.13μg pCMV/Renilla-luc质粒、1.3μg pSG5/hLXRα(或pSG5/hLXRβ质粒)、1.3μg pSG5/hRXRα质粒与19μL P3000试剂，混合于500μL DMEM(高糖)培养基中。
③将质粒混合物加入到脂质体混合物中，室温静置20分钟。
④96孔板中每孔加入10μL脂质体-DNA溶液，轻轻摇动96孔板使其充分混匀。
(3)药物干预。转染5小时后加入待测化合物，放入培养箱中继续培养20小时。
(4)检测。使用双荧光素酶报告基因系统进行检测。具体检测步骤如下：
①吸除96孔板原有培养基，按20μL/孔，在96孔板中加入细胞裂解液，室温快速震荡20分钟。
②按2μL/孔，在384孔板中加入样品。
③按10μL/孔，在各孔中加入萤火虫萤光素酶底物，7秒后测定化学发光。
④按10μL/孔，于同一样品孔加入海肾荧光素酶底物，7秒后测定化学发光。
结果处理。结果分析用海肾荧光素酶活性校正萤火虫荧光素酶活性。化合物的肝X受体反向激动活性如表1所示。分析表1可知，化合物2a、2a-1、2a-2、2b、2c、2d等能反向激动肝X受体，其中化合物2a-1反向激动活性最好，故对其进行降脂活性及机制研究。另外，化合物的肝X受体激动活性如表2所示，由表2可知，化合物3a、3b、3c能激动肝X受体。
表1：化合物的肝X受体反向激动活性
Figure PCTCN2020083073-appb-000027
表2：化合物的肝X受体激动活性
Figure PCTCN2020083073-appb-000028
备注：表1和表2中，NA表示在测试范围内未显示活性，NT表示未检测。
实施例3实施例1所得的化合物2a-1在HepG2细胞和3T3-L1细胞中的降脂活性研究
(1)细胞培养。HepG2细胞(人肝癌细胞)和3T3L1细胞(小鼠前脂肪细胞)使用含有10％胎牛血清、1％双抗的DMEM(高糖)培养基，在37℃，5％CO 2条件下培养。
(2)HepG2细胞接种于12孔板，以DMEM(低糖)培养基饥饿12小时。细胞长至70％密度时，换成DMEM(高糖)培养基，加药作用24小时。
(3)前脂肪细胞3T3-L1的分化步骤如下：
细胞接种于48孔板中，以完全培养基培养至完全接触(第0天)，将培养基换成分化培 养基I(完全培养基中添加2μg/mL胰岛素，100ng/mL地塞米松，0.5mM 3-异丁基-1-甲基黄嘌呤和10ng/mL生物素)培养3天。空白对照组仍使用完全培养基培养。第3天，更换为分化培养基II(完全培养基中添加2μg/mL胰岛素)继续培养3天。第6天，收获细胞进行后续分析。
(4)甘油三酯测试：收获处理后的细胞，冰PBS(0.2M NaCl，10mM Na 2HPO4，3mM KCl，2mM KH 2PO4，pH 7.4)洗涤两次，超声破碎细胞使用甘油三酯检测试剂盒(南京建成)，在510nm处检测吸光度。
甘油三酯含量测定结果(图1)显示，在10μM时，2a-1可以显著降低高糖诱导的HepG2细胞的甘油三酯积累。并且，2a-1具有浓度依赖性地降低3T3-L1细胞的甘油三酯水平，其IC 50为0.27±0.03μM。以上结果证明，2a-1在HepG2细胞和3T3-L1细胞中都具有显著的降脂活性。
实施例4实施例1所得的化合物2a-1在HepG2细胞和3T3-L1细胞中的降脂活性研究
HepG2细胞接种于6孔板，细胞密度为8×10 5个/孔，孵育24小时。加入待测化合物作用24小时后收获细胞。3T3-L1细胞于分化第6天收获细胞。细胞用PBS洗两次，用RNAiso plus试剂提取总RNA，使用ReverTra Ace qPCR RT Master Mix将1μg总RNA逆转录为cDNA，再使用SYBR Green Realtime PCR Master Mix进行PCR扩增。
如图2所示，在3T3-L1细胞中，2a-1具有浓度依赖性地减少了SREBP-1c、ACC、FAS和SCD-1的mRNA含量。在HepG2细胞中，2a-1也能显著降低这四个基因的mRNA含量。以上结果证明，在3T3-L1细胞和HepG2细胞中，2a-1都能通过抑制SREBP-1c、ACC、FAS和SCD-1的表达，从而抑制脂肪合成。
实施例5实施例1所得的化合物2a-1在Triton WR-1339诱发的高脂血症小鼠中的降脂活性研究
6周龄的SPF级雌性C57BL/6J小鼠，购自中山大学实验动物中心。将小鼠随机分为4组，每组6只，分别为正常对照组，模型组，非诺贝特组(100mg/kg)，B1组(100mg/kg)，灌胃给药8天。末次给药前24小时，正常对照组肌肉注射生理盐水，其余组注射Triton WR-1339(1500mg/kg)。末次给药后1小时，摘眼球取血，颈椎脱臼处死，收集肝脏。血浆静置1小时，4℃、3000rpm离心取上清。称取肝脏100mg，加入3倍体积的甲醇，充分匀浆。再加入6倍体积的氯仿，涡旋震荡。3000rpm离心10分钟，取下层氯仿层，于通风橱中过夜自然挥干。加入150μL 1％Triton乙醇，65℃加热使其充分溶解。最后，检测血清和肝脏样品中的甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、 高密度脂蛋白胆固醇(HDL-C)含量。
如图3所示，阳性药非诺贝特(Fenofibrate)和化合物2a-1则能显著抑制Triton WR-1339诱导的TG、TC、LDL-C和HDL-C的水平升高。非诺贝特和化合物2a-1均未对HDL-C/TC产生显著影响，但2a-1能使HDL-C/LDL-C小幅升高。上述结果说明，2a-1能显著降低Triton WR-1339诱发的高脂血症小鼠的血脂水平。同时，2a-1能降低小鼠肝脏的甘油三酯含量。肝脏的胆固醇水平各组之间没有显著性差异。上述结果说明2a-1能显著减少Triton WR-1339诱发的高脂血症小鼠肝脏的甘油三酯积累。综上所述，2a-1在小鼠体内也具有显著的降脂活性。
总结：
上述实验结果表明，本发明所述化合物具有显著的肝X受体反向激动活性，并能通过抑制肝X受体靶基因SREBP-1c、ACC、FAS和SCD-1起到降脂的作用，可作为治疗高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征以及靶向肿瘤能量代谢的先导化合物。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (20)

  1. 一种化合物，其为式(I)所示化合物，或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
    Figure PCTCN2020083073-appb-100001
    其中：
    X 1、X 2独立地为C(R 7a) 2、O、S或NR 8；
    R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-12个原子组成的杂芳基，其中，所述C 6-10芳基、5-12个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
    各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-；
    R 2为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝O)NR 8aR 8b、-C(＝S)NR 8aR 8b、-NR 8C(＝O)R 7c、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7c或R 7cS(＝O) 2-；
    R 3为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、氧代或C 1-6烷基；
    各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH或C 1-6烷基；
    各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基或卤代C 1-6烷基；
    m1、m2和n1独立地为0，1，2，3或4。
  2. 根据权利要求1所述的化合物，其特征在于，R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-10个原子组成的杂芳基，其中，所述C 6-10芳基、5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
    各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
  3. 根据权利要求1所述的化合物，其特征在于，R 1为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b、R 7bS(＝O) 2-、C 6-10芳基或5-10个原子组成的杂芳基，其中，所述C 6-10芳基、5-10个原子组成的杂芳基独立任选地被1、2、3、4或5个R 10所取代；
    各R 10独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
  4. 根据权利要求1所述的化合物，其特征在于，各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH或C 1-4烷基；
    各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基或卤代C 1-4烷基。
  5. 根据权利要求1所述的化合物，其特征在于，各R 4、R 5、R 6独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基或正丁基；
    各R 7a、R 7b、R 7c、R 8、R 8a、R 8b独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基或3,3,3-三氟丙基。
  6. 根据权利要求1所述的化合物，其为式(II-1)或(II-2)所示化合物，或式(II-1)、(II-2)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
    Figure PCTCN2020083073-appb-100002
    其中：
    R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
  7. 根据权利要求6所述的化合物，其特征在于，R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
  8. 根据权利要求6所述的化合物，其特征在于，R 11、R 12、R 13、R 14或R 15独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b、-NR 8C(＝O)R 7b、R 8aR 8bN-S(＝O) 2-、-R 8N-S(＝O) 2R 7b或R 7bS(＝O) 2-。
  9. 根据权利要求6所述的化合物，其为式(II-1-A)、(II-1-B)或(II-1-C)所示化合物，或式(II-1-A)、(II-1-B)、(II-1-C)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
    Figure PCTCN2020083073-appb-100003
    其中：
    R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
    R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
    R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
  10. 根据权利要求9所述的化合物，其特征在于，R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、 -CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基；
    R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
    R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、卤代C 1-4烷基、羟基取代的C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷氧基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
  11. 根据权利要求9所述的化合物，其特征在于，R 2a为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c或R 7cS(＝O) 2-，R 12a为R 7bS(＝O) 2-，R 13a为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基或3,3,3-三羟基丙基；
    R 2b为R 7cS(＝O) 2-，R 12b和R 13b各自独立地为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基、-C(＝O)R 7b、-C(＝O)OR 7b、-OC(＝O)R 7b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b；
    R 2c为-C(＝O)R 7c、-C(＝O)(C(R 7a) 2) n1R 7c、-C(＝O)OR 7c、-OC(＝O)R 7c、-C(＝S)NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7c，R 12c为H、D、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、三氟甲基、1-氯乙基、二氟甲基、2-氟乙基、3,3,3-三氟丙基、羟甲基、1-羟基乙基、二羟基甲基、2-羟基乙基、3,3,3-三羟基丙基，R 13c为-C(＝O)NR 8aR 8b或-NR 8C(＝O)R 7b。
  12. 根据权利要求9所述的化合物，其为式(II-1-A-a)、(II-1-A-b)、(II-1-B-a)、(II-1-B-b)、(II-1-C-a)或(II-1-C-b)所示化合物，或式(II-1-A-a)、(II-1-A-b)、(II-1-B-a)、(II-1-B-b)、(II-1-C-a)、(II-1-C-b)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
    Figure PCTCN2020083073-appb-100004
  13. 根据权利要求1所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它的前药：
    Figure PCTCN2020083073-appb-100005
    Figure PCTCN2020083073-appb-100006
  14. 一种药物组合物，其包含权利要求1～13任一项所述的化合物。
  15. 根据权利要求14所述的药物组合物，其特征在于，其进一步包括药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的任意组合。
  16. 根据权利要求14所述的药物组合物，其特征在于，进一步包括附加治疗剂；
    任选地，所述附加治疗剂为治疗高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征的药物或它们的组合；
    任选地，所述附加治疗剂为治疗胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎或骨质疏松的药物或它们的组合。
  17. 根据权利要求16所述的药物组合物，其特征在于，所述治疗高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征的药物为阿托伐他汀、吉非贝齐、阿莫西司、多烯康丸、二甲双胍、格列美脲、瑞格列奈、恩格列净或它们的任意组合；
    任选地，所述治疗胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎或骨质疏松的药物为替莫唑胺、福莫司汀、他汀类药物、贝特类药物、苯海索、阿司匹林、非甾类抗炎药或它们的任意组合；
    优选地，所述他汀类药物为洛伐他汀或辛伐他汀，所述贝特类药物为氯贝特、利贝特或苯扎贝特，所述非甾类抗炎药为双氯芬酸、萘丁美酮或美洛昔康。
  18. 权利要求1～13任一项所述的化合物或权利要求14～17任一项所述的药物组合物在制备药物或试剂盒中的用途，所述药物或试剂盒用于调节肝X受体；
    任选地，所述药物或试剂盒用于反向激动肝X受体或激动肝X受体。
  19. 权利要求1～13任一项所述的化合物或权利要求14～17任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防高脂血症、脂肪肝、肥胖、糖尿病或代谢综合征，或用于靶向肿瘤能量代谢；或者
    所述药物用于治疗或预防胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎、骨质疏松的药物或它们的组合。
  20. 一种治疗疾病的方法，其特征在于，包括：给与患者权利要求1～13任一项所述的化合物或权利要求14～17任一项所述的药物组合物，其中，
    所述疾病包括选自高脂血症、脂肪肝、肥胖、糖尿病、代谢综合征、胶质母细胞瘤、动脉粥样硬化、血脂异常、代谢综合征、帕金森、阿尔茨海默症、多发性硬化症、特应性皮炎、类风湿关节炎和骨质疏松的至少之一。
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