CN114591201A - Beta-elemene derivative with HDACI pharmacophore and preparation method and application thereof - Google Patents

Beta-elemene derivative with HDACI pharmacophore and preparation method and application thereof Download PDF

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CN114591201A
CN114591201A CN202210185507.3A CN202210185507A CN114591201A CN 114591201 A CN114591201 A CN 114591201A CN 202210185507 A CN202210185507 A CN 202210185507A CN 114591201 A CN114591201 A CN 114591201A
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beta
elemene
compound
derivative
pharmacophore
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谢恬
叶向阳
高园
卓晓韬
何兴瑞
白仁仁
党夏雯
叶杨
罗欣雨
向欢
林颖
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Hangzhou Normal University
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Priority to PCT/CN2022/132521 priority patent/WO2023160039A1/en
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Abstract

The invention discloses a beta-elemene derivative with HDACI pharmacophore and a preparation method and application thereof. The invention provides a beta-elemene derivative with HDACI pharmacophore shown in formula (I), a pharmaceutical composition and a hydrate containing the compound shown in formula (I), and an isotope derivative, a chiral isomer, a variant, different salts, a prodrug, a preparation and the like of the compound. The invention also provides the drug effect group with HDACIThe preparation method and the application of the beta-elemene derivatives, and the proliferation inhibition activity of the compounds on various tumor cell strains. The beta-elemene derivative with HDACI pharmacophore is expected to become candidate antitumor drugs for treating various cancers, such as solid tumors, blood tumors and the like.

Description

Beta-elemene derivative with HDACI pharmacophore and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of beta-elemene derivatives, and particularly relates to a beta-elemene derivative with HDACI (histone deacetylase inhibitor) pharmacophore as well as a preparation method and application thereof.
Background
Elemene is a sesquiterpene compound extracted from Curcuma wenyujin Y.H.Chen et C.Ling of Zingiberaceae, and has broad-spectrum antitumor activity. At present, elemene oral emulsion/injection is approved by the country as a new class-two anti-cancer drug and is widely applied clinically. However, the structure of the terpene volatile oil only contains two elements of carbon and hydrogen, belongs to terpene volatile oil, has the defects of poor water solubility, difficult absorption by organisms, low bioavailability, limited activity of inhibiting the proliferation of tumor cells in vitro and the like, and limits the maximum clinical application of the terpene volatile oil. Therefore, it is necessary to modify the structure of (-) -beta-elemene, the main active ingredient in elemene, to improve water solubility, to improve bioactivity and bioavailability, and to enhance the clinical antitumor effect.
It is reported in the literature that the derivatization of beta-elemene is mainly by allylic halogenSynthesizing beta-elemene chloride, then performing bimolecular nucleophilic substitution reaction (SN)2Reaction), and introducing polar groups such as hydroxyl, amino and the like on the premise that the beta-elemene skeleton and double bonds thereof are not damaged. Currently, β -elemene derivatives are broadly classified into amines, esters, amino acids, ethers, alcohols, glycosides, and organometallic complexes according to the difference of substituents. Although there are many research reports on the structural modification of beta-elemene, no report is found on the design and synthesis of a single anti-tumor molecule (i.e., a fusion drug) based on the synergistic effect of the combination of beta-elemene and other anti-cancer drugs.
Histone Deacetylases (HDACs) are closely associated with tumor development and regulate gene transcription and chromatin remodeling mainly by catalyzing the deacetylation of histone N-terminal lysine residues. In addition, HDACs may also catalyze the deacetylation of non-histones, such as p21, tubulin, HSP90(Heat shock protein 90), and the like. Research shows that inhibiting HDACs can induce tumor cell cycle arrest, differentiation and apoptosis. Therefore, HDACi has become a current research hotspot as an antitumor agent. Meanwhile, based on the synergistic antitumor effect of HDACi and other anticancer drugs, the design and synthesis of single-molecule fusion drugs have become the subject of controversy of research by scientists in recent years.
The invention provides a method for designing and fusing beta-elemene and HDACI into a single anti-tumor molecule, (1) by introducing a polar HDACI pharmacophore, the physicochemical characteristics, water solubility and oral absorption availability of the beta-elemene can be improved to a great extent; (2) hopefully, the anti-tumor mechanism of beta-elemene which confuses people for a long time is clear; (3) is expected to develop a new generation of new anticancer drugs with the antitumor effect superior to that of beta-elemene; (4) compared with the prior art that only simple structural modification is carried out on the beta-elemene, the research work is pioneering.
Disclosure of Invention
The first purpose of the invention is to provide a kind of beta-elemene derivatives with HDACI pharmacophore aiming at the defects of the prior art.
1. Beta-elemene derivative with HDACI pharmacophore, or optical isomer, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof, wherein the structure of the derivative is shown as formula (I):
Figure BDA0003523178870000011
wherein:
Figure BDA0003523178870000021
L1each independently selected from one of the following structural fragments:
Figure BDA0003523178870000022
Figure BDA0003523178870000023
L2each independently selected from one of the following structural fragments:
Figure BDA0003523178870000024
wherein N is any one of natural numbers of 4-6, and X is C or N;
L3selected from one of the following structural fragments:
Figure BDA0003523178870000025
preferably, the beta-elemene derivative with the histone deacetylase inhibitor pharmacophore is any one of compounds 1-48 shown in the following structures:
Figure BDA0003523178870000031
Figure BDA0003523178870000041
the second purpose of the invention is to provide a preparation method of the beta-elemene derivative with HDACI pharmacophore. 1. For the beta-elemene derivative with HDACI pharmacophore with the structure of formula (I), the synthetic route I can be adopted:
Figure BDA0003523178870000042
wherein L is1Each independently selected from one of the following structural fragments:
Figure BDA0003523178870000051
Figure BDA0003523178870000052
L2each independently selected from one of the following structural fragments:
Figure BDA0003523178870000053
wherein n is any natural number from 4 to 6;
L3selected from the following structural fragments:
Figure BDA0003523178870000054
the method specifically comprises the following steps:
(1) the compound
Figure BDA0003523178870000055
Halogenated reaction to obtain intermediate
Figure BDA0003523178870000056
(2) Will contain a nitrogen heteroatom functional group1Structure-fragmenting Compound L1(Boc)2/HL1Boc is connected to a halogenated product intermediate at 13-site or 14-site of beta-elemene through nucleophilic substitution reaction to obtain an intermediate containing Boc, and then the intermediate is subjected to deprotection to obtain an intermediate containing L1Intermediates of structural fragments
Figure BDA0003523178870000057
(4) Will contain L1Intermediates of structural fragments
Figure BDA0003523178870000058
And contain L2And L3Intermediate HO-L of structural fragment2-L3-THP is subjected to amide condensation to obtain beta-elemene derivatives or intermediates with HDACI pharmacophore
Figure BDA0003523178870000059
Further performing deprotection to obtain the beta-elemene derivative with HDACI pharmacophore shown in (I);
2. for the beta-elemene derivative with HDACI pharmacophore of formula (I), the second synthetic route can be adopted:
Figure BDA00035231788700000510
wherein L is1Each independently selected from one of the following structural fragments:
Figure BDA00035231788700000511
Figure BDA00035231788700000512
L2selected from the following structural fragments:
Figure BDA0003523178870000061
wherein n is any natural number from 4 to 6;
L3selected from one of the following structural fragments:
Figure BDA0003523178870000062
the method specifically comprises the following steps:
(1) step (1) of referring to route one;
(2) a step (2) of referring to a route one;
(3) will contain L1Intermediates of structural fragments
Figure BDA0003523178870000063
And contain L2Compounds of the structural fragment
Figure BDA0003523178870000064
By amide condensation reaction followed by ester hydrolysis to give L1And L2Compounds of the structural fragment
Figure BDA0003523178870000065
(4) Will contain L1And L2Compounds of the structural fragment
Figure BDA0003523178870000066
And contain L3The acid of the structural fragment is subjected to substitution reaction to obtain amide condensation reaction, and the beta-elemene derivative with HDACI pharmacophore shown in the (I) is obtained;
3. for the beta-elemene derivative with HDACI pharmacophore with the structure of formula (I), the third synthetic route can be adopted:
Figure BDA0003523178870000067
wherein L is1Each independently selected from one of the following structural fragments:
Figure BDA0003523178870000068
Figure BDA0003523178870000069
L2each independently selected from one of the following structural fragments:
Figure BDA00035231788700000610
x is C or N;
L3selected from one of the following structural fragments:
Figure BDA00035231788700000611
the method specifically comprises the following steps:
(1) step (1) of referring to route one;
(2) a step (2) of referring to a route one;
(3) will contain L1Intermediates of structural fragments
Figure BDA00035231788700000612
And contain L2And L2Compound of structural fragment Cl-L2-L3-THP is substituted to give L1、L2And L3Compounds of the structural fragment
Figure BDA0003523178870000071
Deprotection to obtain beta-elemene derivative with HDACI pharmacophore shown in (I);
the compound represented by the formula (I) of the present invention can be produced by the above method, however, the conditions of the method, such as reactants, solvent, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the above explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Step (1) of each synthetic route of the present invention may be carried out by the methods known in the art, for example, as disclosed in publication No. CN 110683932A.
The third purpose of the invention is to provide the application of the beta-elemene derivative with the HDACI pharmacophore, or the optical isomer, the racemate, the single enantiomer, the possible diastereoisomer, or the pharmaceutically acceptable salt, the prodrug, the deuterated derivative, the hydrate and the solvate thereof in preparing the drugs for treating or preventing tumors.
The fourth purpose of the invention is to provide an anti-tumor drug, which contains safe and effective dose of the beta-elemene derivative with HDACI pharmacophore, or optical isomer, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof.
Preferably, the anti-tumor drug can also comprise a pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier.
Preferably, in the use and the anti-tumor medicament, the tumor comprises a solid tumor and a blood tumor.
The compound has the activity of inhibiting the proliferation of various tumor cell strains, so the compound, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving various diseases, including various cancers.
The "safe and effective amount" of the invention refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0003523178870000072
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release at a site within the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 5000mg, preferably 5 to 2000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Compared with the prior art, the invention has the main advantages that: the invention provides a beta-elemene derivative with HDACI pharmacophore shown in formula (I), a pharmaceutical composition and a hydrate containing the compound shown in formula (I), and an isotope derivative, a chiral isomer, a variant, different salts, a prodrug, a preparation and the like of the compound. The invention also provides a preparation method and application of the beta-elemene derivative with the HDACI pharmacophore, and the activity of the compounds on proliferation inhibition of various tumor cell strains. The beta-elemene derivative with HDACI pharmacophore is expected to become candidate antitumor drugs for treating various cancers, such as solid tumors, blood tumors and the like.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples are conducted under conditions not specified, usually according to conventional conditions, or according to conditions recommended by the manufacturer.
Example 1: preparation of Compound 1
Figure BDA0003523178870000091
Intermediate 1a
To a solution of β -elemene (210mg, 1.029mmol) in acetic acid (3mL) under ice-bath was added N-bromosuccinimide (NBS, 183mg, 1.029 mmol). Stirring for 6h under ice-bath conditions. TLC monitored incomplete reaction of starting material, so the reaction was warmed to room temperature and stirred overnight (25-28 ℃). After complete conversion, the reaction was quenched by slowly adding saturated sodium bicarbonate solution dropwise and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine (2 × 5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane) to give colorless oily liquid 1a (72mg, yield 25.4%).1H NMR(400MHz,CDCl3)δ5.89-5.76(m,1H),5.21(s,1H),5.04(t,J＝1.1Hz,1H),4.97-4.81(m,3H),4.59(dt,J＝1.9,0.9Hz,1H),4.04(d,J＝0.7Hz,2H),2.33-2.17(m,1H),2.06(dd,J＝12.6,3.5Hz,1H),1.74-1.70(m,3H),1.69-1.39(m,6H),1.01(s,3H)。
Intermediate 1b
(i) To a solution of intermediate 1a (168mg, 0.618mmol) in DMF (N, N-dimethylformamide, 3mL) at room temperature was added Bis (tert-butoxycarbonyl) amine (Bis (tert-butoxycarbonyl) amine) (187.75mg, 0.865mmol) and cesium carbonate (Cs)2CO3182mg, 0.558 mmol). The reaction was stirred at 60 ℃ for 10 h. After complete conversion, water (5mL) was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give a colorless oily compound for the next reaction.
(ii) To a solution of the product of (i) (100mg, 0.238mmol) in dichloromethane (3mL) under ice-bath was slowly added trifluoroacetic acid (TFA, 1.5mL) dropwise. After the dropwise addition, the reaction solution was gradually returned to room temperature and stirred for 4 hours. After complete conversion, the solvent was evaporated under reduced pressure. Water (5mL) was added to the residue and the pH was adjusted to slightly alkaline by slowly adding saturated aqueous potassium carbonate solution dropwise, followed by extraction with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the objective product 1b (47.1mg, yield 90.2%).
Intermediate 1d
(i) To a solution of compound 1c (257.2mg, 1.606mmol) in DMF (10mL) at room temperature was added NH in sequence2OTHP (225.7mg, 1.927mmol), DIPEA (622.7mg, 4.818mmol), 1-ethyl-3- (3-dimethylpropylamine) carbodiimide hydrochloride (EDCI, 800.5mg, 4.176mmol) and 1-hydroxybenzotriazole (HOBT, 317.7mg, 2.088 mmol). The reaction was stirred at room temperature for 5 h. After complete conversion, water (5mL) was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating the filtrate under reduced pressure, and subjecting the obtained crude product to silica gel column chromatography (methanol: two)Methyl chloride ═ 1: 9) purification gave the compound as a pale yellow oil (340.3mg, yield 86.4%).
(ii) To a solution of the product obtained in (i) (330mg, 1.273mmol) in methanol (3mL) was slowly added dropwise a NaOH solution (1M, 3mL) at room temperature. After dropping, the reaction mixture was stirred at room temperature for 2 hours. After complete conversion, the solvent was evaporated under reduced pressure. Water (5mL) was added to the residue and the pH was adjusted to 5-6 by slowly adding dropwise HCl (1M) solution, followed by extraction with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product 1d was directly subjected to the next reaction without purification (240.1mg, yield 77%).
Intermediate 1e
To a solution of intermediate 1b (154.3mg, 0.703mmol) in DMF (8mL) at room temperature was added 1d (189.6mg, 0.773mmol), DIPEA (272.57mg, 2.109mmol), EDCI (349.47mg, 1.823mmol) and HOBT (123.5mg, 0.914mmol) in that order. The reaction was stirred at room temperature for 5 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 4) to give compound 1e (220.1mg, yield 70.1%) as a pale yellow oil.
Compound 1
To a solution of intermediate 1e (100.2mg, 0.224mmol) in methanol (3mL) at room temperature was added p-toluenesulfonic acid monohydrate (TsOH. H)2O, 101.5mg, 0.528 mmol). The reaction was stirred at room temperature for 8 h. After complete conversion, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution and water (4mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by C18 column chromatography (acetonitrile: water: 2: 3) to obtain colorless oily liquid 1(51.2mg, yield 63.1%).1H NMR(500MHz,CDCl3)δ6.78(t,J＝5.9Hz,1H),5.80(dd,J＝17.7,10.5Hz,1H),4.97-4.84(m,4H),4.81(s,1H),4.57(s,1H),3.82(d,J＝5.6Hz,2H),2.22(d,J＝40.7Hz,4H),2.04-1.89(m,2H),1.69(s,3H),1.68-1.52(m,7H),1.52-1.39(m,3H),0.99(s,3H)。13C NMR(126MHz,CDCl3)δ173.76,171.43,150.40,150.00,147.41,112.29,110.07,108.18,52.65,42.99,42.69,39.87,39.77,35.87,33.08,32.33,27.21,24.97,24.92,24.87,16.61。LCMS[M+H]+:363.2。
Example 2: preparation of Compound 2
Figure BDA0003523178870000101
Referring to the procedure for the synthesis of intermediate 1d in example 1, compound 2b (252mg, yield 70.9%) was obtained.
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to give compound 2c (130mg, 80.1%).
Referring to the last synthesis step in example 1, colorless oily liquid 2 was obtained in yield: 58.9 percent.1H NMR(500MHz,CDCl3)δ6.35(s,1H),5.80(dd,J＝17.7,10.5Hz,1H),4.95-4.87(m,3H),4.86(s,1H),4.82(t,J＝1.7Hz,1H),4.57(d,J＝1.9Hz,1H),3.85(d,J＝5.6Hz,2H),2.29-2.11(m,4H),2.04-1.90(m,2H),1.70(s,3H),1.68-1.53(m,5H),1.52-1.40(m,3H),1.40-1.24(m,4H),0.99(s,3H)。13C NMR(126MHz,CDCl3)δ173.67,171.44,150.52,149.99,147.40,112.27,110.06,108.32,52.67,43.00,42.72,39.85,39.77,36.16,33.11,32.36,27.20,25.08,24.89,24.84,16.61。LCMS[M+H]+:377.2。
Example 3: preparation of Compound 3
Figure BDA0003523178870000111
Referring to the procedure for the synthesis of intermediate 1d in example 1, compound 3b (216.4mg, 77% yield) was obtained.1H NMR(400MHz,CDCl3)δ8.90(s,1H),4.95(s,1H),3.97(t,J＝10.2Hz,1H),3.65(dd,J＝10.9,5.4Hz,1H),2.34(t,J＝7.4Hz,2H),2.12(t,J＝7.4Hz,2H),1.91-1.74(m,3H),1.63(ttd,J＝18.5,13.0,11.4,5.6Hz,7H),1.35(p,J＝3.9Hz,4H)。
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to give compound 3c (140mg, 80.1%).
Reference was made to the last synthesis in example 1, except that the crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 9) to give compound 3 as a rust red oil (59.6mg, yield 72.3%).1H NMR(500MHz,CDCl3)δ6.35(s,1H),5.80(dd,J＝17.7,10.5Hz,1H),5.00-4.79(m,5H),4.57(s,1H),3.85(d,J＝5.6Hz,2H),2.23(t,J＝7.2Hz,2H),2.16(s,2H),2.05-1.89(m,2H),1.70(s,3H),1.69-1.22(m,14H),0.99(s,3H)。13C NMR(126MHz,CDCl3)δ173.67,171.44,150.52,149.99,147.40,112.27,110.06,108.32,77.23,52.67,43.00,42.72,39.81(d,J＝10.8Hz),36.16,33.11,32.36,28.32,27.20,25.08,24.87(d,J＝5.4Hz),16.61。LCMS[M+H]+:391.6。
Example 4: preparation of Compound 4
Figure BDA0003523178870000112
Intermediate 4a
(i) To a solution of intermediate 1a (114.3mg, 0.404mmol) in DMF (3mL) at room temperature was added N-tert-butoxycarbonylpiperazine (1-Boc-piperazine) (90.3mg, 0.485mmol) and N, N-diisopropylethylamine (DIPEA, 157.96mg, 0.485mmol) in that order. The reaction was stirred at 60 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give a colorless oily compound (88mg, 56.2%) which was used in the next reaction.
(ii) Referring to the synthesis procedure (ii) of intermediate 1b in example 1, Compound 4a was obtained as a pale yellow oil (56mg, yield 85.7%).1H NMR(400MHz,CD3OD)δ5.80(dd,J＝17.6,10.8Hz,1H),4.98(d,J＝6.1Hz,2H),4.85-4.82(m,1H),4.78(s,1H),4.58(d,J＝15.1Hz,2H),3.17(t,J＝5.2Hz,4H),3.01(d,J＝2.8Hz,2H),2.58(s,4H),2.08(m,1H),2.00(dd,J＝12.4,3.7Hz,1H),1.68(s,3H),1.62(m,2H),1.58-1.45(m,3H),1.45-1.38(m,1H),0.99(s,3H)。LCMS[M+H]+:289.6。
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to give compound 4b (120mg, 83.4%).
Referring to the last synthesis step in example 1, a rust red oily liquid compound 4 was obtained in yield: 70.3 percent.1H NMR(500MHz,CDCl3)δ8.29(s,1H),5.80(dd,J＝17.8,10.5Hz,1H),5.12(d,J＝10.0Hz,2H),4.96-4.86(m,2H),4.82(s,1H),4.57(s,1H),3.68(d,J＝46.1Hz,4H),3.28(d,J＝15.4Hz,2H),2.76(d,J＝40.0Hz,4H),2.36(t,J＝6.6Hz,2H),2.20(t,J＝5.9Hz,2H),2.04(ddd,J＝37.4,12.2,6.2Hz,2H),1.70(s,3H),1.69-1.35(m,10H),0.99(s,3H)。13C NMR(126MHz,CDCl3)δ171.96,166.12,149.99,147.48,147.05,115.06,112.21,110.07,62.15,52.58(d,J＝18.0Hz),52.05,44.13,41.63,40.26,39.76(d,J＝2.0Hz),33.08,32.38,29.69,27.14,24.82(d,J＝11.0Hz),24.19,16.55。LCMS[M+H]+:432.2。
Example 5: preparation of Compound 5
Figure BDA0003523178870000121
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to give compound 5a (138mg, 85.2%).
Referring to the last synthesis step in example 1, except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 2: 3) to give colorless oily liquid 5, yield: 60.7 percent.1H NMR(500MHz,CDCl3)δ5.82(dd,J＝17.4,10.9Hz,1H),5.00-4.87(m,4H),4.82(t,J＝1.9Hz,1H),4.58(d,J＝2.0Hz,1H),3.59(s,2H),3.45(s,2H),2.93(q,J＝13.5Hz,2H),2.48-1.97(m,10H),1.71(s,3H),1.69-1.39(m,6H),1.38-1.19(m,6H),1.01(s,3H)。13C NMR(126MHz,CDCl3)δ150.23,112.12,111.26,109.91,76.79,63.29,52.90,52.73,45.69,42.07,41.79,41.69,39.97,39.88,33.30,31.65,29.70,29.66,27.23,24.85,16.61。LCMS[M+H]+:446.2。
Example 6: preparation of Compound 6
Figure BDA0003523178870000122
Referring to the procedure for the synthesis of intermediate 1e in example 1, Compound 6a (100mg, 84.3%) was obtained.
Referring to the last synthesis step in example 1, rust red oily liquid compound 6 was obtained in yield: 73.2 percent. 1H NMR (400MHz, CD3OD) δ 5.86(dd, J ═ 17.6,10.8Hz,1H),5.01(d, J ═ 3.1Hz,2H),4.94(s,1H),4.88(s,1H),4.84(s,1H),4.62(d, J ═ 1.9Hz,1H),3.59(dt, J ═ 14.3,5.0Hz,4H),3.08-2.96(m,2H),2.50-2.36(m,6H),2.21-2.03(m,4H),1.74(s,3H),1.72-1.35(m,14H),1.05(s, 3H). LCMS [ M + H ] +: 460.8.
Example 7: preparation of Compound 13
Figure BDA0003523178870000131
Intermediate 13a
To beta-elemene (3.8g, 18.627mmoL) in dichloromethane (25mL) and glacial acetic acid (CH) under ice bath3CO2H, 22mL), tetrabutylammonium fluoride (TBAF, 0.06mL, 0.060mmoL) was added, and then an aqueous NaClO solution (28mL, 84mmoL) was slowly added over 5H using a constant pressure dropping funnel. After the addition, the mixture was kept at 0 ℃ and stirred for 1 hour. After complete conversion, the reaction was quenched with 10% aqueous sodium sulfite (40mL) and saturated aqueous sodium bicarbonate (20mL), and extracted with ethyl acetate (3X 50 mL). The combined organic phases were washed with saturated brine (2X 50mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (100% petroleum ether) to give compound 13a (1.84g, yield 37%) as a colorless liquid.1H NMR(400MHz,CDCl3)δ5.79(dd,J＝17.2,11.1Hz,1H),5.28(s,1H),5.18(s,1H),5.04(s,1H),4.99-4.89(m,3H),4.13-4.08(m,3H),3.98(d,J＝11.7Hz,1H),2.36-2.21(m,2H),1.78-1.40(m,6H),0.99(s,3H)。
Intermediate 13b
To a solution of intermediate 13a (168mg, 0.618mmol) in DMF (3mL) at room temperature was added Cs in sequence2CO3(182mg, 0.558mmol) and Bis (tert-butoxycarbonyl) amine (Bis (tert-butoxycarbonyl) amine) (187.75mg, 0.865 mmol). The reaction was stirred at 50 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give compound 13b (210mg, yield 74.9%) as a colorless oily substance.1H NMR(400MHz,CDCl3)5.83-5.73(m,1H),5.26(d,J＝1.0Hz,1H),4.98-4.86(m,4H),4.77(s,1H),4.20(d,J＝1.7Hz,2H),3.96(dd,J＝11.6,0.8Hz,1H),2.98-2.87(m,1H),2.31-2.20(m,1H),2.00(dd,J＝11.1,4.0Hz,1H),1.74-1.61(m,3H),1.59-1.50(m,2H),1.48(s,18H),1.46-1.41(m,1H),0.98(s,3H)。
Intermediate 13c
(i) To a solution of intermediate 13b (70mg, 0.155mmol) in DMF (3mL) at room temperature was added Cs in sequence2CO3(75.75mg, 0.233mmol) and pyrazole (15.86mg, 0.233 mmol). The reaction was stirred at 60 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 3) to give a colorless oily compound (57mg, 75.77%) which was used in the step (ii) of the reaction.1H NMR(400MHz,CDCl3)7.50(d,J＝1.8Hz,1H),7.31(d,J＝2.3Hz,1H),6.25(t,J＝2.1Hz,1H),5.83(dd,J＝17.4,10.8Hz,1H),5.05-4.96(m,2H),4.85(d,J＝14.9Hz,2H),4.78(s,1H),4.73(dd,J＝8.8,7.0Hz,2H),4.65(d,J＝15.6Hz,1H),4.13(d,J＝1.9Hz,2H),1.94-1.80(m,2H),1.72-1.49(m,6H),1.47(s,18H),1.02(s,3H)。
(ii) Referring to step (ii) of the synthesis of intermediate 1b in example 1, compound 13c was obtained as a yellow oil in yield: 96 percent.1H NMR(400MHz,CD3OD)7.45(d,J＝2.4Hz,1H),7.39(d,J＝1.9Hz,1H),6.22(t,J＝2.1Hz,1H),5.80(dd,J＝17.4,10.9Hz,1H),5.04(s,1H),4.98-4.90(m,3H),4.83(s,1H),4.69(s,1H),4.63(s,2H),3.38(s,2H),1.96-1.77(m,2H),1.64-1.36(m,6H),0.98(s,3H)。
Referring to the synthesis of intermediate 1e in example 1, compound 13d was obtained.
Referring to the last synthesis step in example 1, except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 2: 3) to give compound 13 as colorless oil in yield: 50.6 percent.1H NMR(500MHz,CDCl3)δ7.48(d,J＝1.8Hz,1H),7.33(d,J＝2.3Hz,1H),6.25(t,J＝2.1Hz,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.04-4.95(m,2H),4.84(t,J＝5.9Hz,3H),4.67(d,J＝5.0Hz,3H),3.79(d,J＝5.3Hz,2H),2.19(d,J＝40.0Hz,4H),1.96-1.80(m,2H),1.73-1.36(m,10H),1.00(s,3H)。13C NMR(126MHz,CDCl3)δ173.54,150.18,149.34,147.43,139.13,129.85,113.93,111.41,108.73,105.73,58.73,48.08,42.99,42.30,39.81,39.65,35.87,33.33,26.88,25.02(d,J＝7.6Hz),15.81。LCMS[M+H]+:429.2。
Example 8: preparation of Compound 14
Figure BDA0003523178870000141
Referring to the synthesis of intermediate 1e in example 1, compound 14a was obtained.
Referring to the last synthesis step in example 1, except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 2: 3) to give compound 14 as colorless oil in yield: 42.8 percent.1H NMR(500MHz,CDCl3)δ7.48(s,1H),7.33(d,J＝2.3Hz,1H),6.25(t,J＝2.0Hz,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.10-4.94(m,2H),4.85(t,J＝4.1Hz,3H),4.78-4.61(m,3H),3.80(s,2H),2.32-2.06(m,4H),1.97-1.81(m,2H),1.76-1.18(m,12H),1.01(s,3H)。LCMS[M+H]+:443.2。
Example 9: preparation of Compound 15
Figure BDA0003523178870000142
Referring to the synthesis of intermediate 1e in example 1, compound 15a was obtained.
Referring to the last synthesis step in example 1, except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 2: 3) to give compound 15 as colorless oil in yield: 53.5 percent.1H NMR(500MHz,CDCl3)δ7.48(d,J＝2.0Hz,1H),7.33(d,J＝1.8Hz,1H),6.25(t,J＝2.1Hz,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.04-4.95(m,2H),4.85(d,J＝5.9Hz,3H),4.67(dd,J＝28.0,15.6Hz,3H),3.81(s,2H),2.28-2.03(m,4H),1.95-1.81(m,2H),1.72-1.16(m,14H),1.01(s,3H)。LCMS[M+H]+:457.2。
Example 10: preparation of Compound 16
Figure BDA0003523178870000151
Intermediate 16a
To a solution of intermediate 13a (225.6mg, 0.829mmol) in DMF (3mL) at room temperature were added DIPEA (139.1mg, 1.078mmol) and N-tert-butoxycarbonylpiperazine (1-Boc-piperazine) (200.8mg, 1.078mmol) in that order. The reaction was stirred at 50 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give compound 16a (221mg, yield 65%) as a colorless oily substance.1H NMR(400MHz,CDCl3)δ5.79(dd,J＝17.4,10.8Hz,1H),5.27(s,1H),4.97-4.86(m,5H),4.10(dd,J＝11.6,1.1Hz,1H),3.97(d,J＝11.7Hz,1H),3.41(t,J＝4.9Hz,4H),2.98-2.86(m,2H),2.32(q,J＝4.4,3.8Hz,4H),2.30-2.25(m,1H),2.14(ddd,J＝11.6,8.9,6.1Hz,1H),1.69-1.57(m,3H),1.57-1.47(m,3H),1.46(s,9H),0.98(s,3H)。LCMS[M+H]+:423.5。
Intermediate 16b
(i) Reference example 7 Synthesis step (i) of intermediate 13c gave a colorless oily compound (106mg, yield 78.2%) which was used in step (ii) of the reaction.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.9Hz,1H),7.33(d,J＝2.2Hz,1H),6.25(t,J＝2.1Hz,1H),5.84(dd,J＝17.4,10.8Hz,1H),5.04-4.96(m,2H),4.95-4.88(m,2H),4.87(s,1H),4.78(s,1H),4.71(d,J＝1.4Hz,1H),4.66(d,J＝15.7Hz,1H),3.39(s,4H),2.88(q,J＝13.5Hz,2H),2.36-2.25(m,4H),2.00(m,1H),1.93(dd,J＝12.7,3.4Hz,1H),1.60-1.48(m,3H),1.47-1.36(m,13H),1.03(s,3H)。LCMS[M+H]+:455.5。
(ii) Referring to step (ii) of the synthesis of intermediate 1b in example 1, compound 16b was obtained as a yellow oil in yield: 96 percent.1H NMR(400MHz,CD3OD)δ7.49(d,J＝2.0Hz,1H),7.43(d,J＝2.0Hz,1H),6.26(q,J＝2.0Hz,1H),5.83(dd,J＝17.5,10.9,1.6Hz,1H),5.00-4.94(d,2H),4.92(s,3H),4.74(s,1H),4.65(d,J＝3.9Hz,2H),3.07(t,J＝5.2Hz,4H),2.93(s,2H),2.50(s,4H),2.00-1.84(m,2H),1.64-1.51(m,2H),1.48-1.37(m,4H),1.00(d,J＝1.6Hz,3H)。
Referring to the synthesis of intermediate 1e in example 1, compound 16c was obtained.
Referring to the last synthesis in example 1, colorless oily compound 16 was obtained except that the crude product was purified by C18 column chromatography (acetonitrile: water 9: 11) with yield: 58.9 percent.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.8Hz,1H),7.34(d,J＝2.2Hz,1H),6.25(t,J＝2.1Hz,1H),5.83(dd,J＝17.4,10.8Hz,1H),5.10-4.83(m,5H),4.81-4.62(m,3H),3.57(s,2H),3.43(s,2H),2.89(q,J＝13.4Hz,2H),2.47-2.13(m,8H),2.07-1.89(m,2H),1.80-1.40(m,10H),1.03(s,3H)。13C NMR(126MHz,CDCl3)δ171.60,149.99,149.45,147.59,139.11,129.46,114.20,111.43,111.27,105.58,63.25,59.02,53.16,52.81,48.09,45.63,41.86,41.80,39.89,39.70,33.66,32.60,29.68,26.92,24.34,15.82。LCMS[M+H]+:498.0。
Example 11: preparation of Compound 17
Figure BDA0003523178870000161
Referring to the synthesis of intermediate 1e in example 1, compound 17a was obtained.
Referring to the last synthesis in example 1, colorless oily compound 17 was obtained except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 3: 2) with yield: 51.5 percent.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.9Hz,1H),7.34(d,J＝2.3Hz,1H),6.25(t,J＝2.1Hz,1H),5.84(dd,J＝17.4,10.8Hz,1H),5.06-4.95(m,2H),4.95-4.83(m,3H),4.81-4.62(m,3H),3.50(d,J＝76.2Hz,4H),2.89(q,J＝13.4Hz,2H),2.33(d,J＝8.6Hz,6H),2.26-2.13(m,2H),2.05-1.90(m,2H),1.77-1.41(m,9H),1.40-1.20(m,3H),1.03(s,3H)。LCMS[M+H]+:512.4。
Example 12: preparation of Compound 18
Figure BDA0003523178870000162
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to afford compound 18 a.
Referring to the last synthesis step in example 1, rust red oily compound 18 was obtained in yield: 68.7 percent.1H NMR(500MHz,CDCl3)δ7.51(d,J＝1.8Hz,1H),7.35(d,J＝2.3Hz,1H),6.26(t,J＝2.1Hz,1H),5.81(dd,J＝17.4,10.8Hz,1H),5.07-4.95(m,4H),4.85(s,1H),4.75-4.65(m,3H),3.78-3.46(m,4H),3.20-2.98(m,2H),2.68-2.39(m,4H),2.33(t,J＝7.4Hz,2H),2.15(t,J＝7.0Hz,2H),2.04-1.90(m,2H),1.67-1.44(m,10H),1.39-1.31(m,4H),1.03(s,3H)。13C NMR(126MHz,CDCl3)δ172.03,171.09,149.34,148.38,147.55,139.10,129.76,113.92,113.34,111.37,105.62,62.75,58.84,53.03,52.47,48.15,45.02,41.63,40.94,39.85,39.62,33.59,32.79,32.53,29.70,28.32(d,J＝19.2Hz),26.82,24.91(d,J＝18.9Hz),15.83。[M-H]-:525.0。
Example 13: preparation of Compound 25
Figure BDA0003523178870000163
Intermediate 25a
To a solution of intermediate 13a (225mg, 0.827mmol) in DMF (3mL) at room temperature was added Cs in sequence2CO3(351.56mg, 1.079mmol) and pyrazole (73.46mg, 1.079 mmol). The reaction was stirred at 45 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1: 4) to give compound 25a (191.0mg, yield 90%) as a colorless oily substance. LCMS (liquid Crystal display Module) [ M + H ]]+:305.3。
Intermediate 25b
(i) To a solution of intermediate 25a (42mg, 0.156mmol) in DMF (3mL) at room temperature was added Cs in sequence2CO3(81.40mg, 0.249mmol) and Bis (tert-butoxycarbonyl) amine (Bis (tert-butyloxycarbonyl) amine) (74.5mg, 0.343 mmol). The reaction was stirred at 80 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give a colorless oily compound (67.38mg, yield 88.9%).1H NMR(400MHz,CDCl3)δ7.51(d,J＝1.8Hz,1H),7.39(d,J＝2.2Hz,1H),6.27(t,J＝2.1Hz,1H),5.85-5.76(m,1H),5.01(s,1H),4.94(q,J＝1.3Hz,1H),4.92-4.89(m,1H),4.86(d,J＝1.8Hz,1H),4.74(d,J＝7.0Hz,4H),4.22(dt,J＝17.0,2.0Hz,1H),3.89(d,J＝17.0Hz,1H),1.94-1.83(m,2H),1.72-1.53(m,3H),1.48(s,3H),1.47(s,18H),0.99(s,3H)。
(ii) Ice bathNext, to a solution of the product of (i) (75mg, 0.155mmol) in dichloromethane (2mL) was slowly added TFA (1.5mL) dropwise. After dropping, the temperature is returned to room temperature and stirred for 4 h. After complete conversion, the solvent was evaporated under reduced pressure. Water (5mL) was added to the residue and the pH was adjusted to slightly alkaline by slowly adding saturated aqueous potassium carbonate solution dropwise, followed by extraction with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 25b (36.84mg, yield 83.6%) as a yellow oil.1H NMR(400MHz,CD3OD)δ7.45(d,J＝2.3Hz,1H),7.39(d,J＝1.8Hz,1H),6.22(t,J＝2.2Hz,1H),5.80(dd,J＝17.4,10.9Hz,1H),5.03(s,1H),5.00-4.89(m,3H),4.80-4.66(m,2H),4.63(s,2H),3.37(s,2H),1.96-1.82(m,2H),1.58(q,J＝12.7Hz,2H),1.50-1.29(m,4H),0.98(s,3H)。
Referring to the procedure for the synthesis of intermediate 1e in example 1, compound 25c was obtained.
Referring to the last synthesis step in example 1, colorless oily compound 25 was obtained in yield: 70.4 percent.1H NMR(500MHz,CDCl3)δ7.49(s,1H),7.40(d,J＝2.3Hz,1H),6.28(t,J＝2.1Hz,1H),5.76(dd,J＝17.4,10.8Hz,1H),5.08-4.62(m,8H),3.83(dd,J＝15.6,6.4Hz,1H),3.61(dd,J＝15.8,4.6Hz,1H),2.19(d,J＝28.1Hz,4H),1.93(d,J＝10.9Hz,1H),1.83(s,1H),1.72-1.38(m,10H),0.96(s,3H)。13C NMR(126MHz,CDCl3)δ173.40,149.46,149.14,147.90,139.12,129.66,112.34,111.63,110.98,106.00,56.17,48.97,46.09,41.57,39.68,39.41,35.90,33.45,32.32,26.76,24.93(d,J＝14.8Hz),16.04。LCMS[M+H]+:429.2。
Example 14: preparation of Compound 26
Figure BDA0003523178870000171
Referring to the synthesis of intermediate 1e in example 1, compound 26a was obtained.
Referring to the last synthesis step in example 1, colorless oily compound 26 was obtained except that the crude product was subjected to C18 column chromatography (B)Nitrile: water 3: 17) purification and yield: 72.5 percent.1H NMR(500MHz,CDCl3)δ7.49(s,1H),7.40(d,J＝2.2Hz,1H),6.27(s,1H),5.76(dd,J＝17.4,10.8Hz,1H),4.97(d,J＝11.2Hz,2H),4.89(dd,J＝14.2,10.5Hz,2H),4.73(q,J＝9.9,8.5Hz,4H),3.80(d,J＝17.2Hz,1H),3.63(d,J＝13.7Hz,1H),2.16(d,J＝36.6Hz,4H),1.98-1.79(m,2H),1.72-1.37(m,8H),1.36-1.20(m,4H),0.96(s,3H)。13C NMR(126MHz,CDCl3)δ173.46,149.47,149.18,147.95,139.16,129.61,111.61,110.95,105.94,56.11,49.13,45.89,41.70,39.67,39.40,36.11,33.33,29.70,26.78,16.12。LCMS[M+K]+:481.0。
Example 15: preparation of Compound 27
Figure BDA0003523178870000181
Referring to the procedure for the synthesis of intermediate 1e in example 1, compound 27a was obtained.
Referring to the last synthesis step in example 1, compound 27 was obtained as colorless oil in yield: 63.1 percent.1H NMR(400MHz,CD3OD)δ7.60(s,1H),7.46(s,1H),6.29(s,1H),5.80(dd,J＝17.3,10.4Hz,1H),5.04-4.89(m,5H),4.80-4.55(m,3H),3.78(d,J＝15.2Hz,1H),3.66-3.48(m,1H),2.17(s,2H),2.11-1.80(m,4H),1.67-1.28(m,14H),0.97(s,3H)。LCMS[M+H]+:457.7。
Example 16: preparation of Compound 28
Figure BDA0003523178870000182
Intermediate 28a
(i) To a solution of intermediate 25a (103.1mg, 0.382mmol) in DMF (3mL) was added DIPEA (64.23mg, 0.497mmol) and N-tert-butoxycarbonylpiperazine (1-Boc-piperazine) (92.5mg, 0.497mmol) sequentially at room temperature. The reaction was stirred at 80 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with brine (2X5mL) and washed withDried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 4) to give a colorless oily compound (107.6mg, yield 62%).1H NMR(400MHz,CDCl3)δ7.55(d,J＝1.8Hz,1H),7.42(d,J＝2.3Hz,1H),6.31(t,J＝2.1Hz,1H),5.80(dd,J＝17.5,10.7Hz,1H),5.06(d,J＝8.0Hz,2H),4.94-4.86(m,2H),4.80(d,J＝3.8Hz,4H),3.43(s,4H),3.06(d,J＝13.8Hz,1H),2.64(d,J＝13.7Hz,1H),2.42-2.31(m,2H),2.22(s,2H),1.91(d,J＝11.1Hz,1H),1.80(s,1H),1.69-1.56(m,2H),1.55-1.50(m,1H),1.50-1.425(m,12H),1.00(s,3H)。LCMS[M+H]+:454.9。
(ii) Reference example 13, intermediate 25b synthesis step (ii), gave compound 28a as a yellow oil (32.25mg, 96.1% yield).1H NMR(400MHz,CD3OD)δ7.62(d,J＝2.3Hz,1H),7.50(d,J＝1.9Hz,1H),6.33(t,J＝2.2Hz,1H),5.81(dd,J＝17.6,10.8Hz,1H),5.05(d,J＝15.7Hz,2H),4.89-4.85(m,2H),4.84(s,1H),4.81(d,J＝2.1Hz,2H),4.77(s,1H),3.13(d,J＝13.4Hz,1H),3.07-2.95(m,3H),2.66(d,J＝13.4Hz,1H),2.44(d,J＝49.7Hz,4H),2.23(dd,J＝12.9,3.3Hz,1H),1.90(s,2H),1.66-1.60(m,1H),1.56-1.38(m,5H),1.00(s,3H)。
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to afford compound 28 b.
Referring to the last synthesis in example 1, colorless oily compound 28 was obtained except that the crude product was purified by C18 column chromatography (acetonitrile: water ═ 2: 3) with yield: 72.5 percent.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.9Hz,1H),7.40(d,J＝2.2Hz,1H),6.27(t,J＝2.1Hz,1H),5.75(dd,J＝17.5,10.8Hz,1H),5.02(d,J＝11.3Hz,2H),4.91-4.83(m,2H),4.76(d,J＝1.8Hz,4H),3.58(s,2H),3.50-3.34(m,2H),3.02(d,J＝13.8Hz,1H),2.60(d,J＝13.8Hz,1H),2.43-2.12(m,9H),1.90(dt,J＝11.4,6.9Hz,1H),1.71-1.21(m,10H),0.96(s,3H)。13C NMR(126MHz,CDCl3)δ171.75,149.75,149.70,147.71,139.16,129.35,114.09,111.60,110.42,105.79,66.01,56.31,53.09,52.89,47.77,45.64,41.90,39.77(d,J＝7.9Hz),36.50,33.57,32.68,26.97,25.28,24.63,15.86。LCMS[M+H]+:498.1。
Example 17: preparation of Compound 29
Figure BDA0003523178870000191
Reference was made to the procedure for the synthesis of intermediate 1e in example 1 to give compound 29 a.
Referring to the last synthesis in example 1, colorless oily compound 29 was obtained except that the crude product was purified by C18 column chromatography (acetonitrile: water 1: 1) with yield: 35.8 percent.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.9Hz,1H),7.39(d,J＝2.3Hz,1H),6.27(t,J＝2.1Hz,1H),5.76(dd,J＝17.5,10.8Hz,1H),5.03(d,J＝11.0Hz,2H),4.94-4.69(m,6H),3.58(s,2H),3.43(d,J＝15.9Hz,2H),3.04(d,J＝13.7Hz,1H),2.62(d,J＝13.7Hz,1H),2.44-2.13(m,8H),2.06-1.98(m,1H),1.94-1.86(m,1H),1.76-1.29(m,12H),0.97(s,3H)。LCMS[M+H]+:512.4。
Example 18: preparation of Compound 30
Figure BDA0003523178870000192
Referring to the synthesis of intermediate 1e in example 1, compound 30a was obtained.
Referring to the last synthesis step in example 1, colorless oily compound 30 was obtained in yield: 60.3 percent.1H NMR(500MHz,CDCl3)δ7.50(d,J＝1.8Hz,1H),7.40(d,J＝2.2Hz,1H),6.28(t,J＝2.1Hz,1H),5.76(dd,J＝17.5,10.7Hz,1H),5.03(d,J＝10.4Hz,2H),4.95-4.83(m,2H),4.83-4.68(m,4H),3.58(s,2H),3.45(tdd,J＝15.2,7.5,4.0Hz,2H),3.04(d,J＝13.6Hz,1H),2.61(d,J＝13.7Hz,1H),2.49-2.10(m,9H),1.96-1.84(m,1H),1.74-1.18(m,14H),0.97(s,3H)。13C NMR(126MHz,CDCl3)δ171.89,149.72,149.68,147.66,139.15,129.37,114.31,111.71,110.44,105.84,66.12,56.38,53.19,52.84,47.78,45.75,41.82,41.70,39.76(d,J＝2.4Hz),33.64,32.95,32.44,28.47(d,J＝18.9Hz),26.96,25.01(d,J＝17.6Hz),15.84。LCMS[M+H]+:527.4。
Example 19: preparation of Compound 40
Figure BDA0003523178870000201
Intermediate 40b
Dried CH3OH (10mL) in a round bottom flask, N2Under the protection of the solution, slowly dropping cobalt chloride (SOCl) at-78 DEG C20.82mL), 5min was added dropwise, then compound 40a (1.4g, 8.54mmol) was added slowly. After the addition, the temperature was removed to-78 ℃, the mixture was returned to room temperature and stirred for 1 hour, and then refluxed at 70 ℃ overnight. After complete conversion, the reaction was spin dried, diluted with water (10mL) and saturated NaHCO3The solution was adjusted to pH 8 and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the objective product 40b (1.0g, yield 65.7%). LCMS [ M + H ]]+:179.1。
Intermediate 40c
(i) Reference example 1 Synthesis of intermediate 1b step (i) gave the product of (i).
(ii) Reference example 1, in the synthesis of intermediate 1d, step (ii), gives intermediate 40 c.
Reference example 1, synthesis step (i) of intermediate 1d therein, gave 40d as a yellow oily liquid in yield: 89.3 percent.1H NMR(400MHz,CDCl3)δ8.21(d,J＝2.5Hz,1H),7.59(t,J＝14.2Hz,2H),6.35(d,J＝8.7Hz,1H),5.80(dd,J＝17.7,10.5Hz,1H),5.45(t,J＝5.8Hz,1H),5.10-4.78(m,6H),4.58(s,1H),3.96(m,3H),3.64(m,1H),2.08-1.94(m,2H),1.93-1.40(m,15H),1.00(s,3H)。LCMS[M+H]+:466.8。
Referring to the last synthesis step in example 1, red-brown-red solid 40 was obtained with yield: 60.7 percent.1H NMR(500MHz,DMSO-d6)δ10.58(s,1H),8.89(s,1H),8.11(s,1H),7.60(d,J＝8.8Hz,1H),7.31(d,J＝15.7Hz,1H),7.17(t,J＝6.0Hz,1H),6.53(d,J＝8.7Hz,1H),6.18(d,J＝15.7Hz,1H),5.82(dd,J＝17.8,10.5Hz,1H),4.98-4.84(m,4H),4.79(t,J＝1.9Hz,1H),4.59(d,J＝2.1Hz,1H),3.97(d,J＝5.1Hz,2H),2.01(dtd,J＝12.5,8.7,4.9Hz,2H),1.67(s,3H),1.66-1.33(m,6H),0.97(s,3H)。13C NMR(126MHz,DMSO-d6)δ150.47,147.61,112.71,110.51,108.23,52.39,42.16,33.13,27.29,25.10,16.78。LCMS[M+H]+:382.5。
Example 20: preparation of Compound 43
Figure BDA0003523178870000202
Intermediate 43c
43b (2042.0mg, 17.461mmol) of CH under ice bath2Cl2To the solution (15mL) was added triethylamine (Et)3N, 4.5mL, 31.746 mmol). Then 43a (3000.0mg, 15.873mmol) of CH was dissolved2Cl2(15mL) the solution was slowly added dropwise to the reaction system, and after dropping, the reaction was carried out for 3h in an ice bath. After complete conversion, water (15mL) was added to the reaction mixture to terminate the reaction, and CH was added2Cl2Extraction (3X 15 mL). The combined organic phases were washed with saturated brine (2X 20mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 43c (1031.8mg, 24.1%) as a white solid.
Intermediate 43d
To a solution of intermediate 4a (63mg, 0.219mmol) in DMF (3mL) at room temperature was added DIPEA (34mg, 0.264mmol) and intermediate 43c (71mg, 0.264mmol) in that order. The reaction was stirred at 60 ℃ for 5 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 39) to obtain compound 43d (84.6mg, yield 75%) as a colorless oily compound.
Reference example 1 the final synthesis in example 1 gave rust red oily compound 43 (52.1)mg, yield 85%).1H NMR(400MHz,CD3OD)δ7.71(d,J＝7.2Hz,2H),7.43(d,J＝6.9Hz,2H),5.83(ddd,J＝17.7,10.9,2.8Hz,1H),4.96(d,J＝4.3Hz,3H),4.86(d,J＝5.3Hz,1H),4.80(s,1H),4.58(s,1H),3.60(s,2H),2.98(d,J＝8.2Hz,2H),2.50(s,8H),2.16-1.96(m,2H),1.70(s,3H),1.62(q,J＝8.2,4.7Hz,2H),1.58-1.29(m,4H),1.01(s,3H)。LCMS[M+H]+:438.9。
Example 21: preparation of Compound 44
Figure BDA0003523178870000211
Reference example 20 synthesis of intermediate 43d gave compound 44a as a colorless oil in yield: and 64 percent.1H NMR(400MHz,CDCl3)δ9.00(s,1H),7.71(d,J＝7.9Hz,2H),7.51(d,J＝1.8Hz,1H),7.39(d,J＝7.9Hz,2H),7.33(d,J＝2.3Hz,1H),6.25(t,J＝2.1Hz,1H),5.83(dd,J＝17.4,10.8Hz,1H),5.08(d,J＝3.7Hz,1H),5.04-4.95(m,2H),4.93-4.89(m,1H),4.86(d,J＝2.5Hz,2H),4.77-4.60(m,3H),3.69-3.61(m,1H),3.55(s,2H),2.94-2.82(m,2H),2.42(s,8H),2.10-1.77(m,8H),1.76-1.37(m,6H),1.02(s,3H)。
Referring to the last synthesis step in example 1, compound 44 was obtained as a reddish brown oil in yield: 70.9 percent.1H NMR(400MHz,CD3OD)δ7.88-7.20(m,6H),6.21(s,1H),5.88-5.69(m,1H),4.90(d,J＝17.3Hz,3H),4.79-4.72(m,2H),4.64(d,J＝22.9Hz,3H),3.51(p,J＝7.1,6.1Hz,2H),2.85(s,2H),2.39(s,8H),1.98-1.79(m,2H),1.64-1.46(m,3H),1.46-1.32(m,3H),0.95(s,3H)。LCMS[M+H]+:504.6。
Example 22: preparation of Compound 45
Figure BDA0003523178870000212
Reference example 20, inner intermediate 43d synthesis procedure, gave compound 45a as pale yellow oil, yield: 47.7 percent.
Reference is made to the synthesis of the last step in example 1 to giveRust red oily compound 45, yield: 70.9 percent.1H NMR(400MHz,CD3OD)δ8.18(s,1H),7.83-7.31(m,6H),6.22(s,1H),5.72(d,J＝14.7Hz,1H),5.3-5.17(m,1H),4.98(d,J＝33.1Hz,5H),4.74(s,2H),4.69(s,2H),3.86(s,2H),2.87(s,6H),2.22-2.05(m,2H),1.98-1.78(m,2H),1.58-1.31(m,6H),0.88(s,3H)。LCMS[M+H]+:504.7。
Example 23: preparation of Compound 46
Figure BDA0003523178870000221
Intermediate 46a
(i) To a solution of intermediate 25b (100mg, 0.351mmol) in DMF (5mL) at room temperature was added 3a (79.28mg, 0.421mmol), DIPEA (135.84mg, 1.053mmol), EDCI (174.9mg, 0.913mmol) and HOBT (61.66mg, 0.456mmol) in that order. The reaction was stirred at room temperature for 5 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 99) to obtain a colorless oily compound (153mg, yield 95.7%).
(ii) To a solution of the product obtained in (i) (153mg, 0.336mmol) in methanol (2mL) at room temperature was slowly added dropwise a NaOH solution (1M, 2 mL). After dropping, the reaction mixture was stirred at room temperature for 2 hours. After complete conversion, the solvent was evaporated under reduced pressure. Water (5mL) was added to the residue and the pH was adjusted to 5-6 by slowly adding dropwise HCl (1M) solution, followed by extraction with ethyl acetate (3X5 mL). The combined organic phases were washed with saturated brine (2X5mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 46a (139mg, yield 93.7%) as pale yellow oil without further purification.
Compound 46
To a solution of compound 46a (64mg, 0.145mmol) in DMF (3mL) at room temperature was added o-phenylenediamine (78.40mg, 0.725mmol), DIPEA (56.12mg, 0.435mmol), EDCI in that order(72.38mg, 0.377mmol) and HOBT (25.61mg, 0.189 mmol). The reaction was stirred at room temperature for 5 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by C18 column chromatography (acetonitrile: water: 2: 3) to obtain a colorless oily compound 46, yield: 88 percent.1H NMR(500MHz,CDCl3)δ7.83(s,1H),7.51(d,J＝1.9Hz,1H),7.39(d,J＝2.2Hz,1H),7.16(dd,J＝7.7,1.4Hz,1H),7.03(td,J＝7.7,1.5Hz,1H),6.76(t,J＝7.6Hz,2H),6.28(t,J＝2.1Hz,1H),5.75(dd,J＝17.5,10.8Hz,1H),4.99(s,1H),4.97-4.86(m,3H),4.79-4.69(m,4H),3.84(dd,J＝15.8,6.8Hz,1H),3.62(dd,J＝15.8,5.0Hz,1H),2.37(t,J＝7.5Hz,2H),2.19(t,J＝7.4Hz,2H),1.94-1.80(m,2H),1.77-1.49(m,5H),1.48-1.24(m,9H),0.96(s,3H)。13C NMR(126MHz,CDCl3)δ172.90,172.03,149.41,149.15,148.09,140.83,139.19,129.42,126.98,125.24,124.47,119.31,118.10,112.11,111.70,110.98,105.88,56.18,49.12,45.89,41.73,39.69,39.48,36.65,36.39,33.38,28.62,28.23,26.80,25.51,25.29,15.98。LCMS[M+H]+:532.2。
Example 24: preparation of Compound 47
Figure BDA0003523178870000231
Compound 47
To a solution of compound 46a (53mg, 0.120mmol) in DMF (5mL) at room temperature was added 2-pyridylamine (13.55mg, 0.144mmol), DIPEA (46.44mg, 0.360mmol), EDCI (59.8mg, 0.312mmol) and HOBT (21.08mg, 0.156mmol) in that order. The reaction was stirred at 60 ℃ for 10 h. After complete conversion, the reaction mixture was quenched by addition of water (5mL) and extracted with ethyl acetate (3X 10 mL). The combined organic phases were washed with saturated brine (2X 10mL) and dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating the filtrate under reduced pressure, and purifying the crude product by silica gel column chromatography (methanol: dichloromethane: 1: 49) to obtain colorless oily compoundObject 47(8mg, yield 12.9%).1H NMR(500MHz,CDCl3)δ7.51(d,J＝1.9Hz,1H),7.39(d,J＝2.2Hz,1H),6.28(t,J＝2.1Hz,1H),5.77(dd,J＝17.4,10.8Hz,1H),5.65-5.53(m,1H),5.04-4.88(m,4H),4.77(dt,J＝9.7,1.5Hz,4H),4.71(p,J＝6.8Hz,1H),4.04(p,J＝6.7Hz,1H),3.86(dd,J＝15.9,6.8Hz,1H),3.66(dd,J＝15.9,5.0Hz,1H),3.23(dq,J＝11.8,7.1Hz,2H),2.30(dt,J＝18.9,7.6Hz,2H),2.19(t,J＝7.5Hz,2H),1.95-1.83(m,2H),1.70-1.59(m,6H),1.55(d,J＝2.7Hz,1H),1.48-1.41(m,3H),1.39-1.34(m,4H),0.98(s,3H)。13C NMR(126MHz,CDCl3)δ172.85,149.47,149.20,148.15,139.18,129.32,111.92,111.75,110.97,105.85,56.21,49.28,48.21,45.78,45.12,41.79,39.70,39.50,37.24,36.65(d,J＝2.1Hz),33.65(d,J＝15.3Hz),33.40,29.11(d,J＝3.4Hz),29.03,26.79,25.58,25.40,25.27,21.35,20.56,16.76,16.01,15.00。
Example 25: preparation of Compound 48
Figure BDA0003523178870000232
Intermediate 48b
(i) Reference example 1 Synthesis of intermediate 1b step (i) gave the product of (i).
(ii) Reference example 1, in the synthesis of intermediate 1d, step (ii), gives intermediate 48 b.
Reference example 1, step (i) of the synthesis of intermediate 1d, gave a yellow oily liquid 48c,1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.49(d,J＝2.4Hz,1H),7.86(dd,J＝8.8,2.3Hz,1H),6.36(d,J＝8.8Hz,1H),5.89-5.73(m,1H),5.49(s,1H),5.09-4.87(m,5H),4.83(q,J＝1.7Hz,1H),4.75-4.67(m,1H),4.59(s,1H),4.08-3.80(m,3H),3.75-3.54(m,2H),2.06-1.95(m,2H),1.93-1.42(m,15H),1.01(s,3H)。LCMS[M+H]+:440.8。
referring to the last synthesis in example 1, a white solid 48 was obtained except that the crude product was purified by C18 column chromatography (acetonitrile: water 1: 1) with yield: 41.7 percent. LCMS (liquid Crystal display Module) [ M + H ]]+:356.5。
Example 26: evaluation of in vitro inhibition activity of HDACi 1 and HDAC6 on beta-elemene derivatives having HDACi pharmacophores prepared in examples 1 to 25
1. Experimental materials and instruments
Experimental materials: see table 1.
TABLE 1 Experimental materials
Figure BDA0003523178870000241
An experimental instrument: biosafety cabinets (shanghai baiji biotechnology limited); a thermostated carbon dioxide incubator (THERMO); enzyme linked immunoassay analyzer (Spark); inverted microscope (Nikon); a set of pipette guns (Eppendorf); centrifuge (Beckman coulter).
2. Experimental procedure
1) Preparation work
Dilution of the compound: diluting a compound to be detected and SAHA into a high-concentration stock solution by using 100% DMSO, and then taking the high-concentration stock solution to perform gradient dilution to form 6 concentration points;
enzyme dilution: the enzyme was mixed with Buffer as 1: 2 for dilution;
dilution of the substrate: adding trypsin (trypsin) and substrate containing acetyl (H4(10-12) K12ac-AMC) into Buffer, and diluting by 100 times;
2) in 384-well plates, blank (Ab): 0.25L of DMSO +15L buffer solution +10L substrate diluent without the test compound; control (Ac): 0.25L of DMSO +15L of enzyme diluent +10L of substrate diluent not containing the test compound; experimental group (As): 0.25L of DMSO +15L of enzyme diluent +10L of substrate diluent of the compound to be detected, and incubating for 1h in an incubator at 37 ℃;
3) measuring the absorption value of each hole at the excitation wavelength of 355nm and the emission wavelength of 460nm by using a microplate reader, calculating the inhibition rate of the compound to be detected through the absorption values of a blank group, a control group and an experimental group, and obtaining the enzyme activity inhibition IC50The value is obtained.
4) The inhibition rate was calculated by the following formula
The inhibition rate is [ (Ab-As)/(Ab-Ac) ] x 100%
3. Results of the experiment
The inhibition effect of the β -elemene derivatives having HDACi pharmacophores prepared in examples 1 to 25 on HDAC1 and HDAC6 was determined according to the above experimental methods, and the results are shown in table 2.
TABLE 2 results of HDAC inhibitory Activity of beta-elemene derivatives having HDACI pharmacophore
Figure BDA0003523178870000242
Figure BDA0003523178870000251
aThe values in the table are the average values of three tests, and the value after "+ -" represents the standard deviation;bno test is used as indicated by "n.d. -not determined";cindicating binding in a molar ratio of 1: 1.
4. Discussion of results
On the enzyme level, the synthesized target compound has certain inhibition effect on HDAC1 and HDAC6, and compared with SAHA, part of the compound shows stronger inhibition activity. Among these, compound 18 showed the best inhibitory activity, IC against both HDAC1 and HDAC6 subtypes509nM and 14nM, respectively.
Example 27: evaluation of in vitro antitumor Activity of beta-elemene derivatives having HDACI pharmacophores prepared in examples 1 to 25
1. Experimental materials and instruments
Experimental materials: DMEM (zhejiang senri biotechnology limited); RPMI 1640 (zhejiang senri biotechnology limited); fatal bone Serum (BI); PBS (zhejiang senri biotechnology limited); trypsin (zhejiang senri biotechnology limited); dmso (coolaber); CCK-8 (Coolaber).
An experimental instrument: biosafety cabinets (shanghai baiji biotechnology limited); a thermostated carbon dioxide incubator (THERMO); enzyme linked immunoassay analyzer (Spark); inverted microscope (Nikon); a set of pipette guns (Eppendorf); centrifuge (Beckman coulter).
Different types of human tumor cell lines: lung cancer cell strains H1299, H460, H1975, PC-9 and A549; glioma cell line U87; leukemia cell lines K562 and HEL.
2. Experimental procedure
1) Taking test cells in logarithmic growth phase, after trypsinizing and counting (without trypsinizing K562 and HEL suspension cells), diluting the tumor cell suspension to 5 × 104Each/mL of the cells was inoculated in a 96-well plate, and 100. mu.L of cell-containing medium (5X 10 per well) was added to each well except for the blank group and 100. mu.L of cell-free medium3Individual cells).
2) At a wet content of 5% CO2After incubation at 37 ℃ for 8h in an incubator, the original medium in the 96-well plate was aspirated, 100. mu.L of medium containing no test compound was added to each well except for the control and blank groups, and 100. mu.L of medium containing the test compound was added to each well (using 10% FBS/DMEM or 10% FBS/RPMI 1640 complete medium), 6 duplicate wells were set at each concentration, the wells containing no test compound were used as the blank group, the wells containing no test compound were used as the control group, and the wells containing test compound were used as the test group. Beta-elemene and vorinostat were selected as positive controls for the experiment.
Among them, H1299, H460, H1975, a549 and K562 cells used RPMI 1640 complete medium; PC-9, U87 and HEL cells were in DMEM complete medium.
3) At 37 ℃ with 5% CO2Culturing in a humid incubator for 72h
4) Adding 10 μ L of CCK-8 solution into each well under dark condition, and adding 5% CO at 37 deg.C2Continuously culturing for 1-4h in a humid incubator, and measuring the absorbance value (OD value) of each hole at 450nm of an enzyme-labeling instrument;
5) the survival and inhibition rates were calculated using the following formulas
The cell survival rate is [ (As-Ab)/(Ac-Ab) ]. times.100%
The inhibition rate is [ (Ac-As)/(Ac-Ab) ]. times.100%
Calculating the single concentration inhibition rate by using Excel; GraphPad Prism 7.0 software was applied using a non-lineThe regression model was used to plot the S-shaped dose-survival curve and to calculate IC50The value is obtained.
As: absorbance of test well (cell-containing medium, CCK-8, drug to be tested)
Ac: absorbance of control wells (cell-containing Medium, CCK-8, vehicle (DMSO))
Ab: absorbance of blank wells (cell-free Medium, CCK-8, vehicle (DMSO)))
3. Results of the experiment
The results of the experiments described above on the proliferation inhibition effect of the β -elemene derivatives having HDACi pharmacophores prepared in examples 1 to 25 on 6 solid tumor cell lines were determined, and are shown in table 3. The results of in vitro proliferation inhibition of solid tumor cell lines show that 4 representative compounds were screened out and their proliferation inhibition effect on blood tumor cell lines was further determined, and the results are shown in table 4.
TABLE 3 results of antiproliferative Activity of target Compounds on solid tumor cell lines in vitro
Figure BDA0003523178870000261
Figure BDA0003523178870000271
The numerical values in the table a are the average values of three tests, and the numerical values after +/-represent standard deviation; b the inhibition rate of less than 10% is expressed by 'N.A. -not active'; c is not represented by "n.d. -not determined" for testing; d represents binding in a molar ratio of 1: 1.
TABLE 4 results of antiproliferative Activity of representative Compounds on hematological tumor cell lines in vitro
Figure BDA0003523178870000272
aThe values in the table are the average values of three tests, and the value after "+ -" represents the standard deviation;bnot testedExpressed as "n.d. — not determined";cindicating binding in a molar ratio of 1: 1.
4. Conclusion of the results
At the cellular level, most of the target compounds show a significantly stronger cell proliferation inhibiting activity than beta-elemene. Compound 30 with optimal inhibitory activity on tumor cell proliferation was also shown to have optimal inhibitory activity on IC of both K562 and HEL cell lines503.67. mu.M and 2.01. mu.M, respectively.
Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the above description of the present invention, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims (10)

1. The beta-elemene derivative with a histone deacetylase inhibitor pharmacophore, or an optical isomer, a racemate, a single enantiomer, a possible diastereoisomer thereof, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof, is characterized in that the derivative has a structure shown in a formula (I):
Figure FDA0003523178860000011
wherein:
Figure FDA0003523178860000012
comprises the following steps:
Figure FDA0003523178860000013
L1each independently selected from one of the following structural fragments:
Figure FDA0003523178860000014
Figure FDA0003523178860000015
L2each independently selected from one of the following structural fragments:
Figure FDA0003523178860000016
Figure FDA0003523178860000017
wherein N is any one of 4 to 6 natural numbers, and X is C or N;
L3selected from one of the following structural fragments:
Figure FDA0003523178860000018
2. the beta-elemene derivative with a histone deacetylase inhibitor pharmacophore, or an optical isomer, racemate, single enantiomer, possible diastereoisomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof according to claim 1, wherein the beta-elemene derivative with the histone deacetylase inhibitor pharmacophore is any one of compounds 1 to 48 shown in the following structures:
Figure FDA0003523178860000021
Figure FDA0003523178860000031
3. the use of the β -elemene derivative with a histone deacetylase inhibitor pharmacophore, or an optical isomer, racemate, single enantiomer, possible diastereoisomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, according to claim 1 or 2, for the manufacture of a medicament for the treatment or prevention of tumors.
4. The use of claim 3, wherein the tumor comprises a solid tumor and a hematological tumor.
5. An antitumor agent characterized by comprising a safe and effective amount of the β -elemene derivative having a pharmacophore of a histone deacetylase inhibitor as set forth in claim 1 or 2, or an optical isomer, racemate, single enantiomer, or possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof.
6. The antitumor agent as claimed in claim 5, further comprising a pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier.
7. The antitumor agent as claimed in claim 5, wherein the tumor comprises solid tumor and blood tumor.
8. A preparation method of beta-elemene derivatives with a histone deacetylase inhibitor pharmacophore is characterized in that the synthetic route is as follows:
Figure FDA0003523178860000041
wherein L is1Each independently selected from one of the following structural fragments:
Figure FDA0003523178860000042
Figure FDA0003523178860000043
L2each independently selected from one of the following structural fragments:
Figure FDA0003523178860000044
wherein n is any one of natural numbers from 4 to 6;
L3selected from the following structural fragments:
Figure FDA0003523178860000045
the method specifically comprises the following steps:
(1) the compound is
Figure FDA0003523178860000046
Halogenated reaction is carried out to obtain an intermediate
Figure FDA0003523178860000047
(2) Will contain a nitrogen heteroatom functional group1Structure-fragmenting Compound L1(Boc)2/HL1Boc is connected to a halogenated product intermediate at 13-site or 14-site of beta-elemene through nucleophilic substitution reaction to obtain an intermediate containing Boc, and then the intermediate is subjected to deprotection to obtain an intermediate containing L1Intermediates of structural fragments
Figure FDA0003523178860000048
(4) Will contain L1Intermediates of structural fragments
Figure FDA0003523178860000049
And contain L2And L3Intermediate HO-L of structural fragment2-L3-THP is subjected to amide condensation to obtain beta-elemene derivatives or intermediates with HDACI pharmacophore
Figure FDA0003523178860000051
Further performing deprotection to obtain the beta-elemene derivative with HDACI pharmacophore shown in (I).
9. A preparation method of beta-elemene derivatives with a histone deacetylase inhibitor pharmacophore is characterized in that the synthetic route is as follows:
Figure FDA0003523178860000052
wherein L is1Each independently selected from one of the following structural fragments:
Figure FDA0003523178860000053
Figure FDA0003523178860000054
L2selected from the following structural fragments:
Figure FDA0003523178860000055
wherein n is any natural number from 4 to 6;
L3selected from one of the following structural fragments:
Figure FDA0003523178860000056
the method specifically comprises the following steps:
(1) step (1) of referring to route one;
(2) a step (2) of referring to the route one;
(3) will contain L1Intermediates of structural fragments
Figure FDA0003523178860000057
And contain L2Compounds of the structural fragment
Figure FDA0003523178860000058
By amide condensation reaction followed by ester hydrolysis to give L1And L2Compounds of the structural fragment
Figure FDA0003523178860000059
(4) Will containL1And L2Compounds of structural fragments
Figure FDA00035231788600000510
And contain L3The acid of the structural fragment is subjected to substitution reaction to obtain amide condensation reaction, and the beta-elemene derivative with the HDACI pharmacophore shown in the (I) is obtained.
10. A preparation method of beta-elemene derivatives with a histone deacetylase inhibitor pharmacophore is characterized in that the synthetic route is as follows:
Figure FDA0003523178860000061
wherein L is1Each independently selected from one of the following structural fragments:
Figure FDA0003523178860000062
Figure FDA0003523178860000063
L2each independently selected from one of the following structural fragments:
Figure FDA0003523178860000064
x is C or N;
L3selected from one of the following structural fragments:
Figure FDA0003523178860000065
the method specifically comprises the following steps:
(1) step (1) of referring to route one;
(2) a step (2) of referring to a route one;
(3) will contain L1Intermediates of structural fragments
Figure FDA0003523178860000066
And contain L2And L2Compound of structural fragment Cl-L2-L3-THP is substituted to give L1、L2And L3Compounds of the structural fragment
Figure FDA0003523178860000067
The beta-elemene derivative with HDACI pharmacophore shown in the formula (I) is obtained by deprotection.
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