WO2023103929A1 - Fulvestrant derivative, and preparation method therefor and medical use thereof - Google Patents

Fulvestrant derivative, and preparation method therefor and medical use thereof Download PDF

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Publication number
WO2023103929A1
WO2023103929A1 PCT/CN2022/136446 CN2022136446W WO2023103929A1 WO 2023103929 A1 WO2023103929 A1 WO 2023103929A1 CN 2022136446 W CN2022136446 W CN 2022136446W WO 2023103929 A1 WO2023103929 A1 WO 2023103929A1
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integer
general formula
pharmaceutically acceptable
compound represented
acceptable salt
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PCT/CN2022/136446
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French (fr)
Chinese (zh)
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吴茂江
徐苗焕
杨宝杰
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江苏亚虹医药科技股份有限公司
上海亚虹医药科技有限公司
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Publication of WO2023103929A1 publication Critical patent/WO2023103929A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring

Definitions

  • the invention relates to a fulvestrant derivative, a preparation method thereof, a pharmaceutical composition containing the fulvestrant derivative, and an application thereof for treating breast cancer.
  • Fulvestrant is a new class of estrogen receptor antagonist-estrogen receptor down-regulator anti-breast cancer drug, and is the only anti-estrogen drug that can be widely used after the failure of tamoxifen (TAM) , is currently the drug of choice for the treatment of hormone-sensitive breast cancer.
  • TAM tamoxifen
  • the purpose of the present invention is to improve the oral bioavailability of fulvestrant to solve the problem of fulvestrant administration inconvenience.
  • the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen and the following three structures, wherein R 1 and R 2 are not hydrogen at the same time:
  • R 1 is hydrogen
  • R2 is selected from:
  • R is hydrogen
  • R1 is selected from:
  • n 1 is an integer from 0 to 10;
  • n 2 is an integer from 0 to 10;
  • X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
  • R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  • the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, -X 1 -Y 1 - is selected from -CH 2 -CH 2 - or -SS-.
  • n 1 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
  • n 2 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
  • the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, R 4a and R 5a are the same or different, and are each independently selected from C 5 -C 20 straight or branched chain alkyl groups, preferably C 10 -C 20 straight or branched chain alkyl groups, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
  • n 3 is an integer from 0 to 10;
  • n 4 is an integer from 0 to 10;
  • X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
  • R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups;
  • R 6 is selected from C 1 -C 6 alkyl.
  • the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, -X 2 -Y 2 - is selected from -CH 2 -CH 2 - or -SS-.
  • n 3 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
  • n 4 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
  • the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, R 6 is methyl, ethyl, propyl, butyl, preferably methyl.
  • the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, R 4b and R 5b are the same or different, and each is independently selected from C 5 -C 20 straight or branched chain alkyl, preferably C 10 -C 20 straight or branched chain alkyl, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
  • n 5 is an integer from 0 to 10;
  • n 6 is an integer from 0 to 10;
  • Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein Ra and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, And R a and R b are not hydrogen at the same time, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
  • R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  • the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention wherein, Z Selected from -NR c -, -S- or -O-; R c is hydrogen or C 1 -C 6 alkyl, preferably methyl; Z is preferably selected from -S- or -O-, more preferably -O-.
  • n 5 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, more preferably 1.
  • n 6 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, more preferably 1.
  • R 4a and R 5a are the same or different, and are each independently selected from C 5 -C 20 straight or branched chain alkyl groups, preferably C 10 -C 20 straight or branched chain alkyl groups, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • the compound of formula Ia reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain the compound shown in general formula (I);
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acid halides, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably one of EDCI, DCC, HATU, T3P, thionyl chloride or two or more;
  • R 2 is as defined in general formula (I).
  • the present invention further provides a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • the compound of formula Ib reacts with compound g in the presence of a condensing agent under alkaline conditions to obtain a compound of formula Ic; the compound of formula Ic removes the protecting group under acidic conditions to obtain a compound shown in general formula (I);
  • the basic conditions are selected from pyridine compounds, tertiary amine compounds, preferably DIPEA or DMAP or N-methylmorpholine or triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • the acidic condition is preferably TFA;
  • R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
  • R 1 is as defined in general formula (I).
  • the present invention further provides a method for preparing the compound represented by general formula (IIA) or (IVA) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • the compound of formula IIAa or IVAa reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain a compound represented by general formula (IIA) or (IVA);
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIA);
  • the present invention further provides a method for preparing the compound represented by general formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • the compound of formula IIAa or IVAa reacts with compound g in the presence of a condensing agent under basic conditions to obtain the compound of formula (IIBc) or (IVBc); the compound of formula (IIBc) or (IVBc) is removed under acidic conditions Protecting group, obtains the compound shown in general formula (IIB) or (IVB);
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • the acidic condition is preferably TFA;
  • R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
  • X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIB);
  • the present invention further provides a preparation method of the compound represented by general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • the compound of formula IIIBb reacts with the compound of formula IIIBc in the presence of a catalyst under basic conditions to obtain the compound of formula IIIBd; the compound of formula IIIBd removes the protecting group under acidic conditions to obtain the compound shown in general formula (IIIB) ;
  • the alkaline conditions are preferably inorganic bases, more preferably potassium carbonate, cesium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride;
  • the catalyst is selected from phase transfer catalysts, preferably TBAI;
  • the acidic condition is preferably TFA;
  • R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
  • X 2 , Y 2 , n 3 , n 4 , R 4b , R 5b , and R 6 are as defined in general formula (IIIB).
  • the present invention further provides a preparation method of the compound represented by general formula (IIIA) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
  • Fulvestrant reacts with the acid chloride compound IIIAa to obtain a compound of formula IIIAb, and the compound of formula IIIAb reacts with a compound of formula IIIAc to obtain a compound of general formula (IIIA);
  • the present invention also relates to a pharmaceutical composition, which contains the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier or excipient.
  • the present invention further relates to the use of the compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing it in the preparation of a medicine for treating breast cancer according to the present invention.
  • the present invention further relates to a method for treating breast cancer, which comprises administering a therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or a pharmaceutically acceptable salt thereof or containing its pharmaceutical composition.
  • the present invention further relates to the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it according to the present invention, which is used for treating breast cancer.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the compounds of this invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating breast cancer. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, for example: an alkyl group containing 2 to 20 carbon atoms, containing 2 to 15 carbon atoms An alkyl group containing 10 to 20 carbon atoms, an alkyl group containing 10 to 15 carbon atoms, an alkyl group containing 15 to 20 carbon atoms, or an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include 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-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkenes radical, alkynyl, alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl, or carboxylate.
  • alkenyl refers to a hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. .
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
  • alkynyl refers to a hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, propynyl, butynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
  • hydroxyl protecting group is a suitable group known in the art for the protection of a hydroxy group, see Hydroxyl Protecting Groups in the document “Protective Groups in Organic Synthesis", 5th edition, TW Greene & P. GMWuts.
  • the hydroxyl protecting group may be (C 1-10 alkyl or aryl) silyl , for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl (TBS), tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy Substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl , benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, for example: formyl ,
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • sulfonyl refers to compounds containing the group -S(O) 2R , where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • sulfinyl refers to compounds containing the group -S(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be synthesized by the following scheme.
  • the compound of formula IIAa or IVAa reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain a compound represented by general formula (IIA) or (IVA);
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIA);
  • the preparation method of the compound represented by general formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof of the present invention comprises the following steps:
  • the compound of formula IIAa or IVAa reacts with compound g in the presence of a condensing agent under basic conditions to obtain the compound of formula (IIBc) or (IVBc); the compound of formula (IIBc) or (IVBc) is removed under acidic conditions Protecting group, obtains the compound shown in general formula (IIB) or (IVB);
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • the acidic condition is preferably TFA;
  • R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
  • X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIB);
  • the compound of formula IIAb reacts with the compound of formula IIAc in the presence of a condensing agent under alkaline conditions to obtain a compound of formula IIAa;
  • the basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
  • the condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
  • the compound of formula IIAd reacts with the compound of formula IIAc under basic conditions to obtain the compound of formula IIAa;
  • the basic conditions are selected from organic bases, preferably DIPEA, DMAP or pyridine;
  • X 1 , Y 1 , n 1 , n 2 , R 4a , and R 5a are as defined in general formula (IIA).
  • the compound of formula IVAb reacts with the compound of formula IVAc under alkaline conditions to obtain the compound of formula IVAa;
  • the basic conditions are selected from organic bases, preferably DIPEA, DMAP or pyridine;
  • Z, n 5 , n 6 , R 4c , and R 5c are as defined in general formula (IVA).
  • Step 1 Compound g reacts with an acid chloride compound of formula IIIBa under basic conditions to obtain a compound of formula IIIBb; the basic conditions are preferably pyridine;
  • Step 2 the compound of formula IIIBb reacts with the compound of formula IIIBc in the presence of a catalyst under basic conditions to obtain the compound of formula IIIBd;
  • the basic conditions are preferably inorganic bases, more preferably potassium carbonate, cesium carbonate, hydroxide Sodium, potassium tert-butoxide, sodium hydride;
  • the catalyst is selected from phase transfer catalysts, preferably TBAI;
  • Step 3 the compound of formula IIIBd is deprotected under acidic conditions to obtain the compound shown in general formula (IIIB); said acidic conditions are preferably TFA;
  • R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
  • X 2 , Y 2 , n 3 , n 4 , R 4b , R 5b , and R 6 are as defined in general formula (IIB).
  • the above compound g (intermediate g) can be obtained by combining fulvestrant with (Boc) 2 O, tert-butyldimethylchlorosilane, triisopropylchlorosilane, trimethylchlorosilane, benzyl bromide (BnBr), Benzyl chloride is obtained by reaction, taking (Boc) 2 O as an example, the reaction scheme is as follows:
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • Chromatographic column is Daisogel C18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • TLC Thin-layer chromatography
  • Silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide, Nanjing Yaoshi and other companies.
  • Fulvestrant purchased from Jiaxing Menghui Chemical Co., Ltd., batch number 21210407;
  • EDCI 1-ethyl-3(3-dimethylpropylamine) carbodiimide
  • DIPEA N,N-Diisopropylethylamine
  • DCC N,N'-dicyclohexylcarboimide
  • T3P 1-propyl phosphate cyclic anhydride
  • TFA trifluoroacetic acid
  • TBAI Tetrabutylammonium iodide
  • PE petroleum ether
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Boc tert-butoxycarbonyl
  • Fulvestrant 2.0g, 3.3mmol, 1eq
  • DCM dichloromethane
  • DMAP dimethylaminopyridine
  • (Boc) 2O 872 mg, 4.0 mmol, 1.2 eq)
  • THF tetrahydrofuran
  • Example 1 2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthren-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyl dipalmitate (1)
  • Step 1 2-((4-((4-(((4-(((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methyl-7-( 9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthrene-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propane-1,3-diyl dipalmitate (1a ) preparation
  • Step 2 2-((4-((4-(((4-(((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyl dipalmitate (1)
  • Example 2 2-((3-((3-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthrene-17-yl)oxy)-3-oxopropyl)dithio)propionyl)oxy)propan-1,3-diyl dipalmitate (2)
  • Example 3 2-(2-((2-((((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)dithio)acetyl)propan-1,3-diyl dipalmitate (3)
  • Example 7 2-(2-((2-((((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)thio)acetoxy)propan-1,3-diyl dipalmitate (7)
  • Step 1 2-(2-((2-((((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methyl-7-(9 -((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro- Preparation of 6H-cyclopenta[a]phenanthrene-17-yl)oxy)-2-oxoethyl)thio)acetoxy)propane-1,3-diyl dipalmitate (7a)
  • Step 2 2-(2-((2-((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-((4,4,5, 5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene Preparation of -17-yl)oxy)-2-oxoethyl)thio)acetoxy)prop-1,3-diyl dipalmitate (7)
  • Example 8 2-(2-((2-((((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-3-yl)oxy)-2-oxoethyl)thio)acetoxy)propan-1,3-diyl dipalmitate (8)
  • Example 10 2-(2-(2-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5, 5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene Preparation of -3-yl)oxy)-2-oxoethoxy)acetyl)propan-1,3-diyl dipalmitate (10)
  • Example 11 1,3-bis(palmitoyloxy)prop-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)malonate (11)
  • Example 12 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)succinate (12)
  • Example 13 1,3-bis(palmitoyloxy)prop-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)glutarate (13)
  • Example 14 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)adipate (14)
  • Example 15 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)3-methylglutaric acid diester (15)
  • Example 16 1-(1,3-bis(palmitoyloxy)propan-2-yl)7-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)pimelate (16)
  • Example 17 1-(1,3-bis(palmitoyloxy)propan-2-yl)12-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)dodecanoic acid diester (17)
  • Example 18 1,3-bis(palmitoyloxy)propan-2-yl((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)malonate (18)
  • Example 19 1,3-bis(palmitoyloxy)propan-2-yl((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)succinate (19)
  • Example 20 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)glutarate (20)
  • Example 21 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)3-methylglutaric acid diester (21)
  • Example 22 1-(1,3-bis(palmitoyloxy)propan-2-yl)12-((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)dodecanoic acid diester (22)
  • Step 1 tert-butyl(1-chloroethyl)((7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5- Pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3, Preparation of 17-diyl)bis(carboxylate) (23a)
  • Step 2 2-((4-((4-(1-((((((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methanol yl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16 ,17-Decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethoxy)-4-oxobutyl)dithio)butanoyl)oxy) Preparation of propane-1,3-diyl dipalmitate (23b)
  • Step 3 2-((4-((4-(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-(( 4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-ring Penta[a]phenanthrene-17-yl)oxy)formyloxy)ethoxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyldi Preparation of Palmitate (23)
  • Example 24 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy -13-Methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14 , 15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)oxy)carbonyl)oxy)ethyl)3-methylglutaric acid ester (24)
  • Example 25 2-(2-(2-(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4 ,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl [a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethoxy)-2-oxoethoxy)acetyl)propan-1,3-diyl dipalmitate (25) preparation
  • Example 26 1,3-Bis(palmitoyloxy)prop-2-yl(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)malonate (26)
  • Example 27 1,3-bis(palmitoyloxy)propan-2-yl(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)succinate (27)
  • Example 28 1,3-Bis(palmitoyloxy)prop-2-yl(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 - Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)formyloxy)ethyl)glutarate (28)
  • Step 1 1,3-Bis(palmitoyloxy)propan-2-yl(1-((((((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy Base)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13 , 14,15,16,17-Decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)glutarate (28a)
  • Step 2 1,3-Bis(palmitoyloxy)propan-2-yl(1-((((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7 -(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17- Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)formyloxy)ethyl)glutarate (28)
  • Example 29 2-((N-(2-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)-N-methylaminoacetyl)oxy)propan-1,3-diyl dipalmitate (29)
  • Example 30 2-((N-(2-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-3-yl)oxy)-2-oxoethyl)-N-methylglycyl)oxy)propan-1,3-diyl dipalmitate (30)
  • fulvestrant 500mg, 824 ⁇ mol, 1.00eq
  • intermediate i 1.32g, 1.90mmol, 2.30eq
  • EDCI 474mg, 2.47mmol, 3.00eq
  • DMAP 201mg, 1.65mmol, 2.00 eq
  • DCM 7 mL
  • Example 6 For the above compound 6, except that it is prepared by a method similar to that of Example 4, it can also be prepared by a method similar to that of Example 8, Example 10-Example 12, and Example 30; for the above Compound 13-Compound 17 , except that it is prepared by a method similar to that of Example 11, it can also be prepared by a method similar to that of Example 4, Example 8, Example 10, Example 12, and Example 30, and the specific process will not be repeated.
  • Test Example 1 Pharmacokinetic study of the compound of the present invention
  • Test method 200-250 g female SD rats (SPF grade, purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.), 3 rats for each compound, were randomly divided into groups.
  • the compound to be tested was prepared into a solution with a concentration of 2 mg/mL with 6% dimethylacetamide, 20% HS15, 20% PEG200 and 54% physiological saline.
  • the dosage of the compound of the present invention is 20 mg/kg (mpk), and the dosage of the positive control compound fulvestrant is 10 mg/kg (mpk).
  • Blood was collected from the tail vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, respectively. According to the standard detection method of blood drug concentration.
  • the calculation formula of the bioavailability F% of the compound of the present invention is as follows:
  • AUC cpd is the AUC that the compound of the present invention to be tested releases fulvestrant
  • AUC fulvestrant is the AUC corresponding to fulvestrant intravenous injection 1mpk (IV 1mpk)
  • MW cpd is the compound of the present invention to be tested
  • the molecular weight of fulvestrant, MW fulvestrant is the molecular weight of fulvestrant.
  • the compound of the present invention obtains better oral bioavailability than fulvestrant through prodrug modification.

Abstract

Provided are a fulvestrant derivative, and a preparation method therefor and the medical use thereof. Specifically, provided are a fulvestrant derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof in treating breast cancer.

Description

氟维司群衍生物及其制备方法和医药用途Fulvestrant derivative and its preparation method and medical application 技术领域technical field
本发明涉及一种氟维司群衍生物，其制备方法，包含其的药物组合物，以及其用于治疗乳腺癌的用途。The invention relates to a fulvestrant derivative, a preparation method thereof, a pharmaceutical composition containing the fulvestrant derivative, and an application thereof for treating breast cancer.
背景技术Background technique
氟维司群是一类新的***受体拮抗剂—***受体下调剂类抗乳腺癌治疗药物，是唯一在他莫昔芬(TAM)作用失败后可广泛应用的抗***药物，是目前治疗激素敏感型乳腺癌的首选药物。Fulvestrant is a new class of estrogen receptor antagonist-estrogen receptor down-regulator anti-breast cancer drug, and is the only anti-estrogen drug that can be widely used after the failure of tamoxifen (TAM) , is currently the drug of choice for the treatment of hormone-sensitive breast cancer.
但是，氟维司群的口服生物利用度极低，所以需要每月肌肉注射给药，且需要低温(2～8℃)保存，相比于口服TAM，使用有诸多不便。目前，科学家在努力研发生物利用度高、药代动力学特征更理想且在乳腺中具有强效抗***活性的可以口服的新药，但尚无理想的替代品。However, the oral bioavailability of fulvestrant is extremely low, so monthly intramuscular injection is required, and it needs to be stored at low temperature (2-8°C). Compared with oral TAM, it is more inconvenient to use. At present, scientists are working hard to develop new oral drugs with high bioavailability, better pharmacokinetic characteristics and strong anti-estrogen activity in the breast, but there is no ideal substitute.
发明内容Contents of the invention
本发明的目的是提高氟维司群的口服生物利用度以解决氟维司群给药不便的问题。The purpose of the present invention is to improve the oral bioavailability of fulvestrant to solve the problem of fulvestrant administration inconvenience.
具体的，本发明提供一种通式(I)所示的化合物或其药学上可接受的盐，Specifically, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022136446-appb-000001
Figure PCTCN2022136446-appb-000001
其中，in,
R 1和R 2相同或不同，且各自独立地选自氢及以下三种结构，其中R 1、R 2不同时为氢： R 1 and R 2 are the same or different, and are independently selected from hydrogen and the following three structures, wherein R 1 and R 2 are not hydrogen at the same time:
·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000002
Figure PCTCN2022136446-appb-000002
其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
Figure PCTCN2022136446-appb-000003
其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基； Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
Figure PCTCN2022136446-appb-000003
Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000004
Figure PCTCN2022136446-appb-000004
其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
Figure PCTCN2022136446-appb-000005
其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基； Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
Figure PCTCN2022136446-appb-000005
Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
Figure PCTCN2022136446-appb-000006
Figure PCTCN2022136446-appb-000006
其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
Figure PCTCN2022136446-appb-000007
其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not both hydrogen, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
Figure PCTCN2022136446-appb-000007
Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
根据本发明一个具体的实施方案，通式(I)所示的化合物或其药学上可接受的盐，其中：According to a specific embodiment of the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein:
R 1为氢； R 1 is hydrogen;
R 2选自： R2 is selected from:
·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000008
Figure PCTCN2022136446-appb-000008
其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
Figure PCTCN2022136446-appb-000009
其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基； Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
Figure PCTCN2022136446-appb-000009
Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000010
Figure PCTCN2022136446-appb-000010
其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
Figure PCTCN2022136446-appb-000011
其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基； Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
Figure PCTCN2022136446-appb-000011
Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
Figure PCTCN2022136446-appb-000012
Figure PCTCN2022136446-appb-000012
其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
Figure PCTCN2022136446-appb-000013
其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not both hydrogen, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
Figure PCTCN2022136446-appb-000013
Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
根据本发明另一个具体的实施方案，通式(I)所示的化合物或其药学上可接受的盐，其中：According to another specific embodiment of the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein:
R 2为氢； R is hydrogen;
R 1选自： R1 is selected from:
·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000014
Figure PCTCN2022136446-appb-000014
其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
Figure PCTCN2022136446-appb-000015
其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基； Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
Figure PCTCN2022136446-appb-000015
Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
Figure PCTCN2022136446-appb-000016
Figure PCTCN2022136446-appb-000016
其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
Figure PCTCN2022136446-appb-000017
其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基； Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
Figure PCTCN2022136446-appb-000017
Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
Figure PCTCN2022136446-appb-000018
Figure PCTCN2022136446-appb-000018
其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
Figure PCTCN2022136446-appb-000019
其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not both hydrogen, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
Figure PCTCN2022136446-appb-000019
Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐：In a preferred embodiment of the present invention, according to the compound represented by general formula (I) or its pharmaceutically acceptable salt according to the present invention, it is represented by general formula (IIA) or general formula (IIB) Compound or its pharmaceutically acceptable salt:
Figure PCTCN2022136446-appb-000020
Figure PCTCN2022136446-appb-000020
其中，in,
n 1为0至10的整数； n 1 is an integer from 0 to 10;
n 2为0至10的整数； n 2 is an integer from 0 to 10;
X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-； X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
在本发明一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐，其中，-X 1-Y 1-选自-CH 2-CH 2-或-S-S-。 In a specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, -X 1 -Y 1 - is selected from -CH 2 -CH 2 - or -SS-.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐，其中，n 1为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，进一步优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 1 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐，其中，n 2为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，进一步优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 2 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐，其中，R 4a和R 5a相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIA) or general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, R 4a and R 5a are the same or different, and are each independently selected from C 5 -C 20 straight or branched chain alkyl groups, preferably C 10 -C 20 straight or branched chain alkyl groups, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐：In another preferred embodiment of the present invention, according to the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, it is represented by general formula (IIIA) or general formula (IIIB) A compound or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022136446-appb-000021
Figure PCTCN2022136446-appb-000021
其中，in,
n 3为0至10的整数； n 3 is an integer from 0 to 10;
n 4为0至10的整数； n 4 is an integer from 0 to 10;
X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-； X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基； R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups;
R 6选自C 1-C 6烷基。 R 6 is selected from C 1 -C 6 alkyl.
在本发明一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐，其中，-X 2-Y 2-选自-CH 2-CH 2-或-S-S-。 In a specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, -X 2 -Y 2 - is selected from -CH 2 -CH 2 - or -SS-.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐，其中，n 3为1至5的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，进一步优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 3 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐，其中，n 4为1至5的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，进一步优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 4 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, and still more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐，其中，R 6为甲基、乙基、丙基、丁基，优选甲基。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, R 6 is methyl, ethyl, propyl, butyl, preferably methyl.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐，其中，R 4b和R 5b相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, R 4b and R 5b are the same or different, and each is independently selected from C 5 -C 20 straight or branched chain alkyl, preferably C 10 -C 20 straight or branched chain alkyl, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐：In another preferred embodiment of the present invention, according to the compound represented by general formula (I) or its pharmaceutically acceptable salt according to the present invention, it is represented by general formula (IVA) or general formula (IVB) A compound or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022136446-appb-000022
Figure PCTCN2022136446-appb-000022
其中，in,
n 5为0至10的整数； n 5 is an integer from 0 to 10;
n 6为0至10的整数； n 6 is an integer from 0 to 10;
Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基； Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein Ra and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, And R a and R b are not hydrogen at the same time, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
在本发明一个具体的实施方案中，根据本发明所述的通式(I)、通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐，其中，Z选自-CR aR b-；R a为氢，R b为C 1-C 6烷基优选甲基。 In a specific embodiment of the present invention, according to the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, Z is selected from Since -CR a R b -; R a is hydrogen, R b is C 1 -C 6 alkyl, preferably methyl.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐，其中，Z选自-NR c-、-S-或-O-；R c为氢或C 1-C 6烷基优选甲基；Z优选自-S-或-O-，进一步优选-O-。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, Z Selected from -NR c -, -S- or -O-; R c is hydrogen or C 1 -C 6 alkyl, preferably methyl; Z is preferably selected from -S- or -O-, more preferably -O-.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐，其中，n 5为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，更优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 5 is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐，其中，n 6为1至5的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，更优选1。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, n 6 is an integer of 1 to 5, preferably an integer of 1 to 8, more preferably an integer of 1 to 5, more preferably 1 or 2, more preferably 1.
在本发明另一个具体的实施方案中，根据本发明所述的通式(I)、通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐，其中，R 4a和R 5a相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 In another specific embodiment of the present invention, the compound represented by general formula (I), general formula (IVA) or general formula (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, wherein, R 4a and R 5a are the same or different, and are each independently selected from C 5 -C 20 straight or branched chain alkyl groups, preferably C 10 -C 20 straight or branched chain alkyl groups, more preferably C 15 -C 20 straight-chain or branched-chain alkyl, particularly preferably straight-chain pentadecyl.
本发明典型的化合物，包括但不限于：Typical compounds of the invention include, but are not limited to:
Figure PCTCN2022136446-appb-000023
Figure PCTCN2022136446-appb-000023
Figure PCTCN2022136446-appb-000024
Figure PCTCN2022136446-appb-000024
Figure PCTCN2022136446-appb-000025
Figure PCTCN2022136446-appb-000025
Figure PCTCN2022136446-appb-000026
Figure PCTCN2022136446-appb-000026
Figure PCTCN2022136446-appb-000027
Figure PCTCN2022136446-appb-000027
Figure PCTCN2022136446-appb-000028
Figure PCTCN2022136446-appb-000028
Figure PCTCN2022136446-appb-000029
Figure PCTCN2022136446-appb-000029
Figure PCTCN2022136446-appb-000030
Figure PCTCN2022136446-appb-000030
或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
当R 1为氢时： When R1 is hydrogen:
Figure PCTCN2022136446-appb-000031
Figure PCTCN2022136446-appb-000031
式Ia的化合物与氟维司群在碱性条件下在缩合剂存在下发生反应得到通式(I)所示的化合物；The compound of formula Ia reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain the compound shown in general formula (I);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acid halides, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably one of EDCI, DCC, HATU, T3P, thionyl chloride or two or more;
其中R 2如通式(I)所定义。 Wherein R 2 is as defined in general formula (I).
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
当R 2为氢时： When R2 is hydrogen:
Figure PCTCN2022136446-appb-000032
Figure PCTCN2022136446-appb-000032
式Ib的化合物与化合物g在碱性条件下在缩合剂的存在下发生反应得到式Ic的化合物；式Ic的化合物在酸性条件下脱除保护基，得到通式(I)所示的化合物；The compound of formula Ib reacts with compound g in the presence of a condensing agent under alkaline conditions to obtain a compound of formula Ic; the compound of formula Ic removes the protecting group under acidic conditions to obtain a compound shown in general formula (I);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA或DMAP或N-甲基吗啉或三乙胺；The basic conditions are selected from pyridine compounds, tertiary amine compounds, preferably DIPEA or DMAP or N-methylmorpholine or triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
所述酸性条件优选TFA；The acidic condition is preferably TFA;
其中R x为羟基保护基，优选叔丁氧羰基(Boc基团)或叔丁基二甲基硅烷基或三异丙基硅基或苄基； Wherein R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
其中R 1如通式(I)所定义。 Wherein R 1 is as defined in general formula (I).
本发明进一步提供根据本发明所述的通式(IIA)或(IVA)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a method for preparing the compound represented by general formula (IIA) or (IVA) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
Figure PCTCN2022136446-appb-000033
Figure PCTCN2022136446-appb-000033
式IIAa或IVAa的化合物与氟维司群在碱性条件下在缩合剂存在下发生反应得到通式(IIA)或(IVA)所示的化合物；The compound of formula IIAa or IVAa reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain a compound represented by general formula (IIA) or (IVA);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
其中：in:
X 1、Y 1、n 1、n 2、R 4a、R 5a如通式(IIA)所定义； X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIA);
Z、n 5、n 6、R 4c、R 5c如通式(IVA)所定义。 Z, n 5 , n 6 , R 4c , R 5c are as defined in the general formula (IVA).
本发明进一步提供根据本发明所述的通式(IIB)或(IVB)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a method for preparing the compound represented by general formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
Figure PCTCN2022136446-appb-000034
Figure PCTCN2022136446-appb-000034
式IIAa或IVAa的化合物与化合物g在碱性条件下在缩合剂的存在下发生反应得到式(IIBc)或(IVBc)的化合物；式(IIBc)或(IVBc)的化合物在酸性条件下脱除保护基，得到通式(IIB)或(IVB)所示的化合物；The compound of formula IIAa or IVAa reacts with compound g in the presence of a condensing agent under basic conditions to obtain the compound of formula (IIBc) or (IVBc); the compound of formula (IIBc) or (IVBc) is removed under acidic conditions Protecting group, obtains the compound shown in general formula (IIB) or (IVB);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
所述酸性条件优选TFA；The acidic condition is preferably TFA;
其中：in:
R x为羟基保护基，优选叔丁氧羰基(Boc基团)或叔丁基二甲基硅烷基或三异丙基硅基或苄基； R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
X 1、Y 1、n 1、n 2、R 4a、R 5a如通式(IIB)所定义； X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIB);
Z、n 5、n 6、R 4c、R 5c如通式(IVB)所定义。 Z, n 5 , n 6 , R 4c , R 5c are as defined in general formula (IVB).
本发明进一步提供根据本发明所述的通式(IIIB)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a preparation method of the compound represented by general formula (IIIB) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
Figure PCTCN2022136446-appb-000035
Figure PCTCN2022136446-appb-000035
式IIIBb的化合物与式IIIBc的化合物在碱性条件下在催化剂的存在下发生反应，得到式IIIBd的化合物；式IIIBd的化合物在酸性条件下脱除保护基得到通式(IIIB)所示的化合物；The compound of formula IIIBb reacts with the compound of formula IIIBc in the presence of a catalyst under basic conditions to obtain the compound of formula IIIBd; the compound of formula IIIBd removes the protecting group under acidic conditions to obtain the compound shown in general formula (IIIB) ;
所述碱性条件优选无机碱，进一步优选碳酸钾、碳酸铯、氢氧化钠、叔丁醇钾、氢化钠；The alkaline conditions are preferably inorganic bases, more preferably potassium carbonate, cesium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride;
所述催化剂选自相转移催化剂，优选TBAI；The catalyst is selected from phase transfer catalysts, preferably TBAI;
所述酸性条件优选TFA；The acidic condition is preferably TFA;
其中，in,
R x为羟基保护基，优选叔丁氧羰基(Boc基团)或叔丁基二甲基硅烷基或三异丙基硅基或苄基； R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
X 2、Y 2、n 3、n 4、R 4b、R 5b、R 6如通式(IIIB)所定义。 X 2 , Y 2 , n 3 , n 4 , R 4b , R 5b , and R 6 are as defined in general formula (IIIB).
本发明进一步提供根据本发明所述的通式(IIIA)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The present invention further provides a preparation method of the compound represented by general formula (IIIA) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following steps:
Figure PCTCN2022136446-appb-000036
Figure PCTCN2022136446-appb-000036
氟维司群与酰氯化合物IIIAa反应得到式IIIAb的化合物，式IIIAb的化合物与式IIIAc的化合物反应得到通式(IIIA)的化合物；Fulvestrant reacts with the acid chloride compound IIIAa to obtain a compound of formula IIIAb, and the compound of formula IIIAb reacts with a compound of formula IIIAc to obtain a compound of general formula (IIIA);
其中X 2、Y 2、n 3、n 4、R 4b、R 5b、R 6如通式(IIIA)所定义。 Wherein X 2 , Y 2 , n 3 , n 4 , R 4b , R 5b , and R 6 are as defined in general formula (IIIA).
本发明还涉及一种药物组合物，其含有根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。The present invention also relates to a pharmaceutical composition, which contains the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier or excipient.
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐或者含有其的药物组合物在制备用于治疗乳腺癌的药物中的用途。The present invention further relates to the use of the compound represented by the general formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing it in the preparation of a medicine for treating breast cancer according to the present invention.
本发明进一步涉及一种治疗乳腺癌的方法，其包括向有需要的患者施用治疗 有效量的根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐或者含有其的药物组合物。The present invention further relates to a method for treating breast cancer, which comprises administering a therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or a pharmaceutically acceptable salt thereof or containing its pharmaceutical composition.
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其药学上可接受的盐或者含有其的药物组合物，其用于治疗乳腺癌。The present invention further relates to the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it according to the present invention, which is used for treating breast cancer.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time. For example, water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used. Soft gelatin capsules provide an oral formulation.
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural The resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agents such as sucrose, saccharin, or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨 坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、***的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗乳腺癌的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。The present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating breast cancer. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
发明的详细说明Detailed Description of the Invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，例如：含有2至20个碳原子的烷基，含有2至15个碳原子的烷基，含有10至20个碳原子的烷基，含有10至15个碳原子的烷基，含有15至20个碳原子的烷基，或含有1至6个碳原子的烷基。非限制性实例包括甲基、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、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基、十一烷基、十二烷基、十五烷基、十六烷基、二十烷基，及其各种支 链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, for example: an alkyl group containing 2 to 20 carbon atoms, containing 2 to 15 carbon atoms An alkyl group containing 10 to 20 carbon atoms, an alkyl group containing 10 to 15 carbon atoms, an alkyl group containing 15 to 20 carbon atoms, or an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include 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-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, undecyl, dodecyl, pentadecyl, Hexadecyl, eicosyl, and various branched isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkenes radical, alkynyl, alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl, or carboxylate.
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成烃基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。The term "alkenyl" refers to a hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. . Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的烃基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。The term "alkynyl" refers to a hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022136446-appb-000037
Figure PCTCN2022136446-appb-000037
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2022136446-appb-000038
The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022136446-appb-000038
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022136446-appb-000039
Figure PCTCN2022136446-appb-000039
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:
Figure PCTCN2022136446-appb-000040
Figure PCTCN2022136446-appb-000040
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一 个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2022136446-appb-000041
Figure PCTCN2022136446-appb-000041
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022136446-appb-000042
Figure PCTCN2022136446-appb-000042
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022136446-appb-000043
等。
Figure PCTCN2022136446-appb-000043
wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2022136446-appb-000044
Figure PCTCN2022136446-appb-000044
Figure PCTCN2022136446-appb-000045
Figure PCTCN2022136446-appb-000045
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen, mercapto, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxy or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2022136446-appb-000046
Figure PCTCN2022136446-appb-000046
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、氧代基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, carboxyl or carboxylate.
术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献“Protective Groups in Organic Synthesis”，第5版，T.W.Greene&P.G.M.Wuts中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅烷基(TBS)，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。 The term "hydroxyl protecting group" is a suitable group known in the art for the protection of a hydroxy group, see Hydroxyl Protecting Groups in the document "Protective Groups in Organic Synthesis", 5th edition, TW Greene & P. GMWuts. As an example, preferably, the hydroxyl protecting group may be (C 1-10 alkyl or aryl) silyl , for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl (TBS), tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy Substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl , benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, for example: formyl , acetyl, benzoyl, p-nitrobenzoyl, etc.; it can be (C 1-6 alkyl or C 6-10 aryl) sulfonyl; it can also be (C 1-6 alkoxy or C 6 -10 aryloxy)carbonyl.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代基”指＝O。The term "oxo" refers to =O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
术语“酰基”指含有-C(O)R基团的化合物，其中R为如上所定义的烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
术语“磺酰基”指含有-S(O) 2R基团的化合物，其中R为如上所定义的烷基、环烷基、杂环基、芳基、杂芳基。 The term "sulfonyl" refers to compounds containing the group -S(O) 2R , where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
术语“亚磺酰基”指含有-S(O)R基团的化合物，其中R为如上所定义的烷基、环烷基、杂环基、芳基、杂芳基。The term "sulfinyl" refers to compounds containing the group -S(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
本发明化合物的合成方法The synthetic method of compound of the present invention
本发明化合物或其药学上可接受的盐可以通过以下方案进行合成。The compound of the present invention or a pharmaceutically acceptable salt thereof can be synthesized by the following scheme.
通式(IIA)或(IVA)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：A preparation method of a compound represented by general formula (IIA) or (IVA) or a pharmaceutically acceptable salt thereof, comprising the following steps:
Figure PCTCN2022136446-appb-000047
Figure PCTCN2022136446-appb-000047
方案1plan 1
式IIAa或IVAa的化合物与氟维司群在碱性条件下在缩合剂存在下发生反应得到通式(IIA)或(IVA)所示的化合物；The compound of formula IIAa or IVAa reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain a compound represented by general formula (IIA) or (IVA);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
其中：in:
X 1、Y 1、n 1、n 2、R 4a、R 5a如通式(IIA)所定义； X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIA);
Z、n 5、n 6、R 4c、R 5c如通式(IVA)所定义。 Z, n 5 , n 6 , R 4c , R 5c are as defined in the general formula (IVA).
本发明通式(IIB)或(IVB)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The preparation method of the compound represented by general formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof of the present invention comprises the following steps:
Figure PCTCN2022136446-appb-000048
Figure PCTCN2022136446-appb-000048
方案2Scenario 2
式IIAa或IVAa的化合物与化合物g在碱性条件下在缩合剂的存在下发生反应得到式(IIBc)或(IVBc)的化合物；式(IIBc)或(IVBc)的化合物在酸性条件下脱除保护基，得到通式(IIB)或(IVB)所示的化合物；The compound of formula IIAa or IVAa reacts with compound g in the presence of a condensing agent under basic conditions to obtain the compound of formula (IIBc) or (IVBc); the compound of formula (IIBc) or (IVBc) is removed under acidic conditions Protecting group, obtains the compound shown in general formula (IIB) or (IVB);
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
所述酸性条件优选TFA；The acidic condition is preferably TFA;
其中：in:
R x为羟基保护基，优选叔丁氧羰基(Boc基团)或叔丁基二甲基硅烷基或三异丙基硅基或苄基； R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
X 1、Y 1、n 1、n 2、R 4a、R 5a如通式(IIB)所定义； X 1 , Y 1 , n 1 , n 2 , R 4a , R 5a are as defined in general formula (IIB);
Z、n 5、n 6、R 4c、R 5c如通式(IVB)所定义。 Z, n 5 , n 6 , R 4c , R 5c are as defined in general formula (IVB).
式IIAa的化合物可以通过以下方案制备：Compounds of formula IIAa can be prepared by the following scheme:
·当X 1和Y 1各自独立地选自-S-、-O-或-Se-时，通过以下方案3制备式IIAa的化合物， When X and Y are each independently selected from -S-, -O- or -Se-, the compound of formula IIAa is prepared by the following Scheme 3,
Figure PCTCN2022136446-appb-000049
Figure PCTCN2022136446-appb-000049
方案3Option 3
式IIAb的化合物与式IIAc的化合物在碱性条件下在缩合剂的存在下发生反应得到式IIAa的化合物；The compound of formula IIAb reacts with the compound of formula IIAc in the presence of a condensing agent under alkaline conditions to obtain a compound of formula IIAa;
所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
·当X 1和Y 1各自独立地选自-CH 2-时，通过以下方案4制备式IIAa的化合物， · When X 1 and Y 1 are each independently selected from -CH 2 -, the compound of formula IIAa is prepared by the following Scheme 4,
Figure PCTCN2022136446-appb-000050
Figure PCTCN2022136446-appb-000050
方案4Option 4
式IIAd的化合物与式IIAc的化合物在碱性条件下发生反应得到式IIAa的化合物；The compound of formula IIAd reacts with the compound of formula IIAc under basic conditions to obtain the compound of formula IIAa;
所述碱性条件选自有机碱，优选DIPEA、DMAP或吡啶；The basic conditions are selected from organic bases, preferably DIPEA, DMAP or pyridine;
其中，X 1、Y 1、n 1、n 2、R 4a、R 5a如通式(IIA)所定义。 Wherein, X 1 , Y 1 , n 1 , n 2 , R 4a , and R 5a are as defined in general formula (IIA).
式IVAa的化合物可以通过以下方案5制备：Compounds of formula IVAa can be prepared by the following scheme 5:
Figure PCTCN2022136446-appb-000051
Figure PCTCN2022136446-appb-000051
方案5Option 5
式IVAb的化合物与式IVAc的化合物在碱性条件下发生反应得到式IVAa的化合物；The compound of formula IVAb reacts with the compound of formula IVAc under alkaline conditions to obtain the compound of formula IVAa;
所述碱性条件选自有机碱，优选DIPEA、DMAP或吡啶；The basic conditions are selected from organic bases, preferably DIPEA, DMAP or pyridine;
其中，Z、n 5、n 6、R 4c、R 5c如通式(IVA)所定义。 Wherein, Z, n 5 , n 6 , R 4c , and R 5c are as defined in general formula (IVA).
本发明通式(IIIB)所示的化合物可以通过以下方案6制备：The compound represented by general formula (IIIB) of the present invention can be prepared by the following scheme 6:
Figure PCTCN2022136446-appb-000052
Figure PCTCN2022136446-appb-000052
方案6Option 6
步骤1：化合物g与式IIIBa的酰氯化合物在碱性条件下反应，得到式IIIBb的化合物；所述碱性条件优选吡啶；Step 1: Compound g reacts with an acid chloride compound of formula IIIBa under basic conditions to obtain a compound of formula IIIBb; the basic conditions are preferably pyridine;
步骤2：式IIIBb的化合物与式IIIBc的化合物在碱性条件下在催化剂的存在下发生反应，得到式IIIBd的化合物；所述碱性条件优选无机碱，进一步优选碳酸钾、碳酸铯、氢氧化钠、叔丁醇钾、氢化钠；所述催化剂选自相转移催化剂，优选TBAI；Step 2: the compound of formula IIIBb reacts with the compound of formula IIIBc in the presence of a catalyst under basic conditions to obtain the compound of formula IIIBd; the basic conditions are preferably inorganic bases, more preferably potassium carbonate, cesium carbonate, hydroxide Sodium, potassium tert-butoxide, sodium hydride; The catalyst is selected from phase transfer catalysts, preferably TBAI;
步骤3：式IIIBd的化合物在酸性条件下脱除保护基得到通式(IIIB)所示的化合物；所述酸性条件优选TFA；Step 3: the compound of formula IIIBd is deprotected under acidic conditions to obtain the compound shown in general formula (IIIB); said acidic conditions are preferably TFA;
其中，in,
R x为羟基保护基，优选叔丁氧羰基(Boc基团)或叔丁基二甲基硅烷基或三异丙基硅基或苄基； R x is a hydroxyl protecting group, preferably tert-butoxycarbonyl (Boc group) or tert-butyldimethylsilyl or triisopropylsilyl or benzyl;
X 2、Y 2、n 3、n 4、R 4b、R 5b、R 6如通式(IIB)所定义。 X 2 , Y 2 , n 3 , n 4 , R 4b , R 5b , and R 6 are as defined in general formula (IIB).
上述化合物g(中间体g)可以通过氟维司群与(Boc) 2O、叔丁基二甲基氯硅烷、三异丙基氯硅烷、三甲基氯硅烷、苄基溴(BnBr)、苄基氯反应得到，以(Boc) 2O为例，反应路线如下： The above compound g (intermediate g) can be obtained by combining fulvestrant with (Boc) 2 O, tert-butyldimethylchlorosilane, triisopropylchlorosilane, trimethylchlorosilane, benzyl bromide (BnBr), Benzyl chloride is obtained by reaction, taking (Boc) 2 O as an example, the reaction scheme is as follows:
Figure PCTCN2022136446-appb-000053
Figure PCTCN2022136446-appb-000053
方案7Option 7
将氟维司群与(Boc) 2O在碱性条件下反应得到中间体g，所述碱性条件优选DMAP。 Intermediate g is obtained by reacting fulvestrant with (Boc) 2 O under basic conditions, preferably DMAP.
具体实施方式Detailed ways
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明的范围。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the invention and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. However, it is to be understood that these examples do not limit the scope of the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts are given in units of 10 -6 (ppm). The determination of NMR is carried out by Brukerdps 300 nuclear magnetic analyzer, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl silane (TMS).
MS的测定用LC(Agilent 1260 Infinity)/MS(G6125B)质谱仪(生产商：安捷伦)。LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (manufacturer: Agilent) was used for the determination of MS.
制备液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为Daisogel C18 10μm 100A(30mm×250mm)，流动相：乙腈/水。The lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography. Chromatographic column is Daisogel C18 10μm 100A (30mm×250mm), mobile phase: acetonitrile/water.
薄层色谱法(TLC)使用青岛海洋化工GF254硅胶板，反应监测用薄层色谱法使用的硅胶板采用的规格是0.20mm～0.25mm，分离纯化用薄层色谱法使用的硅胶板采用的规格是0.5mm。Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plate, the specification of the silica gel plate used for reaction monitoring TLC is 0.20mm ~ 0.25mm, and the specification of silica gel plate used for separation and purification TLC It is 0.5mm.
硅胶柱层析色谱法使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得、南京药石等公司。The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide, Nanjing Yaoshi and other companies.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发 明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.
以下实施例中：In the following examples:
氟维司群，购自嘉兴萌辉化工有限公司，批号21210407；Fulvestrant, purchased from Jiaxing Menghui Chemical Co., Ltd., batch number 21210407;
以下实施例中涉及的缩写具体含义如下：The specific meanings of the abbreviations involved in the following examples are as follows:
EDCI：1-乙基-3(3-二甲基丙胺)碳二亚胺；EDCI: 1-ethyl-3(3-dimethylpropylamine) carbodiimide;
DIPEA：N,N-二异丙基乙胺；DIPEA: N,N-Diisopropylethylamine;
DMAP：4-二甲氨基吡啶；DMAP: 4-dimethylaminopyridine;
DCC：N,N'-二环己基碳酰亚胺；DCC: N,N'-dicyclohexylcarboimide;
DCM：二氯甲烷；DCM: dichloromethane;
T3P：1-丙基磷酸环酐；T3P: 1-propyl phosphate cyclic anhydride;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
TBAI：四丁基碘化铵；TBAI: Tetrabutylammonium iodide;
PE：石油醚；PE: petroleum ether;
EA：乙酸乙酯；EA: ethyl acetate;
HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
Boc：叔丁氧羰基。Boc: tert-butoxycarbonyl.
实施例Example
制备实施例1：5-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-3-甲基-5-氧代戊酸(中间体a)的制备Preparation Example 1: Preparation of 5-((1,3-bis(palmitoyloxy)prop-2-yl)oxy)-3-methyl-5-oxopentanoic acid (intermediate a)
Figure PCTCN2022136446-appb-000054
Figure PCTCN2022136446-appb-000054
向2-羟基丙基-1,3-二棕榈酸酯(3.50g，6.15mmol，1.00eq)在二氯甲烷(DCM，15.0mL)和四氢呋喃(THF，15.0mL)的溶液中，加入二甲氨基吡啶(DMAP，752mg，6.15mmol，1.00eq)、4-甲基二氢-2H-吡喃-2,6(3H)-二酮(1.58g，12.3mmol，2.00eq)和吡啶(12.0mL)，于25℃搅拌12h，LC-MS显示有99.7％目标物生成。将反应物减压浓缩，残余物通过快速柱色谱法纯化(洗脱剂：PE/EA＝1/0～2/1)，得化合物5-((1,3-双(棕榈酰氧基)丙基-2-基)氧基)-3-甲基-5-氧代戊酸(中间体a)(3.10g，收率72.3％)，为白色固体。To a solution of 2-hydroxypropyl-1,3-dipalmitate (3.50 g, 6.15 mmol, 1.00 eq) in dichloromethane (DCM, 15.0 mL) and tetrahydrofuran (THF, 15.0 mL) was added dimethyl Aminopyridine (DMAP, 752mg, 6.15mmol, 1.00eq), 4-methyldihydro-2H-pyran-2,6(3H)-dione (1.58g, 12.3mmol, 2.00eq) and pyridine (12.0mL ), stirred at 25°C for 12h, LC-MS showed that 99.7% of the target product was formed. The reactant was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: PE/EA=1/0～2/1) to obtain compound 5-((1,3-bis(palmitoyloxy) Propyl-2-yl)oxy)-3-methyl-5-oxopentanoic acid (intermediate a) (3.10 g, yield 72.3%), as a white solid.
1H NMR(400MHz,CDCl 3)δ5.26-5.31(m,1H),4.29-4.33(m,2H),4.15(dd,J1＝12.0Hz,J1＝11.6Hz,2H),2.43-2.49(m,3H),2.29-2.33(m,6H),1.57-1.63(m,4H),1.26-1.28(m,48H),1.07(d,J＝6.0Hz,3H),0.87-0.90(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ5.26-5.31 (m, 1H), 4.29-4.33 (m, 2H), 4.15 (dd, J1=12.0Hz, J1=11.6Hz, 2H), 2.43-2.49( m,3H),2.29-2.33(m,6H),1.57-1.63(m,4H),1.26-1.28(m,48H),1.07(d,J＝6.0Hz,3H),0.87-0.90(m, 6H).
制备实施例2：2-((2-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-2-氧代乙基)硫基)乙酸(中间体b)的制备Preparation Example 2: 2-((2-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-2-oxoethyl)thio)acetic acid (intermediate b) preparation of
Figure PCTCN2022136446-appb-000055
Figure PCTCN2022136446-appb-000055
采用制备实施例1中类似的方法，将4-甲基二氢-2H-吡喃-2,6(3H)-二酮替换为等摩尔比的1,4-氧硫杂环己烷-2,6-二酮，得到中间体b(2.8g，收率77.5％)，为白色固体。Using a method similar to that in Preparation Example 1, replace 4-methyldihydro-2H-pyran-2,6(3H)-dione with 1,4-oxathione-2 in an equimolar ratio , 6-diketone, intermediate b (2.8 g, yield 77.5%) was obtained as a white solid.
制备实施例3：5-[2-十六酰氧基-1-(十六酰氧基甲基)乙氧基]-5-羰基-戊酸(中间体c)的制备Preparation Example 3: Preparation of 5-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-5-carbonyl-pentanoic acid (intermediate c)
Figure PCTCN2022136446-appb-000056
Figure PCTCN2022136446-appb-000056
采用制备实施例1中类似的方法，将4-甲基二氢-2H-吡喃-2,6(3H)-二酮替换为等摩尔比的戊二酸酐，得到中间体c(3.2g，收率80.5％)，为白色固体。Using a method similar to that in Preparation Example 1, 4-methyldihydro-2H-pyran-2,6(3H)-dione was replaced by glutaric anhydride in an equimolar ratio to obtain intermediate c (3.2g, Yield 80.5%), as a white solid.
制备实施例4：4-((4-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-4-氧代丁基)二硫基)丁酸(中间体d)的制备Preparation Example 4: 4-((4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutyl)dithio)butanoic acid (intermediate d) Preparation
Figure PCTCN2022136446-appb-000057
Figure PCTCN2022136446-appb-000057
向二硫二丁酸(d1)(8.35g，35.2mmol，2.0eq)、二环己基碳二亚胺(DCC)(5.44g，26.4mmol，1.5eq)、DMAP(2.14g，17.5mmol，1.0eq)与THF(200ml)的溶液中，滴加2-羟基丙基-1,3-二棕榈酸酯(10.00g，17.6mmol，1.0eq)溶于THF(100mL)的溶液，室温搅拌4～5小时，过滤，滤液减压浓缩。残余物中加入水(100mL)和1N盐酸(100mL)，用DCM(200mL)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过快速柱色谱法(洗脱剂：石油醚/乙酸乙酯＝1/4)纯化，得4-((4-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-4-氧代丁基)二硫基)丁酸(d)(12.43g，收率90％)，为白色固体。To dithiodibutyric acid (d1) (8.35g, 35.2mmol, 2.0eq), dicyclohexylcarbodiimide (DCC) (5.44g, 26.4mmol, 1.5eq), DMAP (2.14g, 17.5mmol, 1.0 eq) and THF (200ml), add dropwise a solution of 2-hydroxypropyl-1,3-dipalmitate (10.00g, 17.6mmol, 1.0eq) dissolved in THF (100mL), and stir at room temperature for 4～ After 5 hours, filter and concentrate the filtrate under reduced pressure. Water (100 mL) and 1N hydrochloric acid (100 mL) were added to the residue, extracted with DCM (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=1/4) to give 4-((4-((1,3-bis(palmitoyloxy)propan-2-yl )oxy)-4-oxobutyl)dithio)butanoic acid (d) (12.43 g, yield 90%) as a white solid.
1H NMR(400MHz，CHCl 3-d)δ7.31(d,J＝5.2Hz,1H),6.87(dd,J＝8.5,2.5Hz,1H),6.81(d,J＝2.6Hz,1H),5.34–5.24(m,1H),4.35(dd,J＝11.9,4.3Hz,2H),4.22–4.10(m,2H),3.77(t,J＝8.4Hz,1H),2.94(dd,J＝16.8,5.4Hz,1H),2.87–2.61(m,9H),2.51(t,J＝7.2Hz,2H),2.35(t,J＝7.5Hz,5H),2.33–2.25(m,1H),2.25–2.02(m,7H),1.96(dd,J＝12.5,3.1Hz,1H),1.78(q,J＝7.0,6.0Hz,3H),1.65(q,J＝7.0Hz,5H),1.49(ddd,J＝19.9,11.3,4.6Hz,2H),1.32(d,J＝8.3Hz,19H), 1.29(s,21H),1.22(s,1H),1.09–1.01(m,1H),0.91(t,J＝6.7Hz,5H),0.81(s,2H)。 1 H NMR (400MHz, CHCl 3 -d) δ7.31(d, J=5.2Hz, 1H), 6.87(dd, J=8.5, 2.5Hz, 1H), 6.81(d, J=2.6Hz, 1H) ,5.34–5.24(m,1H),4.35(dd,J＝11.9,4.3Hz,2H),4.22–4.10(m,2H),3.77(t,J＝8.4Hz,1H),2.94(dd,J =16.8,5.4Hz,1H),2.87–2.61(m,9H),2.51(t,J=7.2Hz,2H),2.35(t,J=7.5Hz,5H),2.33–2.25(m,1H) ,2.25–2.02(m,7H),1.96(dd,J＝12.5,3.1Hz,1H),1.78(q,J＝7.0,6.0Hz,3H),1.65(q,J＝7.0Hz,5H), 1.49(ddd, J＝19.9, 11.3, 4.6Hz, 2H), 1.32(d, J＝8.3Hz, 19H), 1.29(s, 21H), 1.22(s, 1H), 1.09–1.01(m, 1H) , 0.91(t, J=6.7Hz, 5H), 0.81(s, 2H).
制备实施例5：3-((3-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-3-氧代丙基)二硫基)丙酸(中间体e)的制备Preparation Example 5: 3-((3-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-3-oxopropyl)dithio)propanoic acid (intermediate e) Preparation
Figure PCTCN2022136446-appb-000058
Figure PCTCN2022136446-appb-000058
采用制备实施例4中类似的方法，将二硫二丁酸替换为等摩尔比的二硫二丙酸，得到中间体e(7.5g，收率75.9％)，为白色固体。Using a method similar to that in Preparation Example 4, dithiodibutyric acid was replaced by dithiodipropionic acid in an equimolar ratio to obtain intermediate e (7.5 g, yield 75.9%) as a white solid.
制备实施例6：3-((3-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-2-氧代乙基)二硫基)乙酸(中间体f)的制备Preparation Example 6: 3-((3-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-2-oxoethyl)dithio)acetic acid (intermediate f ) preparation
Figure PCTCN2022136446-appb-000059
Figure PCTCN2022136446-appb-000059
采用制备实施例4中类似的方法，将二硫二丁酸替换为等摩尔比的二硫二乙酸，得到中间体f，(6.4g，收率72.3％)，为白色固体。Using a method similar to that in Preparation Example 4, dithiodibutyric acid was replaced by dithiodiacetic acid in an equimolar ratio to obtain intermediate f (6.4 g, yield 72.3%) as a white solid.
制备实施例7：叔丁基((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)羧酸酯(中间体g)制备Preparation Example 7: tert-butyl ((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5,5,5-penta Fluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl) Carboxylate (intermediate g) preparation
Figure PCTCN2022136446-appb-000060
Figure PCTCN2022136446-appb-000060
将氟维司群(2.0g，3.3mmol，1eq)与二甲氨基吡啶(DMAP，488mg，4.0mmol，1.2eq)溶于二氯甲烷(DCM，50mL)，冷却至-10℃，滴加二碳酸二叔丁酯((Boc) 2O，872mg，4.0mmol，1.2eq)在四氢呋喃(THF，4mL)中的溶液。室温搅拌过夜。浓缩反应液后通过快速柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝1/4)，得到中间体g(1.5g，收率64.3％)，为白色固体。 Fulvestrant (2.0g, 3.3mmol, 1eq) and dimethylaminopyridine (DMAP, 488mg, 4.0mmol, 1.2eq) were dissolved in dichloromethane (DCM, 50mL), cooled to -10°C, and di A solution of di-tert-butyl carbonate ((Boc) 2O , 872 mg, 4.0 mmol, 1.2 eq) in tetrahydrofuran (THF, 4 mL). Stir overnight at room temperature. The reaction solution was concentrated and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=1/4) to obtain intermediate g (1.5 g, yield 64.3%) as a white solid.
LC-MS：m/z 651.3[M+H] +。 LC-MS: m/z 651.3 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.30(d,J＝8.4Hz,1H),6.90-6.85(m,2H),4.49(d,J＝4.4Hz,1H),3.55-3.54(m,1H),2.85-2.82(m,2H),2.80-2.63(m,4H),2.38-2.27(m,4H),1.92-1.79(m,4H),1.61-1.56(m,4H),1.47(s,9H),1.38-1.17(m,19H),0.67(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.30(d, J=8.4Hz, 1H), 6.90-6.85(m, 2H), 4.49(d, J=4.4Hz, 1H), 3.55-3.54(m ,1H),2.85-2.82(m,2H),2.80-2.63(m,4H),2.38-2.27(m,4H),1.92-1.79(m,4H),1.61-1.56(m,4H),1.47 (s, 9H), 1.38-1.17 (m, 19H), 0.67 (s, 3H).
制备实施例8：2-(2-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-2-氧代乙氧基)乙酸(中间体h)的制备Preparation Example 8: Preparation of 2-(2-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-2-oxoethoxy)acetic acid (intermediate h)
Figure PCTCN2022136446-appb-000061
Figure PCTCN2022136446-appb-000061
向1,4-二氧杂六环-2,6-二酮(5.00g，43.1mmol，2.00eq)的DCM(20.0mL)与THF(20.0mL)的溶液中加入DMAP(2.63g，21.5mmol，1.00eq)、2-羟基丙基-1,3-二棕榈酸酯(12.3g，21.5mmol，1.00eq)和吡啶(16.0mL)，于25℃搅拌4小时。反应液浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：PE/EA＝1/0～3/1)，得中间体h(7.00g，产率：23.7％)，为白色固体。To a solution of 1,4-dioxane-2,6-dione (5.00 g, 43.1 mmol, 2.00 eq) in DCM (20.0 mL) and THF (20.0 mL) was added DMAP (2.63 g, 21.5 mmol , 1.00eq), 2-hydroxypropyl-1,3-dipalmitate (12.3g, 21.5mmol, 1.00eq) and pyridine (16.0mL), stirred at 25°C for 4 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (eluent: PE/EA=1/0～3/1) to obtain intermediate h (7.00 g, yield: 23.7%) as a white solid .
1H NMR(400MHz,CDCl 3)δ8.71(d,J＝4.4Hz,1H),5.32-5.37(m,1H),4.39(d,J＝4.0Hz,1H),4.36(d,J＝4.0Hz,1H)，4.28(d,J＝2.0Hz,4H),4.16(dd,J1＝6.0Hz,J2＝12.0Hz,2H),2.32(t,J＝7.6Hz,4H),1.57-1.63(m,4H),1.26-1.28(m,48H),0.87-0.90(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ8.71(d, J=4.4Hz, 1H), 5.32-5.37(m, 1H), 4.39(d, J=4.0Hz, 1H), 4.36(d, J= 4.0Hz, 1H), 4.28(d, J=2.0Hz, 4H), 4.16(dd, J1=6.0Hz, J2=12.0Hz, 2H), 2.32(t, J=7.6Hz, 4H), 1.57-1.63 (m, 4H), 1.26-1.28 (m, 48H), 0.87-0.90 (m, 6H).
制备实施例9：N-(2-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-2-氧代乙基)-N-甲基甘氨酸(中间体i)的制备Preparation Example 9: N-(2-((1,3-bis(palmitoyloxy)prop-2-yl)oxy)-2-oxoethyl)-N-methylglycine (Intermediate i ) preparation
Figure PCTCN2022136446-appb-000062
Figure PCTCN2022136446-appb-000062
向N-甲基亚氨二乙酸(5.00g，33.9mmol，2.00eq)的DCM(40mL)的溶液中加入2-羟丙基-1,3-二棕榈酸酯(9.67g，16.9mmol，1.00eq)、DMAP(2.08g，16.9mmol，1.00eq)、EDCI(4.23g，22.1mmol，1.30eq)，于25℃搅拌过夜。减压浓缩，残余物通过快速柱层析色谱法纯化(PE/EA＝1/0～3/1)，得中间体i(5.10g，粗品，19.4％)，为白色固体。To a solution of N-methyliminodiacetic acid (5.00 g, 33.9 mmol, 2.00 eq) in DCM (40 mL) was added 2-hydroxypropyl-1,3-dipalmitate (9.67 g, 16.9 mmol, 1.00 eq), DMAP (2.08g, 16.9mmol, 1.00eq), EDCI (4.23g, 22.1mmol, 1.30eq), stirred overnight at 25°C. It was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE/EA=1/0-3/1) to obtain intermediate i (5.10 g, crude product, 19.4%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ5.33-5.26(m,1H),4.37-4.33(m,2H),4.23-4.18(m,2H),3.69-3.63(m,3H),2.37-2.31(m,4H),1.63-1.58(m,4H),1.28-1.26(m,52H),0.90-0.87(m,6H)。 1 H NMR (400MHz, CDCl 3 ): δ5.33-5.26(m,1H),4.37-4.33(m,2H),4.23-4.18(m,2H),3.69-3.63(m,3H),2.37- 2.31 (m, 4H), 1.63-1.58 (m, 4H), 1.28-1.26 (m, 52H), 0.90-0.87 (m, 6H).
制备实施例10：5-[2-十六酰氧基-1-(十六酰氧基甲基)乙氧基]-5-羰基-己酸(中间体j)的制备Preparation Example 10: Preparation of 5-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-5-carbonyl-hexanoic acid (intermediate j)
Figure PCTCN2022136446-appb-000063
Figure PCTCN2022136446-appb-000063
将2-羟基丙基-1,3-二棕榈酸酯(3.50g，6.15mmol，1.00eq)、己二酸(1.80g，12.3mmol，2.04mL，2.00eq)、DMAP(751mg，6.15mmol，1.00eq)和EDCI(1.18g，6.15mmol，1.00eq)与DCM(40mL)的混合物用氮气置换3次，25℃搅拌12小时。将反应液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：P/E＝1/0～3/1)，得中间体j(2.38g，3.41mmol，收率55.5％)，为白色固体。2-Hydroxypropyl-1,3-dipalmitate (3.50g, 6.15mmol, 1.00eq), adipic acid (1.80g, 12.3mmol, 2.04mL, 2.00eq), DMAP (751mg, 6.15mmol, 1.00eq) and a mixture of EDCI (1.18g, 6.15mmol, 1.00eq) and DCM (40mL) were replaced with nitrogen 3 times and stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: P/E=1/0～3/1) to obtain intermediate j (2.38g, 3.41mmol, yield 55.5% ), as a white solid.
制备实施例11：5-[2-十六酰氧基-1-(十六酰氧基甲基)乙氧基]-5-羰基-丙酸(中间体k)的制备Preparation Example 11: Preparation of 5-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-5-carbonyl-propionic acid (intermediate k)
Figure PCTCN2022136446-appb-000064
Figure PCTCN2022136446-appb-000064
采用制备实施例10中类似的方法，将己二酸替换为等摩尔比的丙二酸，得到中间体k，为白色固体。Using a method similar to that in Preparation Example 10, adipic acid was replaced by malonic acid in an equimolar ratio to obtain intermediate k as a white solid.
制备实施例12：4-((1,3-双(棕榈酰氧基)丙-2-基)氧基)-4-氧代丁酸(中间体l)的制备Preparation Example 12: Preparation of 4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (intermediate 1)
Figure PCTCN2022136446-appb-000065
Figure PCTCN2022136446-appb-000065
氮气氛下，于25℃，将2-羟基丙基-1,3-二棕榈酸酯(4.50g，7.91mmol，1.00eq)、丁二酸酐(1.58g，15.8mmol，2.00eq)、DMAP(966mg，7.91mmol，1.00eq)、吡啶(10.0mL)、DCM(15.0mL)、THF(15.0mL)的混合物搅拌12小时。反应液减压浓缩，残余物通过快速柱层析色谱法纯化(P/E＝1/0～3/1)，得化合物l(2.80g，4.19mmol，产率：52.9％)，为白色固体。Under a nitrogen atmosphere, at 25°C, 2-hydroxypropyl-1,3-dipalmitate (4.50g, 7.91mmol, 1.00eq), succinic anhydride (1.58g, 15.8mmol, 2.00eq), DMAP ( 966 mg, 7.91 mmol, 1.00 eq), pyridine (10.0 mL), DCM (15.0 mL), THF (15.0 mL) was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (P/E=1/0～3/1) to obtain compound 1 (2.80 g, 4.19 mmol, yield: 52.9%) as a white solid .
制备实施例13：5-[2-十六酰氧基-1-(十六酰氧基甲基)乙氧基]-5-羰基-庚酸(中间体m)的制备Preparation Example 13: Preparation of 5-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-5-carbonyl-heptanoic acid (intermediate m)
Figure PCTCN2022136446-appb-000066
Figure PCTCN2022136446-appb-000066
采用制备实施例10中类似的方法，将己二酸替换为等摩尔比的庚二酸，得到中间体m，为白色固体。Using a method similar to that in Preparation Example 10, adipic acid was replaced by pimelic acid in an equimolar ratio to obtain intermediate m as a white solid.
制备实施例14：5-[2-十六酰氧基-1-(十六酰氧基甲基)乙氧基]-5-羰基-十二酸(中间体n)的制备Preparation Example 14: Preparation of 5-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxy]-5-carbonyl-dodecanoic acid (intermediate n)
Figure PCTCN2022136446-appb-000067
Figure PCTCN2022136446-appb-000067
采用制备实施例10中类似的方法，将己二酸替换为等摩尔比的十二烷二酸，得到中间体n，为白色固体。Using a method similar to that in Preparation Example 10, adipic acid was replaced by dodecanedioic acid in an equimolar ratio to obtain intermediate n as a white solid.
实施例1：2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙-1,3-二基二棕榈酸酯(1)的制备Example 1: 2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthren-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyl dipalmitate (1)
Figure PCTCN2022136446-appb-000068
Figure PCTCN2022136446-appb-000068
步骤1：2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-((叔丁氧羰基)氧基)-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙烷-1,3-二基二棕榈酸酯(1a)的制备Step 1: 2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methyl-7-( 9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthrene-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propane-1,3-diyl dipalmitate (1a ) preparation
中间体1a可通过以下两种方法中的任意一种进行制备：Intermediate 1a can be prepared by either of the following two methods:
方法1method 1
将中间体d(520mg，0.66mmol，1.2eq)、EDCI(422mg，2.2mmol，4.0eq)、DIPEA(284mg，2.2mmol，4.0eq)、DMAP(134mg，1.1mmol，2.0eq)溶解于DCM(5mL)中，室温搅拌10分钟。然后加入中间体g(389mg，0.55mmol，1.0eq)，室温反应过夜。反应液加入水10(mL)，有机相用饱和碳酸氢钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂PE/EA/DCM＝2/1/1)，得中间体1a(520mg，0.26mmol，产率：47.3％)。Intermediate d (520 mg, 0.66 mmol, 1.2 eq), EDCI (422 mg, 2.2 mmol, 4.0 eq), DIPEA (284 mg, 2.2 mmol, 4.0 eq), DMAP (134 mg, 1.1 mmol, 2.0 eq) were dissolved in DCM ( 5 mL), stirred at room temperature for 10 minutes. Then intermediate g (389mg, 0.55mmol, 1.0eq) was added and reacted overnight at room temperature. The reaction solution was added water 10 (mL), the organic phase was washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent PE /EA/DCM=2/1/1) to obtain intermediate 1a (520 mg, 0.26 mmol, yield: 47.3%).
方法2Method 2
将中间体d(520mg，0.66mmol，1.2eq)、DCC(270mg，1.3mmol，2.0eq)、DMAP(134mg，1.1mmol，2.0eq)溶解于THF(5mL)中，室温搅拌10 分钟。然后加入中间体g(389mg，0.55mmol，1.0eq)，室温反应过夜。反应液过滤，滤液加入水(10mL)，有机相用饱和碳酸氢钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂PE/EA/DCM＝2/1/1)，得中间体1a(370mg，0.36mmol，产率：65.5％)。Intermediate d (520mg, 0.66mmol, 1.2eq), DCC (270mg, 1.3mmol, 2.0eq), DMAP (134mg, 1.1mmol, 2.0eq) were dissolved in THF (5mL), and stirred at room temperature for 10 minutes. Then intermediate g (389mg, 0.55mmol, 1.0eq) was added and reacted overnight at room temperature. The reaction solution was filtered, the filtrate was added with water (10 mL), the organic phase was washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (elution Agent PE/EA/DCM=2/1/1) to obtain intermediate 1a (370mg, 0.36mmol, yield: 65.5%).
步骤2：2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙-1,3-二基二棕榈酸酯(1)的制备Step 2: 2-((4-((4-(((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyl dipalmitate (1)
中间体1a(520mg，0.36mmol)溶于DCM(20mL)中，加入TFA3g，室温反应2～4小时。反应液加水20mL，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂PE/EA/DCM＝2/1/1)，得化合物1(320mg，0.23mmol，产率：63.9％)。Intermediate 1a (520mg, 0.36mmol) was dissolved in DCM (20mL), TFA 3g was added, and reacted at room temperature for 2-4 hours. Add 20 mL of water to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by flash column chromatography (eluent PE/EA/DCM=2/1/1) to obtain the compound 1 (320 mg, 0.23 mmol, yield: 63.9%).
1H NMR(400MHz,CDCl 3)δ7.17(d,J＝8.5Hz,1H),6.67(dt,J＝8.5,2.9Hz,1H),6.60(d,J＝2.7Hz,1H),5.30(td,J＝5.8,2.9Hz,1H),4.75(t,J＝8.4Hz,1H),4.35(dd,J＝11.9,4.3Hz,2H),4.18(dd,J＝11.9,5.9Hz,2H),2.99–2.61(m,10H),2.50(q,J＝7.0Hz,4H),2.44–2.16(m,9H),2.07(p,J＝7.2Hz,4H),1.94–1.73(m,4H),1.67(dp,J＝14.2,7.8,6.9Hz,6H),1.30(m,68H),1.08(s,1H),1.01–0.77(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.17 (d, J=8.5Hz, 1H), 6.67 (dt, J=8.5, 2.9Hz, 1H), 6.60 (d, J=2.7Hz, 1H), 5.30 (td,J=5.8,2.9Hz,1H),4.75(t,J=8.4Hz,1H),4.35(dd,J=11.9,4.3Hz,2H),4.18(dd,J=11.9,5.9Hz, 2H),2.99–2.61(m,10H),2.50(q,J=7.0Hz,4H),2.44–2.16(m,9H),2.07(p,J=7.2Hz,4H),1.94–1.73(m , 4H), 1.67 (dp, J=14.2, 7.8, 6.9Hz, 6H), 1.30 (m, 68H), 1.08 (s, 1H), 1.01–0.77 (m, 9H).
实施例2：2-((3-((3-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-3-氧代丙基)二硫基)丙酰基)氧基)丙-1,3-二基二棕榈酸酯(2)的制备Example 2: 2-((3-((3-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthrene-17-yl)oxy)-3-oxopropyl)dithio)propionyl)oxy)propan-1,3-diyl dipalmitate (2)
Figure PCTCN2022136446-appb-000069
Figure PCTCN2022136446-appb-000069
采用与实施例1类似的方法，将中间体d替换为中间体e，制备化合物2(640mg，产率：58.7％)，为白色固体。Using a method similar to Example 1, replacing intermediate d with intermediate e, compound 2 (640 mg, yield: 58.7%) was prepared as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.16(d,J＝8.5Hz,1H),6.68(dd,J＝8.6,2.9Hz,1H),6.60(d,J＝2.7Hz,1H),5.32(td,J＝5.9,2.9Hz,1H),4.77(t,J＝8.4Hz,1H),4.35(dd,J＝12.0,4.3Hz,2H),4.20(dd,J＝11.9,5.9Hz,2H),3.07–2.59(m,12H),2.45–2.08(m,9H),2.00–1.01(m,81H),1.01–0.77(m,9H)。 1 H NMR (400MHz, CDCl 3 ): δ7.16 (d, J = 8.5Hz, 1H), 6.68 (dd, J = 8.6, 2.9Hz, 1H), 6.60 (d, J = 2.7Hz, 1H), 5.32(td, J=5.9, 2.9Hz, 1H), 4.77(t, J=8.4Hz, 1H), 4.35(dd, J=12.0, 4.3Hz, 2H), 4.20(dd, J=11.9, 5.9Hz ,2H), 3.07–2.59(m,12H), 2.45–2.08(m,9H), 2.00–1.01(m,81H), 1.01–0.77(m,9H).
实施例3：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙基)二硫基)乙酰基)丙-1,3-二基二棕榈酸酯(3)的制备Example 3: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)dithio)acetyl)propan-1,3-diyl dipalmitate (3)
Figure PCTCN2022136446-appb-000070
Figure PCTCN2022136446-appb-000070
采用与实施例1类似的方法，将中间体d替换为中间体f，制备化合物3(571mg，产率：57.5％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate f to prepare compound 3 (571 mg, yield: 57.5%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.57-6.65(m,1H),6.41(s,1H),6.13-6.41(m,1H),5.29-5.34(m,1H),4.77(d,J＝8.0Hz,1H),4.32-4.36(m,2H),4.17-4.22(m,2H),3.60(s,4H),2.74-2.84(m,6H),2.31-2.35(m,5H),2.26-2.28(m,5H),1.72-1.75(m,1H),1.64-1.66(m,3H),1.60-1.62(m,3H),1.49-1.52(m,3H),1.42-1.48(m,8H),1.43-1.46(m,7H),1.26-1.42(m,60H),0.95-1.00(m,1H),0.88(t,J＝7.2Hz,6H),0.86(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.57-6.65(m, 1H), 6.41(s, 1H), 6.13-6.41(m, 1H), 5.29 -5.34(m,1H),4.77(d,J＝8.0Hz,1H),4.32-4.36(m,2H),4.17-4.22(m,2H),3.60(s,4H),2.74-2.84(m ,6H),2.31-2.35(m,5H),2.26-2.28(m,5H),1.72-1.75(m,1H),1.64-1.66(m,3H),1.60-1.62(m,3H),1.49 -1.52(m,3H),1.42-1.48(m,8H),1.43-1.46(m,7H),1.26-1.42(m,60H),0.95-1.00(m,1H),0.88(t,J= 7.2Hz, 6H), 0.86(s, 3H).
实施例4：2-((4-((4-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙-1,3-二基二棕榈酸酯(4)的制备Example 4: 2-((4-((4-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthrene-3-yl)oxy)-4-oxobutyl)dithio)butyryl)oxy)propane-1,3-diyl dipalmitate (4)
Figure PCTCN2022136446-appb-000071
Figure PCTCN2022136446-appb-000071
将中间体d(1.31g，3.0mmol，1.4eq)、EDCI(1.53g，8.0mmol，4.0eq)、DMAP(0.49g，4.0mmol，2.0eq)、DIPEA(1.03g，8.0mmol，4.0eq)依次加入DCM(50mL)中，室温搅拌10分钟。然后加入氟维司群(1.21g，2.0mmol，1.0eq)，室温反应过夜。向反应液中加入1N盐酸(20mL)，分离出有机相，水相再用DCM(20mL)萃取一次，合并有机相，无水硫酸钠干燥，过滤，滤液减压 浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：PE/EA＝5/1～3/1)，得化合物4(1.70g，1.23mmol，产率：61.5％)，为白色固体。Intermediate d (1.31g, 3.0mmol, 1.4eq), EDCI (1.53g, 8.0mmol, 4.0eq), DMAP (0.49g, 4.0mmol, 2.0eq), DIPEA (1.03g, 8.0mmol, 4.0eq) Add DCM (50 mL) successively, and stir at room temperature for 10 minutes. Fulvestrant (1.21 g, 2.0 mmol, 1.0 eq) was then added and reacted overnight at room temperature. Add 1N hydrochloric acid (20mL) to the reaction solution, separate the organic phase, extract the aqueous phase with DCM (20mL) again, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through flash column Purification by chromatography (eluent: PE/EA=5/1-3/1) gave compound 4 (1.70 g, 1.23 mmol, yield: 61.5%) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.31(t,J＝4.3Hz,1H),6.87(dd,J＝8.5,2.5Hz,1H),6.81(d,J＝2.7Hz,1H),5.39–5.11(m,1H),4.35(dd,J＝11.9,4.3Hz,2H),4.27–4.07(m,2H),3.77(t,J＝8.5Hz,1H),2.94(dd,J＝16.8,5.4Hz,1H),2.88–2.61(m,10H),2.51(t,J＝7.2Hz,2H),2.48–2.01(m,14H),1.96(dd,J＝12.5,3.3Hz,1H),1.88–1.11(m,77H),1.06(q,J＝5.8Hz,1H),0.91(t,J＝6.8Hz,6H),0.81(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.31(t, J=4.3Hz, 1H), 6.87(dd, J=8.5, 2.5Hz, 1H), 6.81(d, J=2.7Hz, 1H), 5.39 –5.11(m, 1H), 4.35(dd, J=11.9, 4.3Hz, 2H), 4.27–4.07(m, 2H), 3.77(t, J=8.5Hz, 1H), 2.94(dd, J=16.8 ,5.4Hz,1H),2.88–2.61(m,10H),2.51(t,J＝7.2Hz,2H),2.48–2.01(m,14H),1.96(dd,J＝12.5,3.3Hz,1H) , 1.88–1.11 (m, 77H), 1.06 (q, J = 5.8Hz, 1H), 0.91 (t, J = 6.8Hz, 6H), 0.81 (s, 3H).
实施例5：2-((3-((3-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-3-氧代丙基)二硫基)丙酰基)氧基)丙-1,3-二基二棕榈酸酯(5)的制备Example 5: 2-((3-((3-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4, 5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a Preparation of ]phenanthrene-3-yl)oxy)-3-oxopropyl)dithio)propionyl)oxy)propan-1,3-diyl dipalmitate (5)
Figure PCTCN2022136446-appb-000072
Figure PCTCN2022136446-appb-000072
采用与实施例4类似的方法，将中间体d替换为中间体e，制备化合物5(1.3g，产率：65.1％)，为白色固体。Using a method similar to Example 4, intermediate d was replaced by intermediate e to prepare compound 5 (1.3 g, yield: 65.1%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.29(s,1H),6.85(dd,J＝8.5,2.4Hz,1H),6.79(d,J＝2.3Hz,1H),5.28(t,J＝4.3Hz,1H),4.31(dd,J＝12.0,4.3Hz,2H),4.16(dd,J＝12.0,5.9Hz,2H),3.75(t,J＝8.5Hz,1H),3.04–2.87(m,7H),2.75(dt,J＝39.7,15.1Hz,7H),2.40–2.07(m,12H),1.92(d,J＝12.3Hz,1H),1.76(s,3H),1.67(s,8H),1.62(s,3H),1.52–1.35(m,8H),1.27(d,J＝10.6Hz,50H),1.18(s,2H),1.03(s,1H),0.88(t,J＝6.8Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s,1H),6.85(dd,J=8.5,2.4Hz,1H),6.79(d,J=2.3Hz,1H),5.28(t,J =4.3Hz,1H),4.31(dd,J=12.0,4.3Hz,2H),4.16(dd,J=12.0,5.9Hz,2H),3.75(t,J=8.5Hz,1H),3.04–2.87 (m,7H),2.75(dt,J=39.7,15.1Hz,7H),2.40–2.07(m,12H),1.92(d,J=12.3Hz,1H),1.76(s,3H),1.67( s,8H),1.62(s,3H),1.52–1.35(m,8H),1.27(d,J＝10.6Hz,50H),1.18(s,2H),1.03(s,1H),0.88(t , J=6.8Hz, 6H), 0.78(s, 3H).
实施例6：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-2-氧代乙基)二硫基)乙酰基)丙-1,3-二基二棕榈酸酯(6)的制备Example 6: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-3-yl)oxy)-2-oxoethyl)dithio)acetyl)propan-1,3-diyl dipalmitate (6)
Figure PCTCN2022136446-appb-000073
Figure PCTCN2022136446-appb-000073
采用与实施例4类似的方法，将中间体d替换为中间体f，制备化合物6(1.5g，产率：64.3％)，为白色固体。Using a method similar to Example 4, intermediate d was replaced by intermediate f to prepare compound 6 (1.5 g, yield: 64.3%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.89-6.92(m,1H),6.82-6.83(m,1H),5.29-5.34(m,1H),4.33(dd,J1＝4.0Hz,J2＝8.0Hz,2H),4.18(dd,J1＝6.0Hz,J2＝6.0Hz,2H),3.74-3.79(m,3H),3.65(s,2H),2.78-2.90(m,1H),2.73- 2.78(m,4H),2.71-2.73(m,1H),2.34-2.36(m,6H),2.30-2.32(m,1H),2.16-2.19(m,3H),1.93(d,J＝12.0Hz,1H),1.75-1.77(m,3H),1.59-1.62(m,9H),1.36-1.48(m,9H),1.26(s,56H),0.89-0.9(m,1H),0.88(t,J＝6.4Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13 (d, J=8.4Hz, 1H), 6.89-6.92 (m, 1H), 6.82-6.83 (m, 1H), 5.29-5.34 (m, 1H) ,4.33(dd,J1=4.0Hz,J2=8.0Hz,2H),4.18(dd,J1=6.0Hz,J2=6.0Hz,2H),3.74-3.79(m,3H),3.65(s,2H) ,2.78-2.90(m,1H),2.73-2.78(m,4H),2.71-2.73(m,1H),2.34-2.36(m,6H),2.30-2.32(m,1H),2.16-2.19( m,3H),1.93(d,J＝12.0Hz,1H),1.75-1.77(m,3H),1.59-1.62(m,9H),1.36-1.48(m,9H),1.26(s,56H) , 0.89-0.9 (m, 1H), 0.88 (t, J=6.4Hz, 6H), 0.78 (s, 3H).
实施例7：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙基)硫基)乙酰氧基)丙-1,3-二基二棕榈酸酯(7)的制备Example 7: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)thio)acetoxy)propan-1,3-diyl dipalmitate (7)
Figure PCTCN2022136446-appb-000074
Figure PCTCN2022136446-appb-000074
步骤1：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-((叔丁氧羰基)氧基)-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙基)硫基)乙酰氧基)丙烷-1,3-二基二棕榈酸酯(7a)的制备Step 1: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methyl-7-(9 -((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro- Preparation of 6H-cyclopenta[a]phenanthrene-17-yl)oxy)-2-oxoethyl)thio)acetoxy)propane-1,3-diyl dipalmitate (7a)
向中间体g(800mg，1.13mmol，1.00eq)、中间体b(793mg，1.13mmol，1.00eq)在DCM(15.0mL)的溶液中加入DMAP(138mg，1.13mmol，1.00eq)、EDCI(434mg，2.26mmol，2.00eq)，25℃搅拌3小时。反应混合物浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：PE:EtOAc＝100:1～3:1)，得化合物7a(1.00g，719μmol，产率：63.5％)，为黄色油状物。To a solution of Intermediate g (800 mg, 1.13 mmol, 1.00 eq), Intermediate b (793 mg, 1.13 mmol, 1.00 eq) in DCM (15.0 mL) was added DMAP (138 mg, 1.13 mmol, 1.00 eq), EDCI (434 mg , 2.26mmol, 2.00eq), stirred at 25°C for 3 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (eluent: PE:EtOAc=100:1～3:1) to obtain compound 7a (1.00 g, 719 μmol, yield: 63.5%) as yellow Oil.
1H NMR(400MHz,CDCl 3)：δ7.29(s,1H),6.95-6.92(m,1H),6.90-6.89(m,1H),5.30--5.29(m,1H),4.77(t,J＝8.4Hz,1H),4.37-4.33(m,2H),4.22-4.17(m,2H),3.42(d,J＝6.8Hz,4H),2.95-2.63(m,6H),2.34(t,J＝7.2Hz,6H),2.29-2.15(m,5H),1.89-1.73(m,6H),1.69-1.59(m,7H),1.57(m,9H),1.54-1.41(m,8H),1.29-1.27(m,56H),0.90(t,J＝6.4Hz,3H),0.86(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s,1H),6.95-6.92(m,1H),6.90-6.89(m,1H),5.30--5.29(m,1H),4.77(t ,J=8.4Hz,1H),4.37-4.33(m,2H),4.22-4.17(m,2H),3.42(d,J=6.8Hz,4H),2.95-2.63(m,6H),2.34( t,J＝7.2Hz,6H),2.29-2.15(m,5H),1.89-1.73(m,6H),1.69-1.59(m,7H),1.57(m,9H),1.54-1.41(m, 8H), 1.29-1.27(m, 56H), 0.90(t, J=6.4Hz, 3H), 0.86(s, 3H).
步骤2：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙基)硫基)乙酰氧基)丙-1,3-二基二棕榈酸酯(7)的制备Step 2: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-((4,4,5, 5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene Preparation of -17-yl)oxy)-2-oxoethyl)thio)acetoxy)prop-1,3-diyl dipalmitate (7)
于0℃，向化合物7a(500mg，359μmol,1.00eq)溶于DCM(10mL)的溶液中，加入TFA(1.03g，8.99mmol，665μL，25.0eq)。升温至25℃，搅拌2小时。反应混合物用饱和碳酸氢钠调节pH＝8，用EtOAc(15.0mL×3)萃取，并用盐水洗(30.0mL)，无水硫酸钠干燥，过滤，减压浓缩，得化合物7(204.19mg，158μmol，产率：43.9％)，为黄色油状物。To a solution of compound 7a (500 mg, 359 μmol, 1.00 eq) dissolved in DCM (10 mL) was added TFA (1.03 g, 8.99 mmol, 665 μL, 25.0 eq) at 0°C. The temperature was raised to 25°C and stirred for 2 hours. The reaction mixture was adjusted to pH=8 with saturated sodium bicarbonate, extracted with EtOAc (15.0 mL×3), washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7 (204.19 mg, 158 μmol , yield: 43.9%), as a yellow oil.
1H NMR(400MHz,CDCl 3)：δ7.29(s,1H),6.95-6.92(m,1H),6.90-6.89(m,1H),5.30--5.29(m,1H),4.77(t,J＝8.4Hz,1H),4.37-4.33(m,2H),4.22-4.17(m,2H),3.42(d,J＝6.8Hz,4H),2.95-2.63(m,6H),2.34(t,J＝7.2Hz,6H),2.29-2.15(m,5H),1.89-1.73(m,6H),1.69-1.59(m,7H),1.57(m,9H),1.54-1.41(m,8H),1.29-1.27(m,56H),0.90(t,J＝6.4Hz,3H),0.86(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s,1H),6.95-6.92(m,1H),6.90-6.89(m,1H),5.30--5.29(m,1H),4.77(t ,J=8.4Hz,1H),4.37-4.33(m,2H),4.22-4.17(m,2H),3.42(d,J=6.8Hz,4H),2.95-2.63(m,6H),2.34( t,J＝7.2Hz,6H),2.29-2.15(m,5H),1.89-1.73(m,6H),1.69-1.59(m,7H),1.57(m,9H),1.54-1.41(m, 8H), 1.29-1.27(m, 56H), 0.90(t, J=6.4Hz, 3H), 0.86(s, 3H).
实施例8：2-(2-((2-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-2-氧代乙基)硫基)乙酰氧基)丙-1,3-二基二棕榈酸酯(8)的制备Example 8: 2-(2-((2-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-3-yl)oxy)-2-oxoethyl)thio)acetoxy)propan-1,3-diyl dipalmitate (8)
Figure PCTCN2022136446-appb-000075
Figure PCTCN2022136446-appb-000075
氟维司群(0.500g，824μmol，1.00eq)、中间体b(866mg，1.24mmol，1.50eq)溶于DCM(5mL)，加入HATU(471mg，1.24mmol，1.5eq)、DMAP(201mg，1.65mmol，2.00eq)，于25℃搅拌12小时。将反应液减压浓缩，残余物通过快速柱层析色谱法(PE/EA＝1/0～3/1)纯化，得化合物8(0.120g，93.0μmol，产率：11.2％)，为微黄色油状物。Fulvestrant (0.500g, 824μmol, 1.00eq), intermediate b (866mg, 1.24mmol, 1.50eq) was dissolved in DCM (5mL), and HATU (471mg, 1.24mmol, 1.5eq), DMAP (201mg, 1.65 mmol, 2.00eq), stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE/EA=1/0～3/1) to obtain compound 8 (0.120 g, 93.0 μmol, yield: 11.2%) as micro Yellow oil.
1H NMR:(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.62-6.66(m,1H),6.57(d,J＝2.0Hz,1H),5.29-5.32(m,1H),4.75(t,J＝8.0Hz,1H),4.32-4.36(m,2H),4.16-4.21(m,2H),3.42(s,2H),3.40(s,2H),2.74-2.81(m,6H),2.31-2.35(m,6H),2.13-2.17(m,5H),1.76-1.87(m,1H),1.62-1.63(m,3H),1.59-1.60(m,6H),1.41-1.43(m,7H),1.26-1.34(m,60H),1.01-1.05(m,1H),0.88(t,J＝6.4Hz,6H),0.86(s,3H)。 1 H NMR: (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.62-6.66(m, 1H), 6.57(d, J=2.0Hz, 1H), 5.29-5.32( m,1H),4.75(t,J＝8.0Hz,1H),4.32-4.36(m,2H),4.16-4.21(m,2H),3.42(s,2H),3.40(s,2H),2.74 -2.81(m,6H),2.31-2.35(m,6H),2.13-2.17(m,5H),1.76-1.87(m,1H),1.62-1.63(m,3H),1.59-1.60(m, 6H), 1.41-1.43(m, 7H), 1.26-1.34(m, 60H), 1.01-1.05(m, 1H), 0.88(t, J=6.4Hz, 6H), 0.86(s, 3H).
实施例9：2-(2-(2-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五 氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙氧基)乙酰氧基)丙-1,3-二基二棕榈酸酯(9)的制备Example 9: 2-(2-(2-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5, 5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene Preparation of -17-yl)oxy)-2-oxoethoxy)acetoxy)propan-1,3-diyl dipalmitate (9)
Figure PCTCN2022136446-appb-000076
Figure PCTCN2022136446-appb-000076
采用与实施例1类似的方法，将中间体d替换为中间体h，制备化合物9(1.23g，产率：77.2％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate h to prepare compound 9 (1.23 g, yield: 77.2%) as a white solid.
1H NMR((400MHz,CDCl 3)：δ7.28(s,1H),6.95-6.92(m,1H),6.90-6.89(m,1H),5.37--5.32(m,1H),4.81(t,J＝8.4Hz,1H),4.39-4.35(m,2H),4.28-4.26(m,3H),4.19-4.13(m,2H),2.91-2.66(m,6H),2.33(t,J＝7.2Hz,6H),2.29-2.15(m,5H),1.89-1.76(m,6H),1.69-1.59(m,7H),1.57(m,9H),1.54-1.41(m,8H),1.29-1.27(m,56H),0.90(t,J＝6.4Hz,3H),0.83(s,3H)。 1 H NMR ((400MHz, CDCl 3 ): δ7.28(s, 1H), 6.95-6.92(m, 1H), 6.90-6.89(m, 1H), 5.37--5.32(m, 1H), 4.81( t,J＝8.4Hz,1H),4.39-4.35(m,2H),4.28-4.26(m,3H),4.19-4.13(m,2H),2.91-2.66(m,6H),2.33(t, J＝7.2Hz, 6H), 2.29-2.15(m, 5H), 1.89-1.76(m, 6H), 1.69-1.59(m, 7H), 1.57(m, 9H), 1.54-1.41(m, 8H) , 1.29-1.27 (m, 56H), 0.90 (t, J=6.4Hz, 3H), 0.83 (s, 3H).
实施例10：2-(2-(2-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-2-氧代乙氧基)乙酰基)丙-1,3-二基二棕榈酸酯(10)的制备Example 10: 2-(2-(2-(((7R,8R,9S,13S,14S,17S)-17-hydroxyl-13-methyl-7-(9-((4,4,5, 5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene Preparation of -3-yl)oxy)-2-oxoethoxy)acetyl)propan-1,3-diyl dipalmitate (10)
Figure PCTCN2022136446-appb-000077
Figure PCTCN2022136446-appb-000077
将氟维司群(0.500g，824μmol，1.00eq)、中间体h(847mg，1.24mmol，1.50eq)、T3P(655mg，2.06mmol，2.50eq)、DMAP(201mg，1.65mmol，2.00eq)溶解于DCM(5.00mL)，氮气氛下，于25℃搅拌12小时。反应液减压浓缩，残余物通过快速柱层析色谱法纯化(PE/EA＝1/0～3/1)，得化合物10(119mg，93.4μmol，产率：11.3％)，为无色膏状物。Fulvestrant (0.500 g, 824 μmol, 1.00 eq), intermediate h (847 mg, 1.24 mmol, 1.50 eq), T3P (655 mg, 2.06 mmol, 2.50 eq), DMAP (201 mg, 1.65 mmol, 2.00 eq) were dissolved Stir in DCM (5.00 mL) at 25 °C for 12 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE/EA=1/0～3/1) to obtain compound 10 (119 mg, 93.4 μmol, yield: 11.3%) as a colorless paste shape.
1H NMR(400MHz,CDCl 3)：δ7.30(d,J＝8.4Hz,1H),6.90(dd,J1＝2.4Hz,J2＝6.0Hz,1H),6.82(d,J＝2.4Hz,1H),5.34-5.38(m,1H),4.49(s,2H),4.38(dd,J1＝7.6Hz,J2＝8.0Hz,2H),4.34(s,2H),4.17(dd,J1＝5.6Hz,J2＝3.6Hz,2H),3.76(t,J＝8.4Hz,1H),2.77-2.78(m,1H),2.74-2.75(m,4H),2.33-2.36(m,7H),2.31-2.33(m, 4H),1.63(d,J＝8.0Hz,1H),1.61-1.63(m,3H),1.59-1.61(m,6H),1.37-1.42(m,7H),1.28-1.32(m,60H),1.19-1.26(m,1H),1.18-1.19(m,1H),0.87-0.90(m,6H),0.79(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.30(d, J=8.4Hz, 1H), 6.90(dd, J1=2.4Hz, J2=6.0Hz, 1H), 6.82(d, J=2.4Hz, 1H), 5.34-5.38(m, 1H), 4.49(s, 2H), 4.38(dd, J1=7.6Hz, J2=8.0Hz, 2H), 4.34(s, 2H), 4.17(dd, J1=5.6 Hz, J2＝3.6Hz, 2H), 3.76(t, J＝8.4Hz, 1H), 2.77-2.78(m, 1H), 2.74-2.75(m, 4H), 2.33-2.36(m, 7H), 2.31 -2.33(m, 4H), 1.63(d, J＝8.0Hz, 1H), 1.61-1.63(m, 3H), 1.59-1.61(m, 6H), 1.37-1.42(m, 7H), 1.28-1.32 (m,60H),1.19-1.26(m,1H),1.18-1.19(m,1H),0.87-0.90(m,6H),0.79(s,3H).
实施例11：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)丙二酸酯(11)的制备Example 11: 1,3-bis(palmitoyloxy)prop-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)malonate (11)
Figure PCTCN2022136446-appb-000078
Figure PCTCN2022136446-appb-000078
将中间体k(809mg，1.24mmol，1.50eq)中溶于DCM(5.00mL)中，加入SOCl 2(0.15g，1.24mmol，1.50eq)，加DMF 5滴，室温搅拌2小时。将溶剂减压浓缩，然后加入DCM溶解(20mL)，再次减压浓缩，得中间体k的酰氯。再加入DCM(10.00mL)溶解，加入三乙胺(333mg，3.3mmol，4.00eq)、氟维司群(0.500g，824μmol，1.00eq)，于25℃搅拌72小时。反应液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：PE/EA＝1/0～2/1)，得化合物11(466mg，374μmol，产率：45.5％)，为白色固体。 Intermediate k (809mg, 1.24mmol, 1.50eq) was dissolved in DCM (5.00mL), SOCl 2 (0.15g, 1.24mmol, 1.50eq) was added, 5 drops of DMF was added, and stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure, then DCM was added to dissolve (20 mL), and concentrated under reduced pressure again to obtain the acid chloride of intermediate k. Then DCM (10.00 mL) was added to dissolve, triethylamine (333 mg, 3.3 mmol, 4.00 eq) and fulvestrant (0.500 g, 824 μmol, 1.00 eq) were added, and stirred at 25° C. for 72 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: PE/EA=1/0～2/1) to obtain compound 11 (466mg, 374μmol, yield: 45.5%), as white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.5Hz,1H),6.63-6.66(m,1H),6.57(d,J＝2.4Hz,1H),5.28-5.35(m,1H),4.77-4.79(m,1H),4.29-4.34(m,4H),3.41(d,J＝7.6Hz,2H),2.76-2.81(m,5H),2.30-2.34(m,14H),1.86(d,J＝10.4Hz,1H),1.60-1.63(m,3H),1.40-1.43(m,7H),1.29-1.34(m,6H),1.26-1.29(m,58H),0.89-0.90(m,1H),0.83-0.89(m,6H),0.83(d,J＝1.6Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.5Hz, 1H), 6.63-6.66(m, 1H), 6.57(d, J=2.4Hz, 1H), 5.28-5.35(m ,1H),4.77-4.79(m,1H),4.29-4.34(m,4H),3.41(d,J＝7.6Hz,2H),2.76-2.81(m,5H),2.30-2.34(m,14H ),1.86(d,J＝10.4Hz,1H),1.60-1.63(m,3H),1.40-1.43(m,7H),1.29-1.34(m,6H),1.26-1.29(m,58H), 0.89-0.90 (m, 1H), 0.83-0.89 (m, 6H), 0.83 (d, J=1.6Hz, 3H).
实施例12：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)琥珀酸酯(12)的制备Example 12: 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)succinate (12)
Figure PCTCN2022136446-appb-000079
Figure PCTCN2022136446-appb-000079
Figure PCTCN2022136446-appb-000080
Figure PCTCN2022136446-appb-000080
于0℃，氮气氛下，向氟维司群(727mg，1.2mmol，1eq)在DCM(12mL)的溶液中加入氯甲酸对硝基苯酚酯(290mg，1.44mmol，1.2eq)与三乙胺(0.66mL,4.8mmol，4eq)，室温搅拌3小时。加入中间体l(964mg，1.44mmol，1.2eq)，室温搅拌2小时。反应液依次用20％NaOH 10mL、盐水10mL洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过快速柱层析色谱法纯化(洗脱剂：PE/EA＝1/0～2/1)，得化合物12(0.69g，0.55mmol，产率：45.5％)，为白色固体。To a solution of fulvestrant (727 mg, 1.2 mmol, 1 eq) in DCM (12 mL) was added p-nitrophenol chloroformate (290 mg, 1.44 mmol, 1.2 eq) and triethylamine at 0 °C under nitrogen atmosphere (0.66mL, 4.8mmol, 4eq), stirred at room temperature for 3 hours. Intermediate 1 (964mg, 1.44mmol, 1.2eq) was added and stirred at room temperature for 2 hours. The reaction solution was washed successively with 20% NaOH 10mL and brine 10mL, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: PE/EA=1/ 0～2/1), compound 12 (0.69 g, 0.55 mmol, yield: 45.5%) was obtained as a white solid.
1H NMR(400MHz,CDCl 3):δ7.26-7.29(m,1H),6.84-6.86(m,1H),6.79(d,J＝2.4Hz,1H),5.28-5.33(m,1H),4.32(dd,J＝4.4,7.6Hz,2H),4.18(dd,J＝5.6,6.4Hz,2H),3.74(d,J＝8.8Hz,1H),2.86-2.89(m,3H),2.73-2.77(m,6H),2.32-2.36(m,2H),2.28-2.30(m,4H),2.17-2.23(m,4H),1.77-1.76(m,1H),1.61(brs,3H),1.58-1.60(m,3H),1.50-1.52(m,3H),1.43-1.47(m,8H),1.26-1.39(m,60H),1.19-1.25(m,1H),1.03-1.07(m,1H),0.88(d,J＝6.8Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.26-7.29 (m, 1H), 6.84-6.86 (m, 1H), 6.79 (d, J=2.4Hz, 1H), 5.28-5.33 (m, 1H) ,4.32(dd,J=4.4,7.6Hz,2H),4.18(dd,J=5.6,6.4Hz,2H),3.74(d,J=8.8Hz,1H),2.86-2.89(m,3H), 2.73-2.77(m,6H),2.32-2.36(m,2H),2.28-2.30(m,4H),2.17-2.23(m,4H),1.77-1.76(m,1H),1.61(brs,3H ),1.58-1.60(m,3H),1.50-1.52(m,3H),1.43-1.47(m,8H),1.26-1.39(m,60H),1.19-1.25(m,1H),1.03-1.07 (m, 1H), 0.88 (d, J=6.8Hz, 6H), 0.78 (s, 3H).
实施例13：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)戊二酸酯(13)的制备Example 13: 1,3-bis(palmitoyloxy)prop-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)glutarate (13)
Figure PCTCN2022136446-appb-000081
Figure PCTCN2022136446-appb-000081
采用与实施例11类似的方法，将中间体k替换为等摩尔比的中间体c，制备化合物13(1.5g，产率：63.5％)，为白色固体。Using a method similar to Example 11, intermediate k was replaced by intermediate c in an equimolar ratio to prepare compound 13 (1.5 g, yield: 63.5%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.26-7.29(m,1H),6.84(dd,J1＝5.6Hz,J2＝6.0Hz,1H),6.78(d,J＝2.0Hz,1H),5.28-5.32(m,1H),4.33(dd,J＝4.4,7.6Hz,2H),4.16(dd,J1＝6.0Hz,J2＝6.0Hz,2H),3.76(d,J＝8.4Hz,1H),2.90-2.92(m,1H),2.65-2.78(m,4H),2.61-2.63(m,2H),2.47-2.51(m,2H),2.30-2.34(m,7H),2.21-2.26(m,1H),2.13-2.17(m,3H),2.05-2.09(m,2H),1.90-1.92(m,1H),1.63-1.72(m,2H),1.59-1.61(m,6H),1.39-1.43(m,7H),1.26-1.37(m,62H),0.95-1.02(m,1H), 0.88(d,J＝6.4Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.26-7.29 (m, 1H), 6.84 (dd, J1 = 5.6Hz, J2 = 6.0Hz, 1H), 6.78 (d, J = 2.0Hz, 1H), 5.28-5.32(m,1H),4.33(dd,J=4.4,7.6Hz,2H),4.16(dd,J1=6.0Hz,J2=6.0Hz,2H),3.76(d,J=8.4Hz,1H ),2.90-2.92(m,1H),2.65-2.78(m,4H),2.61-2.63(m,2H),2.47-2.51(m,2H),2.30-2.34(m,7H),2.21-2.26 (m,1H),2.13-2.17(m,3H),2.05-2.09(m,2H),1.90-1.92(m,1H),1.63-1.72(m,2H),1.59-1.61(m,6H) , 1.39-1.43 (m, 7H), 1.26-1.37 (m, 62H), 0.95-1.02 (m, 1H), 0.88 (d, J=6.4Hz, 6H), 0.78 (s, 3H).
实施例14：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)己二酸酯(14)的制备Example 14: 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-3-yl)adipate (14)
Figure PCTCN2022136446-appb-000082
Figure PCTCN2022136446-appb-000082
采用与实施例11类似的方法，将中间体k替换为等摩尔比的中间体j，制备化合物14(1.3g，产率：57.8％)，为白色固体。Using a method similar to Example 11, intermediate k was replaced by intermediate j in an equimolar ratio to prepare compound 14 (1.3 g, yield: 57.8%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.29(s,1H),6.83(dd,J1＝8.4Hz,J2＝8.4Hz,1H),6.77(d,J＝2.0Hz,1H),5.25-5.30(m,1H),4.32(dd,J1＝12.0Hz,J2＝12.0Hz,2H),4.15-4.18(m,2H),3.75(t,J＝8.4Hz,8.8Hz,1H),2.88-2.93(m,1H),2.71-2.78(m,4H),2.63-2.68(m,1H),2.57(t,J＝7.2Hz,14.8Hz,2H),2.38-2.42(m,2H),2.32(t,J＝7.6Hz,8.4Hz,6H),2.23-2.28(m,1H),2.13-2.19(m,3H),1.91-1.94(m,1H),1.74-1.80(m,8H),1.57-1.64(m,8H),1.37-1.46(m,8H),1.26-1.28(m,58H),0.88(t,J＝6.8Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s, 1H), 6.83(dd, J1=8.4Hz, J2=8.4Hz, 1H), 6.77(d, J=2.0Hz, 1H), 5.25- 5.30(m, 1H), 4.32(dd, J1=12.0Hz, J2=12.0Hz, 2H), 4.15-4.18(m, 2H), 3.75(t, J=8.4Hz, 8.8Hz, 1H), 2.88- 2.93(m,1H),2.71-2.78(m,4H),2.63-2.68(m,1H),2.57(t,J＝7.2Hz,14.8Hz,2H),2.38-2.42(m,2H),2.32 (t,J=7.6Hz,8.4Hz,6H),2.23-2.28(m,1H),2.13-2.19(m,3H),1.91-1.94(m,1H),1.74-1.80(m,8H), 1.57-1.64 (m, 8H), 1.37-1.46 (m, 8H), 1.26-1.28 (m, 58H), 0.88 (t, J=6.8Hz, 6H), 0.78 (s, 3H).
实施例15：1-(1,3-双(棕榈酰氧基)丙-2-基)5-((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)3-甲基戊二酸二酯(15)的制备Example 15: 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)3-methylglutaric acid diester (15)
Figure PCTCN2022136446-appb-000083
Figure PCTCN2022136446-appb-000083
采用与实施例11类似的方法，将中间体k替换为等摩尔比的中间体a，制备化合物15(0.95g，产率：48.8％)，为白色固体。Using a method similar to Example 11, intermediate k was replaced by intermediate a in an equimolar ratio to prepare compound 15 (0.95 g, yield: 48.8%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.39–7.19(m,1H),6.86(dd,J＝8.5,2.5Hz,1H),6.80(d,J＝2.5Hz,1H),5.41–5.16(m,1H),4.35(ddd,J＝12.0,4.3,1.9Hz,2H),4.27–4.08(m,2H),3.77(t,J＝8.4Hz,1H),2.93(dd,J＝16.9,5.4Hz,1H),2.86–2.45(m,9H),2.45–2.10(m,11H),2.07(d,J＝3.1Hz,1H),2.03–1.91(m,1H),1.91–1.72(m,3H),1.73–1.00(m,76H),0.91(t,J＝6.7Hz,6H),0.80(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.39–7.19 (m, 1H), 6.86 (dd, J=8.5, 2.5Hz, 1H), 6.80 (d, J=2.5Hz, 1H), 5.41–5.16 (m,1H),4.35(ddd,J=12.0,4.3,1.9Hz,2H),4.27–4.08(m,2H),3.77(t,J=8.4Hz,1H),2.93(dd,J=16.9 ,5.4Hz,1H),2.86–2.45(m,9H),2.45–2.10(m,11H),2.07(d,J＝3.1Hz,1H),2.03–1.91(m,1H),1.91–1.72( m, 3H), 1.73–1.00 (m, 76H), 0.91 (t, J=6.7Hz, 6H), 0.80 (s, 3H).
实施例16：1-(1,3-双(棕榈酰氧基)丙-2-基)7-((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)庚二酸酯(16)的制备Example 16: 1-(1,3-bis(palmitoyloxy)propan-2-yl)7-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)pimelate (16)
Figure PCTCN2022136446-appb-000084
Figure PCTCN2022136446-appb-000084
采用与实施例11类似的方法，将中间体k替换为等摩尔比的中间体m，制备化合物16(1.21g，产率：65.6％)，为白色固体状。Using a method similar to Example 11, intermediate k was replaced by intermediate m in an equimolar ratio to prepare compound 16 (1.21 g, yield: 65.6%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.29(s,1H),6.83(dd,J1＝8.4Hz,J2＝8.8Hz,1H),6.7(d,J＝2.0Hz,1H),5.24-5.29(m,1H),4.31(dd,J1＝12.0Hz,J2＝11.6Hz,2H),4.10-4.17(m,2H),3.75(t,J＝8.4Hz,1H),2.87-2.88(m,1H),2.71-2.77(m,4H),2.61-2.68(m,1H),2.54(t,J＝7.6Hz,2H),2.30-2.38(m,9H),2.23-2.29(m,1H),2.13-2.19(m,3H),1.91-1.94(m,1H),1.75-1.79(m,6H),1.59-1.69(m,12H),1.44-1.50(m,6H),1.36-1.39(m,3H),1.25-1.28(m,56H),0.88(t,J＝6.8Hz,6H),0.78(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s, 1H), 6.83(dd, J1=8.4Hz, J2=8.8Hz, 1H), 6.7(d, J=2.0Hz, 1H), 5.24- 5.29(m, 1H), 4.31(dd, J1=12.0Hz, J2=11.6Hz, 2H), 4.10-4.17(m, 2H), 3.75(t, J=8.4Hz, 1H), 2.87-2.88(m ,1H),2.71-2.77(m,4H),2.61-2.68(m,1H),2.54(t,J＝7.6Hz,2H),2.30-2.38(m,9H),2.23-2.29(m,1H ),2.13-2.19(m,3H),1.91-1.94(m,1H),1.75-1.79(m,6H),1.59-1.69(m,12H),1.44-1.50(m,6H),1.36-1.39 (m, 3H), 1.25-1.28 (m, 56H), 0.88 (t, J=6.8Hz, 6H), 0.78 (s, 3H).
实施例17：1-(1,3-双(棕榈酰氧基)丙-2-基)12-((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)十二烷酸二酯(17)的制备Example 17: 1-(1,3-bis(palmitoyloxy)propan-2-yl)12-((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-3-yl)dodecanoic acid diester (17)
Figure PCTCN2022136446-appb-000085
Figure PCTCN2022136446-appb-000085
采用与实施例4类似的方法，将中间体d替换为等摩尔比的中间体n，制备化合物17(0.87g，产率：56.5％)，为白色固体。Using a method similar to Example 4, intermediate d was replaced by intermediate n in an equimolar ratio to prepare compound 17 (0.87 g, yield: 56.5%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.30(s,1H),6.87(d,J＝8.4Hz,1H),6.81(s,1H),5.30(s,1H),4.33(dd,J＝12.0,4.3Hz,2H),4.19(dd,J＝11.9,5.9Hz,2H),3.79(s,1H),3.03–2.86(m,1H),2.86–2.63(m,5H),2.56(t,J＝7.6Hz,2H),2.50–2.11(m,13H),1.96(d,J＝12.1Hz,2H),1.88–1.05(m,91H),0.92(t,J＝6.7Hz,6H),0.82(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.30(s,1H),6.87(d,J＝8.4Hz,1H),6.81(s,1H),5.30(s,1H),4.33(dd,J ＝12.0,4.3Hz,2H),4.19(dd,J＝11.9,5.9Hz,2H),3.79(s,1H),3.03–2.86(m,1H),2.86–2.63(m,5H),2.56( t, J＝7.6Hz, 2H), 2.50–2.11(m, 13H), 1.96(d, J＝12.1Hz, 2H), 1.88–1.05(m, 91H), 0.92(t, J＝6.7Hz, 6H ), 0.82(s,3H).
实施例18：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)丙二酸酯(18)的制备Example 18: 1,3-bis(palmitoyloxy)propan-2-yl((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)malonate (18)
Figure PCTCN2022136446-appb-000086
Figure PCTCN2022136446-appb-000086
采用与实施例1类似的方法，将中间体d替换为中间体k，制备化合物18 (0.63g，产率：55.7％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate k to prepare compound 18 (0.63 g, yield: 55.7%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.12(d,J＝8.4Hz,1H),6.62-6.66(m,1H),6.57(d,J＝2.4Hz,1H),5.28-5.33(m,1H),4.75-4.79(m,1H),4.75-4.79(m,2H),4.27-4.30(m,2H),3.41(d,J＝2.0Hz,2H),2.77-2.83(m,5H),2.30-2.34(m,11H),1.78-1.81(m,1H),1.62-1.76(m,3H),1.41-1.46(m,7H),1.34-1.40(m,7H),1.26-1.29(m,60H),1.09-1.05(m,1H),0.88(d,J＝6.4Hz,6H),0.83(d,J＝1.6Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.12(d, J=8.4Hz, 1H), 6.62-6.66(m, 1H), 6.57(d, J=2.4Hz, 1H), 5.28-5.33(m ,1H),4.75-4.79(m,1H),4.75-4.79(m,2H),4.27-4.30(m,2H),3.41(d,J=2.0Hz,2H),2.77-2.83(m,5H ),2.30-2.34(m,11H),1.78-1.81(m,1H),1.62-1.76(m,3H),1.41-1.46(m,7H),1.34-1.40(m,7H),1.26-1.29 (m, 60H), 1.09-1.05 (m, 1H), 0.88 (d, J=6.4Hz, 6H), 0.83 (d, J=1.6Hz, 3H).
实施例19：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)琥珀酸酯(19)的制备Example 19: 1,3-bis(palmitoyloxy)propan-2-yl((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)succinate (19)
Figure PCTCN2022136446-appb-000087
Figure PCTCN2022136446-appb-000087
采用与实施例1类似的方法，将中间体d替换为中间体l，制备化合物19(0.46g，产率：48.6％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate 1 to prepare compound 19 (0.46 g, yield: 48.6%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.13(d,J＝8.8Hz,1H),6.62-6.65(m,1H),6.57(d,J＝2.0Hz,1H),5.27-5.29(m,1H),4.69-4.74(m,1H),4.29-4.33(m,2H),4.14-4.19(m,2H),2.74-2.80(m,5H),2.65(s,5H),2.31-2.35(m,6H),2.10-2.19(m,5H),1.64-1.77(m,1H),1.63-1.65(m,4H),1.60-1.62(m,3H),1.51-1.57(m,4H),1.40-1.43(m,7H),1.26-1.34(m,58H),1 0.99-1.05(m,1H),0.88(t,J＝6.8Hz,6H),0.84(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.8Hz, 1H), 6.62-6.65(m, 1H), 6.57(d, J=2.0Hz, 1H), 5.27-5.29(m ,1H),4.69-4.74(m,1H),4.29-4.33(m,2H),4.14-4.19(m,2H),2.74-2.80(m,5H),2.65(s,5H),2.31-2.35 (m,6H),2.10-2.19(m,5H),1.64-1.77(m,1H),1.63-1.65(m,4H),1.60-1.62(m,3H),1.51-1.57(m,4H) , 1.40-1.43 (m, 7H), 1.26-1.34 (m, 58H), 1 0.99-1.05 (m, 1H), 0.88 (t, J=6.8Hz, 6H), 0.84 (s, 3H).
实施例20：1,3-双(棕榈酰氧基)丙-2-基((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)戊二酸酯(20)的制备Example 20: 1,3-bis(palmitoyloxy)propan-2-yl ((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Preparation of cyclopenta[a]phenanthrene-17-yl)glutarate (20)
Figure PCTCN2022136446-appb-000088
Figure PCTCN2022136446-appb-000088
采用与实施例1类似的方法，将中间体d替换为等摩尔比的中间体c，制备化合物20(0.58g，产率：64.2％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate c in an equimolar ratio to prepare compound 20 (0.58 g, yield: 64.2%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.29(s,1H),6.95-6.92(m,1H),6.89-6.88(m,1H),5.30--5.26(m,1H),4.72(t,J＝8.0Hz,1H),4.35-4.30(m,2H),4.18-4.13(m,2H),2.95-2.66(m,6H),2.44-2.39(m,5H),2.33(t,J＝7.6Hz,6H),2.27-2.17(m, 4H),2.01-1.94(m,2H),1.87-1.78(m,7H),1.67-1.60(m,7H),1.57(s,9H),1.53-1.38(m,9H),1.29-1.27(m,54H),0.90(t,J＝6.4Hz,3H),0.83(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.29(s, 1H), 6.95-6.92(m, 1H), 6.89-6.88(m, 1H), 5.30--5.26(m, 1H), 4.72(t ,J＝8.0Hz,1H),4.35-4.30(m,2H),4.18-4.13(m,2H),2.95-2.66(m,6H),2.44-2.39(m,5H),2.33(t,J ＝7.6Hz,6H),2.27-2.17(m,4H),2.01-1.94(m,2H),1.87-1.78(m,7H),1.67-1.60(m,7H),1.57(s,9H), 1.53-1.38 (m, 9H), 1.29-1.27 (m, 54H), 0.90 (t, J=6.4Hz, 3H), 0.83 (s, 3H).
实施例21：1-(1,3-双(棕榈酰氧基)丙-2-基)5-((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)3-甲基戊二酸二酯(21)的制备Example 21: 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)3-methylglutaric acid diester (21)
Figure PCTCN2022136446-appb-000089
Figure PCTCN2022136446-appb-000089
采用与实施例1类似的方法，将中间体d替换为等摩尔比的中间体a，制备化合物21(0.45g，产率：57.8％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate a in an equimolar ratio to prepare compound 21 (0.45 g, yield: 57.8%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.16(d,J＝8.5Hz,1H),6.67(dt,J＝8.4,3.0Hz,1H),6.61(d,J＝2.7Hz,1H),5.42–5.24(m,1H),4.75(t,J＝8.4Hz,1H),4.34(dt,J＝11.8,3.0Hz,2H),4.18(dd,J＝12.0,6.0Hz,2H),3.01–2.61(m,5H),2.63–2.39(m,3H),2.39–2.14(m,9H),1.93–1.16(m,81H),1.08(d,J＝6.2Hz,4H),1.01–0.74(m,9H)。 1 H NMR (400MHz, CDCl 3 ): δ7.16 (d, J = 8.5Hz, 1H), 6.67 (dt, J = 8.4, 3.0Hz, 1H), 6.61 (d, J = 2.7Hz, 1H), 5.42–5.24(m,1H),4.75(t,J=8.4Hz,1H),4.34(dt,J=11.8,3.0Hz,2H),4.18(dd,J=12.0,6.0Hz,2H),3.01 –2.61(m,5H),2.63–2.39(m,3H),2.39–2.14(m,9H),1.93–1.16(m,81H),1.08(d,J＝6.2Hz,4H),1.01–0.74 (m,9H).
实施例22：1-(1,3-双(棕榈酰氧基)丙-2-基)12-((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)十二烷酸二酯(22)的制备Example 22: 1-(1,3-bis(palmitoyloxy)propan-2-yl)12-((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)dodecanoic acid diester (22)
Figure PCTCN2022136446-appb-000090
Figure PCTCN2022136446-appb-000090
采用与实施例1类似的方法，将中间体d替换为等摩尔比的中间体n，制备化合物22(0.63g，产率：62.1％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate n in an equimolar ratio to prepare compound 22 (0.63 g, yield: 62.1%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.17(d,J＝8.5Hz,1H),6.68(dd,J＝8.4,2.9Hz,1H),6.61(d,J＝2.7Hz,1H),5.30(t,J＝5.1Hz,1H),4.75(t,J＝8.4Hz,1H),4.34(dd,J＝11.9,4.3Hz,2H),4.19(dd,J＝11.9,5.9Hz,2H),3.00–2.58(m,6H),2.51–2.10(m,16H),1.94–0.99(m,92H),0.99–0.75(m,9H)。 1 H NMR (400MHz, CDCl 3 ): δ7.17 (d, J = 8.5Hz, 1H), 6.68 (dd, J = 8.4, 2.9Hz, 1H), 6.61 (d, J = 2.7Hz, 1H), 5.30(t, J=5.1Hz, 1H), 4.75(t, J=8.4Hz, 1H), 4.34(dd, J=11.9, 4.3Hz, 2H), 4.19(dd, J=11.9, 5.9Hz, 2H ), 3.00–2.58(m,6H), 2.51–2.10(m,16H), 1.94–0.99(m,92H), 0.99–0.75(m,9H).
实施例23：2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)甲酰氧基)乙氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙-1,3-二基二棕榈酸酯(23)的制备Example 23: 2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-( (4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H- Cyclopenta[a]phenanthrene-17-yl)oxy)formyloxy)ethoxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyl Preparation of dipalmitate (23)
Figure PCTCN2022136446-appb-000091
Figure PCTCN2022136446-appb-000091
步骤1：叔丁基(1-氯乙基)((7R,8R,9S,13S,14S,17S)-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲e-3,17-二基)双(羧酸酯)(23a)的制备Step 1: tert-butyl(1-chloroethyl)((7R,8R,9S,13S,14S,17S)-13-methyl-7-(9-((4,4,5,5,5- Pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3, Preparation of 17-diyl)bis(carboxylate) (23a)
将中间体g(4.45g，6.3mmol，1.0eq)、吡啶(1.0g，12.6mmol，2.0eq)溶解于DCM 20mL中。加入氯甲酸-1-氯乙酯(1.35g，9.5mmol，1.5eq)，室温搅拌4小时。反应液中加水15mL，有机相用饱和氯化钠10mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物23a(5.38g，收率105％)，不经纯化，直接用于下一步。Intermediate g (4.45 g, 6.3 mmol, 1.0 eq), pyridine (1.0 g, 12.6 mmol, 2.0 eq) were dissolved in DCM 20 mL. Add 1-chloroethyl chloroformate (1.35g, 9.5mmol, 1.5eq) and stir at room temperature for 4 hours. Add 15 mL of water to the reaction solution, wash the organic phase with 10 mL of saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 23a (5.38 g, yield 105%), which is directly used in the following step.
步骤2：2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-((叔丁氧羰基)氧基)-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙烷-1,3-二基二棕榈酸酯(23b)的制备Step 2: 2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy)-13-methanol yl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16 ,17-Decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethoxy)-4-oxobutyl)dithio)butanoyl)oxy) Preparation of propane-1,3-diyl dipalmitate (23b)
在氮气氛下，于100℃，将化合物23a(0.500g，614μmol，1.00eq)、中间体d(533mg，676μmol，1.10eq)、TBAI(22.7mg，61.4μmol，0.100eq)、 K 2CO 3(254mg，1.84mmol，3.00eq)和甲苯(2.00mL)的溶液搅拌2小时。将反应液减压浓缩，残余物通过薄层色谱法纯化(PE:EA＝2:1)，得化合物23b(180mg，114μmol，收率：18.7％)，为无色油状物。 Under nitrogen atmosphere, at 100°C, compound 23a (0.500g, 614μmol, 1.00eq), intermediate d (533mg, 676μmol, 1.10eq), TBAI (22.7mg, 61.4μmol, 0.100eq), K 2 CO 3 (254mg, 1.84mmol, 3.00eq) and toluene (2.00mL) was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (PE:EA=2:1) to obtain compound 23b (180 mg, 114 μmol, yield: 18.7%) as a colorless oil.
1H NMR(400MHz,CDCl 3)：δ7.26-7.28(m,1H),6.92(dd,J＝2.0,6.4Hz,1H),6.87(d,J＝1.6Hz,1H),6.76(d,J＝5.2Hz,1H),5.25-5.27(m,1H),4.61-4.66(m,1H),4.31(d,J＝4.4,7.6Hz,2H),4.13-4.17(m,2H),2.91-2.93(m,1H),2.70-2.73(m,8H),2.51-2.60(m,1H),2.47-2.49(m,4H),2.30-2.34(m,5H),2.19-2.27(m,5H),2.03(s,2H),1.88-1.91(m,1H),1.56-1.61(m,6H),1.53-1.54(m,5H),1.52(m,9H),1.46-1.48(m,3H),1.39-1.45(m,7H),1.25-1.28(m,60H),0.90(brs,1H),0.88-0.87(m,6H),0.84(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.26-7.28(m, 1H), 6.92(dd, J=2.0, 6.4Hz, 1H), 6.87(d, J=1.6Hz, 1H), 6.76(d ,J=5.2Hz,1H),5.25-5.27(m,1H),4.61-4.66(m,1H),4.31(d,J=4.4,7.6Hz,2H),4.13-4.17(m,2H), 2.91-2.93(m,1H),2.70-2.73(m,8H),2.51-2.60(m,1H),2.47-2.49(m,4H),2.30-2.34(m,5H),2.19-2.27(m ,5H),2.03(s,2H),1.88-1.91(m,1H),1.56-1.61(m,6H),1.53-1.54(m,5H),1.52(m,9H),1.46-1.48(m ,3H), 1.39-1.45(m,7H), 1.25-1.28(m,60H), 0.90(brs,1H), 0.88-0.87(m,6H), 0.84(s,3H).
步骤3：2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)甲酰氧基)乙氧基)-4-氧代丁基)二硫基)丁酰基)氧基)丙-1,3-二基二棕榈酸酯(23)的制备Step 3: 2-((4-((4-(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7-(9-(( 4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-ring Penta[a]phenanthrene-17-yl)oxy)formyloxy)ethoxy)-4-oxobutyl)dithio)butyryl)oxy)propan-1,3-diyldi Preparation of Palmitate (23)
于0℃，将化合物23b(180mg，114μmol，1.00eq)溶于DCM(5mL)中，然后加入TFA(393mg，3.45mmol，255μL，30.0eq)。升温至25℃，搅拌3小时。反应液用饱和碳酸氢钠溶液调节pH＝7～8，用水(50mL)稀释，EA萃取(20mL×3)，水洗(20mL×2)，盐水洗(20mL×2)，无水Na 2SO 4干燥，过滤并减压浓缩，得化合物23(151mg，103μmol，产率：89.6％)。 Compound 23b (180 mg, 114 μmol, 1.00 eq) was dissolved in DCM (5 mL) at 0° C., then TFA (393 mg, 3.45 mmol, 255 μL, 30.0 eq) was added. The temperature was raised to 25°C and stirred for 3 hours. The reaction solution was adjusted to pH=7~8 with saturated sodium bicarbonate solution, diluted with water (50mL), extracted with EA (20mL×3), washed with water (20mL×2), washed with brine (20mL×2), anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give compound 23 (151 mg, 103 μmol, yield: 89.6%).
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.76-6.78(m,1H),6.63-6.65(m,1H),6.64(d,J＝2.8Hz,1H),611-6.57(m,1H),5.25-5.29(m,1H),4.61-4.67(m,1H),4.32(d,J＝4.0,7.6Hz,2H),4.13-4.17(m,2H),2.91-2.93(m,4H),2.74-2.76(m,5H),2.51-2.60(m,1H),2.47-2.49(m,4H),2.30-2.34(m,5H),2.19-2.27(m,5H),2.03-2.05(m,4H),1.88-1.91(m,1H),1.61-1.63(m,4H),1.55-1.56(m,4H),1.52-1.54(m,3H),1.33-1.38(m,7H),1.26-1.29(m,60H),0.98-1.01(m,1H),0.88-0.87(m,6H),0.84(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.76-6.78(m, 1H), 6.63-6.65(m, 1H), 6.64(d, J=2.8Hz ,1H),611-6.57(m,1H),5.25-5.29(m,1H),4.61-4.67(m,1H),4.32(d,J＝4.0,7.6Hz,2H),4.13-4.17(m ,2H),2.91-2.93(m,4H),2.74-2.76(m,5H),2.51-2.60(m,1H),2.47-2.49(m,4H),2.30-2.34(m,5H),2.19 -2.27(m,5H),2.03-2.05(m,4H),1.88-1.91(m,1H),1.61-1.63(m,4H),1.55-1.56(m,4H),1.52-1.54(m, 3H), 1.33-1.38(m, 7H), 1.26-1.29(m, 60H), 0.98-1.01(m, 1H), 0.88-0.87(m, 6H), 0.84(s, 3H).
实施例24：1-(1,3-双(棕榈酰氧基)丙-2-基)5-(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙基)3-甲基戊二酸酯(24)的制备Example 24: 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy -13-Methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14 , 15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)oxy)carbonyl)oxy)ethyl)3-methylglutaric acid ester (24)
Figure PCTCN2022136446-appb-000092
Figure PCTCN2022136446-appb-000092
采用与实施例23类似的方法，将中间体d替换为等摩尔比的中间体a，制备 化合物24(200mg，最后步骤产率：87.2％)，为白色固体。Using a method similar to Example 23, intermediate d was replaced by intermediate a in an equimolar ratio to prepare compound 24 (200 mg, last step yield: 87.2%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.0Hz,1H),6.76-6.81(m,1H),6.62-6.66(m,1H),6.57(d,J＝2.4Hz,1H),5.26-5.29(m,1H),4.61-4.66(m,1H),4.31(dd,J1＝12.0Hz,J2＝12.0Hz,2H),4.15(dd,J1＝11.6Hz,J2＝12.8Hz,2H),2.77-2.89(m,4H),2.74-2.76(m,1H),2.34-2.47(m,2H),2.28-2.34(m,7H),2.25-2.27(m,2H),2.16-2.20(m,2H),1.89-1.94(m,1H),1.73-1.78(m,3H),1.59-1.65(m,10H),1.53(dd,J1＝5.6Hz,J2＝5.2Hz,4H),1.39-1.47(m,7H),1.26-1.29(m,60H),1.05(dd,J1＝6.0Hz,J2＝6.4Hz,3H),0.87-0.90(m,6H),0.85(d,J＝0.8Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.0Hz, 1H), 6.76-6.81(m, 1H), 6.62-6.66(m, 1H), 6.57(d, J=2.4Hz ,1H),5.26-5.29(m,1H),4.61-4.66(m,1H),4.31(dd,J1=12.0Hz,J2=12.0Hz,2H),4.15(dd,J1=11.6Hz,J2= 12.8Hz, 2H), 2.77-2.89(m, 4H), 2.74-2.76(m, 1H), 2.34-2.47(m, 2H), 2.28-2.34(m, 7H), 2.25-2.27(m, 2H) ,2.16-2.20(m,2H),1.89-1.94(m,1H),1.73-1.78(m,3H),1.59-1.65(m,10H),1.53(dd,J1=5.6Hz,J2=5.2Hz ,4H),1.39-1.47(m,7H),1.26-1.29(m,60H),1.05(dd,J1＝6.0Hz,J2＝6.4Hz,3H),0.87-0.90(m,6H),0.85( d, J=0.8Hz, 3H).
实施例25：2-(2-(2-(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙氧基)-2-氧代乙氧基)乙酰基)丙-1,3-二基二棕榈酸酯(25)的制备Example 25: 2-(2-(2-(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4 ,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentyl [a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethoxy)-2-oxoethoxy)acetyl)propan-1,3-diyl dipalmitate (25) preparation
Figure PCTCN2022136446-appb-000093
Figure PCTCN2022136446-appb-000093
采用与实施例23类似的方法，将中间体d替换为等摩尔比的中间体h，制备化合物25(405mg，最后步骤产率：91.2％)，为白色固体。Using a method similar to Example 23, intermediate d was replaced by intermediate h in an equimolar ratio to prepare compound 25 (405 mg, last step yield: 91.2%) as a white solid.
1H NMR(400MHz,CDCl 3):δ7.13(d,J＝8.4Hz,1H),6.85-6.80(m,1H),6.66-6.62(m,1H),6.57-6.56(m,1H),5.36-5.31(m,1H),4.63(t,J＝8.0Hz,1H),4.38-4.31(m,2H),4.28-4.27(m,4H),4.18-4.13(m,2H),2.93-2.59(m,7H),2.34-2.15(m,12H),1.92(t,J＝8.0Hz,1H),1.80-1.55(m,21H),1.50-1.39(m,7H),1.28-1.26(m,49H),1.09-1.03(m,1H),0.90-0.87(m,6H),0.85(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.85-6.80(m, 1H), 6.66-6.62(m, 1H), 6.57-6.56(m, 1H) ,5.36-5.31(m,1H),4.63(t,J＝8.0Hz,1H),4.38-4.31(m,2H),4.28-4.27(m,4H),4.18-4.13(m,2H),2.93 -2.59(m,7H),2.34-2.15(m,12H),1.92(t,J＝8.0Hz,1H),1.80-1.55(m,21H),1.50-1.39(m,7H),1.28-1.26 (m, 49H), 1.09-1.03 (m, 1H), 0.90-0.87 (m, 6H), 0.85 (s, 3H).
实施例26：1,3-双(棕榈酰氧基)丙-2-基(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙基)丙二酸酯(26)的制备Example 26: 1,3-Bis(palmitoyloxy)prop-2-yl(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)malonate (26)
Figure PCTCN2022136446-appb-000094
Figure PCTCN2022136446-appb-000094
采用与实施例23类似的方法，将中间体d替换为等摩尔比的中间体k，制备化合物26(533mg，最后步骤产率：92.4％)，为白色固体。Using a method similar to Example 23, intermediate d was replaced by intermediate k in an equimolar ratio to prepare compound 26 (533 mg, last step yield: 92.4%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.63-6.66(m,1H), 6.57-6.62(m,1H),6.07-6.37(m,1H),5.10-5.31(m,1H),4.63-4.67(m,1H),4.32-4.36(m,2H),4.18-4.22(m,2H),2.74-2.84(m,5H),2.65-2.70(m,1H),2.26-2.35(m,11H),1.80-1.87(m,1H),1.74-1.76(m,4H),1.62(s,12H),1.50-1.52(m,1H),1.39-1.44(m,7H),1.26-1.29(m,58H),0.99-1.03(m,1H),0.88(t,J＝7.2Hz,6H),0.86(d,J＝3.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.63-6.66(m, 1H), 6.57-6.62(m, 1H), 6.07-6.37(m, 1H) ,5.10-5.31(m,1H),4.63-4.67(m,1H),4.32-4.36(m,2H),4.18-4.22(m,2H),2.74-2.84(m,5H),2.65-2.70( m,1H),2.26-2.35(m,11H),1.80-1.87(m,1H),1.74-1.76(m,4H),1.62(s,12H),1.50-1.52(m,1H),1.39- 1.44 (m, 7H), 1.26-1.29 (m, 58H), 0.99-1.03 (m, 1H), 0.88 (t, J=7.2Hz, 6H), 0.86 (d, J=3.2Hz, 3H).
实施例27：1,3-双(棕榈酰氧基)丙-2-基(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙基)琥珀酸酯(27)的制备Example 27: 1,3-bis(palmitoyloxy)propan-2-yl(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 -Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)succinate (27)
Figure PCTCN2022136446-appb-000095
Figure PCTCN2022136446-appb-000095
采用与实施例23类似的方法，将中间体d替换为等摩尔比的中间体l，制备化合物27(605g，最后步骤产率：88.5％)，为白色固体。Using a method similar to Example 23, intermediate d was replaced by intermediate 1 in an equimolar ratio to prepare compound 27 (605 g, last step yield: 88.5%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.76-6.78(m,1H),6.63-6.65(m,1H),6.56-6.57(m,1H),5.26-5.29(m,1H),4.63-4.65(m,1H),4.29-4.33(m,2H),4.16-4.18(m,2H),2.74-2.89(m,5H),2.67-2.69(m,4H),2.66-2.67(m,1H),2.34-2.66(m,6H),2.30-2.32(m,3H),1.61-1.63(m,1H),1.54-1.60(m,4H),1.53-1.54(m,14H),1.53(dd,J1＝5.6Hz,J2＝5.2Hz,3H),1.26-1.29(m,60H),0.87-0.90(m,7H),0.85(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.76-6.78(m, 1H), 6.63-6.65(m, 1H), 6.56-6.57(m, 1H) ,5.26-5.29(m,1H),4.63-4.65(m,1H),4.29-4.33(m,2H),4.16-4.18(m,2H),2.74-2.89(m,5H),2.67-2.69( m,4H),2.66-2.67(m,1H),2.34-2.66(m,6H),2.30-2.32(m,3H),1.61-1.63(m,1H),1.54-1.60(m,4H), 1.53-1.54(m,14H),1.53(dd,J1=5.6Hz,J2=5.2Hz,3H),1.26-1.29(m,60H),0.87-0.90(m,7H),0.85(s,3H) .
实施例28：1,3-双(棕榈酰氧基)丙-2-基(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)甲酰氧基)乙基)戊二酸酯(28)的制备Example 28: 1,3-Bis(palmitoyloxy)prop-2-yl(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl- 7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17 - Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)formyloxy)ethyl)glutarate (28)
Figure PCTCN2022136446-appb-000096
Figure PCTCN2022136446-appb-000096
Figure PCTCN2022136446-appb-000097
Figure PCTCN2022136446-appb-000097
步骤1：1,3-双(棕榈酰氧基)丙-2-基(1-(((((7R,8R,9S,13S,14S,17S)-3-((叔丁氧羰基)氧基)-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)羰基)氧基)乙基)戊二酸酯(28a)的制备Step 1: 1,3-Bis(palmitoyloxy)propan-2-yl(1-(((((7R,8R,9S,13S,14S,17S)-3-((tert-butoxycarbonyl)oxy Base)-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13 , 14,15,16,17-Decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)carbonyl)oxy)ethyl)glutarate (28a)
向化合物23a(500mg，615μmol，1.00eq)、中间体c(420mg，615μmol，1.00eq)的甲苯(10.0mL)的溶液中加入Cs 2CO 3(601mg，1.84mmol，3.00eq)、TBAI(22.7mg，61.4μmol，0.100eq)，于100℃搅拌2小时。将反应液过滤，用EtOAc(20.0mL)稀释，依次用水洗(20.0mL×2)、盐水洗(20.0mL)，然后用无水Na 2SO 4干燥，过滤并减压浓缩，残余物通过快速柱层析色谱法纯化(PE/EA＝100:1～2:1)，得化合物28a(500mg，342μmol，产率：55.7％)。 To a solution of compound 23a (500 mg, 615 μmol, 1.00 eq), intermediate c (420 mg, 615 μmol, 1.00 eq) in toluene (10.0 mL) was added Cs 2 CO 3 (601 mg, 1.84 mmol, 3.00 eq), TBAI (22.7 mg, 61.4μmol, 0.100eq), stirred at 100°C for 2 hours. The reaction solution was filtered, diluted with EtOAc (20.0 mL), washed with water (20.0 mL×2) and brine (20.0 mL) successively, then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure, and the residue was passed through flash Purified by column chromatography (PE/EA=100:1～2:1) to obtain compound 28a (500 mg, 342 μmol, yield: 55.7%).
1H NMR(400MHz,CDCl 3)：δ7.28(s,1H),6.95-6.92(d,J＝8.0Hz,1H),6.89-6.88(m,1H),6.79-6.77(m,1H),5.30-5.27(m,1H),4.64(t,J＝8.0Hz,1H),4.35-4.30(m,2H),4.18-4.13(m,2H),2.96-2.64(m,6H),2.46-2.41(m,5H),2.33(t,J＝7.2Hz,6H),2.29-2.14(m,5H),2.00-1.94(m,3H),1.79-1.71(m,4H),1.68-1.50(m,9H),1.57(s,9H),1.53-1.49(m,3H),1.49-1.38(m,8H),1.29-1.27(m,54H),0.90(t,J＝7.2Hz,6H),0.85(m,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.28(s, 1H), 6.95-6.92(d, J=8.0Hz, 1H), 6.89-6.88(m, 1H), 6.79-6.77(m, 1H) ,5.30-5.27(m,1H),4.64(t,J＝8.0Hz,1H),4.35-4.30(m,2H),4.18-4.13(m,2H),2.96-2.64(m,6H),2.46 -2.41(m,5H),2.33(t,J＝7.2Hz,6H),2.29-2.14(m,5H),2.00-1.94(m,3H),1.79-1.71(m,4H),1.68-1.50 (m,9H),1.57(s,9H),1.53-1.49(m,3H),1.49-1.38(m,8H),1.29-1.27(m,54H),0.90(t,J＝7.2Hz,6H ), 0.85(m,3H).
步骤2：1,3-双(棕榈酰氧基)丙-2-基(1-(((((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)甲酰氧基)乙基)戊二酸酯(28)的制备Step 2: 1,3-Bis(palmitoyloxy)propan-2-yl(1-(((((7R,8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-7 -(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17- Preparation of decahydro-6H-cyclopenta[a]phenanthrene-17-yl)oxy)formyloxy)ethyl)glutarate (28)
于0℃，向化合物28a(500mg，34μmol，1.00eq)的DCM(5.00mL)溶液中加入TFA(976mg，8.56mmol，634μL，25.0eq)。升温至25℃搅拌2小时。于0℃，反应混合物用饱和碳酸氢钠调pH＝8，然后用EtAOC萃取(10.0mL×3)，有机相用盐水洗(20.0mL)，过滤并浓缩，得到化合物28(163.30mg，294μmol，产率：35.0％)，为黄色膏状物。To a solution of compound 28a (500 mg, 34 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (976 mg, 8.56 mmol, 634 μL, 25.0 eq) at 0°C. The temperature was raised to 25°C and stirred for 2 hours. At 0°C, the reaction mixture was adjusted to pH=8 with saturated sodium bicarbonate, then extracted with EtAOC (10.0 mL×3), the organic phase was washed with brine (20.0 mL), filtered and concentrated to obtain compound 28 (163.30 mg, 294 μmol, Yield: 35.0%) as a yellow paste.
1H NMR(400MHz,CDCl 3):δ7.12(d,J＝8.0Hz,1H),6.77-6.75(m,1H),6.64-6.62(m,1H),6.57-6.56(m,1H),5.27-5.25(m,1H),4.63(t,J＝8.0Hz,1H),4.33-4.28(m,2H),4.16-411(m,2H),2.83-2.68(m,6H),2.44-2.39(m,4H),2.31(t,J＝7.2Hz,6H),2.27-2.14(m,5H),1.98-1.91(m,4H),1.77-1.71(m,4H),1.67-1.57(m,7H),1.53-1.49(m,3H),1.46-1.38(m,8H),1.28-1.25(m,56H),0.88(t,J＝7.2Hz,6H),0.85(m,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.12(d, J=8.0Hz, 1H), 6.77-6.75(m, 1H), 6.64-6.62(m, 1H), 6.57-6.56(m, 1H) ,5.27-5.25(m,1H),4.63(t,J＝8.0Hz,1H),4.33-4.28(m,2H),4.16-411(m,2H),2.83-2.68(m,6H),2.44 -2.39(m,4H),2.31(t,J＝7.2Hz,6H),2.27-2.14(m,5H),1.98-1.91(m,4H),1.77-1.71(m,4H),1.67-1.57 (m,7H),1.53-1.49(m,3H),1.46-1.38(m,8H),1.28-1.25(m,56H),0.88(t,J＝7.2Hz,6H),0.85(m,3H ).
实施例29：2-((N-(2-(((7R,8R,9S,13S,14S,17S)-3-羟基-13-甲基-7-(9-((4,4,5,5,5- 五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-17-基)氧基)-2-氧代乙基)-N-甲基氨基乙酰基)氧基)丙-1,3-二基二棕榈酸酯(29)的制备Example 29: 2-((N-(2-(((7R,8R,9S,13S,14S,17S)-3-hydroxyl-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-17-yl)oxy)-2-oxoethyl)-N-methylaminoacetyl)oxy)propan-1,3-diyl dipalmitate (29)
Figure PCTCN2022136446-appb-000098
Figure PCTCN2022136446-appb-000098
采用与实施例1类似的方法，将中间体d替换为等摩尔比的中间体i，制备化合物29(0.88g，产率：77.2％)，为白色固体。Using a method similar to Example 1, intermediate d was replaced by intermediate i in an equimolar ratio to prepare compound 29 (0.88 g, yield: 77.2%) as a white solid.
1H NMR(400MHz,CDCl 3)：δ7.13(d,J＝8.4Hz,1H),6.66-6.62(m,1H),6.57(d,J＝2.0Hz,1H),5.33-5.31(m,1H),4.76(t,J＝8.0Hz,1H),4.34(dd,J＝12.0,4.4Hz,2H),4.16(dd,J＝12.0,6.0Hz,2H),3.56(s,2H),3.51(s,2H),2.88-2.62(m,6H),2.55(s,3H),2.34-2.15(m,11H),1.85-1.82(m,1H),1.80-1.57(m,12H),1.54-1.38(m,8H),1.36-1.27(m,50H),1.26(s,6H),1.05-1.02(m,1H),0.89(t,J＝6.4Hz,6H),0.83(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.13(d, J=8.4Hz, 1H), 6.66-6.62(m, 1H), 6.57(d, J=2.0Hz, 1H), 5.33-5.31(m ,1H),4.76(t,J=8.0Hz,1H),4.34(dd,J=12.0,4.4Hz,2H),4.16(dd,J=12.0,6.0Hz,2H),3.56(s,2H) ,3.51(s,2H),2.88-2.62(m,6H),2.55(s,3H),2.34-2.15(m,11H),1.85-1.82(m,1H),1.80-1.57(m,12H) ,1.54-1.38(m,8H),1.36-1.27(m,50H),1.26(s,6H),1.05-1.02(m,1H),0.89(t,J＝6.4Hz,6H),0.83(s ,3H).
实施例30：2-((N-(2-(((7R,8R,9S,13S,14S,17S)-17-羟基-13-甲基-7-(9-((4,4,5,5,5-五氟戊烷基)亚磺酰基)壬基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊并[a]菲-3-基)氧基)-2-氧代乙基)-N-甲基甘氨酰基)氧基)丙-1,3-二基二棕榈酸酯(30)的制备Example 30: 2-((N-(2-(((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5 ,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] Preparation of phenanthrene-3-yl)oxy)-2-oxoethyl)-N-methylglycyl)oxy)propan-1,3-diyl dipalmitate (30)
Figure PCTCN2022136446-appb-000099
Figure PCTCN2022136446-appb-000099
于25℃，将氟维司群(500mg，824μmol，1.00eq)、中间体i(1.32g，1.90mmol，2.30eq)、EDCI(474mg，2.47mmol，3.00eq)、DMAP(201mg，1.65mmol，2.00eq)和DCM(7mL)的溶液搅拌12小时。将反应液减压浓缩，残余物通过快速柱层析色谱法纯化(PE/EA＝1/0～3/1)，得化合物30(266.96mg，207μmol，产率：25.2％)，为无色油状物。At 25°C, fulvestrant (500mg, 824μmol, 1.00eq), intermediate i (1.32g, 1.90mmol, 2.30eq), EDCI (474mg, 2.47mmol, 3.00eq), DMAP (201mg, 1.65mmol, 2.00 eq) and DCM (7 mL) was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE/EA=1/0～3/1) to obtain compound 30 (266.96 mg, 207 μmol, yield: 25.2%) as a colorless Oil.
对于以上的化合物6，除采用与实施例4类似的方法制备外，还可以采用与实施例8、实施例10～实施例12、实施例30类似的方法制备；对于以上的化合物13～化合物17，除采用与实施例11类似的方法制备外，还可以采用与实施例 4、实施例8、实施例10、实施例12、实施例30类似的方法制备，具体过程不再赘述。For the above compound 6, except that it is prepared by a method similar to that of Example 4, it can also be prepared by a method similar to that of Example 8, Example 10-Example 12, and Example 30; for the above Compound 13-Compound 17 , except that it is prepared by a method similar to that of Example 11, it can also be prepared by a method similar to that of Example 4, Example 8, Example 10, Example 12, and Example 30, and the specific process will not be repeated.
生物学试验biological test
试验例1：本发明化合物的药代动力学研究Test Example 1: Pharmacokinetic study of the compound of the present invention
试验方法：雌性SD大鼠200～250g(SPF级别，购于湖南斯莱克景达实验动物有限公司)，每个化合物3只，随机分组。待测化合物用6％二甲基乙酰胺、20％HS15、20％PEG200和54％的生理盐水，配成浓度为2mg/mL的溶液。本发明化合物的给药量为20mg/kg(mpk)，阳性对照化合物氟维司群的给药量为10mg/kg(mpk)。分别在给药后0.25、0.5、1、2、4、8和24h尾静脉采血。按标准的血药浓度检测方法检测。测试方法参考文献：杨毅等，大鼠血浆中奥莫替尼浓度的检测及其药动学特征，《中国临床药学杂志》，2018年第27卷第005期，321-324。Test method: 200-250 g female SD rats (SPF grade, purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.), 3 rats for each compound, were randomly divided into groups. The compound to be tested was prepared into a solution with a concentration of 2 mg/mL with 6% dimethylacetamide, 20% HS15, 20% PEG200 and 54% physiological saline. The dosage of the compound of the present invention is 20 mg/kg (mpk), and the dosage of the positive control compound fulvestrant is 10 mg/kg (mpk). Blood was collected from the tail vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, respectively. According to the standard detection method of blood drug concentration. Test method reference: Yang Yi et al., Detection of Omotinib Concentration in Rat Plasma and Its Pharmacokinetic Characteristics, "Chinese Journal of Clinical Pharmacy", Volume 27, Issue 005, 2018, 321-324.
本发明化合物的药代动力学测试结果如下表1所示。The pharmacokinetic test results of the compounds of the present invention are shown in Table 1 below.
本发明化合物的生物利用度F％的计算公式如下：The calculation formula of the bioavailability F% of the compound of the present invention is as follows:
F％＝AUC cpd/AUC 氟维司群/10×MW cpd/MW 氟维司群/2×100％＝AUC cpd/7230×MW cpd/606.32/2×100％＝AUC cpd×MW cpd/8767387.2×100％， F%=AUC cpd /AUC fulvestrant /10×MW cpd /MW fulvestrant /2×100%=AUC cpd /7230×MW cpd /606.32/2×100%=AUC cpd ×MW cpd /8767387.2 ×100%,
其中：AUC cpd为待测试的本发明化合物释放出氟维司群的AUC，AUC 氟维司群为氟维司群静脉注射1mpk(IV 1mpk)对应的AUC，MW cpd为待测试的本发明化合物的分子量，MW 氟维司群为氟维司群的分子量。 Wherein: AUC cpd is the AUC that the compound of the present invention to be tested releases fulvestrant, AUC fulvestrant is the AUC corresponding to fulvestrant intravenous injection 1mpk (IV 1mpk), and MW cpd is the compound of the present invention to be tested The molecular weight of fulvestrant, MW fulvestrant is the molecular weight of fulvestrant.
表1中，对于氟维司群口服给药(PO 10mpk)情形，由于给药量是本发明化合物的一半，因此其生物利用度F％为采用上述公式计算所得的2倍；以氟维司群静脉注射给药(IV 1mpk)情形的生物利用度为100％。In Table 1, for the situation of oral administration of fulvestrant (PO 10mpk), since the dosage is half of the compound of the present invention, its bioavailability F% is 2 times that calculated by the above formula; The bioavailability of swarm intravenous administration (IV 1mpk) is 100%.
表1 发明化合物的药代动力学测试结果Table 1 Pharmacokinetic test results of inventive compounds
Figure PCTCN2022136446-appb-000100
Figure PCTCN2022136446-appb-000100
Figure PCTCN2022136446-appb-000101
Figure PCTCN2022136446-appb-000101
注：以上药代动力学数据由平均血浆浓度-时间数据利用Phoenix WinNonlin 8.1(非房室模型)计算得出，NA表示通过该模型未测出。Note: The above pharmacokinetic data are calculated from the average plasma concentration-time data using Phoenix WinNonlin 8.1 (non-compartmental model), and NA means not detected by this model.
结论：本发明化合物通过前药改造，获得比氟维司群更好的口服生物利用度。Conclusion: The compound of the present invention obtains better oral bioavailability than fulvestrant through prodrug modification.

Claims (25)

  1. 一种通式(I)所示的化合物或其药学上可接受的盐，A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022136446-appb-100001
    Figure PCTCN2022136446-appb-100001
    其中，in,
    R 1和R 2相同或不同，且各自独立地选自氢及以下三种结构，其中R 1、R 2不同时为氢： R 1 and R 2 are the same or different, and are independently selected from hydrogen and the following three structures, wherein R 1 and R 2 are not hydrogen at the same time:
    ·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100002
    Figure PCTCN2022136446-appb-100002
    其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
    Figure PCTCN2022136446-appb-100003
    其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；     Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
    Figure PCTCN2022136446-appb-100003
    Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
    ·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100004
    Figure PCTCN2022136446-appb-100004
    其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
    Figure PCTCN2022136446-appb-100005
    其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基；     Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
    Figure PCTCN2022136446-appb-100005
    Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
    ·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
    Figure PCTCN2022136446-appb-100006
    Figure PCTCN2022136446-appb-100006
    其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b 不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
    Figure PCTCN2022136446-appb-100007
    其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。     Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not both hydrogen, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
    Figure PCTCN2022136446-appb-100007
    Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  2. 根据权利要求1所述的通式(I)所示的化合物或其药学上可接受的盐，The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1,
    其中：in:
    R 1为氢； R 1 is hydrogen;
    R 2选自： R2 is selected from:
    ·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100008
    Figure PCTCN2022136446-appb-100008
    其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
    Figure PCTCN2022136446-appb-100009
    其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；     Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
    Figure PCTCN2022136446-appb-100009
    Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
    ·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100010
    Figure PCTCN2022136446-appb-100010
    其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
    Figure PCTCN2022136446-appb-100011
    其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基；     Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
    Figure PCTCN2022136446-appb-100011
    Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
    ·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
    Figure PCTCN2022136446-appb-100012
    Figure PCTCN2022136446-appb-100012
    其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b 不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
    Figure PCTCN2022136446-appb-100013
    其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。     Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not hydrogen at the same time, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
    Figure PCTCN2022136446-appb-100013
    Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  3. 根据权利要求1所述的通式(I)所示的化合物或其药学上可接受的盐，The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1,
    其中：in:
    R 2为氢； R is hydrogen;
    R 1选自： R1 is selected from:
    ·含有双杂原子或非杂原子的二酰基形式：Diacyl forms containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100014
    Figure PCTCN2022136446-appb-100014
    其中，n 1为0至10的整数；n 2为0至10的整数；X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3a为
    Figure PCTCN2022136446-appb-100015
    其中R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；     Wherein, n 1 is an integer from 0 to 10; n 2 is an integer from 0 to 10; X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3a is
    Figure PCTCN2022136446-appb-100015
    Wherein R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups;
    ·含有双杂原子或非杂原子的如下所示的酰基形式：- Acyl forms as shown below containing diheteroatoms or non-heteroatoms:
    Figure PCTCN2022136446-appb-100016
    Figure PCTCN2022136446-appb-100016
    其中，n 3为0至10的整数；n 4为0至10的整数；X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-；R 3b为
    Figure PCTCN2022136446-appb-100017
    其中R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基；R 6选自C 1-C 6烷基；     Wherein, n 3 is an integer from 0 to 10; n 4 is an integer from 0 to 10; X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-; R 3b is
    Figure PCTCN2022136446-appb-100017
    Wherein R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups; R 6 is selected from C 1 -C 6 alkyl groups;
    ·含有单杂原子或非杂原子的二酰基形式：· Diacyl forms containing a single heteroatom or non-heteroatom:
    Figure PCTCN2022136446-appb-100018
    Figure PCTCN2022136446-appb-100018
    其中，n 5为0至10的整数；n 6为0至10的整数；Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b 不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基；R 3c为
    Figure PCTCN2022136446-appb-100019
    其中R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。     Wherein, n 5 is an integer from 0 to 10; n 6 is an integer from 0 to 10; Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein R a and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, and R a and R b are not hydrogen at the same time, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl ; R 3c is
    Figure PCTCN2022136446-appb-100019
    Wherein R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  4. 根据权利要求1或2所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IIA)或通式(IIB)所示的化合物或其药学上可接受的盐，The compound represented by general formula (I) or its pharmaceutically acceptable salt according to claim 1 or 2, which is the compound represented by general formula (IIA) or general formula (IIB) or its pharmaceutically acceptable of salt,
    Figure PCTCN2022136446-appb-100020
    Figure PCTCN2022136446-appb-100020
    其中，in,
    n 1为0至10的整数； n 1 is an integer from 0 to 10;
    n 2为0至10的整数； n 2 is an integer from 0 to 10;
    X 1和Y 1各自独立地选自-CH 2-、-S-、-O-或-Se-； X 1 and Y 1 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
    R 4a和R 5a相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 R 4a and R 5a are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  5. 根据权利要求4所述的通式(I)所示的化合物或其药学上可接受的盐，其中，-X 1-Y 1-选自-CH 2-CH 2-或-S-S-。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein -X 1 -Y 1 - is selected from -CH 2 -CH 2 - or -SS-.
  6. 根据权利要求4或5所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 1为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，进一步优选1。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably 1 to 5 An integer of , more preferably 1 or 2, further preferably 1.
  7. 根据权利要求4至6中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 2为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选 1或2，进一步优选1。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more An integer of 1 to 5 is preferable, 1 or 2 is more preferable, and 1 is still more preferable.
  8. 根据权利要求4至7中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，R 4a和R 5a相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 7, wherein R 4a and R 5a are the same or different, and are each independently selected from C 5 -C 20 straight chain or branched chain alkyl, preferably C 10 -C 20 straight chain or branched chain alkyl, more preferably C 15 -C 20 straight chain or branched chain alkyl, especially preferably straight chain pentadecane base.
  9. 根据权利要求1或2所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IIIA)或通式(IIIB)所示的化合物或其药学上可接受的盐：The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (IIIA) or general formula (IIIB) or a pharmaceutically acceptable salt thereof the salt:
    Figure PCTCN2022136446-appb-100021
    Figure PCTCN2022136446-appb-100021
    其中，in,
    n 3为0至10的整数； n 3 is an integer from 0 to 10;
    n 4为0至10的整数； n 4 is an integer from 0 to 10;
    X 2和Y 2各自独立地选自-CH 2-、-S-、-O-或-Se-； X 2 and Y 2 are each independently selected from -CH 2 -, -S-, -O- or -Se-;
    R 4b和R 5b相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基； R 4b and R 5b are the same or different, and are each independently selected from C 2 -C 20 straight or branched chain alkyl groups;
    R 6选自C 1-C 6烷基。 R 6 is selected from C 1 -C 6 alkyl.
  10. 根据权利要求9所述的通式(I)所示的化合物或其药学上可接受的盐，其中，-X 2-Y 2-选自-CH 2-CH 2-或-S-S-。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, wherein -X 2 -Y 2 - is selected from -CH 2 -CH 2 - or -SS-.
  11. 根据权利要求9或10所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 3为1至10的整数，优选1至8的整数，更优选1至5的整数。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 9 or 10, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more preferably 1 to 5 an integer of .
  12. 根据权利要求9至11中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 4为1至10的整数，优选1至8的整数，更优选1至5的整数。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 11, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more An integer of 1 to 5 is preferred.
  13. 根据权利要求9至12中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，R 6为甲基、乙基、丙基、丁基，优选甲基。 According to the compound represented by general formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, wherein, R is methyl, ethyl, propyl, butyl, preferably methyl base.
  14. 根据权利要求9至13中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，R 4b和R 5b相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 13, wherein R 4b and R 5b are the same or different, and are each independently selected from C 5 -C 20 straight chain or branched chain alkyl, preferably C 10 -C 20 straight chain or branched chain alkyl, more preferably C 15 -C 20 straight chain or branched chain alkyl, especially preferably straight chain pentadecane base.
  15. 根据权利要求1或2所述的通式(I)所示的化合物或其药学上可接受的盐，其为通式(IVA)或通式(IVB)所示的化合物或其药学上可接受的盐：The compound represented by general formula (I) or its pharmaceutically acceptable salt according to claim 1 or 2, which is the compound represented by general formula (IVA) or general formula (IVB) or its pharmaceutically acceptable the salt:
    Figure PCTCN2022136446-appb-100022
    Figure PCTCN2022136446-appb-100022
    其中，in,
    n 5为0至10的整数； n 5 is an integer from 0 to 10;
    n 6为0至10的整数； n 6 is an integer from 0 to 10;
    Z选自-CR aR b-、-NR c-、-O-、-S-，其中R a和R b各自独立地选自氢、烷基、环烷基、芳基或杂芳基，并且R a和R b不同时为氢，R c选自氢、烷基、环烷基、芳基或杂芳基； Z is selected from -CR a R b -, -NR c -, -O-, -S-, wherein Ra and R b are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, And R a and R b are not hydrogen at the same time, R c is selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
    R 4c和R 5c相同或不同，且各自独立地选自C 2-C 20的直链或支链烷基。 R 4c and R 5c are the same or different, and are each independently selected from C 2 -C 20 linear or branched chain alkyl groups.
  16. 根据权利要求15所述的通式(I)所示的化合物或其药学上可接受的盐，其中，Z选自-CR aR b-；R a为氢；R b为C 1-C 6烷基，优选甲基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein Z is selected from -CR a R b -; R a is hydrogen; R b is C 1 -C 6 Alkyl, preferably methyl.
  17. 根据权利要求15所述的通式(I)所示的化合物或其药学上可接受的盐，其中，Z选自-NR c-、-S-或-O-；R c为氢或C 1-C 6烷基，优选甲基；Z优选自-S-或-O-，进一步优选-O-。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein Z is selected from -NR c -, -S- or -O-; R c is hydrogen or C 1 -C 6 alkyl, preferably methyl; Z is preferably selected from -S- or -O-, more preferably -O-.
  18. 根据权利要求15至17中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 5为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，更优选1。 According to the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 17, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more An integer of 1 to 5 is preferable, 1 or 2 is more preferable, and 1 is more preferable.
  19. 根据权利要求15至18中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，n 6为1至10的整数，优选1至8的整数，更优选1至5的整数，更优选1或2，更优选1。 The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 18, wherein n is an integer of 1 to 10, preferably an integer of 1 to 8, more An integer of 1 to 5 is preferable, 1 or 2 is more preferable, and 1 is more preferable.
  20. 根据权利要求15至19中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其中，R 4c和R 5c相同或不同，且各自独立地选自C 5-C 20的直链或支链烷基，优选C 10-C 20的直链或支链烷基，更优选C 15-C 20的直链或支链烷基，特别优选直链十五烷基。 The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 19, wherein R 4c and R 5c are the same or different, and are each independently selected from C 5 -C 20 straight chain or branched chain alkyl, preferably C 10 -C 20 straight chain or branched chain alkyl, more preferably C 15 -C 20 straight chain or branched chain alkyl, especially preferably straight chain pentadecane base.
  21. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，其选自：The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, which is selected from:
    Figure PCTCN2022136446-appb-100023
    Figure PCTCN2022136446-appb-100023
    Figure PCTCN2022136446-appb-100024
    Figure PCTCN2022136446-appb-100024
    Figure PCTCN2022136446-appb-100025
    Figure PCTCN2022136446-appb-100025
    Figure PCTCN2022136446-appb-100026
    Figure PCTCN2022136446-appb-100026
  22. 根据权利要求1至21中任一项所述的通式(I)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The preparation method of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, which comprises the following steps:
    当R 1为氢时： When R1 is hydrogen:
    Figure PCTCN2022136446-appb-100027
    Figure PCTCN2022136446-appb-100027
    式Ia的化合物与氟维司群在碱性条件下在缩合剂存在下发生反应得到通式(I)所示的化合物；The compound of formula Ia reacts with fulvestrant in the presence of a condensing agent under alkaline conditions to obtain the compound shown in general formula (I);
    所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
    所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
    其中R 2如权利要求1所定义。 wherein R 2 is as defined in claim 1.
  23. 根据权利要求1至21中任一项所述的通式(I)所示的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：The preparation method of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, which comprises the following steps:
    当R 2为氢时： When R2 is hydrogen:
    Figure PCTCN2022136446-appb-100028
    Figure PCTCN2022136446-appb-100028
    式Ib的化合物与化合物g在碱性条件下在缩合剂的存在下发生反应得到式Ic的化合物；式Ic的化合物在酸性条件下脱除保护基，得到通式(I)所示的化合物；The compound of formula Ib reacts with compound g in the presence of a condensing agent under alkaline conditions to obtain a compound of formula Ic; the compound of formula Ic removes the protecting group under acidic conditions to obtain a compound shown in general formula (I);
    所述碱性条件选自吡啶类化合物、三级胺类化合物，优选DIPEA、DMAP、N-甲基吗啉、三乙胺中的一种或两种以上；The basic conditions are selected from pyridine compounds and tertiary amine compounds, preferably one or more of DIPEA, DMAP, N-methylmorpholine and triethylamine;
    所述缩合剂选自酸酐、酰卤、酰氯化试剂、碳二亚胺类化合物、碳鎓盐、鏻鎓盐、有机磷类缩合剂，优选EDCI、DCC、HATU、T3P、氯化亚砜中的一种或两种以上；The condensing agent is selected from acid anhydrides, acyl halides, acyl chloride reagents, carbodiimide compounds, carbonium salts, phosphonium onium salts, organic phosphorus condensing agents, preferably EDCI, DCC, HATU, T3P, and thionyl chloride one or more of
    所述酸性条件优选TFA；The acidic condition is preferably TFA;
    其中R x为羟基保护基，优选Boc基团或叔丁基二甲基硅烷基或三异丙基硅基或苄基； Wherein R x is a hydroxyl protecting group, preferably a Boc group or a tert-butyldimethylsilyl group or a triisopropylsilyl group or a benzyl group;
    其中R 1如权利要求1所定义。 wherein R 1 is as defined in claim 1.
  24. 一种药物组合物，其含有根据权利要求1至21中任一项所述的通式(I)所示的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。A pharmaceutical composition, which contains the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, and a pharmaceutically acceptable carrier or excipient .
  25. 根据权利要求1至21中任一项所述的通式(I)所示的化合物或其药学上可接受的盐或根据权利要求24所述的药物组合物在制备用于治疗乳腺癌的药物中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 24 are used in the preparation of a medicament for the treatment of breast cancer use in .
PCT/CN2022/136446 2021-12-06 2022-12-05 Fulvestrant derivative, and preparation method therefor and medical use thereof WO2023103929A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715456A (en) * 2014-08-12 2017-05-24 莫纳什大学 Lymph directing prodrugs
CN108137482A (en) * 2015-09-08 2018-06-08 莫纳什大学 Orient the prodrug of lymph
WO2019046491A1 (en) * 2017-08-29 2019-03-07 Ariya Therapeutics, Inc. Lymphatic system-directing lipid prodrugs
WO2019224790A2 (en) * 2018-05-24 2019-11-28 Kashiv Biosciences, Llc Prodrugs of fulvestrant
WO2021100029A2 (en) * 2019-11-24 2021-05-27 Kashiv Biosciences, Llc Prodrugs of fulvestrant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715456A (en) * 2014-08-12 2017-05-24 莫纳什大学 Lymph directing prodrugs
CN108137482A (en) * 2015-09-08 2018-06-08 莫纳什大学 Orient the prodrug of lymph
WO2019046491A1 (en) * 2017-08-29 2019-03-07 Ariya Therapeutics, Inc. Lymphatic system-directing lipid prodrugs
WO2019224790A2 (en) * 2018-05-24 2019-11-28 Kashiv Biosciences, Llc Prodrugs of fulvestrant
WO2021100029A2 (en) * 2019-11-24 2021-05-27 Kashiv Biosciences, Llc Prodrugs of fulvestrant

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