WO2022228409A1 - 视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用 - Google Patents

视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用 Download PDF

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WO2022228409A1
WO2022228409A1 PCT/CN2022/089139 CN2022089139W WO2022228409A1 WO 2022228409 A1 WO2022228409 A1 WO 2022228409A1 CN 2022089139 W CN2022089139 W CN 2022089139W WO 2022228409 A1 WO2022228409 A1 WO 2022228409A1
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formula
compound represented
independently
alkyl
compound
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徐文方
谭云
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Shanghai Xucheng Pharmatech Co Ltd
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Shanghai Xucheng Pharmatech Co Ltd
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Priority to EP22794879.1A priority Critical patent/EP4332108A4/en
Priority to KR1020237040753A priority patent/KR20240000600A/ko
Priority to US18/556,376 priority patent/US20240217992A1/en
Priority to JP2023566529A priority patent/JP2024516232A/ja
Publication of WO2022228409A1 publication Critical patent/WO2022228409A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/0832—Other preparations

Definitions

  • the present invention relates to a retinoic acid receptor agonist, its preparation method, intermediate, pharmaceutical composition and application.
  • Retinoic acid is a kind of metabolite of vitamin A. It initiates and regulates gene expression by activating nuclear receptors. It is a key regulator of cell growth, differentiation and proliferation and programmed apoptosis. It is involved in embryonic development, tissue differentiation and tumor physiology. pathological process.
  • the physiological effects of retinoic acid are mediated by two types of receptors, namely retinoic acid receptor (RAR) and retinoid X receptor (RXR).
  • RAR retinoic acid receptor
  • RXR retinoid X receptor
  • the retinoic acid receptor RAR belongs to the nuclear receptor superfamily, including ⁇ , ⁇ , and ⁇ . RAR ⁇ is further divided into ⁇ 1, ⁇ 2, ⁇ 3, ⁇ 4 and so on.
  • retinoic acid receptor signaling The function of retinoic acid receptor signaling is ultimately achieved through gene transcriptional regulation.
  • a complete retinoic acid signaling pathway consists of ligand retinoic acid, receptor doubletization, retinoic acid response element (RA response element, RARE), and co-regulatory factors, etc.
  • RAR ⁇ is most widely expressed in cells and exists in most tissues; RAR ⁇ is highly expressed in the central nervous system; while RAR ⁇ is only expressed in skin, epithelial and cartilage tissues. In humans and adult rats, the expression product of RAR ⁇ is highly restricted to the skin, with low expression in other organs. Studies have shown that RAR ⁇ selective agonists have efficacy in the treatment of facial acne, psoriasis and other diseases.
  • Trifarotene (trade name Aklief) is a RAR ⁇ selective agonist developed by Galderma Research and Development, and was approved by the US FDA in 2019 for the treatment of facial acne in adolescents aged 9 years and older (Lesley J.Scott, Drugs 2019, 79, 1905–1909). Thoreau et al. reported compound 10d in the literature (Bioorganic & Medicinal Chemistry Letters 2018, 28, 1736–1741), which is also a selective agonist of RAR ⁇ :
  • the purpose of the present invention is to provide a retinoic acid receptor agonist, its preparation method, intermediate, pharmaceutical composition and application.
  • the present invention provides a compound of formula (I):
  • R 1 , R 2 and R 3 are each independently C 1-6 alkyl; alternatively, any two of R 1 , R 2 and R 3 together with the Si atom connecting them form a 4-12 membered heterocycloalkyl, wherein the 4-12 membered heterocycloalkyl has 1, 2, 3 or 4 heteroatoms independently selected from Si, N, O and S;
  • R 4 is C 1-6 alkyl, -NR 4a R 4b or -SiR 4c R 4d R 4e ; alternatively, any one of R 1 , R 2 and R 3 and R 4 together with the atom connecting them are used together form
  • R 4a and R 4b are each independently C 1-6 alkyl; alternatively, R 4a and R 4b together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl which has 1, 2 or 3 N atoms; R 4c , R 4d and R 4e are each independently C 1-6 alkyl;
  • Ring A, Ring B and Ring C are each independently a 4-12 membered heterocycle having 1, 2, 3 or 4 heteroatoms independently selected from Si, N, O and S ;
  • R 4f , R 4g or R 4h are each independently C 1-6 alkyl;
  • m, n and q are each independently 0, 1, 2 or 3;
  • R 5 is C 1-6 alkoxy or is a or multiple R 5a substituted C 1-6 alkoxy groups;
  • R 5a are each independently halogen or hydroxy
  • R 6 is H or C 1-6 alkyl.
  • the C 1-6 alkyl groups may each independently be C 1-4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl or tert-butyl, for example methyl.
  • the Said 4-12-membered heterocycloalkyl can each independently be a 5-10-membered heterocycloalkyl, for example, a 5-6-membered heterocycloalkyl.
  • the 4-12 membered heterocycloalkyl groups may each independently have 2 Si atoms and 0, 1 or 2 heteroatoms independently selected from N, O and S, eg 2 Si atoms.
  • the C 1-6 alkyl groups may each independently be C 1-4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl or tert-butyl.
  • the C 1-6 alkyl groups may each independently be C 1-4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-, iso- or tert-butyl, eg ethyl.
  • the 4-6 membered heterocycloalkyl group may be is a 5-membered heterocycloalkyl; the 4-6 membered heterocycloalkyl may have 1 N atom.
  • the 4-6 membered heterocycloalkyl can be
  • the -NR 4a R 4b can be
  • the C 1-6 alkyl groups may each independently be C 1-4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl or tert-butyl.
  • the C 1-6 alkyl groups may each independently be C 1-4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl or tert-butyl, for example methyl.
  • the 4-12 membered heterocycle may each independently be a 5-10 membered heterocycle, such as a 5-6 membered heterocycle, or a 6 membered heterocycle.
  • the 4-12 membered heterocycles may each independently have 2 Si atoms and 0, 1 or 2 heteroatoms independently selected from N, O and S, eg 2 Si atoms.
  • the 4-12 membered heterocycle may be a 6 membered heterocycle having 2 Si atoms.
  • the C 1-6 alkoxy group may be a C 1-4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example again ethoxy, n-propoxy or n-butoxy.
  • the halogen in the definition of R 5a , can be fluorine, chlorine, bromine, or iodine.
  • the C 1-6 alkoxy group substituted with one or more R 5a may be C 1-6 alkoxy group substituted with one R 5a , such as a hydroxy group Substituted C 1-6 alkoxy, for example -OCH 2 CH 2 OH, -OCH 2 CH 2 CH 2 OH or -OCH 2 CH 2 CH 2 CH 2 OH.
  • the C 1-6 alkyl group can be a C 1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base or tert-butyl.
  • R 1 , R 2 and R 3 can each independently be C 1-6 alkyl, such as methyl.
  • any two or three of R 1 , R 2 , and R 3 may each independently be C 1-6 alkyl, eg, methyl.
  • R 4 can be -NR 4a R 4b , such as
  • R 4a can be ethyl
  • R 4b can be ethyl
  • R 4a and R 4b can be ethyl.
  • the R 4fs can each independently be methyl.
  • R 4g can each independently be methyl.
  • R 4h can each independently be methyl.
  • m may be 2.
  • n can be 2.
  • q can be 2.
  • R 5 can be C 1-6 alkoxy substituted with one or more R 5a , such as C 1-6 alkoxy substituted with one R 5a , another example —OCH 2 CH 2 OH , –OCH2CH2CH2OH , or –OCH2CH2CH2CH2OH . _
  • R 5a can be hydroxyl
  • R 6 can be H.
  • R 5a is hydroxy and R 6 is H.
  • R 1 , R 2 and R 3 are each independently C 1-6 alkyl
  • R 4 is -NR 4a R 4b ;
  • R 4a and R 4b are each independently C 1-6 alkyl; alternatively, R 4a and R 4b together with the N atom to which they are attached form a 4-6 membered heterocycloalkyl which has 1, 2 or 3 N atoms;
  • R 5 is C 1-6 alkoxy substituted with one or more R 5a ;
  • R 5a are each independently halogen or hydroxy
  • R 6 is H or C 1-6 alkyl.
  • two of R 1 , R 2 and R 3 are each independently C 1-6 alkyl
  • Ring A, Ring B and Ring C are each independently a 4-12-membered heterocycle, and the 4-12-membered heterocycle has 1, 2, 3 or 4 rings independently selected from Si, N, O and S. heteroatom;
  • R 4f , R 4g or R 4h are each independently C 1-6 alkyl
  • n, q are each independently 0, 1, 2 or 3;
  • R 5 is C 1-6 alkoxy substituted with one or more R 5a ;
  • R 5a are each independently halogen or hydroxy
  • R 6 is H or C 1-6 alkyl.
  • the compound of formula (I) has the structure of formula (I-a):
  • R 1 , R 2 , R 3 , R 4a , R 4b , R 5 and R 6 are as described in any embodiment of the present invention.
  • the compound of formula (I) has the structure of formula (I-b):
  • the compound of formula (I) has the structure of formula (I-c):
  • ring B, n, R 4g , R 1 , R 3 , R 5 and R 6 are as described in any embodiment of the present invention.
  • the compound of formula (I) has the structure of formula (I-d):
  • the compound of formula (I) has the structure of formula (I-b-1):
  • R 4f , R 2 , R 3 , R 5 and R 6 are as described in any one of the embodiments of the present invention.
  • the compound represented by the formula (I) has the structure represented by the formula (I-c-1):
  • R 4g , R 1 , R 3 , R 5 and R 6 are as described in any one of the embodiments of the present invention.
  • the compound of formula (I) has the structure of formula (I-d-1):
  • R 4h the definitions of R 4h , R 1 , R 2 , R 5 and R 6 are as described in any embodiment of the present invention.
  • the compound represented by the formula (I) can be:
  • the present invention also provides a preparation method of the compound shown in the above-mentioned formula (I), which is any one of the following methods:
  • the method (A) includes the following steps: in a solvent, the compound represented by the formula (II-a) is subjected to the following reaction in the presence of a base to obtain the compound represented by the formula (I); wherein, R 5 contains a hydroxyl group, R 5a' is a group in which the hydroxyl group in R 5 is protected by a hydroxyl protecting group (such as an acetyl group), and R 6 is H, for A group protected by a carboxyl protecting group (e.g. );
  • the method (B) comprises the following steps: in a solvent, the compound represented by the formula (II-b) is subjected to the following reaction in the presence of a base to obtain the compound represented by the formula (I); wherein, R 5 does not contain hydroxyl, R 6 is H, R 5b and R 5 are the same, for A group protected by a carboxyl protecting group (e.g. );
  • the method (C) comprises the following steps: in a solvent, the compound represented by the formula (II-c) is subjected to the following reaction in the presence of a base to obtain the compound represented by the formula (I); wherein, R 5 contains a hydroxyl group, R 6 is not H, R 5c is a group in which the hydroxyl group in R 5 is protected by a hydroxyl protecting group (such as an acetyl group), and R 6c and R 6 are the same;
  • reaction conditions and reagents of method (A), method (B) or method (C) can be conventional conditions and reagents for this type of reaction in the field, and the present invention is preferably the following Conditions and Reagents.
  • the solvent may be an ether solvent (eg, tetrahydrofuran).
  • the alkali can be an inorganic alkali (eg, sodium hydroxide); the alkali can be used in the form of an aqueous solution, and the concentration of the aqueous solution of the alkali can be 1-2M.
  • the temperature of the reaction may be 20-50°C (eg, 40°C).
  • the progress of the reaction can be carried out using conventional testing methods in the art (eg, TLC, GC, HPLC or NMR, etc.). Monitoring, those skilled in the art can determine when to terminate the reaction according to the monitoring results (including the degree of conversion of raw materials, impurity generation, etc.) to obtain a better reaction result, and the reaction time of the reaction can be 2 hours.
  • conventional testing methods eg, TLC, GC, HPLC or NMR, etc.
  • the preparation method of the compound represented by the formula (II-a) comprises the following steps: in a solvent, the compound represented by the formula (III-a) and the compound represented by the formula (IV) (
  • the coupling reaction shown below can be carried out in the presence of a base and a catalyst to obtain a compound represented by formula (II-a);
  • the preparation method of the compound represented by the formula (II-b) includes the following steps: in a solvent, the compound represented by the formula (III-b) and the compound represented by the formula (IV) (for example, can be and the presence of a catalyst) to carry out the coupling reaction shown below to obtain a compound represented by formula (II-b);
  • the preparation method of the compound represented by the formula (II-c) includes the following steps: in a solvent, the compound represented by the formula (III-c) and the compound represented by the formula (IV) (for example, can be and the presence of a catalyst) to carry out the coupling reaction shown below to obtain a compound represented by formula (II-c);
  • X is Br or I (eg Br)
  • [B] is boronic acid or boronic acid ester (eg ), other groups are defined as before.
  • the preparation method of the compound represented by the above formula (I) may further include the preparation method of the compound represented by the formula (II-a), (II-b) or (II-c).
  • reaction conditions and reagents of the coupling reaction can be conventional conditions and reagents for this type of reaction in the field , the present invention preferably the following conditions and reagents.
  • the solvent in the preparation method of the compound represented by formula (II-a), (II-b) or (II-c), the solvent may be an ether solvent (eg dioxane) mixed solvent with water; in the mixed solvent, the volume ratio of the ether solvent and water can be 4:1.
  • the base may be an inorganic base (eg, sodium bicarbonate).
  • the catalyst is a palladium-based catalyst (eg, Pd(dppf)Cl 2 ).
  • the temperature of the coupling reaction may be 90-130°C (eg, 120°C).
  • the coupling reaction can be carried out under microwave conditions and/or under an inert (eg, nitrogen) atmosphere.
  • the progress of the coupling reaction can be tested by routine tests in the art Methods (such as TLC, GC, HPLC or NMR, etc.) are monitored, and those skilled in the art can determine when to terminate the reaction according to the monitoring results (including the degree of raw material conversion, impurity generation, etc.) to obtain better reaction results.
  • the reaction time of the coupling reaction may be 1 hour.
  • R 4 is C 1-6 alkyl, -NR 4a R 4b or -SiR 4c R 4d R 4e , [B] is , the preparation method includes the following steps: in a solvent, the compound represented by the formula (V) and pinacol biboronate (for example, in the presence of a base and a catalyst) are coupled as shown below reaction to obtain the compound shown in formula (IV);
  • Y is Br or I (eg Br);
  • the preparation method comprises the following steps: in a solvent In the compound, the compound represented by formula (VI-a), (VI-b) or (VI-c) and 2-acetylene-4,4,5,5-tetramethyl-[1,3,2]di Oxaborane (eg, in the presence of a cobalt-based catalyst (eg, cobalt iodide) and zinc) is subjected to a cyclization reaction as shown below to give formula (IV-a-1), (IV-b-1) or The compound shown in (IV-c-1);
  • a cobalt-based catalyst eg, cobalt iodide
  • each group is defined as before.
  • the preparation method of the compound represented by formula (I), (II-a), (II-b) or (II-c) may further comprise the preparation of the compound represented by the above formula (IV) method.
  • reaction conditions and reagents of the reaction can be conventional conditions and reagents for this type of reaction in the art, and the following conditions and reagents are preferred in the present invention.
  • the solvent of the coupling reaction may be an ether solvent (eg, dioxane).
  • the base of the coupling reaction can be an inorganic base (eg potassium acetate).
  • the catalyst for the coupling reaction is a palladium catalyst (eg Pd(dppf)Cl 2 ).
  • the temperature of the coupling reaction may be 90-130°C (eg, 120°C).
  • the coupling reaction can be carried out under microwave conditions and/or under an inert (eg, nitrogen) atmosphere.
  • the solvent for the cyclization reaction may be acetonitrile (anhydrous acetonitrile).
  • the temperature of the cyclization reaction may be 20-60°C (eg, 50°C).
  • the cyclization reaction can be carried out under an inert (eg, argon) atmosphere.
  • the progress of the reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC, or NMR, etc.). Those skilled in the art can determine when to terminate the reaction according to the monitoring results (including the degree of conversion of raw materials, the generation of impurities, etc.) to obtain better reaction results.
  • the reaction time of the coupling reaction may be 1 hour.
  • the reaction time of the cyclization reaction may be 1 hour.
  • the present invention also provides a compound represented by formula (V), (IV), (II-a), (II-b) or (II-c):
  • R 1 , R 2 , R 3 , R 4 , R 5a′ , R 5b , R 5c , R 6a , R 6b , R 6c , [B] and Y are as described in any one of the schemes of the present invention.
  • the compound represented by the formula (V) can be:
  • the compound represented by the formula (IV) can be:
  • the compound represented by the formula (II-a) can be:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) the compound represented by the above formula (I), or a tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable compound thereof. an accepted salt; and (ii) a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound represented by the above formula (I), or a tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt thereof as a medicine.
  • the present invention also provides a compound represented by the above formula (I), or a tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition Use as retinoic acid receptor (eg retinoic acid receptor gamma) agonists.
  • retinoic acid receptor eg retinoic acid receptor gamma
  • the present invention also provides a compound represented by the above formula (I), or its tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of therapeutic or Use in a medicament for the prevention of diseases associated with retinoic acid receptors (eg, retinoic acid receptor gamma).
  • retinoic acid receptors eg, retinoic acid receptor gamma
  • the disease associated with retinoic acid receptors can be acne (including acne vulgaris, rosacea, nodular cystic acne, acne aggregation, and sun or drug therapy) secondary acne), comedones, psoriasis (psoriasis), ichthyosis, keratoderma, hyperpigmentation, dry eye, etc.
  • the present invention also provides a method of treating a disease associated with a retinoic acid receptor (eg, retinoic acid receptor gamma), comprising administering to a subject in need of such treatment the above-mentioned formula (I)
  • a retinoic acid receptor eg, retinoic acid receptor gamma
  • the compound shown preferably, a therapeutically effective amount of the compound shown in the above formula (I) is applied to the subject in need of this treatment
  • its tautomer, stereoisomer, isotopic derivative or pharmaceutically an acceptable salt or a pharmaceutical composition of the above.
  • the positive progress effect of the present invention is to provide a retinoic acid receptor agonist, its preparation method, intermediate, pharmaceutical composition and application. These compounds have strong agonist activity of retinoic acid receptor ⁇ and selectivity to retinoic acid receptor ⁇ , and have weak liver cell stability; After entering the systemic circulation, metabolism is faster in hepatocytes. It indicates that the drug is safer and has excellent druggability, and can potentially be used to treat diseases related to retinoic acid receptors (such as retinoic acid receptor gamma).
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid movement of hydrogen atoms on oxygen and ⁇ -carbon.
  • stereoisomer refers to the isomers caused by the same order in which atoms or atomic groups are connected to each other in the molecule, but different spatial arrangements, such as cis-trans isomers (such as Z-isomers, E-isomers) , optical isomers (eg enantiomers, diastereomers), atropisomers, etc.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • Optical isomers include enantiomers and diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention.
  • isotopic derivative refers to the substitution of one or more atoms in a compound with one or more atoms having a specified atomic mass or mass number.
  • isotopes that can be incorporated into compounds include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (eg, 2H, 3H , 13C , 14C , 15N , 18O , 17O ) . , 18 F, 35 S and 36 Cl).
  • Isotopic compounds can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Typical examples of isotopic derivatives include deuterated compounds.
  • pharmaceutically acceptable salts refers to salts of compounds prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt When compounds contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • halogen means fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to the -OH group.
  • alkyl refers to a saturated straight or branched chain monovalent hydrocarbon group having a certain number of carbon atoms.
  • C 1-6 alkyl refers to an alkyl group having 1-6 (eg 1, 2, 3, 4, 5, 6) carbon atoms, including C 1 alkyl, C 2 alkyl, C 3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl , n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-d
  • alkoxy refers to the group -OR X , wherein R X is an alkyl group as defined above.
  • x-y members in the description of a cyclic group herein means that the number of atoms in the ring is x-y.
  • cyclopropyl is 3-membered
  • tetrahydropyrrolyl is 5-membered
  • piperidinyl is 6-membered.
  • substituted or “substituent” refers to the replacement of one or more hydrogen atoms with the designated group.
  • substitution may be at any position, but is permissible only if a stable or chemically feasible chemical is formed.
  • protecting group includes, but is not limited to, "hydroxy protecting group” or “carboxyl protecting group” and refers to a protecting group suitable for preventing side reactions of the group.
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat or prevent the disease or disorder described herein.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art. Dosages outside this range may also be employed, depending on the dosage form and the severity of the disease.
  • compositions can be formulated into various types of administration unit dosage forms according to the therapeutic purpose.
  • the compounds of the present invention can be administered in a routine clinical manner.
  • subject refers to any animal, preferably a mammal, and most preferably a human, to which a compound or composition is to be or has been administered.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • K2CO3 for potassium carbonate ; CH3CN or MeCN for acetonitrile; n-BuLi for n-butyllithium; TMSCl for trimethylchlorosilane; TMS for trimethylsilyl;
  • B 2 Pin 2 stands for pinacol diboronate;
  • KOAc stands for potassium acetate;
  • Pd(dppf)Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; MW stands for microwave ;
  • NBS stands for N-bromosuccinimide;
  • KI stands for potassium iodide; NaOH stands for hydroxide Sodium; PE for petroleum ether; EA for ethyl acetate; THF for tetrahydrofuran
  • the reagents and raw materials used in the present invention are all commercially available or prepared according to existing methods.
  • Step 2 Synthesis of 1-(4-bromo-2-(trimethylsilyl)phenyl)pyrrolidine (compound 1-3)
  • Step 3 1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxolane-2-yl)-2-(trimethylsilyl)phenyl) Synthesis of pyrroles (compounds 1-4)
  • reaction solution was diluted with petroleum ether (9 mL), a small amount of silica gel layer was used for rapid column separation, and the inorganic salts and palladium black were removed by filtration. The filtrate was concentrated to give compound 1-4 (242 mg) as a light brown crude product. The crude product was directly used in the next reaction without purification.
  • Step 4 Synthesis of ethyl 3'-bromo-4'-hydroxy-[1,1'-biphenyl]-4-carboxylate (compound 1-6)
  • Step 5 Synthesis of 4'-(2-acetoxyethoxy)-3'-bromo-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (compound 1-7)
  • 3'-Bromo-4'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (compound 1-6, 1.1 g, 3.4 mmol) was placed in a 50 mL single-necked flask, and DMF ( 10 mL) dissolved. NaH (163 mg, 60%, 1.2 eq) was added slowly in an ice-water bath at 0°C. After the reaction was stirred for 0.5 h, 2-bromoethyl acetate (678 mg, 4.1 mmol) was added dropwise to the above reaction solution. After the dropwise addition was completed, stirring was continued overnight.
  • Step 6 4'-(2-Acetoxyethoxy)-4'-(pyrrolidin-1-yl)-3'-(trimethylsilyl)-[1,1':3',1 Synthesis of '-triphenyl]-4-carboxylic acid ethyl ester (compound 1-8)
  • reaction solution was directly purified by reverse-phase column chromatography (H 2 O/MeCN, 30%-100%, 0.05% FA), and the obtained eluent was concentrated until a large amount of solid was precipitated, filtered, washed with acetonitrile (1 mL x 2), and dried. , a white solid product compound I-1 (87 mg) was obtained with a yield of 26.2%.
  • Step 1 Synthesis of 4'-(3-acetoxypropoxy)-3'-bromo-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (compound 2-2)
  • Step 2 4'-(3-Acetoxypropoxy)-4"-(pyrrolidin-1-yl)-3"-(trimethylsilyl)-[1,1':3' Synthesis of ,1"-terphenyl]-4-carboxylic acid ethyl ester (compound 2-3)
  • reaction solution was directly purified by reversed-phase column chromatography (H 2 O/MeCN, 30%-100%, 0.05% FA). , the obtained eluate was concentrated until a large amount of solid was precipitated, filtered, washed with acetonitrile (1 mL x 2), and dried to obtain compound I-2 (19 mg) as a white solid product.
  • Step 1 Synthesis of 4'-(4-acetoxybutoxy)-3'-bromo-[1,1'-biphenyl]-4-carboxylic acid ethyl ester (compound 3-2)
  • Step 2 4'-(4-Acetoxybutoxy)-4"-(pyrrolidin-1-yl)-3"-(trimethylsilyl)-[1,1':3' , Synthesis of 1"-terphenyl]-4-carboxylic acid ethyl ester (compound 3-3)
  • reaction solution was directly purified by reversed-phase column chromatography (H 2 O/MeCN, 30%-100%, 0.05% FA). , the obtained eluate was concentrated until a large amount of solid was precipitated, filtered, washed with acetonitrile (1 mL x 2), and dried to obtain compound I-3 (26 mg) as a white solid product.
  • reaction solution was diluted with petroleum ether (9 mL), a small amount of silica gel layer was used for rapid column separation, and the inorganic salts and palladium black were removed by filtration. The filtrate was concentrated to obtain compound 4-4 (180 mg) as a light brown crude product. The crude product was directly used in the next reaction without purification.
  • reaction solution is directly purified by reverse-phase column chromatography (H 2 O/MeCN, 30%-100%, 0.05% FA), and the obtained eluent Concentrated until a large amount of solid was precipitated, filtered, washed with acetonitrile (1 mL ⁇ 2), and dried to obtain compound I-4 (17 mg) as a white solid product.
  • Step 1 Synthesis of 1,2-bis(ethyldimethylsilyl)ethane (compound 5-2)
  • 1,2-bis(chlorodimethylsilyl)ethane (compound 5-1, 3.00 g, 13.94 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran solution, and the system was filled with argon.
  • Ethynylmagnesium chloride (70 mL, 0.5 mol/L, 35.00 mmol) was slowly added dropwise at room temperature. Stir at room temperature for 1 h and reflux for 1 h. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution. An appropriate amount of ethyl acetate was added to the reaction system, washed twice with saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate.
  • Step 2 1,1,4,4-Tetramethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1,2, Synthesis of 3,4-Tetrahydrobenzo[b][1,4]diphenylamine (Compound 5-3)
  • the system was transferred to react at 50°C, monitored by TLC, and the reaction was stopped after the consumption of compound 5-2 was complete.
  • the crude product was purified again by silica gel column chromatography (n-hexane) to obtain colorless crystal compound 5-3 (0.50 g) in a yield of 20.3%.
  • Step 3 Ethyl 4'-(2-acetoxyethoxy)-3'-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydrobenzo[b] Synthesis of [1,4]Disil-6-yl)-[1,1'-biphenyl]-4-carboxylate (Compound 5-4)
  • Ethyl 4'-(2-acetoxyethoxy)-3'-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydrobenzo[b][1 ,4] Disilyl-6-yl)-[1,1'-biphenyl]-4-carboxylate (compound 5-4, 70 mg, 0.128 mmol) was placed in a 25 mL single-necked vial. Dissolve with tetrahydrofuran (3 mL). To the above reaction system, an aqueous NaOH solution (1 M, 1 mL) was added. The reaction system was stirred at 40 °C for 2 h. After the reaction, the reaction system was slowly adjusted to neutrality with formic acid.
  • HEK-293 cell line ATCC #CRL-1573
  • compounds were tested for agonist activity on RAR ⁇ and RAR ⁇ .
  • Day 1 Cell culture. The dishes were trypsinized and then seeded with cells at an appropriate concentration in 10 mL of culture medium. Cell culture conditions: 37 degrees Celsius, 5% carbon dioxide, humid environment.
  • Day 4 Add the compound to be tested.
  • Compounds were prepared in DMSO stock solutions at 210x concentration and diluted to a 21x solution by adding 9x the amount of vehicle. Add 5 microliters of 21x compound solution to each well and incubate for 24 hours under the same conditions as in step 1.
  • Day 5 Board reading.
  • the dual-luciferase reporter gene detection system was placed at room temperature for 30 minutes before use, and fluorescent reagent II was added to each well of the 96-well plate to detect the fluorescence intensity of fireflies in an appropriate manner. Then Stop&Glo reagent was added to detect the intensity of Renilla fluorescein.

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Abstract

本发明公开了一种视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用。该类化合物具体式(I)所示的结构。该类化合物具有较强的视黄酸受体γ的激动剂活性以及对视黄酸受体γ选择性，具有较弱的肝细胞稳定性；提示该类化合物在皮肤局部有更好的活性，进入体循环后，肝细胞中代谢更快。预示药物更加安全，成药性优异，可以潜在用于治疗与视黄酸受体相关的疾病。

Description

视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用
本申请要求申请日为2021/4/27的中国专利申请202110459864X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用。
背景技术
视黄酸是一类维生素A的代谢产物，通过激活核受体来启动和调节基因表达，是细胞生长、分化增殖和程序性凋亡的关键调节因子，参与胚胎发育、组织分化和肿瘤等生理病理过程。视黄酸的生理作用由两类受体介导，即视黄酸受体(retinoic acid receptor,RAR)和视黄醇类物质-X受体(retinoid X receptor,RXR)。其中，视黄酸受体RAR属于核受体超家族，包括α、β、γ三种。RARβ又分β1、β2、β3、β4等。视黄酸受体信号的功能最终是通过基因转录调控来实现，一个完整的视黄酸信号通路组成包括配体视黄酸，受体二联体化，视黄酸反应元件(RA response element,RARE)，以及辅助调节因子等。
在细胞发育的过程中，视黄酸受体RAR的分布具有时间和空间的特异性，不同的视黄酸受体途径对细胞的发育具有不同的功能。一般情况下，RARα在细胞中的表达最为广泛，存在与绝大多数组织中；RARβ在中枢神经系统高度表达；而RARγ则只表达与皮肤、上皮和软骨组织中。在人类和成年大鼠中，RARγ的表达产物高度限制在皮肤中，在其他器官中的表达量很低。研究表明，RARγ选择性激动剂具有治疗面部痤疮、银屑病等疾病的药效。
例如，Trifarotene(商品名Aklief)是由Galderma Research and Development公司开发的RARγ选择性激动剂，2019年由美国FDA批准用于9岁及以上青少年的面部痤疮的治疗(Lesley J.Scott,Drugs 2019,79,1905–1909)。Thoreau等人在文献(Bioorganic&Medicinal Chemistry Letters 2018,28,1736–1741)中报道了化合物10d，也是RARγ的选择性激动剂：
Figure PCTCN2022089139-appb-000001
发明内容
本发明的目的在于提供了一种视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用。
一方面，本发明提供了一种式(I)所示的化合物：
Figure PCTCN2022089139-appb-000002
或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐；其中，
R 1、R 2和R 3分别独立地为C 1-6烷基；或者，R 1、R 2和R 3中的任意两个连同连接它们的Si原子形成4-12元杂环烷基，其中所述4-12元杂环烷基具有1、2、3或4个独立地选自Si、N、O和S的杂原子；
R 4为C 1-6烷基、–NR 4aR 4b或–SiR 4cR 4dR 4e；或者，R 1、R 2和R 3中的任一个与R 4连同连接它们的原子一起使
Figure PCTCN2022089139-appb-000003
形成
Figure PCTCN2022089139-appb-000004
Figure PCTCN2022089139-appb-000005
R 4a和R 4b分别独立地为C 1-6烷基；或者，R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基具有1、2或3个N原子；R 4c、R 4d和R 4e分别独立地为C 1-6烷基；
环A、环B和环C分别独立地为4-12元杂环，所述4-12元杂环具有1、2、3或4个独立地选自Si、N、O和S的杂原子；R 4f、R 4g或R 4h分别独立地为C 1-6烷基；m、n和q分别独立地为0、1、2或3；R 5为C 1-6烷氧基或被一个或多个R 5a取代的C 1-6烷氧基；
R 5a分别独立地为卤素或羟基；
R 6为H或C 1-6烷基。
在一些实施方案中，R 1、R 2和R 3的定义中，所述C 1-6烷基可以分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，又例如甲基。
在一些实施方案中，R 1、R 2和R 3的定义中，当R 1、R 2和R 3中的任意两个连同连接它们的Si原子形成4-12元杂环烷基时，所述4-12元杂环烷基可以分别独立地为5-10元杂环烷基，例如5-6元杂环烷基。所述4-12元杂环烷基可以分别独立地具有2个Si原子以及0、1或2个独立地选自N、O和S的杂原子，例如具有2个Si原子。
在一些实施方案中，R 4的定义中，所述C 1-6烷基可以分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在一些实施方案中，R 4a和R 4b的定义中，所述C 1-6烷基可以分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如乙基。
在一些实施方案中，R 4a和R 4b的定义中，当R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基时，所述4-6元杂环烷基可以为5元杂环烷基；所述4-6元杂环烷基可以具有1个N原子。所述4-6元杂环烷基可以为
Figure PCTCN2022089139-appb-000006
在一些实施方案中，R 4的定义中，所述–NR 4aR 4b可以为
Figure PCTCN2022089139-appb-000007
在一些实施方案中，R 4c、R 4d和R 4e的定义中，所述C 1-6烷基可以分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在一些实施方案中，R 4f、R 4g和R 4h的定义中，所述C 1-6烷基可以分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，又例如甲基。
在一些实施方案中，环A、环B和环C的定义中，所述4-12元杂环可以分别独立地为5-10元杂环，例如5-6元杂环，又例如6元杂环。所述4-12元杂环可以分别独立地具有2个Si原子以及0、1或2个独立地选自N、O和S的杂原子，例如具有2个Si原子。所述4-12元杂环可以为具有2个Si原子的6元杂环。
在一些实施方案中，R 5的定义中，所述C 1-6烷氧基可以为C 1-4烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，又例如乙氧基、正丙氧基或正丁氧基。
在一些实施方案中，R 5a的定义中，所述卤素可以为氟、氯、溴或碘。
在一些实施方案中，R 5的定义中，所述被一个或多个R 5a取代的C 1-6烷氧基可以为被一个R 5a取代的C 1-6烷氧基，例如被一个羟基取代的C 1-6烷氧基，又例如–OCH 2CH 2OH、–OCH 2CH 2CH 2OH或–OCH 2CH 2CH 2CH 2OH。
在一些实施方案中，R 6的定义中，所述C 1-6烷基可以为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在一些实施方案中，R 1、R 2和R 3可以分别独立地为C 1-6烷基，例如甲基。
在一些实施方案中，R 1、R 2和R 3中的任意两个或三个可以分别独立地为C 1-6烷基，例如甲基。
在一些实施方案中，R 4可以为–NR 4aR 4b，例如
Figure PCTCN2022089139-appb-000008
在一些实施方案中，R 4a可以为乙基。
在一些实施方案中，R 4b可以为乙基。
在一些实施方案中，R 4a和R 4b可以为乙基。
在一些实施方案中，R 4f可以分别独立地为甲基。
在一些实施方案中，R 4g可以分别独立地为甲基。
在一些实施方案中，R 4h可以分别独立地为甲基。
在一些实施方案中，m可以为2。
在一些实施方案中，n可以为2。
在一些实施方案中，q可以为2。
在一些实施方案中，
Figure PCTCN2022089139-appb-000009
可以为
Figure PCTCN2022089139-appb-000010
例如
Figure PCTCN2022089139-appb-000011
在一些实施方案中，
Figure PCTCN2022089139-appb-000012
可以为
Figure PCTCN2022089139-appb-000013
例如
Figure PCTCN2022089139-appb-000014
在一些实施方案中，
Figure PCTCN2022089139-appb-000015
可以为
Figure PCTCN2022089139-appb-000016
例如
Figure PCTCN2022089139-appb-000017
在一些实施方案中，R 5可以为被一个或多个R 5a取代的C 1-6烷氧基，例如被一个R 5a取代的C 1-6烷氧基，又例如–OCH 2CH 2OH、–OCH 2CH 2CH 2OH或–OCH 2CH 2CH 2CH 2OH。
在一些实施方案中，R 5a可以为羟基。
在一些实施方案中，R 6可以为H。
在一些实施方案中，R 5a为羟基，R 6为H。
在一些实施方案中，R 1、R 2和R 3分别独立地为C 1-6烷基；
R 4为–NR 4aR 4b；
R 4a和R 4b分别独立地为C 1-6烷基；或者，R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基具有1、2或3个N原子；
R 5为被一个或多个R 5a取代的C 1-6烷氧基；
R 5a分别独立地为卤素或羟基；
R 6为H或C 1-6烷基。
在一些实施方案中，R 1、R 2和R 3中的两个分别独立地为C 1-6烷基；
R 1、R 2和R 3中的任一个与R 4连同连接它们的原子一起使
Figure PCTCN2022089139-appb-000018
形成
Figure PCTCN2022089139-appb-000019
其中，环A、环B和环C分别独立地为4-12元杂环，所述4-12元杂环具有1、2、3或4个独立地选自Si、N、O和S的杂原子；
R 4f、R 4g或R 4h分别独立地为C 1-6烷基；
m、n和q分别独立地为0、1、2或3；
R 5为一个或多个R 5a取代的C 1-6烷氧基；
R 5a分别独立地为卤素或羟基；
R 6为H或C 1-6烷基。
在一些实施方案中，所述式(I)所示的化合物具有式(I-a)所示的结构：
Figure PCTCN2022089139-appb-000020
其中，R 1、R 2、R 3、R 4a、R 4b、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-b)所示的结构：
Figure PCTCN2022089139-appb-000021
其中，环A、m、R 4f、R 2、R 3、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-c)所示的结构：
Figure PCTCN2022089139-appb-000022
其中，环B、n、R 4g、R 1、R 3、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-d)所示的结构：
Figure PCTCN2022089139-appb-000023
其中，环C、q、R 4h、R 1、R 2、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-b-1)所示的结构：
Figure PCTCN2022089139-appb-000024
其中，R 4f、R 2、R 3、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-c-1)所示的结构：
Figure PCTCN2022089139-appb-000025
其中，R 4g、R 1、R 3、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物具有式(I-d-1)所示的结构：
Figure PCTCN2022089139-appb-000026
其中，R 4h、R 1、R 2、R 5和R 6的定义如本发明任一方案所述。
在一些实施方案中，所述式(I)所示的化合物可以为：
Figure PCTCN2022089139-appb-000027
Figure PCTCN2022089139-appb-000028
另一方面，本发明还提供了一种上述式(I)所示的化合物的制备方法，其为以下方法中的任一种：
方法(A)包括如下步骤：在溶剂中，将式(II-a)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中含有羟基，R 5a’为R 5中的羟基被羟基保护基(例如乙酰基)保护后的基团，R 6为H，
Figure PCTCN2022089139-appb-000029
为
Figure PCTCN2022089139-appb-000030
被羧基保护基保护后的基团(例如
Figure PCTCN2022089139-appb-000031
)；
Figure PCTCN2022089139-appb-000032
方法(B)包括如下步骤：在溶剂中，将式(II-b)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中不含有羟基，R 6为H，R 5b和R 5相同，
Figure PCTCN2022089139-appb-000033
为
Figure PCTCN2022089139-appb-000034
被羧基保护基保护后的基团(例如
Figure PCTCN2022089139-appb-000035
)；
Figure PCTCN2022089139-appb-000036
方法(C)包括如下步骤：在溶剂中，将式(II-c)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中含有羟基，R 6不为H，R 5c为R 5中的羟基被羟基保护基(例如乙酰基)保护后的基团，R 6c和R 6相同；
Figure PCTCN2022089139-appb-000037
其余各基团定义同前。
上述式(I)所示的化合物的制备方法中，方法(A)、方法(B)或方法(C)的反应条件和试剂可以为本领域该类型反应的常规条件和试剂，本发明优选以下条件和试剂。
在一些实施方案中，所述方法(A)、方法(B)或方法(C)中，所述溶剂可以为醚类溶剂(例如四氢呋喃)。所述碱可以为无机碱(例如氢氧化钠)；所述碱可以以水溶液的形式使用，所述碱的水溶液的浓度可以为1～2M。所述反应的温度可以为20～50℃(例如40℃)。
在一些实施方案中，所述方法(A)、方法(B)或方法(C)中，所述反应的进程可采用本领域中的常规测试方法(例如TLC、GC、HPLC或NMR等)进行监控，本领域技术人员可依据监测结果(包括原料转化程度、杂质生成情况等)确定何时终止反应，以获得较佳的反应结果，所述反应的反应时间可以为2小时。
在一些实施方案中，所述式(II-a)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-a)所示的化合物和式(IV)所示的化合物(例如，可以在在碱和催化剂存在的条件下)进行如下所示的偶联反应，得到式(II-a)所示的化合物；
Figure PCTCN2022089139-appb-000038
所述式(II-b)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-b)所示的化合物和式(IV)所示的化合物(例如，可以在在碱和催化剂存在的条件下)进行如下所示的偶联反应，得到式(II-b)所示的化合物；
Figure PCTCN2022089139-appb-000039
所述式(II-c)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-c)所示的化合物和式(IV)所示的化合物(例如，可以在在碱和催化剂存在的条件下)进行如下所示的偶联反应，得到式(II-c)所示的化合物；
Figure PCTCN2022089139-appb-000040
其中，X为Br或I(例如Br)，[B]为硼酸或硼酸酯(例如
Figure PCTCN2022089139-appb-000041
)，其它基团定义同前。
在一些实施方案中，上述式(I)所示的化合物的制备方法还可以进一步包括式(II-a)、(II-b)或(II-c)所示的化合物的制备方法。
上述式(II-a)、(II-b)或(II-c)所示的化合物的制备方法中，所述偶联反应的反应条件和试剂可以为本领域该类型反应的常规条件和试剂，本发明优选以下条件和试剂。
在一些实施方案中，所述式(II-a)、(II-b)或(II-c)所示的化合物的制备方法中，所述溶剂可以为醚类溶剂(例如二氧六环)和水的混合溶剂；所述混合溶剂中，所述醚类溶剂和水的体积比可以为4:1。所述碱可以为无机碱(例如碳酸氢钠)。所述催化剂为钯 类催化剂(例如Pd(dppf)Cl 2)。所述偶联反应的温度可以为90～130℃(例如120℃)。所述偶联反应可以在微波条件和/或惰性(例如氮气)气氛下进行。
在一些实施方案中，所述式(II-a)、(II-b)或(II-c)所示的化合物的制备方法中，所述偶联反应的进程可采用本领域中的常规测试方法(例如TLC、GC、HPLC或NMR等)进行监控，本领域技术人员可依据监测结果(包括原料转化程度、杂质生成情况等)确定何时终止反应，以获得较佳的反应结果，所述偶联反应的反应时间可以为1小时。
在一些实施方案中，式(IV)所示的化合物的制备方法：
当式(IV)所示的化合物中，R 4为C 1-6烷基、–NR 4aR 4b或–SiR 4cR 4dR 4e，[B]为
Figure PCTCN2022089139-appb-000042
时，所述制备方法包括如下步骤：在溶剂中，将式(V)所示的化合物和联硼酸频那醇酯(例如，可以在碱和催化剂存在的条件下)进行如下所示的偶联反应，得到式(IV)所示的化合物；
Figure PCTCN2022089139-appb-000043
其中，Y为Br或I(例如Br)；
当式(IV)所示的化合物为式(IV-a-1)、(IV-b-1)或(IV-c-1)所示的化合物时，所述制备方法包括如下步骤：在溶剂中，将式(VI-a)、(VI-b)或(VI-c)所示的化合物和2-乙炔-4,4,5,5-四甲基-[1,3,2]二噁硼烷(例如，在钴类催化剂(例如，碘化钴)和锌存在下)进行如下所示的环化反应，分别得到式(IV-a-1)、(IV-b-1)或(IV-c-1)所示的化合物；
Figure PCTCN2022089139-appb-000044
Figure PCTCN2022089139-appb-000045
其中，各基团定义同前。
在一些实施方案中，式(I)、(II-a)、(II-b)或(II-c)所示的化合物的制备方法还可以进一步包括上述式(IV)所示的化合物的制备方法。
上述式(IV)所示的化合物的制备方法中，所述反应的反应条件和试剂可以为本领域该类型反应的常规条件和试剂，本发明优选以下条件和试剂。
在一些实施方案中，所述式(IV)所示的化合物的制备方法中，所述偶联反应的溶剂可以为醚类溶剂(例如二氧六环)。所述偶联反应的碱可以为无机碱(例如乙酸钾)。所述偶联反应的催化剂为钯类催化剂(例如Pd(dppf)Cl 2)。所述偶联反应的温度可以为90～130℃(例如120℃)。所述偶联反应可以在微波条件和/或惰性(例如氮气)气氛下进行。所述环化反应的溶剂可以为乙腈(无水乙腈)。所述环化反应的温度可以为20～60℃(例如50℃)。所述环化反应可以在惰性(例如氩气)气氛下进行。
在一些实施方案中，所述式(IV)所示的化合物的制备方法中，所述反应的进程可采用本领域中的常规测试方法(例如TLC、GC、HPLC或NMR等)进行监控，本领域技术人员可依据监测结果(包括原料转化程度、杂质生成情况等)确定何时终止反应，以获得较佳的反应结果。所述偶联反应的反应时间可以为1小时。所述环化反应的反应时间可以为1小时。
另一方面，本发明还提供了一种式(V)、(IV)、(II-a)、(II-b)或(II-c)所示的化合物：
Figure PCTCN2022089139-appb-000046
其中，R 1、R 2、R 3、R 4、R 5a’、R 5b、R 5c、R 6a、R 6b、R 6c、[B]和Y的定义如本发明任一方案所述。
在一些实施方案中，所述式(V)所示的化合物可以为：
Figure PCTCN2022089139-appb-000047
Figure PCTCN2022089139-appb-000048
在一些实施方案中，所述式(IV)所示的化合物可以为：
Figure PCTCN2022089139-appb-000049
在一些实施方案中，所述式(II-a)所示的化合物可以为：
Figure PCTCN2022089139-appb-000050
另一方面，本发明还提供了一种药物组合物，其包含(i)上述式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐；和(ii)药学上可接受 的载体。
另一方面，本发明还提供了一种上述式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐作为药物的应用。
另一方面，本发明还提供了一种上述式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐，或上述药物组合物作为视黄酸受体(例如视黄酸受体γ)激动剂的应用。
本发明还提供了一种上述式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐，或上述药物组合物在制备治疗或预防视与视黄酸受体(例如视黄酸受体γ)相关的疾病的药物中的应用。
本发明中，所述与视黄酸受体(例如视黄酸受体γ)相关的疾病可以为痤疮(包括寻常痤疮、红斑痤疮、结节囊肿性痤疮、聚合性痤疮、以及日光或药物治疗引起的继发性痤疮)、粉刺、银屑病(牛皮癣)、鱼鳞癣、皮肤角化病症、色素沉着、干眼症等。
另一方面，本发明还提供了一种治疗与视黄酸受体(例如视黄酸受体γ)相关疾病的方法，其包括向需要此治疗的受试者施加的上述式(I)所示的化合物(优选地，向需要此治疗的受试者施加治疗有效量的上述式(I)所示的化合物)，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐，或上述药物组合物。
本发明的积极进步效果在于提供一种视黄酸受体激动剂、其制备方法、中间体、药物组合物和应用。该类化合物具有较强的视黄酸受体γ的激动剂活性以及对视黄酸受体γ选择性，具有较弱的肝细胞稳定性；提示该类化合物在皮肤局部有更好的活性，进入体循环后，肝细胞中代谢更快。预示药物更加安全，成药性优异，可以潜在用于治疗与视黄酸受体(例如视黄酸受体γ)相关的疾病。
除非另外说明，本发明所使用的术语具有如下定义，下文中未涉及的术语的定义如本发明所属领域技术人员的通常理解。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。例如，丙酮和1-丙烯-2-醇可以通过氢原子在氧上和α-碳上的迅速移动而互相转变。
术语“立体异构体”是指分子中原子或原子团相互连接次序相同，但空间排列不同而引起的异构体，例如顺反异构体(例如Z-异构体、E-异构体)、旋光异构体(例如对映异构体、非对映异构体)、阻转异构体等。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。旋光异构体包括对映异构体和非对映异构体。所有的这些异构 体以及它们的混合物，均包括在本发明的范围之内。
术语“同位素衍生物”是指化合物中的一个或多个原子被一个或多个具有特定原子质量或质量数的原子取代。可以掺入化合物中的同位素的实例包括但不限于氢、碳、氮、氧、氟、硫和氯的同位素(例如 2H、 3H、 13C、 14C、 15N、 18O、 17O、 18F、 35S和 36Cl)。同位素化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。同位素衍生物的典型实例包括氘代化合物。
术语“药学上可接受的盐”是指化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。当化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。
术语“卤素”表示氟、氯、溴或碘。
术语“羟基”表示–OH基团。
术语“烷基”是指具有一定数目碳原子的饱和的直链或支链的一价烃基。C 1–6烷基是指具有1–6个(例如1、2、3、4、5、6个)碳原子的烷基，包括C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基和C 6烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“术语“烷氧基”是指团-O-R X，其中，R X为如上所定义的烷基。
本文中描述环状基团中的“x–y元”是指环上的原子数目为x–y。例如，环丙基是3元的，四氢吡咯基是5元的，哌啶基是6元的。
术语“取代”或“取代基”是指一个或多个氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。
术语“保护基”包括但不限于“羟基保护基”或“羧基保护基”，是指适合用于阻止所述基团副反应的保护基团。其中，术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm) 和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“治疗有效量”是指在给予患者时足以有效治疗或预防本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型。
本发明所述化合物在临床上可采用常规给药方式。
术语“受试者”是指即将或已经接受了化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
本文采用下述缩略词：K 2CO 3代表碳酸钾；CH 3CN或MeCN代表乙腈；n-BuLi代表正丁基锂；TMSCl代表三甲基氯硅烷；TMS代表三甲基甲硅烷基；B 2Pin 2代表联硼酸频那醇酯；KOAc代表乙酸钾；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；MW代表微波；NBS代表N-溴代琥珀酰亚胺；DCM代表二氯甲烷；NaH代表氢化钠；DMF代表N,N-二甲基甲酰胺；NaHCO 3代表碳酸氢钠；KI代表碘化钾；NaOH代表氢氧化钠；PE代表石油醚；EA代表乙酸乙酯；THF代表四氢呋喃；TLC代表薄层色谱；HPLC代表高压液相色谱；LCMS代表液质联用色谱。
本文涉及的所有专利和公开出版物通过引用方式整体并入本文中。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售或根据已有方法制得可得。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照 商品说明书选择。
实施例1：4'-(2-羟基乙氧基)-4'-(吡咯烷-1-基)-3'-(三甲基硅基)-[1,1'：3'，1'-三苯基]-4-羧酸(化合物I-1)的制备：
Figure PCTCN2022089139-appb-000051
步骤1：1-(4-溴-2-碘苯基)吡咯烷(化合物1-2)的合成
在100mL的单口瓶中，将4-溴-2-碘苯胺(化合物1-1,5g,16.8mmol)用乙腈(50mL)溶解，室温下依次加入二溴丁烷(7.2g,33.6mmol)，碳酸钾(7g，50.4mmol)。加毕，油浴升温至80度，搅拌过夜。将固体不溶物过滤，滤液旋干，残余物用硅胶柱层析纯化(流动相：石油醚)得化合物1-2(2.6g，7.3mmol)为黄色油，收率：43.5％。
LCMS[M+1] +＝351.9，353.9。
步骤2：1-(4-溴-2-(三甲基硅烷基)苯基)吡咯烷(化合物1-3)的合成
在100mL三口瓶中，加入1-(4-溴-2-碘苯基)吡咯烷(化合物1-2，2.6g，7.3mmol)用四氢呋喃(30mL)溶解，干冰丙酮浴下(-78℃)，搅拌5分钟。在氮气保护下，向上述溶液中缓慢滴加正丁基锂(0.5mL，2.5M)的四氢呋喃溶液，滴加完毕后，持续在该温 度下-78℃，反应搅拌1h。然后，再向反应液中，缓慢滴加三甲基氯硅烷(1.6g，14.7mmol)，保持温度恒定在-78℃。滴加完后，搅拌下反应液缓慢升温至室温过夜。饱和氯化铵水溶液(10mL)淬灭反应，反应液用乙醚(3 x 20mL)萃取。合并的有机相用饱和食盐水(1 x 10mL)洗涤，无水硫酸钠干燥，过滤后，滤液旋干得浅黄色残余物。硅胶柱层析(乙酸乙酯:石油醚＝1:20)得到化合物1-3为浅黄色油状物(1.2g，4.0mmol)。收率54.5％。
LCMS[M+1] +＝298.0，300.0。
1H NMR(CDCl 3,300MHz)δ7.55(d,J＝3Hz,1H),7.45(dd,J＝9Hz,3Hz,1H),7.55(d,J＝9Hz,1H),3.02-2.96(m,4H),1.98-1.88(m,4H),0.30(s,1H)。
步骤3：1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)-2-(三甲基硅烷基)苯基)吡咯(化合物1-4)的合成
在10mL微波管中，加入1-(4-溴-2-(三甲基硅烷基)苯基)吡咯烷(化合物1-3,210mg,0.7mmol)，联硼酸频那醇酯(200mg,0.8mmol)，乙酸钾(186mg,2.0mmol)以及Pd(dppf)Cl 2(16mg,0.02mmol)。并在管中加入二氧六环(4mL)。在氮气氛围下，将微波管密封后，在120℃下加热反应1h。反应结束后，用石油醚(9mL)稀释反应液，用少量硅胶层，快速柱分离，过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗产品化合物1-4(242mg)。粗品不用纯化，直接用于下一步反应。
LCMS[M+1] +＝346.2。
1H NMR(DMSO-d 6，800MHz)δ7.72(d,J＝1.5Hz,1H),7.58(dd,J＝1.6,8.1Hz,1H),7.04(d,J＝8.1Hz,1H),3.03(t,J＝6.4Hz,4H),1.86(td,J＝3.2,6.4Hz,4H),1.26(s,12H),0.24(s,9H)。
步骤4：3'-溴-4'-羟基-[1,1'-联苯]-4-羧酸乙酯(化合物1-6)的合成
将4'-羟基-[1,1'-联苯]-4-羧酸乙酯(化合物1-5，1g,4.1mmol)用DCM(15mL)溶于50mL的单口瓶中。25℃下，分五批加入NBS(728mg,4.1mmol)，加毕后，反应物在室温下，继续搅拌1h。结束后浓缩，粗品用柱层析色谱纯化(石油醚：乙酸乙酯＝10：1到1：1)得到白色固体化合物1-6(1.1g,)，收率83.5％。
LCMS[M+1] +＝321.0,323.0。
步骤5：4'-(2-乙酰氧基乙氧基)-3'-溴-[1,1'-联苯]-4-羧酸乙酯(化合物1-7)的合成
将3'-溴-4'-羟基-[1,1'-联苯]-4-羧酸乙酯(化合物1-6，1.1g,3.4mmol)放置在50mL的单口瓶中，用DMF(10mL)溶解。冰水浴0℃下，缓慢加入NaH(163mg,60％,1.2eq)。搅拌反应0.5h后，向上述反应液中，滴加2-溴乙基乙酸酯(678mg,4.1mmol)，滴 加完毕，继续搅拌过夜，然后在体系中加入30mL水，乙酸乙酯萃取，无水硫酸钠钠干燥后，过滤浓缩，硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1到1：1)得到白色固体化合物1-7(1.0g)，收率：72.2％。
1H NMR DMSO-d 6,800MHz)δ8.02-8.00(m,2H),7.98(d,J＝2.3Hz,1H),7.84-7.81(m,J＝8.4Hz,2H),7.75(dd,J＝2.3,8.6Hz,1H),7.27(d,J＝8.7Hz,1H),4.42-4.38(m,2H),4.36-4.31(m,4H),2.06(s,3H),1.34(t,J＝7.2Hz,3H)。
步骤6：4'-(2-乙酰氧基乙氧基)-4'-(吡咯烷-1-基)-3'-(三甲基硅烷基)-[1,1'：3'，1'-三苯基]-4-羧酸乙酯(化合物1-8)的合成
在10mL微波管中，加入化合物1-4(242mg,0.7mmol)，化合物1-7(284mg,0.7mmol)，碳酸氢钠(168mg,2.0mmol)以及Pd(dppf)Cl 2(16mg,0.02mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃下微波反应1h。反应结束后，用石油醚(9mL)和乙酸乙酯(2mL)稀释反应液。用无水硫酸钠干燥后，用少量硅胶层过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗品化合物1-8(382mg)，粗品直接用于下一步，无需进一步纯化。
LCMS[M+1] +＝546.2。
步骤7：4'-(2-羟基乙氧基)-4'-(吡咯烷-1-基)-3'-(三甲基硅基)-[1,1'：3',1'-三苯基]-4-羧酸(化合物I-1)的合成
将4'-(2-乙酰氧基乙氧基)-4'-(吡咯烷-1-基)-3'-(三甲基硅烷基)-[1,1'：3',1'-三苯基]-4-羧酸乙酯(化合物1-8，382mg,0.7mmol)置于25mL的单口瓶中。用四氢呋喃(3mL)中溶解。上述反应体系中，加入NaOH水溶液(2M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。反应液直接用反相柱色谱纯化(H 2O/MeCN,30％-100％,0.05％FA)，得到的洗脱液浓缩至有大量固体析出，过滤，乙腈(1mL x 2)洗涤，干燥，得到白色固体产物化合物I-1(87mg)，收率26.2％。
LCMS[M+1] +＝476.2。
1H NMR(DMSO-d 6,800MHz)δ7.98-7.96(m,2H),7.81-7.79(m,2H),7.66-7.64(m,2H),7.61-7.58(m,2H),7.28(d,J＝8.3Hz,1H),7.22(d,J＝8.7Hz,1H),4.09(t,J＝5.2Hz,2H),3.72-3.69(m,2H),2.99(t,J＝5.4Hz,4H),1.88(td,J＝3.1,6.3Hz,4H),0.28-0.26(m,9H)。
实施例2：4'-(3-羟基丙氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基硅基)-[1,1'：3'，1”-三苯基]-4-羧酸(化合物I-2)的制备：
Figure PCTCN2022089139-appb-000052
步骤1：4'-(3-乙酰氧基丙氧基)-3'-溴-[1,1'-联苯]-4-羧酸乙酯(化合物2-2)的合成
反应瓶中加入3'-溴-4'-羟基-[1,1'-联苯]-4-羧酸乙酯(化合物1-6，110mg,0.34mmol)、乙腈(4mL)、3-氯丙基乙酸酯(136mg,1mmol)、碳酸钾(138mg,1mmol)和催化量的碘化钾，然后，在80℃下搅拌反应12h。过滤浓缩，硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1到1：1)得到白色固体化合物2-2(112mg)，收率78.2％。
LCMS[M+1] +＝421.0,423.0。
步骤2：4'-(3-乙酰氧基丙氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基甲硅烷基)-[1,1'：3',1”-三联苯基]-4-羧酸乙酯(化合物2-3)的合成
在10mL微波管中，加入化合物1-4(60mg,0.17mmol)，化合物2-2(71.4mg,0.17mmol)，碳酸氢钠(42mg,0.5mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃下微波反应1h。反应结束后，用石油醚(9mL)和乙酸乙酯(2mL)稀释反应液。用无水硫酸钠干燥后，用少量硅胶层过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗品化合物2-3(90mg)，粗品直接用于下一步，无需进一步纯化。
LCMS[M+1] +＝560.2。
步骤3：4'-(3-羟基丙氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基甲硅烷基)-[1,1':3',1”-三苯基]-4-羧酸(化合物I-2)的合成
将4'-(3-乙酰氧基丙氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基甲硅烷基)-[1,1':3',1”-三联苯基]-4-羧酸乙酯(化合物2-3,90mg粗品)置于25mL的单口瓶中。用四氢呋喃(3mL)中溶解。上述反应体系中，加入NaOH水溶液(1M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。反应液直接用反相柱色谱纯化(H 2O/MeCN,30％-100％,0.05％FA)，得到的洗脱液浓缩至有大量固体析出，过滤，乙腈(1mL x 2)洗涤，干燥，得到白色固体产物化合物I-2(19mg)。
LCMS[M+1] +＝490.2。
1H NMR(800MHz,DMSO-d 6)δ8.00-7.96(m,J＝8.5Hz,2H),7.83-7.80(m,J＝8.5Hz,2H),7.68(dd,J＝2.4,8.5Hz,1H),7.62(dd,J＝2.3,9.7Hz,2H),7.55(dd,J＝2.2,8.3Hz,1H),7.30(d,J＝8.3Hz,1H),7.21(d,J＝8.7Hz,1H),4.12(t,J＝6.3Hz,2H),3.53(t,J＝6.2Hz,2H),3.01(br.s.,4H),1.89(br.s.,4H),1.85(t,J＝6.3Hz,2H),0.28(s,9H)
实施例3：4'-(4-羟基丁氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基硅基)-[1,1'：3'，1”-三苯基]-4-羧酸(化合物I-3)的制备：
Figure PCTCN2022089139-appb-000053
步骤1：4'-(4-乙酰氧基丁氧基)-3'-溴-[1,1'-联苯]-4-羧酸乙酯(化合物3-2)的合成
反应瓶中加入3'-溴-4'-羟基-[1,1'-联苯]-4-羧酸乙酯(化合物1-6，110mg,0.34mmol)、乙腈(4mL)、4-氯丁基乙酸酯(150mg，1mmol)、碳酸钾(138mg，1mmol)和催化量的碘化钾，然后，在80℃下搅拌反应12h。过滤浓缩，硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1到1：1)得到白色固体化合物3-2(103mg)，收率：70％。
LCMS[M+1] +＝435.0,437.0。
步骤2：4'-(4-乙酰氧基丁氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基甲硅烷基)-[1,1'：3'，1”-三联苯基]-4-羧酸乙酯(化合物3-3)的合成
在10mL微波管中，加入化合物1-4(60mg，0.17mmol)，化合物3-2(73.9mg，0.17mmol)，碳酸氢钠(42mg,0.5mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃下微波反应1h。反应结束后，用石油醚(9mL)和乙酸乙酯(2mL)稀释反应液。用无水硫酸钠干燥后，用少量硅胶层过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗品化合物3-3(88mg)，粗品直接用于下一步，无需进一步纯化。
LCMS[M+1] +＝574.2。
步骤3：4'-(4-羟基丁氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基硅基)-[1,1':3',1”-三苯基]-4-羧酸(化合物I-3)的合成
将4'-(4-乙酰氧基丁氧基)-4”-(吡咯烷基-1-基)-3”-(三甲基甲硅烷基)-[1,1':3',1”-三联苯基]-4-羧酸乙酯(化合物3-3，88mg粗品)置于25mL的单口瓶中。用四氢呋喃(3mL)中溶解。上述反应体系中，加入NaOH水溶液(1M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。反应液直接用反相柱色谱纯化(H 2O/MeCN,30％-100％,0.05％FA)，得到的洗脱液浓缩至有大量固体析出，过滤，乙腈(1mL x 2)洗涤，干燥，得到白色固体产物化合物I-3(26mg)。
LCMS[M+1] +＝504.2。
1H NMR(800MHz,DMSO-d 6)＝8.04-7.95(m,J＝8.4Hz,2H),7.83-7.78(m,J＝8.5Hz,2H),7.67(dd,J＝2.4,8.5Hz,1H),7.61(d,J＝2.4Hz,1H),7.63(d,J＝2.2Hz,1H),7.54(dd,J＝2.2,8.3Hz,1H),7.31(d,J＝8.4Hz,1H),7.21(d,J＝8.7Hz,1H),4.06(t,J＝6.5Hz,2H),3.42(t,J＝6.4Hz,2H),3.00(br.s.,4H),1.89(t,J＝2.9Hz,4H),1.76-1.72(m,2H),1.56-1.51(m,2H),0.28-0.26(s,9H)
实施例4：4'-(二乙氨基)-4'-(2-羟基乙氧基)-3'-(三甲基硅基)-[1,1'：3'，1”-三苯基]-4-羧酸(化合物I-4)的制备：
Figure PCTCN2022089139-appb-000054
步骤1:4-溴-N，N-二乙基-2-碘代苯胺(化合物4-2)的合成
在50mL的密封管中，将4-溴-2-碘苯胺(化合物4-1,0.9g,3mmol)用乙腈(20mL)溶解，室温下依次加入碘乙烷(3.1g，20mmol)，碳酸钾(810mg，6mmol)，加毕后，密闭瓶口，80℃搅拌12h。将固体不溶物过滤，滤液旋干，残余物用硅胶柱层析纯化(流动相：石油醚：乙酸乙酯＝100到20：1)得化合物4-2(350mg，1.0mmol)为黄色油状物，收率：33％。
LCMS[M+1] +＝353.9，355.9。
步骤2：4-溴-N,N-二乙基-2-(三甲基硅基)苯胺(化合物4-3)的合成
在50mL三口瓶中，加入4-溴-N,N-二乙基-2-碘代苯胺(化合物4-2，350mg，1.0mmol)用四氢呋喃(10mL)溶解，干冰丙酮浴下(-78℃)，搅拌5分钟。在氮气保护下，向上述溶液中缓慢滴加正丁基锂(0.5mL，2.5M)滴加完毕后，持续在该温度下-78℃，反应搅拌1h。然后，再向反应液中，缓慢滴加三甲基氯硅烷(180mg，1.7mmol)，保持温度恒定在-78℃。滴加完后，搅拌下反应液缓慢升温至室温过夜。饱和氯化铵水溶液(10mL)淬灭反应，反应液用乙醚(3 x 20mL)萃取。合并的有机相用饱和食盐水(1 x 10mL)洗涤，无水硫酸钠干燥，过滤后，滤液旋干得浅黄色残余物。硅胶柱层析(乙酸乙酯:石油醚＝1:20)得到化合物4-3为浅黄色油状物(150mg，0.5mmol)。收率50％。
LCMS[M+1] +＝300.0，302.0。
步骤3：N,N-二乙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼环-2-基)-2-(三甲基硅基)苯胺(化合物4-4)的合成
在10mL微波管中，加入4-溴-N,N-二乙基-2-(三甲基硅基)苯胺(化合物4-3,150mg,0.5mmol)，联硼酸频那醇酯(153mg,0.6mmol)，乙酸钾(98mg,1.0mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。并在管中加入二氧六环(4mL)。在氮气氛围下，将微波管密封后，在120℃下加热反应1h。反应结束后，用石油醚(9mL)稀释反应液，用少量硅胶层，快速柱分离，过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗产品化合物4-4(180mg)。粗品不用纯化，直接用于下一步反应。
LCMS[M+1] +＝348.2。
步骤4：4'-(2-乙酰氧基乙氧基)-4'-(二乙氨基)-3'-(三甲基硅基)-[1,1':3',1”-三苯基]-4-羧酸乙酯(化合物4-5)的合成
在10mL微波管中，加入化合物4-4(60mg,0.17mmol)，化合物1-7(68mg,0.17mmol)，碳酸氢钠(42mg,0.5mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃℃下微波反应1h。反应结束后，用石油醚(9mL)和乙酸乙酯(2mL)稀释反应液。用无水硫酸钠 干燥后，用少量硅胶层过滤除去无机盐和钯黑。滤液浓缩得到的浅棕色粗品化合物4-5(80mg)，粗品直接用于下一步，无需进一步纯化。
LCMS[M+1] +＝548.2。
步骤5：4'-(二乙氨基)-4'-(2-羟基乙氧基)-3'-(三甲基硅基)-[1,1':3',1”-三苯基]-4-羧酸(化合物I-4)的合成
将4'-(2-乙酰氧基乙氧基)-4'-(二乙氨基)-3'-(三甲基硅基)-[1,1':3',1”-三苯基]-4-羧酸乙酯(化合物4-5,80mg粗品)置于25mL的单口瓶中。用四氢呋喃(3mL)溶解。上述反应体系中，加入NaOH水溶液(1M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。反应液直接用反相柱色谱纯化(H 2O/MeCN,30％-100％,0.05％FA)，得到的洗脱液浓缩至有大量固体析出，过滤，乙腈(1mLx2)洗涤，干燥，得到白色固体产物化合物I-4(17mg)。
LCMS[M+1] +＝478.2。
1H NMR(DMSO-d 6,800MHz)δ7.93-7.90(m,2H),7.80-7.77(m,2H),7.65-7.63(m,2H),7.60-7.58(m,2H),7.26(d,J＝8.2Hz,1H),7.20(d,J＝8.5Hz,1H),4.08(t,J＝5.2Hz,2H),3.70-3.67(m,2H),3.05-2.94(m,4H),1.12-1.04(m,6H),0.27-0.25(m,9H)。
实施例5：4'-(2-羟基乙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1，1'-联苯]-4-羧酸(化合物I-5)的制备：
Figure PCTCN2022089139-appb-000055
步骤1:1,2-双(乙基二甲基硅基)乙烷(化合物5-2)的合成
取1,2-双(氯二甲基硅基)乙烷(化合物5-1，3.00g，13.94mmol)溶于30mL无水四氢呋喃溶液中，体系充入氩气。室温下缓慢滴加乙炔基氯化镁(70mL，0.5mol/L，35.00mmol)。室温下搅拌1h后回流1h。反应完成后，加入饱和氯化铵溶液淬灭。向反应体 系中加入适量乙酸乙酯，用饱和食盐水洗涤两遍，收集有机相，用无水硫酸钠干燥。过滤，减压蒸干有机相，粗产品经硅胶柱层析纯化(石油醚)得到无色液体化合物5-2(1.80g，9.26mmol)，收率66％。
1H NMR(300MHz,CDCl 3)δ2.37(s,2H),0.61(s,4H),0.18(s,12H).
步骤2:1,1,4,4-四甲基-6-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,2,3,4-四氢苯并[b][1,4]二苯胺(化合物5-3)的合成
将碘(20.00mg，0.08mmol)溶于10mL无水乙腈中，加入锌(45.00mg，0.69mmol)，室温下搅拌直至黄色消失并出现灰色悬浮物。将体系充入氩气，室温下依次加入化合物5-2(1.38g，7.10mmol)、2-乙炔-4,4,5,5-四甲基-[1,3,2]二噁硼烷(1.40mg，9.21mmol)和0.1M的碘化钴溶液(2.00mL，0.20mmol)。体系转至50℃下反应，TLC监测，待化合物5-2消耗完全后停止反应。体系经硅胶柱层析初次提纯(乙醚：正己烷＝4:1)，合并，减压蒸干溶剂，得到黄色液体的粗品。粗品经硅胶柱层析再次纯化(正己烷)得到无色晶体化合物5-3(0.50g)收率20.3％。
1H NMR(300MHz,CDCl 3)δ7.84(s,1H),7.68(br s,1H),7.41(br s,1H),1.22(s,12H),0.90(s,4H),0.16(s,6H),0.12(s,6H).
步骤3：乙基4'-(2-乙酰氧基乙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1,1'-联苯]-4-羧酸盐(化合物5-4)的合成
在10mL微波管中，加入化合物1-7(61mg,0.15mmol)，化合物5-3(52mg，0.15mmol)，碳酸氢钠(42mg,0.5mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃℃下微波反应1h。反应结束后，用石油醚(2mL)和乙酸乙酯(9mL)稀释反应液。用无水硫酸钠干燥后，浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝100-10/1)，得到无色油状化合物5-4(70mg)，收率85.3％。
LCMS[M+1] +＝547.2。
1H NMR(800MHz,DMSO-d 6)δ7.78(d,J＝8.4,2H),7.63(d,J＝8.4,2H),,7.52(d,J＝1.2Hz,1H),7.50(dd,J＝2.5,8.5Hz,1H),7.43(d,J＝2.4Hz,1H),7.37-7.31(m,2H),7.05(d,J＝8.6Hz,1H),4.11(q,J＝7.1Hz,2H),4.09-4.05(m,4H),1.76(s,3H),1.11(t,J＝7.1Hz,3H),0.78(s,4H),0.02至-0.02(m,12H)
步骤4：4'-(2-羟基乙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1，1'-联苯]-4-羧酸(化合物I-5)的合成
将乙基4'-(2-乙酰氧基乙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷 基-6-基)-[1,1'-联苯]-4-羧酸盐(化合物5-4，70mg，0.128mmol)置于25mL的单口瓶中。用四氢呋喃(3mL)溶解。上述反应体系中，加入NaOH水溶液(1M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。乙酸乙酯(20mL)萃取，无水硫酸钠干燥，浓缩至约1mL溶剂时加入10mL乙腈，有大量固体析出，过滤，干燥得到I-5(21mg)作为白色固体，收率34.4％。
LCMS[M+1] +＝477.2。
1H NMR(800MHz,DMSO-d 6)δ7.74(d,J＝8.4Hz,2H),7.59-7.53(m,3H),7.45(dd,J＝2.4,8.6Hz,1H),7.42-7.36(m,1H),7.36-7.30(m,2H),7.00(d,J＝8.6Hz,1H),3.87(t,J＝5.1Hz,2H),3.48(t,J＝5.1Hz,2H),0.76(s,4H),0.03-0.02(m,12H).
实施例6：4'-(3-羟基丙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1,1'-联苯]-4-羧酸(化合物I-6)的制备：
Figure PCTCN2022089139-appb-000056
步骤1：乙基4'-(3-乙酰氧基丙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1,1'-联苯]-4-羧酸盐(化合物6-2)的合成
在10mL微波管中，加入化合物2-2(63mg,0.15mmol)，化合物5-3(52mg,0.15mmol)，碳酸氢钠(42mg,0.5mmol)以及Pd(dppf)Cl 2(8mg,0.01mmol)。向上述体系中，加入二氧六环(4mL)和H 2O(1mL)。氮气氛围下，将管密封，在120℃下微波反应1h。反应结束后，用石油醚(2mL)和乙酸乙酯(9mL)稀释反应液。用无水硫酸钠干燥后，浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝100-10/1)，得到无色油状化合物6-2(75mg)，收率89.2％。
LCMS[M+1] +＝561.2。
1H NMR(800MHz,DMSO-d 6)δ7.79-7.78(m,2H),7.64-7.62(m,2H),7.51-7.49(m,2H),7.41(d,J＝2.5Hz,1H),7.35(d,J＝7.6Hz,1H),7.30(dd,J＝1.8,7.6Hz,1H),7.03(d,J＝8.7Hz,1H),4.11(q,J＝7.2Hz,2H),3.91(t,J＝6.2Hz,2H),3.88(t,J＝6.4Hz,2H),1.80-1.78(m,2H),1.73(s,3H),1.12(t,J＝7.1Hz,3H),0.78(s,4H),0.02(s,6H),0.00(s,6H)
步骤2：4'-(3-羟基丙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1,1'-联苯]-4-羧酸(化合物I-6)的合成
将乙基4'-(3-乙酰氧基丙氧基)-3'-(1,1,4,4-四甲基-1,2,3,4-四氢苯并[b][1,4]二硅烷基-6-基)-[1,1'-联苯]-4-羧酸盐(化合物6-2，75mg，0.133mmol)置于25mL的单口瓶中。用四氢呋喃(3mL)溶解。上述反应体系中，加入NaOH水溶液(1M，1mL)。反应体系在40℃搅拌2h。反应结束后，用甲酸缓慢调节反应体系至中性。乙酸乙酯(20mL)萃取，无水硫酸钠干燥，浓缩至约1mL溶剂时加入10mL乙腈，有大量固体析出，过滤，干燥得到I-6(40mg)作为白色固体，收率61.2％。
LCMS[M+1] +＝491.2。
1H NMR(800MHz,DMSO-d 6)δ7.78-7.74(m,2H),7.61-7.58(m,2H),7.51(d,J＝1.3Hz,1H),7.50-7.47(m,1H),7.39(d,J＝2.5Hz,1H),7.37-7.33(m,1H),7.31(d,J＝1.8Hz,1H),7.01(d,J＝8.7Hz,1H),3.90(t,J＝6.3Hz,2H),3.30(t,J＝6.2Hz,2H),1.62(t,J＝6.3Hz,2H),0.77(s,4H),0.02-0.02(m,12H)
生物测试例1：RARγ和RARα的激动剂活性
采用HEK-293细胞系(ATCC#CRL-1573)，测试化合物对于RARγ和RARα的激动剂活性。
实验材料如表1所示：
表1
Figure PCTCN2022089139-appb-000057
实验步骤：
1.第一天：细胞培养。培养皿以胰蛋白酶处理，之后以合适的浓度种入细胞，培养基10mL。细胞培养条件：37摄氏度，5％二氧化碳，潮湿环境。
2.第三天：用FuGENE转染试剂进行转染。采用供应商说明书方法进行转染混合物的制备，剧烈震摇试管以混合均匀，转染混合物室温放置孵化15分钟。胰蛋白酶处理，鉴定细胞密度，适当稀释细胞旋液至适合体积和密度。加入适当的转染 试剂混合物，以100微升每孔的量将细胞悬液加至96孔板中。96孔板以步骤1中细胞培养的条件孵化培育24小时。
3.第四天：加入待测化合物。化合物按照210x浓度配制DMSO储备液，加入9倍量溶媒稀释至21x溶液。每孔加入5微升21x化合物溶液，同步骤1条件孵化24小时。
4.第五天：读板。双荧光素酶报告基因检测系统使用前室温放置30分钟，96孔板每孔加入荧光试剂II，以适当的方式检测萤火虫荧光强度。之后加入Stop&Glo试剂，检测海肾荧光素的强度。
5.数据处理。信号＝萤火虫荧光素强度/海肾荧光素强度，激动剂的激活倍数＝化合物信号/基线信号，基线信号强度由不加化合物的DMSO溶液获得。GraphPad Prism处理数据，得pEC 50值，进一步转换为EC 50值。
本发明部分化合物的实验结果如表2所示。
表2
Figure PCTCN2022089139-appb-000058
从表2数据可以看出，化合物I-1，I-2，I-5对RARγ的激动剂活性等于或强于Trifarotene，化合物I-1，I-2，I-3和I-5对RARγ的选择性优于Trifarotene。
生物测试例2：肝细胞稳定性
采用人肝细胞对化合物的代谢稳定性进行测试。
试验材料：
种属 细胞 产品编号 批次 来源
人 LiverPoor TM10-捐献 X008000 RHZ BioIVT
试验步骤：
1.将化合物和肝细胞在如下体系内孵育240分钟。
化合物浓度 10uM
肝细胞浓度 1.0×10 6细胞/mL
孵育体系 WEM+GlutaMAX
时间 0，240分钟，37℃
体积 200uL
2.用2体积的乙腈(0.1％的FA)将培养物灭活，然后16000g离心力下，离心15分钟。
3.上清液用LC-MS/MS分析化合物原型及代谢产物情况。
结果：
化合物I-1肝细胞代谢结果：
峰 保留时间(min) 分子量(m/z) 分子量偏移 归一化面积(240min)
1 3.60 329.16 -147.06 4.84％
2 4.19 492.24 16.02 8.84％
3 5.03 652.27 176.05 11.60％
4 7.34 476.24 0.02 68.15％
5 7.76 474.23 -1.99 6.45％
6 9.72 476.22 0.00 0.12％
Trifarotene肝细胞代谢结果：
峰 保留时间(min) 分子量(m/z) 分子量偏移 归一化面积(240min)
1 4.18 492.24 31.99 9.35％
2 5.03 652.27 192.03 9.98％
3 7.32 476.24 16.00 54.29％
4 7.76 492.24 31.99 9.10％
5 9.50 460.25 0.00 13.57％
以上结果显示化合物I-1在人肝细胞中的代谢更快，肝细胞孵育240min后剩余原型化合物小于1％，而Trifarotene经240min孵育后仍有13.57％的原型化合物，表明化合物I-1进入血液循环系统后有较低的全身暴露量，预计有更好的安全性。

Claims (15)

  1. 一种式(I)所示的化合物：
    Figure PCTCN2022089139-appb-100001
    或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐；其中，
    R 1、R 2和R 3分别独立地为C 1-6烷基；或者，R 1、R 2和R 3中的任意两个连同连接它们的Si原子形成4-12元杂环烷基，其中所述4-12元杂环烷基具有1、2、3或4个独立地选自Si、N、O和S的杂原子；
    R 4为C 1-6烷基、–NR 4aR 4b或–SiR 4cR 4dR 4e；或者，R 1、R 2和R 3中的任一个与R 4连同连接它们的原子一起使
    Figure PCTCN2022089139-appb-100002
    形成
    Figure PCTCN2022089139-appb-100003
    Figure PCTCN2022089139-appb-100004
    R 4a和R 4b分别独立地为C 1-6烷基；或者，R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基具有1、2或3个N原子；R 4c、R 4d和R 4e分别独立地为C 1-6烷基；
    环A、环B和环C分别独立地为4-12元杂环，所述4-12元杂环具有1、2、3或4个独立地选自Si、N、O和S的杂原子；R 4f、R 4g或R 4h分别独立地为C 1-6烷基；m、n和q分别独立地为0、1、2或3；
    R 5为C 1-6烷氧基或被一个或多个R 5a取代的C 1-6烷氧基；
    R 5a分别独立地为卤素或羟基；
    R 6为H或C 1-6烷基。
  2. 如权利要求1所述的式(I)所示的化合物，其特征在于，
    R 1、R 2和R 3的定义中，所述C 1-6烷基分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，又例如甲基；
    和/或，R 1、R 2和R 3的定义中，当R 1、R 2和R 3中的任意两个连同连接它们的Si原子形成4-12元杂环烷基时，所述4-12元杂环烷基分别独立地为5-10元杂环烷基，例如5-6元杂环烷基；
    和/或，R 1、R 2和R 3的定义中，当R 1、R 2和R 3中的任意两个连同连接它们的Si原子形成4-12元杂环烷基时，所述4-12元杂环烷基分别独立地具有2个Si原子以及0、1或2个独立地选自N、O和S的杂原子，例如具有2个Si原子；
    和/或，R 4的定义中，所述C 1-6烷基分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，R 4a和R 4b的定义中，所述C 1-6烷基分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如乙基；
    和/或，R 4a和R 4b的定义中，当R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基时，所述4-6元杂环烷基为5元杂环烷基；
    和/或，R 4a和R 4b的定义中，当R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基时，所述4-6元杂环烷基具有1个N原子；例如，所述4-6元杂环烷基为
    Figure PCTCN2022089139-appb-100005
    和/或，R 4c、R 4d和R 4e的定义中，所述C 1-6烷基分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，R 4f、R 4g和R 4h的定义中，所述C 1-6烷基分别独立地为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，又例如甲基；
    和/或，环A、环B和环C的定义中，所述4-12元杂环分别独立地为5-10元杂环烷基，例如5-6元杂环，又例如6元杂环；
    和/或，环A、环B和环C的定义中，所述4-12元杂环分别独立地具有2个Si原子以及0、1或2个独立地选自N、O和S的杂原子，例如具有2个Si原子；
    和/或，R 5的定义中，所述C 1-6烷氧基为C 1-4烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，又例如乙氧基、正丙氧基或正丁氧基；
    和/或，R 5a的定义中，所述卤素为氟、氯、溴或碘；
    和/或，R 6的定义中，所述C 1-6烷基为C 1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
  3. 如权利要求1或2所述的式(I)所示的化合物，其特征在于，
    R 1、R 2和R 3分别独立地为C 1-6烷基，例如甲基；
    和/或，R 1、R 2和R 3中的任意两个分别独立地为C 1-6烷基，例如甲基；
    和/或，R 4为–NR 4aR 4b，例如
    Figure PCTCN2022089139-appb-100006
    和/或，R 4a为C 1-6烷基，例如乙基；
    和/或，R 4b为C 1-6烷基，例如乙基；
    和/或，R 4a和R 4b为C 1-6烷基，例如乙基；
    和/或，R 4f分别独立地为C 1-6烷基，例如甲基；
    和/或，R 4g分别独立地为C 1-6烷基，例如甲基；
    和/或，R 4h分别独立地为C 1-6烷基，例如甲基；
    和/或，m为2；
    和/或，n为2；
    和/或，q为2；
    和/或，
    Figure PCTCN2022089139-appb-100007
    为
    Figure PCTCN2022089139-appb-100008
    例如
    Figure PCTCN2022089139-appb-100009
    和/或，
    Figure PCTCN2022089139-appb-100010
    为
    Figure PCTCN2022089139-appb-100011
    例如
    Figure PCTCN2022089139-appb-100012
    和/或，
    Figure PCTCN2022089139-appb-100013
    为
    Figure PCTCN2022089139-appb-100014
    例如
    Figure PCTCN2022089139-appb-100015
    和/或，R 5为被一个或多个R 5a取代的C 1-6烷氧基，例如被一个R 5a取代的C 1-6烷氧基，又例如–OCH 2CH 2OH、–OCH 2CH 2CH 2OH或–OCH 2CH 2CH 2CH 2OH；
    和/或，R 5a为羟基；
    和/或，R 6为H。
  4. 如权利要求1至3中任一项所述的式(I)所示的化合物，其特征在于，
    R 1、R 2和R 3分别独立地为C 1-6烷基；
    R 4为–NR 4aR 4b；
    R 4a和R 4b分别独立地为C 1-6烷基；或者，R 4a和R 4b连同连接它们的N原子一起形成4-6元杂环烷基，所述4-6元杂环烷基具有1、2或3个N原子；
    R 5为被一个或多个R 5a取代的C 1-6烷氧基；
    R 5a分别独立地为卤素或羟基；
    R 6为H或C 1-6烷基。
  5. 如权利要求1至3中任一项所述的式(I)所示的化合物，其特征在于，
    R 1、R 2和R 3中的两个分别独立地为C 1-6烷基；
    R 1、R 2和R 3中的任一个与R 4连同连接它们的原子一起使
    Figure PCTCN2022089139-appb-100016
    形成
    Figure PCTCN2022089139-appb-100017
    其中，环A、环B和环C分别独立地为4-12元杂环，所述4-12元杂环具有1、2、3或4个独立地选自Si、N、O和S的杂原子；
    R 4f、R 4g和R 4h分别独立地为C 1-6烷基；
    m、n和q分别独立地为0、1、2或3；
    R 5为一个或多个R 5a取代的C 1-6烷氧基；
    R 5a分别独立地为卤素或羟基；
    R 6为H或C 1-6烷基。
  6. 如权利要求1至5中任一项所述的式(I)所示的化合物，其特征在于，所述式(I)所示的化合物具有式(I-a)、(I-b)、(I-c)或(I-d)所示的结构：
    Figure PCTCN2022089139-appb-100018
    Figure PCTCN2022089139-appb-100019
    其中，环A、环B、环C、m、n、q、R 4a、R 4b、R 4f、R 4g、R 4h、R 1、R 2、R 3、R 5和R 6的定义如权利要求1至5中任一项所述。
  7. 如权利要求1至6中任一项所述的式(I)所示的化合物，其特征在于，所述式(I)所示的化合物具有式(I-b-1)、(I-c-1)或(I-d-1)所示的结构：
    Figure PCTCN2022089139-appb-100020
    其中，R 4f、R 4g、R 4h、R 1、R 2、R 3、R 5和R 6的定义如权利要求1至6中任一项所述。
  8. 如权利要求1至7中任一项所述的式(I)所示的化合物，其特征在于，所述式(I)所示的化合物为：
    Figure PCTCN2022089139-appb-100021
    Figure PCTCN2022089139-appb-100022
  9. 一种如权利要求1至8中任一项所述的式(I)所示的化合物的制备方法，其特征在于，其为以下方法中的任一种：
    方法(A)包括如下步骤：在溶剂中，将式(II-a)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中含有羟基，R 5a’为R 5中的羟基被羟基保护基保护后的基团，R 6为H，
    Figure PCTCN2022089139-appb-100023
    为
    Figure PCTCN2022089139-appb-100024
    被羧基保护基保护后的基团；
    Figure PCTCN2022089139-appb-100025
    方法(B)包括如下步骤：在溶剂中，将式(II-b)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中不含有羟基，R 6为H，R 5b和R 5相同，
    Figure PCTCN2022089139-appb-100026
    为
    Figure PCTCN2022089139-appb-100027
    被羧基保护基保护后的基团；
    Figure PCTCN2022089139-appb-100028
    方法(C)包括如下步骤：在溶剂中，将式(II-c)所示的化合物在碱存在的条件下进行如下所示的反应，得到式(I)所示的化合物；其中，R 5中含有羟基，R 6不为H，R 5c为R 5中的羟基被羟基保护基保护后的基团，R 6c和R 6相同；
    Figure PCTCN2022089139-appb-100029
    R 1、R 2、R 3和R 4的定义如权利要求1至5中任一项所述。
  10. 一种式(II-a)、(II-b)或(II-c)所示的化合物的制备方法，其特征在于，
    所述式(II-a)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-a)所示的化合物和式(IV)所示的化合物进行如下所示的偶联反应，得到式(II-a)所示的化合物；
    Figure PCTCN2022089139-appb-100030
    所述式(II-b)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-b)所示的化合物和式(IV)所示的化合物进行如下所示的偶联反应，得到式(II-b)所示的化合物；
    Figure PCTCN2022089139-appb-100031
    所述式(II-c)所示的化合物的制备方法包括如下步骤：在溶剂中，将式(III-c)所示的化合物和式(IV)所示的化合物进行如下所示的偶联反应，得到式(II-c)所示的化合物；
    Figure PCTCN2022089139-appb-100032
    其中，[B]为硼酸或硼酸酯，例如
    Figure PCTCN2022089139-appb-100033
    R 1、R 2、R 3、R 4的定义如权利要求1至5中任一项所述；R 5a’、R 5b、R 5c、R 6a、R 6b和R 6c的定义如权利要求9所述。
  11. 一种式(IV)所示的化合物的制备方法，其特征在于，
    当式(IV)所示的化合物中，R 4为C 1-6烷基、–NR 4aR 4b或–SiR 4cR 4dR 4e，[B]为
    Figure PCTCN2022089139-appb-100034
    时，所述制备方法包括如下步骤：在溶剂中，将式(V)所示的化合物和联硼酸频那醇酯进行如下所示的偶联反应，得到式(IV)所示的化合物；
    Figure PCTCN2022089139-appb-100035
    其中，Y为Br或I，例如Br；
    当式(IV)所示的化合物为式(IV-a-1)、(IV-b-1)或(IV-c-1)所示的化合物时，所述制备方法包括如下步骤：在溶剂中，将式(VI-a)、(VI-b)或(VI-c)所示的化合物和2-乙炔-4,4,5,5-四甲基-[1,3,2]二噁硼烷进行如下所示的环化反应，分别得到式(IV-a-1)、(IV-b-1)或(IV-c-1)所示的化合物；
    Figure PCTCN2022089139-appb-100036
    Figure PCTCN2022089139-appb-100037
    其中，R 1、R 2、R 3、R 4f、R 4g和R 4h的定义如权利要求1至5中任一项所述。
  12. 一种式(V)、(IV)、(II-a)、(II-b)或(II-c)所示的化合物：
    Figure PCTCN2022089139-appb-100038
    其中，R 1、R 2、R 3和R 4的定义如权利要求1至5中任一项所述，R 5a’、R 5b、R 5c、R 6a、R 6b和R 6c的定义如权利要求9所述、[B]的定义如权利要求10所述、Y的定义如权利要求11所述。
  13. 如权利要求12所述的化合物，其特征在于，所述式(V)、(IV)或(II-a)所示的化合物为：
    Figure PCTCN2022089139-appb-100039
    Figure PCTCN2022089139-appb-100040
  14. 一种药物组合物，其包含(i)如权利要求1至8中任一项所述的式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐；和(ii)药学上可接受的载体。
  15. 一种如权利要求1至8中任一项所述的式(I)所示的化合物，或其互变异构体、立体异构体、同位素衍生物或药学上可接受的盐，或如权利要求14所述的药物组合物在制备治疗或预防视与视黄酸受体相关的疾病的药物中的应用；
    其中，所述与视黄酸受体相关的疾病优选为与视黄酸受体γ相关的疾病，例如痤疮、粉刺、银屑病、鱼鳞癣、皮肤角化病症、色素沉着、干眼症等，所述痤疮优选为寻常痤疮、红斑痤疮、结节囊肿性痤疮、聚合性痤疮、以及日光或药物治疗引起的继发性痤疮。
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