CN113698401A - Beta-elemene macrocyclic derivatives, preparation method and application thereof - Google Patents

Beta-elemene macrocyclic derivatives, preparation method and application thereof Download PDF

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CN113698401A
CN113698401A CN202111074276.0A CN202111074276A CN113698401A CN 113698401 A CN113698401 A CN 113698401A CN 202111074276 A CN202111074276 A CN 202111074276A CN 113698401 A CN113698401 A CN 113698401A
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elemene
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谢恬
戚香
卓晓韬
高园
白仁仁
叶向阳
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Abstract

The invention discloses a beta-elemene macrocyclic derivative, a preparation method thereof and application thereof in preparing antitumor drugs. The structure of the beta-elemene macrocyclic derivative is shown in any one of formulas (I) to (III):

Description

Beta-elemene macrocyclic derivatives, preparation method and application thereof
Technical Field
The invention relates to the technical field of preparation of beta-elemene derivatives, in particular to a beta-elemene macrocyclic derivative and a preparation method and application thereof.
Background
Elemene is a kind of small molecule volatile oil compounds, and is mainly extracted from the root tuber of common turmeric. Elemene reported in the literature at present mainly comprises alpha-elemene, (+/-) -beta-elemene, gamma-elemene and delta-elemene, wherein (-) -beta-elemene is a main active component of the elemene which plays an anti-tumor role, has broad-spectrum anti-tumor activity and has certain curative effect on various cancers, such as liver cancer, breast cancer, lung cancer and the like. At present, various preparations taking elemene as a main component have certain anticancer curative effect clinically.
However, elemene has low polarity, poor water solubility and low bioavailability for oral administration, so that clinical application of elemene is limited. Therefore, the elemene derivative has to be structurally modified to obtain the elemene derivative with good water solubility, higher bioavailability, better bioactivity than elemene and less toxic and side effects.
In the past 20-30 years, researchers have carried out a great deal of structural modification and activity research work on beta-elemene. On the premise of not damaging the basic skeleton of elemene and double bonds thereof, most of researches mainly focus on modification at the 13-site of beta-elemene, and some researches report that the modification is carried out at the 13-site and the 14-site by the same substituent, and relatively few reports relate to structural modification of the 14-site beta-elemene independently.
Natural macrocyclic compounds and their synthetic derivatives have long been of significant clinical value. The macrocyclic compound has strong structural advantages, can provide diversified functions and stereochemical complexity, and has good drug-like properties (such as good solubility, lipophilicity, membrane penetration, metabolic stability and ideal pharmacokinetic and pharmacodynamic properties). Therefore, the 13-position and the 14-position of the beta-elemene are connected by a specific structural fragment to form a macrocyclic compound with novel structure. The brand new molecular entity reserves the original three carbon-carbon double bonds of the elemene (the three carbon-carbon double bonds are main contributing elements of the antitumor activity of the elemene), and introduces 1 to more heteroatoms in the link part of a macrocyclic ring, so that the antitumor activity of the elemene is improved, and the development of antitumor drugs is expected.
Disclosure of Invention
The invention provides a beta-elemene macrocyclic derivative.
The beta-elemene macrocyclic derivative is characterized by comprising a beta-elemene macrocyclic derivative, or an optical isomer, a racemate, a single enantiomer, a possible diastereoisomer, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate or a solvate thereof, wherein the beta-elemene macrocyclic derivative has a structure shown in any one of formulas (I) to (III):
Figure BDA0003261639710000021
in the formulae (I), (II):
R1each independently selected from the following structural fragments:
Figure BDA0003261639710000022
Figure BDA0003261639710000023
R2each independently selected from the following structural fragments:
Figure BDA0003261639710000024
Figure BDA0003261639710000025
L1each independently selected from the following structural fragments:
Figure BDA0003261639710000026
Figure BDA0003261639710000027
in the formula (III):
R1selected from the following structural fragments:
Figure BDA0003261639710000031
Figure BDA0003261639710000032
L2selected from the following structural fragments:
Figure BDA0003261639710000033
Figure BDA0003261639710000034
further, the beta-elemene macrocyclic derivative is any one of compounds 1-55 shown in the following structures:
Figure BDA0003261639710000041
Figure BDA0003261639710000051
the invention also provides a preparation method of the beta-elemene macrocyclic derivative.
For the beta-elemene macrocyclic derivatives of formula (I), the first synthetic route can be used:
Figure BDA0003261639710000061
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-4;
(3) r is to be2And L1The connected structural fragment A-5 is connected to 14-beta-elemene through selective nucleophilic substitution reaction to obtain an intermediate A-6;
(4) sequentially deprotecting the structural fragments at the 13 and 14 positions of the beta-elemene to obtain an intermediate A-7;
(5) finally, R is1、R2The two unprotected ends are condensed into a ring by intramolecular lactam to obtain the beta-elemene macrocyclic derivative shown in the formula (I).
For the beta-elemene macrocyclic derivatives of formula (I), synthetic route two can also be used:
Figure BDA0003261639710000062
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-4;
(3) carrying out Boc deprotection on the intermediate A-4 to obtain an intermediate A-8;
(4) r is to be2And L1The connected structural segment A-9 is connected to R at the 13-position of the beta-elemene through an amide condensation reaction1Ending to obtain an intermediate A-10;
(5) carrying out Boc deprotection on the intermediate A-10 to obtain an intermediate A-11;
(6) finally, the R at the 13 th position on the beta-elemene is put into2The structural fragment is deprotected, and then the end is connected to 14-beta-elemene by intramolecular nucleophilic substitution reaction to obtain the beta-elemene macrocyclic derivative shown in the formula (I).
For the beta-elemene macrocyclic derivatives of the structure of formula (II), the third synthetic route can be adopted:
Figure BDA0003261639710000071
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r is to be2And L1The connected structural fragment A-5 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-12;
(3) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to 14-beta-elemene through selective nucleophilic substitution reaction to obtain an intermediate A-13;
(4) sequentially deprotecting the structural fragments at positions 14 and 13 of beta-elemene to obtain intermediate A-14;
(5) finally, R is1、R2The two unprotected ends are condensed into a ring by intramolecular lactam to obtain the beta-elemene macrocyclic derivative shown in the formula (II).
For the partial β -elemene macrocyclic derivatives of the structure of formula (III), the four synthetic routes can be used:
Figure BDA0003261639710000081
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1Nucleophilic substitution reaction of structural fragment A-3Should be connected to beta-elemene at the 13 and 14 positions to obtain an intermediate A-15;
(3) carrying out Boc deprotection on the intermediate A-15 to obtain an intermediate A-16;
(4) finally, the L is2Structural fragments A-17 and R1The tail ends are connected to form a ring, so as to obtain the beta-elemene macrocyclic derivative shown in the formula (III);
wherein L is2Selected from the following structural fragments:
Figure BDA0003261639710000082
Figure BDA0003261639710000083
for the partial β -elemene macrocyclic derivatives of the structure of formula (III), scheme five may be used:
Figure BDA0003261639710000084
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is subjected to nucleophilic substitution reaction and is connected to the beta-elemene at the 13 and 14 positions to obtain an intermediate A-15;
(3) carrying out Boc deprotection on the intermediate A-12 to obtain an intermediate A-18;
(4) carrying out nucleophilic substitution reaction on two ends of the intermediate A-18 and the intermediate A-19 to obtain an intermediate A-20;
(5) the structural fragments A-21 and R1The tail ends are connected to form a ring, so as to obtain the beta-elemene macrocyclic derivative shown in the formula (III);
wherein L is2Selected from the following structural fragments:
Figure BDA0003261639710000091
Figure BDA0003261639710000092
the compounds represented by the formulae (I), (II), (III) of the present invention can be produced by the above-mentioned methods, however, the conditions of the methods, such as reactants, solvents, amounts of the compounds used, reaction temperature, time required for the reaction, and the like are not limited to the above explanations. 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 invention also provides application of the beta-elemene macrocyclic derivative, or an optical isomer, a racemate, a single enantiomer, a possible diastereoisomer, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof in preparation of antitumor drugs.
The invention also provides an anti-tumor medicament which contains safe and effective dose of the beta-elemene macrocyclic derivative, or optical isomer, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof.
The anti-tumor drug can also comprise a pharmaceutically acceptable carrier.
In the application and the anti-tumor medicine, the tumor comprises colon cancer, lung cancer, prostatic cancer and brain glioma.
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 pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: 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 with the compounds of the present invention without significantly diminishing the 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 BDA0003261639710000101
) 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 macrocyclic derivative with a structure shown in formulas (I), (II) and (III), a pharmaceutical composition and a hydrate containing the compounds of formulas (I), (II) and (III), and an isotope derivative, a chiral isomer, a variant, different salts, a prodrug, a preparation and the like of the compounds. The invention also provides a preparation method and application of the beta-elemene macrocyclic derivatives, and the proliferation activity of the compounds on various tumor cell strains. The beta-elemene macrocyclic derivative is expected to become an anti-tumor candidate drug for treating various cancers, such as lung cancer, liver cancer, colorectal cancer, gastric cancer, prostatic cancer, ovarian cancer, breast cancer or brain glioma 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 BDA0003261639710000121
To a solution of compound 1a (1042mg, 3.84mmol) in anhydrous N, N-Dimethylformamide (DMF) (8mL) was added 1b (536mg, 3.84mmol) at room temperature, and after clarification by stirring, N-Diisopropylethylamine (DIPEA) (1092mg, 8.45mmol), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) (1460mg, 3.84mmol) were added in sequence and stirred overnight. The DMF was evaporated under reduced pressure, the reaction quenched by the addition of ice water (40mL) and extracted with ethyl acetate (15 mL. times.3). The combined organic phases were washed successively with water (10 mL. times.2) and saturated brine (10 mL. times.2) and then 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 (elution with ethyl acetate/petroleum ether/triethylamine (0.1%) system) to give compound 1c (1275mg, yield 93%) as a yellow oil.1H NMR(500MHz,CD3OD)δ4.04(d,J＝13.2Hz,2H),3.67(s,3H),3.42(t,J＝6.6Hz,2H),2.73(s,2H),2.53(t,J＝6.6Hz,2H),2.15(t,J＝7.4Hz,2H),1.69(d,J＝11.5Hz,2H),1.66–1.56(m,2H),1.45(s,10H),1.28–1.19(m,2H),1.03(qd,J＝12.7,4.3Hz,2H)。
To a solution of compound 1c (433mg, 1.22mmol) in methanol (2mL) under ice bath conditions was added a solution of dioxane hydrochloride (4M, 3mL), the ice bath was removed after stirring for about 10min, and the mixture was further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the hydrochloride of compound 1d (355mg, 1.22mmol), and the crude product was used in the next reaction without purification.
To a solution of compound 1d (355mg, 1.22mmol) in anhydrous DMF (5mL) at room temperature was added compound 1e (459mg, 1.0mmol) and cesium carbonate (652mg, 2.0mmol) in that order, and the mixture was gradually warmed to 90 ℃ and stirred for about 7 hours. The DMF was evaporated under reduced pressure, saturated aqueous sodium bicarbonate (8mL) was added and extracted with ethyl acetate (5mL x 3). The combined organic phases were successively treated with saturated sodium bicarbonateThe aqueous solution (6mL x 2), water (6mL x 2) and saturated brine (6mL x 2) were washed, and then 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 (elution with ethyl acetate/petroleum ether/triethylamine (0.1%) system) to give compound 1f (337mg, yield 50%) as a yellow oil.1H NMR(500MHz,CDCl3)δ6.04(s,1H),5.80(dd,J＝17.5,10.8Hz,1H),5.02(s,1H),4.91–4.82(m,3H),4.74(d,J＝9.5Hz,2H),4.18(s,2H),3.70(s,3H),3.51(q,J＝6.1Hz,2H),2.96(d,J＝13.9Hz,1H),2.76(d,J＝9.7Hz,2H),2.60(d,J＝13.9Hz,1H),2.57–2.48(m,2H),2.18(dd,J＝12.9,3.1Hz,1H),2.13(t,J＝7.6Hz,2H),1.99–1.83(m,2H),1.69–1.55(m,8H),1.54–1.49(m,2H),1.47(s,19H),1.45–1.40(m,2H),1.23–1.19(m,3H),0.98(s,3H)。
To a solution of compound 1f (264mg, 0.39mmol) in methanol (2mL) under ice bath conditions was added a solution of dioxane hydrochloride (4M, 3.5mL), the ice bath was removed after stirring for about 10min, and the mixture was further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 1g of hydrochloride (199mg, 0.39mmol) of the compound, LCMS M/z 474.4[ M + H ]]+. The crude product was used in the next reaction without purification.
To a solution of compound 1g (120mg, 0.24mmol) in methanol (2mL) under ice bath conditions was added a cooled NaOH (1M, 3.5mL) solution, the ice bath was removed after stirring for about 10min, and the mixture was further stirred at room temperature overnight. Evaporating methanol under reduced pressure, slowly adding 5% HCl solution dropwise into the reaction solution under ice bath condition while stirring, adjusting pH to about 7, and concentrating under reduced pressure to obtain compound 1H (108mg, 0.39mmol), LCMS M/z 460.4[ M + H ], (LCMS M/z)]+. The crude product was used in the next reaction without purification.
To a solution of compound 1h (78mg, 0.17mmol) in anhydrous DMF (8mL) under ice-bath conditions was added DIPEA (53mg, 0.41mmol), EDCI (179mg, 0.94mmol), 1-hydroxybenzotriazole (HOBt) (60mg, 0.44mmol) in that order, stirred for about 5min, gradually warmed to room temperature, and stirring was continued for about 8 h. DMF was evaporated under reduced pressure and to the residue was added saturated aqueous sodium bicarbonate (6mL) followed by acetic acidExtraction with ethyl ester (4 mL. times.3). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (5mL x 2), water (5mL x 2) and saturated brine (5mL x 2) and then 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 (eluting with a dichloromethane/methanol/triethylamine (0.1%) system) to give compound 1(29mg, yield 37%) as a yellow oil.1H NMR(500MHz,CDCl3)δ6.89–6.81(m,1H),5.74(dd,J＝17.5,10.8Hz,1H),5.48(s,1H),4.98(s,1H),4.94(s,1H),4.91–4.83(m,3H),4.69(s,1H),4.21(dd,J＝13.8,7.0Hz,1H),3.84(ddt,J＝13.4,8.4,4.3Hz,1H),3.57(dd,J＝13.9,3.0Hz,1H),3.22(tq,J＝10.4,3.1Hz,1H),3.00(d,J＝12.2Hz,1H),2.76(d,J＝10.9Hz,1H),2.67(d,J＝10.2Hz,1H),2.56–2.47(m,2H),2.43(dd,J＝10.4,3.4Hz,1H),2.38–2.26(m,2H),2.17(ddd,J＝14.7,9.3,5.8Hz,1H),2.04(t,J＝10.9Hz,1H),1.97(dt,J＝10.2,4.5Hz,1H),1.73–1.42(m,11H),1.38(dtd,J＝13.6,10.2,6.3Hz,1H),1.32(d,J＝12.9Hz,1H),1.11(ddd,J＝16.4,12.0,5.7Hz,2H),1.02(s,3H),1.00–0.93(m,1H).LCMS m/z442.2[M+H]+。
Example 2: preparation of Compound 2
Figure BDA0003261639710000151
According to the synthesis method of example 1, compound 2f (252mg, yield 46%) was obtained.1H NMR(500MHz,CDCl3)δ6.13(t,J＝4.9Hz,1H),5.79(dd,J＝17.5,10.8Hz,1H),5.00(s,1H),4.95–4.81(m,4H),4.74(s,1H),3.68(s,3H),3.50(q,J＝6.1Hz,2H),3.39(s,4H),2.97(d,J＝13.9Hz,1H),2.90(q,J＝13.3Hz,2H),2.81–2.71(m,2H),2.59(d,J＝13.9Hz,1H),2.53(t,J＝6.0Hz,2H),2.31(s,4H),2.20(dd,J＝12.7,3.1Hz,1H),2.14–2.09(m,2H),2.07(d,J＝12.1Hz,1H),1.89(t,J＝11.3Hz,1H),1.56(dq,J＝42.1,13.9,13.0Hz,9H),1.44(s,9H),1.40(d,J＝12.7Hz,1H),1.30–1.05(m,6H),0.98(s,3H).LCMS m/z643.0[M+H]+。
Referring to the synthesis of example 1, compound 2f (245mg, 0.38mmol) was Boc deprotected, ester hydrolyzed, and amide-treated in that orderThe condensation reaction was carried out to obtain Compound 2(97mg, yield 76%) as a white solid.1H NMR(400MHz,CDCl3)δ6.30–6.20(m,1H),5.76(dd,J＝17.5,10.8Hz,1H),4.93–4.87(m,3H),4.86(d,J＝1.2Hz,1H),4.84–4.82(m,1H),4.70(d,J＝1.6Hz,1H),3.96(d,J＝13.1Hz,1H),3.81–3.67(m,1H),3.49(dt,J＝11.9,3.2Hz,1H),3.31(tdd,J＝12.5,8.1,4.2Hz,2H),3.15–2.94(m,3H),2.87(d,J＝12.6Hz,1H),2.76(dd,J＝28.1,11.1Hz,2H),2.66–2.50(m,3H),2.49–2.33(m,3H),2.33–2.19(m,3H),2.14–2.05(m,2H),2.03–2.00(m,1H),1.95(td,J＝11.8,2.1Hz,1H),1.50(tdt,J＝24.6,16.8,11.7Hz,11H),1.23–1.02(m,3H),1.00(s,3H),0.83(qd,J＝12.0,3.9Hz,1H).LCMS m/z 511.0[M+H]+。
Example 3: preparation of Compound 3
Figure BDA0003261639710000161
Referring to the synthesis procedure of example 1, compound 3c (1602mg, yield 85%) was obtained in the first step.1H NMR(500MHz,CDCl3)δ5.59(s,1H),3.65(s,3H),3.24(q,J＝7.0Hz,2H),2.72(t,J＝11.0Hz,2H),2.30(t,J＝7.4Hz,2H),2.19(tt,J＝11.6,3.7Hz,1H),1.78(d,J＝12.6Hz,2H),1.66–1.58(m,4H),1.50(dt,J＝14.8,7.4Hz,3H),1.44(s,9H),1.39–1.28(m,3H)。
The second step yielded the hydrochloride salt of compound 3d (763mg, 2.61mmol), LCMS M/z 257.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step gave compound 3f (142mg, yield 66%).1H NMR(500MHz,CDCl3)δ5.80(dd,J＝17.5,10.8Hz,1H),5.58(t,J＝5.1Hz,1H),5.01(s,1H),4.92(d,J＝7.3Hz,2H),4.90–4.81(m,2H),4.75(s,1H),3.65(s,3H),3.40(t,J＝5.1Hz,4H),3.24(q,J＝6.7Hz,2H),3.02(d,J＝13.8Hz,1H),2.96–2.87(m,2H),2.87–2.78(m,2H),2.61(d,J＝13.9Hz,1H),2.38–2.25(m,6H),2.21(dd,J＝12.9,3.2Hz,1H),2.11–1.92(m,5H),1.81–1.57(m,9H),1.49(td,J＝13.3,12.2,8.9Hz,5H),1.44(s,9H),1.41(t,J＝2.6Hz,1H),1.40–1.29(m,3H).LCMS m/z 643.4[M+H]+。
Referring to the synthesis method of example 1, compound 3f (190mg, 0.30mmol) was Boc-deprotected, ester-hydrolyzed, and amide-condensed in this order to finally obtain compound 3(30mg, yield 20%) as a white solid.1H NMR(500MHz,CDCl3)δ5.78(dd,J＝17.5,10.8Hz,1H),5.54(dd,J＝8.0,4.0Hz,1H),4.96–4.90(m,3H),4.89–4.81(m,2H),4.11(d,J＝13.0Hz,1H),3.69–3.59(m,2H),3.33(ddd,J＝13.0,10.0,3.2Hz,1H),3.24–3.18(m,1H),3.00(d,J＝12.4Hz,1H),2.98–2.91(m,1H),2.89–2.71(m,4H),2.61(tt,J＝12.1,3.5Hz,2H),2.57–2.48(m,3H),2.41(d,J＝12.5Hz,1H),2.35–2.22(m,3H),2.20(d,J＝5.2Hz,1H),2.17(dd,J＝10.4,3.0Hz,1H),2.10(ddt,J＝10.9,8.1,3.5Hz,1H),2.02–1.88(m,4H),1.76–1.35(m,13H),0.99(s,3H).LCMS m/z 511.4[M+H]+。
Example 4: preparation of Compound 4
Figure BDA0003261639710000171
According to the synthesis method of example 1, compound 4f (170mg, yield 50%) was obtained.1H NMR(500MHz,CDCl3)δ5.79(dd,J＝17.5,10.8Hz,1H),5.62(t,J＝5.8Hz,1H),5.00(s,1H),4.89–4.81(m,3H),4.76–4.69(m,2H),4.17(dt,J＝3.7,1.8Hz,2H),3.64(s,3H),3.23(q,J＝6.7Hz,2H),3.00(d,J＝13.8Hz,1H),2.87–2.77(m,2H),2.59(d,J＝13.8Hz,1H),2.29(t,J＝7.4Hz,2H),2.21(dd,J＝12.7,3.3Hz,1H),2.06–1.98(m,1H),1.98–1.88(m,3H),1.82–1.57(m,10H),1.49(t,J＝7.5Hz,4H),1.46(s,18H),1.43–1.38(m,2H),0.97(s,3H).LCMS m/z 674.4[M+H]+。
Referring to the synthesis method of example 1, compound 4f (150mg, 0.22mmol) was Boc-deprotected, ester-hydrolyzed, and amide-condensed in this order to finally obtain compound 4(36mg, yield 37%) as a white solid.1H NMR(500MHz,CDCl3)δ6.74(s,1H),5.74(dd,J＝17.5,10.8Hz,1H),5.32(dd,J＝14.2,5.7Hz,1H),4.93–4.83(m,5H),4.72(s,1H),4.40(dd,J＝13.9,8.8Hz,1H),3.64(dq,J＝12.6,6.9,5.9Hz,1H),3.41(dd,J＝14.0,2.9Hz,1H),3.12(ddd,J＝13.7,10.5,3.6Hz,1H),2.96(d,J＝12.1Hz,1H),2.88(d,J＝12.1Hz,1H),2.80(d,J＝10.9Hz,1H),2.57(d,J＝12.2Hz,1H),2.50(dd,J＝12.8,2.6Hz,1H),2.31–2.14(m,3H),2.14–2.06(m,1H),1.97(dq,J＝19.9,12.5,9.2Hz,2H),1.82(dt,J＝10.4,5.6Hz,2H),1.75–1.68(m,2H),1.65–1.39(m,11H),1.34(d,J＝12.9Hz,1H),1.03(s,3H).LCMS m/z 442.2[M+H]+。
Example 5: preparation of Compound 5
Figure BDA0003261639710000181
According to the synthesis method of example 1, compound 5f (256mg, yield 66.8%) was obtained.1H NMR(400MHz,CDCl3)δ5.81(dd,J＝17.5,10.8Hz,1H),5.03(s,1H),4.93(s,1H),4.91–4.81(m,3H),4.77(s,1H),3.67(s,3H),3.57(s,2H),3.31–3.12(m,4H),3.10–2.90(m,3H),2.90–2.81(m,2H),2.77(s,2H),2.60(d,J＝13.8Hz,1H),2.41(d,J＝8.6Hz,3H),2.32(t,J＝7.4Hz,2H),2.24(d,J＝7.6Hz,1H),1.95(s,2H),1.84–1.75(m,3H),1.73–1.67(m,2H),1.63(dd,J＝15.0,7.4Hz,4H),1.59–1.48(m,5H),1.46(s,10H),1.43(s,1H),1.41–1.27(m,4H),0.98(s,3H).LCMS m/z 669.4[M+H]+。
Referring to the synthesis method of example 1, compound 5f (230mg, 0.34mmol) was Boc-deprotected, ester-hydrolyzed, and amide-condensed in this order to finally obtain compound 5(20mg, yield 11%) as a white solid.1H NMR(500MHz,CDCl3)δ6.91–6.72(m,1H),6.00(dd,J＝17.6,10.7Hz,1H),4.88(ddd,J＝35.6,19.7,9.3Hz,5H),4.72(d,J＝11.5Hz,1H),4.05(dd,J＝11.5,9.4Hz,1H),3.97–3.82(m,1H),3.82–3.71(m,1H),3.41(d,J＝13.1Hz,1H),3.32–3.21(m,2H),3.18–3.04(m,1H),3.04–2.94(m,1H),2.94–2.57(m,8H),2.57–2.30(m,4H),2.30–2.12(m,3H),2.02(dd,J＝9.3,3.3Hz,2H),1.98–1.92(m,1H),1.92–1.71(m,3H),1.66–1.48(m,6H),1.47–1.38(m,3H),1.27(d,J＝15.0Hz,3H),0.95(d,J＝3.0Hz,3H).LCMS m/z 537.4[M+H]+。
Example 6: preparation of Compound 6
Figure BDA0003261639710000191
Referring to the synthesis of example 1, compound 6c (1784mg, yield 90%) was obtained in the first step.1H NMR(500MHz,CDCl3)δ6.04(t,J＝5.7Hz,1H),3.98(t,J＝8.5Hz,2H),3.63(d,J＝1.0Hz,3H),3.23(q,J＝6.7Hz,2H),3.15(ddd,J＝14.8,8.5,6.2Hz,1H),2.28(t,J＝7.3Hz,2H),1.60(p,J＝7.3Hz,2H),1.49(p,J＝7.3Hz,3H),1.39(d,J＝1.1Hz,10H),1.33(d,J＝8.3Hz,1H),1.25–1.20(m,1H).LCMS m/z 351.2[M+Na]+。
The second step provided the hydrochloride salt of compound 6d (885mg, 3.35mmol), LCMS M/z 229.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step gave compound 6f (321mg, yield 45%).1H NMR(500MHz,CDCl3)δ6.24(t,J＝5.5Hz,1H),5.83–5.67(m,1H),4.98(s,1H),4.90(s,1H),4.88–4.83(m,2H),4.74(d,J＝4.1Hz,2H),4.19–4.15(m,2H),3.65(s,3H),3.38(t,J＝7.4Hz,1H),3.31(t,J＝7.4Hz,1H),3.26(q,J＝6.8Hz,2H),3.21(t,J＝6.6Hz,2H),3.05–2.98(m,2H),2.88(d,J＝14.1Hz,1H),2.31(t,J＝7.4Hz,2H),1.99(dd,J＝12.5,3.3Hz,1H),1.94(d,J＝8.0Hz,1H),1.67–1.62(m,3H),1.61–1.57(m,1H),1.53(dt,J＝15.1,7.3Hz,4H),1.47(s,19H),1.41–1.30(m,3H),0.98(s,3H).LCMS m/z 646.4[M+H]+。
Referring to the synthesis method of example 1, compound 6f (280mg, 0.43mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 6(32mg, yield 18%) as a white solid.1H NMR(500MHz,CDCl3)δ7.51(s,1H),5.81(dd,J＝17.5,10.7Hz,1H),5.41(t,J＝5.6Hz,1H),5.00(s,1H),4.95(s,1H),4.92–4.85(m,3H),4.71(s,1H),3.77(dd,J＝13.9,5.2Hz,1H),3.61(dtd,J＝13.6,7.3,4.8Hz,1H),3.45–3.39(m,2H),3.21(dt,J＝7.3,2.4Hz,1H),3.15(t,J＝7.4Hz,1H),3.13–3.07(m,1H),3.04(t,J＝7.6Hz,1H),2.84(ddd,J＝7.7,5.5,2.2Hz,1H),2.58(d,J＝8.5Hz,1H),2.56(d,J＝3.6Hz,1H),2.29(dd,J＝12.9,3.1Hz,1H),2.20(t,J＝6.2Hz,2H),1.93–1.90(m,1H),1.74(ddd,J＝13.3,6.7,3.2Hz,1H),1.71–1.64(m,2H),1.64–1.59(m,3H),1.45(d,J＝7.3Hz,2H),1.39(dtd,J＝14.7,6.4,5.2,3.5Hz,2H),1.05(t,J＝7.2Hz,2H),0.94(s,3H).LCMS m/z 414.2[M+H]+。
Example 7: preparation of Compound 7
Figure BDA0003261639710000211
Referring to the synthesis of example 1, compound 7c (440mg, yield 97%) was obtained in the first step.1H NMR(500MHz,CDCl3)δ6.04(s,1H),4.00(s,1H),3.62(s,3H),3.23(q,J＝6.8Hz,2H),2.61(s,2H),2.32(t,J＝7.2Hz,2H),2.10(t,J＝7.6Hz,2H),1.78(p,J＝7.0Hz,2H),1.65–1.54(m,4H),1.40(s,9H),1.32(dtt,J＝14.5,6.9,3.8Hz,1H),1.24–1.14(m,3H),1.01(qd,J＝12.6,4.2Hz,2H).LCMS m/z 393.2[M+Na]+。
The second step yielded the hydrochloride salt of compound 7d (364mg, 1.19mmol), LCMS M/z 271.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step gave compound 7f (333mg, yield 40%).1H NMR(500MHz,CDCl3)δ5.79(dd,J＝17.5,10.8Hz,1H),5.71(s,1H),5.01(s,1H),4.90–4.81(m,3H),4.73(d,J＝8.4Hz,2H),4.17(s,2H),3.67(s,3H),3.28(q,J＝6.5Hz,2H),2.96(d,J＝14.0Hz,1H),2.75(d,J＝9.7Hz,2H),2.60(d,J＝14.0Hz,1H),2.36(t,J＝7.1Hz,2H),2.17(dd,J＝12.6,2.8Hz,1H),2.12(t,J＝7.6Hz,2H),1.94(t,J＝10.9Hz,1H),1.91–1.85(m,1H),1.85–1.80(m,2H),1.61(q,J＝12.5,9.9Hz,8H),1.52(s,2H),1.47(s,20H),1.44–1.38(m,2H),1.13(dd,J＝20.8,8.9Hz,2H),0.98(s,3H)。
Referring to the synthesis method of example 1, compound 7f (317mg, 0.46mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 7(79.5mg, yield 38%) as a white solid.1H NMR(500MHz,CDCl3)δ6.72(s,1H),5.74(dd,J＝17.5,10.8Hz,1H),4.95(s,1H),4.91(s,1H),4.90–4.88(m,2H),4.87–4.83(m,2H),4.72(s,1H),3.98(dd,J＝14.0,6.2Hz,1H),3.79(dd,J＝14.1,5.0Hz,1H),3.45–3.33(m,1H),3.28(ddd,J＝13.6,10.6,5.0Hz,1H),3.01(d,J＝12.3Hz,1H),2.78(d,J＝10.3Hz,1H),2.71(d,J＝10.6Hz,1H),2.53(d,J＝12.4Hz,1H),2.47(dd,J＝12.7,2.9Hz,1H),2.29(t,J＝7.0Hz,2H),2.25(t,J＝6.8Hz,1H),2.14(dt,J＝14.5,7.3Hz,1H),2.09–1.90(m,3H),1.85(ddq,J＝9.6,4.7,2.1Hz,2H),1.69–1.59(m,5H),1.58–1.49(m,4H),1.46(dd,J＝12.2,5.3Hz,2H),1.43–1.34(m,3H),1.05(d,J＝7.2Hz,1H),1.01(s,3H).LCMS m/z 456.4[M+H]+。
Example 8: preparation of Compound 8
Figure BDA0003261639710000221
According to the synthesis method of example 1, compound 8c (141mg, yield 88%) was obtained as the first step.1H NMR(500MHz,CDCl3)δ5.51(s,1H),4.16–3.99(m,2H),3.67(s,3H),3.25(q,J＝6.7Hz,2H),2.71(t,J＝11.8Hz,2H),2.31(t,J＝7.3Hz,2H),2.06(d,J＝7.1Hz,2H),1.98(ddq,J＝14.9,7.7,4.0Hz,1H),1.65(dq,J＝15.0,9.1,7.4Hz,6H),1.51(dt,J＝14.8,7.2Hz,2H),1.44(s,9H),1.11(qd,J＝12.6,4.1Hz,2H).LCMS m/z 393.2[M+Na]+。
To a solution of compound 8c (136mg, 0.37mmol) in methanol (2mL) under ice-bath conditions was added a cooled solution of NaOH (1M, 2mL), the ice-bath was removed after stirring for about 10min, and the mixture was stirred at room temperature for about 4 h. After methanol was evaporated under reduced pressure, an HCl solution (1M) was slowly added dropwise to the reaction solution under ice-bath conditions while stirring, the pH was adjusted to about 2, and the mixture was extracted with ethyl acetate (8mL × 3). The combined organic phases were washed successively with water (6 mL. times.2) and saturated brine (6 mL. times.2) and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give colorless transparent liquid 8d (111.7mg, yield 85%), LCMS M/z 355.2[ M-H ]]-. The crude product was used in the next reaction without purification.
To a solution of compound 1e (796mg, 1.76mmol) in methanol (5mL) under ice bath conditions was added a solution of dioxane hydrochloride (4M, 8mL), the ice bath was removed after stirring for about 10min, and the mixture was further stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and a cooled aqueous potassium carbonate solution (10%) was added to the aqueous phase while stirring, and the pH was adjusted to about 12, followed by extraction with ethyl acetate (10mL × 3). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (10mL x3), water (10mL x3) and saturated brine (10mL x3) and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain colorless transparent liquid 8e (402.4 mg. yield 90%). The crude product was used in the next reaction without purification.
To a solution of compound 8d (51mg, 0.2mmol) in anhydrous DMF (2mL) at room temperature was added compound 8e (72mg, 0.2mmol), DIPEA (78.4mg, 0.6mmol) in that order, and after stirring for about 5min, EDCI (101mg, 0.5mmol) and HOBt (36mg, 0.3mmol) were added and stirred for about 6 h. DMF was evaporated under reduced pressure, quenched by the addition of ice water (5mL), and extracted with ethyl acetate (4 mL. times.3). The combined organic phases were washed successively with water (5 mL. times.2) and saturated brine (5 mL. times.2) and then 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 (eluting with a methylene chloride/methanol system) to give compound 8f (29mg, yield 34%).1H NMR(500MHz,CDCl3)δ5.87(t,J＝5.4Hz,1H),5.75(dd,J＝17.3,10.9Hz,2H),4.94–4.92(m,1H),4.92–4.87(m,3H),4.86(s,1H),4.07(d,J＝11.6Hz,2H),3.95(d,J＝11.6Hz,1H),3.93–3.88(m,1H),3.83(dd,J＝15.9,5.7Hz,1H),3.23(q,J＝6.8Hz,2H),2.69(s,2H),2.26(dd,J＝11.3,4.7Hz,1H),2.21(t,J＝7.4Hz,2H),2.05(d,J＝7.1Hz,2H),1.97(ddq,J＝14.7,7.6,4.2Hz,4H),1.66(dt,J＝14.7,7.5Hz,6H),1.62–1.58(m,2H),1.57–1.44(m,3H),1.43(s,11H),1.11(ddt,J＝19.9,11.9,5.9Hz,3H),0.96(s,3H).LCMS m/z 592.2[M+H]+。
With reference to the synthesis of example 1, compound 8g of hydrochloride (18mg, 0.034mmol), LCMS M/z 492.2[ M + H ] was obtained]+. The crude product was used in the next reaction without purification.
To a solution of compound 8g (18mg, 0.034mmol) in anhydrous DMF (4mL) at room temperature was added cesium carbonate (17.6mg, 0.054mmol), and the mixture was gradually warmed to 90 ℃ and stirred overnight. DMF was evaporated under reduced pressure, quenched by addition of ice water (4mL), and extracted with ethyl acetate: (A)3mL x 3). The combined organic phases were washed successively with water (5 mL. times.2) and saturated brine (5 mL. times.2) and then 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 (eluting with a dichloromethane/methanol/triethylamine (0.1%) system) to give compound 8(10.8mg, yield 70%).1H NMR(500MHz,CDCl3)δ6.21(s,1H),5.79(dd,J＝17.5,10.8Hz,1H),5.64(s,1H),4.94(d,J＝6.6Hz,2H),4.92–4.83(m,3H),4.76(s,1H),3.96–3.81(m,2H),3.44(ddd,J＝18.5,13.2,7.3Hz,1H),3.23–3.13(m,1H),3.05(d,J＝12.4Hz,1H),2.77(d,J＝8.9Hz,2H),2.55(d,J＝12.3Hz,1H),2.37–2.31(m,1H),2.31–2.21(m,2H),2.21–2.12(m,1H),2.11–2.03(m,1H),2.03–1.94(m,2H),1.94–1.87(m,1H),1.69–1.56(m,8H),1.55–1.45(m,5H),1.44–1.32(m,4H),1.03(s,3H).LCMS m/z 456.4[M+H]+。
Example 9: preparation of Compound 9
Figure BDA0003261639710000241
Referring to the synthesis of example 8, compound 9b (462.5mg, 98.6% yield) was obtained and the crude product was used in the next reaction without purification.
To a solution of compound 9b (81mg, 0.22mmol) in anhydrous dichloromethane (2.5mL) was added DIPEA (62mg, 0.48mmol) and compound 9c (43mg, 0.22mmol) under ice-bath conditions, and the mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting with a dichloromethane/methanol/aqueous ammonia (0.1%) system) to obtain compound 9(43mg, yield 40%) as a white solid.1H NMR(400MHz,CDCl3)δ5.74(dd,J＝17.4,10.9Hz,1H),4.95(d,J＝5.6Hz,2H),4.93–4.87(m,2H),4.86(s,1H),4.81(s,1H),3.97(d,J＝12.9Hz,1H),3.70–3.42(m,4H),3.34(ddd,J＝11.8,7.5,2.8Hz,1H),3.19(dt,J＝12.2,6.3Hz,2H),3.09(d,J＝12.4Hz,1H),3.01(d,J＝12.6Hz,1H),2.86(d,J＝12.6Hz,1H),2.58(t,J＝12.7Hz,2H),2.53–2.43(m,2H),2.42–2.21(m,9H),2.11(ddd,J＝15.1,9.1,3.4Hz,1H),1.98(t,J＝9.3Hz,1H),1.70(dq,J＝13.4,7.0Hz,1H),1.54(dtd,J＝35.8,13.2,8.8Hz,9H),1.35(q,J＝6.7Hz,2H),1.02(s,3H).LCMS m/z 497[M+H]+。
Example 10: preparation of Compound 10
Figure BDA0003261639710000251
According to the synthesis method of example 9, compound 10(57mg, yield 54%) was obtained as a white solid.1H NMR(400MHz,CDCl3)δ5.74(dd,J＝17.8,10.5Hz,1H),4.96(d,J＝6.7Hz,2H),4.93(s,1H),4.89(dd,J＝5.8,1.2Hz,1H),4.86(s,1H),4.84(d,J＝1.5Hz,1H),3.75–3.55(m,2H),3.53–3.35(m,5H),3.34–3.23(m,1H),3.06(d,J＝12.8Hz,1H),2.97(s,2H),2.71(d,J＝13.0Hz,1H),2.53–2.11(m,14H),2.00(d,J＝8.2Hz,1H),1.60(dddd,J＝51.2,23.7,11.6,6.0Hz,9H),1.01(s,3H)。
Example 11: preparation of Compound 11
Figure BDA0003261639710000252
According to the synthesis method of example 9, compound 11(29mg, yield 13%) was obtained.1H NMR(500MHz,CDCl3)δ5.78(dd,J＝17.5,10.8Hz,1H),5.05(s,1H),4.93(d,J＝5.9Hz,2H),4.90–4.82(m,2H),4.79(d,J＝1.7Hz,1H),3.58(s,4H),3.51–3.40(m,4H),3.03(d,J＝14.0Hz,1H),2.91(q,J＝13.4Hz,2H),2.64(d,J＝14.0Hz,1H),2.39(dt,J＝7.1,3.5Hz,5H),2.37–2.33(m,3H),2.29–2.22(m,2H),2.17(dd,J＝12.8,2.8Hz,1H),2.05(dd,J＝20.7,7.2Hz,3H),1.96–1.88(m,2H),1.60(t,J＝12.5Hz,2H),1.53–1.38(m,4H),0.98(s,3H).LCMS m/z 469.4[M+H]+。
Example 12: preparation of Compound 12
Figure BDA0003261639710000261
With reference to the synthesis method of example 9, foamy solid compound 12 was obtained(9mg, yield 9%).1H NMR(500MHz,CDCl3)δ5.79(dd,J＝17.5,10.8Hz,1H),5.03(d,J＝9.2Hz,1H),4.94(s,1H),4.93–4.82(m,3H),4.79(s,1H),3.54(dd,J＝31.4,12.9Hz,8H),3.06(t,J＝11.6Hz,1H),3.00–2.82(m,2H),2.66(s,3H),2.61(d,J＝12.4Hz,1H),2.50–2.15(m,9H),2.07(t,J＝11.0Hz,1H),1.91(s,1H),1.70–1.38(m,6H),0.98(s,3H)。
Example 13: preparation of Compound 13
Figure BDA0003261639710000262
Referring to the synthesis of example 9, compound 13b was obtained as a yellow oil in the first step (181.5mg, yield 73%), and the crude product was used in the next reaction without purification.
The second step yielded compound 13 as a white solid (20mg, yield 27%).1H NMR(400MHz,CDCl3)δ5.86(dd,J＝17.5,10.7Hz,1H),5.77–5.67(m,1H),5.56–5.45(m,1H),5.06(s,1H),5.01–4.99(m,1H),4.96(dd,J＝10.8,1.3Hz,1H),4.93–4.86(m,2H),4.74–4.71(m,1H),4.26–4.14(m,2H),3.79(dd,J＝14.4,4.6Hz,1H),3.28(dd,J＝13.7,2.8Hz,1H),2.40–2.29(m,1H),2.29–2.09(m,4H),2.05–1.84(m,3H),1.80–1.71(m,2H),1.57–1.53(m,2H),1.50(dd,J＝5.3,3.6Hz,2H),1.43–1.35(m,2H),0.99(s,3H)。
Example 14: preparation of Compound 14
Figure BDA0003261639710000271
Compound 14(20mg, yield 9%) was obtained as a white solid according to the synthesis method of example 9.1H NMR(500MHz,CDCl3)δ5.75(dd,J＝17.4,10.9Hz,2H),5.42(t,J＝6.1Hz,1H),5.07(s,1H),4.94(s,1H),4.92(d,J＝3.3Hz,1H),4.91–4.88(m,1H),4.87(s,1H),4.80(s,1H),3.84(dd,J＝14.4,5.4Hz,1H),3.78(dd,J＝13.2,7.2Hz,1H),3.63–3.58(m,1H),2.56(dt,J＝14.9,5.7Hz,1H),2.45(ddd,J＝14.9,9.4,5.1Hz,1H),2.37–2.31(m,2H),2.10–2.05(m,1H),2.03–1.95(m,2H),1.93(d,J＝11.0Hz,1H),1.85(ddd,J＝14.8,9.1,5.7Hz,1H),1.62–1.45(m,6H),1.03(s,3H)。
Example 15: preparation of Compound 15
Figure BDA0003261639710000272
To a solution of compound 13b (110mg, 0.47mmol) in anhydrous dichloromethane (3mL) under ice-bath conditions, compound 15c (117mg, 1.00mmol) was slowly added, gradually warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice water (5mL), followed by addition of saturated aqueous sodium bicarbonate (5mL) and extraction with dichloromethane (4mL x 3). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (5mL x 2), water (5mL x 2) and saturated brine (5mL x 2) and then 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 (eluting with dichloromethane/methanol/triethylamine (0.1%) system) to give compound 15d (60mg, yield 33%), LCMS M/z 387.2[ M + H ], (M + H)]+。
To a solution of compound 15d (60mg, 0.155mmol) in anhydrous acetonitrile (2mL) under ice-bath conditions was added a solution of compound 15e (14mg, 0.155mmol) in anhydrous acetonitrile (4mL), and finally Cs was added2CO3(17.6mg, 0.054mmol), gradually warmed to 40 ℃ and stirred overnight. The reaction was concentrated under reduced pressure, quenched by the addition of ice water (2mL), adjusted to pH 9 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4 mL. times.3). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (5mL x 2), water (5mL x 2) and saturated brine (5mL x 2) and then 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 (eluting with a dichloromethane/methanol/triethylamine (0.1%) system) to give compound 15(24.6mg, yield 39%).1H NMR(500MHz,CDCl3)δ7.25(d,J＝7.8Hz,1H),7.12(s,1H),5.84(dd,J＝17.4,10.8Hz,1H),5.15(s,1H),5.08(s,1H),4.99–4.88(m,3H),4.83(s,1H),4.15(dd,J＝13.4,8.2Hz,1H),4.06(dd,J＝14.0,7.1Hz,1H),3.78(dd,J＝14.0,4.6Hz,1H),3.47(dd,J＝13.6,3.7Hz,1H),3.04(qd,J＝16.8,5.4Hz,4H),2.56(dddd,J＝24.2,14.7,8.7,4.7Hz,4H),2.35(s,6H),2.01(dd,J＝12.9,3.1Hz,1H),1.91(td,J＝14.8,11.8,3.2Hz,1H),1.62(q,J＝12.9Hz,1H),1.48(dtd,J＝16.5,11.5,10.8,4.7Hz,4H),1.06(t,J＝7.1Hz,1H),1.03(s,3H).LCMS m/z 403.2[M+H]+。
Example 16: preparation of Compound 16
Figure BDA0003261639710000281
To a solution of compound 16a (510mg, 9mmol) in dry methanol (8mL) at room temperature was added compound 16b (1923mg, 22mmol), and the mixture was gradually warmed to 50 ℃ and stirred for 2 days. The reaction mixture was concentrated under reduced pressure to obtain compound 16c (1.8g, yield 88%).1H NMR(500MHz,CDCl3)δ3.65(s,6H),2.91(t,J＝7.3Hz,4H),2.51(t,J＝7.3Hz,4H),1.71(tt,J＝6.7,3.8Hz,1H),0.48–0.36(m,4H).LCMS m/z 230.2[M+H]+。
With reference to the synthesis procedure of example 1, compound 16d (1474mg, 7.3mmol), LCMS M/z 200.0[ M-H ] was obtained]-. The crude product was used in the next reaction without purification.
Compound 16(30mg, yellow oil, yield 29%) was synthesized from compounds 16d and 9b according to the synthesis method of example 1.1H NMR(500MHz,CDCl3)δ5.75(dd,J＝17.5,10.8Hz,1H),4.99(s,1H),4.95(s,1H),4.93(s,1H),4.90(dd,J＝9.5,1.1Hz,1H),4.88–4.86(m,1H),4.83(d,J＝1.3Hz,1H),4.02(d,J＝13.0Hz,1H),3.75(d,J＝13.6Hz,1H),3.57–3.47(m,2H),3.37–3.20(m,2H),3.19–3.09(m,3H),3.06(d,J＝12.6Hz,1H),2.99–2.91(m,2H),2.91–2.83(m,2H),2.83–2.75(m,1H),2.65(d,J＝12.7Hz,1H),2.52(tdq,J＝22.3,15.6,8.1Hz,7H),2.44–2.38(m,1H),2.38–2.30(m,2H),2.30–2.22(m,2H),2.09(ddd,J＝14.8,9.9,3.5Hz,1H),2.04–1.97(m,1H),1.76(dq,J＝6.7,3.4Hz,1H),1.67–1.61(m,1H),1.58–1.41(m,5H),1.02(s,3H),0.48(dt,J＝5.7,2.7Hz,2H),0.44–0.34(m,2H).LCMS m/z 538.0[M+H]+。
Example 17: preparation of Compound 17
Figure BDA0003261639710000291
Compound 17(27mg, yield 17%) was obtained as a white solid according to the synthesis method of example 1.1H NMR(500MHz,CDCl3)δ6.04(d,J＝6.2Hz,1H),5.83(dd,J＝17.5,10.8Hz,1H),5.75–5.61(m,1H),5.06(s,1H),4.98–4.86(m,3H),4.84(s,1H),4.75(s,1H),4.53(dd,J＝14.5,9.1Hz,1H),4.11(dd,J＝13.6,7.4Hz,1H),3.47(ddd,J＝12.8,8.7,3.8Hz,2H),3.14(ddd,J＝12.8,10.4,2.7Hz,1H),3.04(ddd,J＝12.8,9.1,3.4Hz,1H),2.71(ddd,J＝13.0,6.7,3.5Hz,1H),2.65–2.54(m,2H),2.45(ddd,J＝14.8,9.1,3.6Hz,1H),2.32(dddd,J＝17.8,14.6,6.5,2.7Hz,2H),2.02(s,1H),1.94(dt,J＝13.3,3.6Hz,3H),1.62(td,J＝6.6,3.3Hz,1H),1.59–1.52(m,2H),1.49(dd,J＝9.6,5.7Hz,2H),1.01(s,3H),0.55(td,J＝6.4,1.7Hz,1H),0.48(dd,J＝10.4,6.6Hz,1H),0.39(d,J＝3.8Hz,2H).LCMS m/z 400.0[M+H]+。
Example 18: preparation of Compound 18
Figure BDA0003261639710000301
According to the synthesis method of example 1, compound 18f (194mg, yield 42%) was obtained.1H NMR(500MHz,CDCl3)δ6.31(t,J＝5.8Hz,1H),5.74(dd,J＝18.0,10.3Hz,1H),5.00(s,1H),4.94–4.91(m,1H),4.90(d,J＝3.6Hz,2H),4.88–4.85(m,1H),4.76(s,1H),3.71(q,J＝7.0Hz,1H),3.65(s,3H),3.45(t,J＝8.4Hz,1H),3.39(dt,J＝13.9,6.2Hz,5H),3.29–3.22(m,4H),3.11–3.04(m,2H),2.96–2.85(m,3H),2.31(dd,J＝9.3,5.5Hz,6H),2.08(t,J＝11.0Hz,1H),2.01(dd,J＝12.7,3.2Hz,1H),1.68–1.46(m,7H),1.44(s,9H),1.40–1.29(m,3H),1.23(t,J＝7.0Hz,1H),0.98(s,3H).LCMS m/z 615.0[M+H]+。
With reference to the synthesis method of example 1, compound 18f (190mg, 0.31mmol) was subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction in this order to finally obtain compound 18(53mg, v/v) as a white solidRate 35.5%).1H NMR(500MHz,CDCl3)δ5.91(t,J＝6.1Hz,1H),5.75(dd,J＝17.4,10.9Hz,1H),5.03(d,J＝1.5Hz,1H),4.97–4.90(m,2H),4.88(dd,J＝8.9,1.4Hz,1H),4.85(q,J＝1.4Hz,1H),4.76(d,J＝1.6Hz,1H),3.76(s,1H),3.45(dt,J＝14.0,6.2Hz,3H),3.40–3.18(m,5H),3.18–3.00(m,4H),2.89(dd,J＝17.3,12.6Hz,2H),2.51(dt,J＝15.1,3.4Hz,1H),2.46–2.30(m,4H),2.23(ddd,J＝11.3,7.8,3.2Hz,1H),2.18(dd,J＝13.0,3.1Hz,1H),2.11–1.91(m,4H),1.79–1.65(m,2H),1.60(ddd,J＝13.3,6.9,3.2Hz,2H),1.55–1.38(m,5H),1.00(s,3H).LCMS m/z 483.4[M+H]+。
Example 19: preparation of Compound 19
Figure BDA0003261639710000311
Referring to the synthesis of example 1, compound 19c was obtained as a yellow solid in the first step (1170mg, 86% yield).1H NMR(500MHz,CDCl3)δ6.09(s,1H),4.05(s,2H),3.69(s,3H),3.50(q,J＝6.0Hz,2H),2.64(s,2H),2.57–2.46(m,2H),2.17(t,J＝7.8Hz,2H),1.69–1.50(m,4H),1.43(s,9H),1.38(ddq,J＝11.3,7.5,3.7Hz,1H),1.07(qd,J＝12.5,4.4Hz,2H).LCMS m/z 343.2[M+H]+。
The second step provided the hydrochloride salt of compound 19d (300mg, 1.08mmol), LCMS M/z 243.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step gave compound 19f (287mg, yield 40%).1H NMR(500MHz,CDCl3)δ6.13(t,J＝5.6Hz,1H),5.77(dd,J＝17.5,10.8Hz,1H),4.99(s,1H),4.87–4.80(m,3H),4.71(d,J＝7.6Hz,2H),4.15(s,2H),3.67(s,3H),3.48(q,J＝6.0Hz,2H),2.94(d,J＝13.9Hz,1H),2.74(d,J＝9.3Hz,2H),2.57(d,J＝14.0Hz,1H),2.51(t,J＝6.0Hz,2H),2.20–2.11(m,3H),2.01(s,1H),1.92(t,J＝11.1Hz,1H),1.84(d,J＝11.5Hz,1H),1.56(ddd,J＝34.3,18.6,7.8Hz,10H),1.45(s,19H),1.42–1.37(m,2H),0.95(s,3H).LCMS m/z 660.4[M+H]+。
With reference to the synthesis method of example 1, compound 19f (200mg, 0.30mmol) was sequentially subjected toBoc deprotection, ester hydrolysis, amide condensation gave compound 19 as a white solid (30mg, 23% yield).1H NMR(500MHz,CDCl3)δ6.52(t,J＝6.2Hz,1H),5.75(dd,J＝17.5,10.8Hz,1H),5.40–5.30(m,1H),5.00(d,J＝1.1Hz,1H),4.97(d,J＝1.1Hz,1H),4.91(d,J＝1.7Hz,1H),4.88(dd,J＝11.1,1.5Hz,1H),4.86–4.83(m,1H),4.68(d,J＝1.6Hz,1H),3.96(dd,J＝13.5,6.4Hz,1H),3.84(dd,J＝13.5,5.0Hz,1H),3.63(dtd,J＝14.1,7.2,2.5Hz,1H),3.42(dddd,J＝13.8,8.0,5.3,2.4Hz,1H),3.17(d,J＝12.8Hz,1H),2.75–2.62(m,2H),2.55(d,J＝12.8Hz,1H),2.51–2.41(m,2H),2.34–2.24(m,1H),2.24–2.19(m,1H),2.12(ddd,J＝15.0,9.1,2.2Hz,1H),1.98(dddd,J＝19.0,10.0,4.1,2.2Hz,3H),1.66–1.59(m,2H),1.57–1.37(m,10H),1.04(dd,J＝12.0,3.7Hz,1H),0.98(s,3H)。
Example 20: preparation of Compound 20
Figure BDA0003261639710000321
According to the synthesis method of example 1, compound 20f (242mg, yield 75% (minus recovered raw material 2e)) was obtained.1H NMR(500MHz,CDCl3)δ6.17(t,J＝6.3Hz,1H),5.79(dd,J＝17.5,10.8Hz,1H),5.01(s,1H),4.95–4.89(m,2H),4.89–4.81(m,2H),4.75(s,1H),3.69(s,3H),3.50(q,J＝6.1Hz,2H),3.40(d,J＝5.1Hz,4H),3.05–2.96(m,1H),2.95–2.85(m,2H),2.79(s,2H),2.60(d,J＝13.7Hz,1H),2.53(t,J＝6.0Hz,2H),2.31(t,J＝5.2Hz,4H),2.20(dd,J＝12.7,3.2Hz,1H),2.14(t,J＝7.9Hz,2H),2.12–2.04(m,2H),1.98–1.83(m,1H),1.74–1.46(m,10H),1.44(s,9H),1.43–1.38(m,1H),1.19(s,2H),0.98(s,3H).LCMS m/z 629.4[M+H]+。
Referring to the synthesis method of example 1, compound 20f (150mg, 0.22mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 20 as a white solid (74mg, yield 49%).1H NMR(500MHz,CDCl3)δ6.15(t,J＝6.1Hz,1H),5.76(dd,J＝17.5,10.8Hz,1H),4.97–4.90(m,3H),4.89–4.82(m,2H),4.76(s,1H),3.78(d,J＝13.0Hz,1H),3.72–3.60(m,1H),3.51–3.31(m,3H),3.20(ddd,J＝12.4,8.7,3.5Hz,1H),3.04(t,J＝14.1Hz,2H),2.88–2.68(m,3H),2.58(ddt,J＝11.7,8.9,3.3Hz,3H),2.52–2.43(m,2H),2.36(ddd,J＝11.5,8.5,3.4Hz,1H),2.32–1.87(m,7H),1.75–1.32(m,12H),1.16(ddt,J＝11.1,7.2,3.8Hz,1H),1.00(s,3H).LCMS m/z 497.4[M+H]+。
Example 21: preparation of Compound 21
Figure BDA0003261639710000341
Referring to the synthesis of example 1, compound 21c was obtained as a yellow solid in the first step (195mg, 94% yield).1H NMR(500MHz,CDCl3)δ6.21–6.08(m,1H),4.00(s,2H),3.61(s,3H),3.29–3.15(m,2H),2.60(s,2H),2.30(td,J＝7.2,1.4Hz,2H),2.13(t,J＝7.8Hz,2H),1.77(pd,J＝7.1,1.5Hz,2H),1.55(dd,J＝36.2,10.2Hz,4H),1.38(d,J＝1.5Hz,9H),1.34(dt,J＝11.0,3.6Hz,1H),1.02(qd,J＝12.3,4.3Hz,2H).LCMS m/z 379.2[M+Na]+。
The second step yielded the hydrochloride salt of compound 21d (136mg, 0.53mmol), LCMS M/z 257.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step yielded compound 21f (135mg, yield 73% (minus recovered starting material 2 e)).1H NMR(500MHz,CDCl3)δ6.00(t,J＝5.8Hz,1H),5.79(dd,J＝17.5,10.9Hz,1H),5.02(s,1H),4.91(d,J＝5.2Hz,2H),4.88–4.82(m,2H),4.76(s,1H),3.66(s,3H),3.44–3.31(m,4H),3.26(q,J＝6.6Hz,2H),3.03(d,J＝13.1Hz,1H),2.90(s,2H),2.80(s,2H),2.61(d,J＝12.6Hz,1H),2.35(t,J＝7.2Hz,3H),2.31(s,3H),2.23(d,J＝12.1Hz,1H),2.17–2.04(m,3H),1.94(s,1H),1.82(p,J＝7.1Hz,2H),1.69(s,1H),1.64–1.45(m,10H),1.43(s,9H),1.42–1.37(m,2H),1.30(s,1H),0.97(s,3H).LCMS m/z 643.4[M+H]+。
Referring to the synthesis method of example 1, compound 21f (130mg, 0.20mmol) was Boc-deprotected, ester-hydrolyzed, and amide-condensed in this order to finally obtain compound 21 as a white solid (30mg, yield 29%).1H NMR(500MHz,CDCl3)δ6.29(dd,J＝6.5,3.4Hz,1H),5.84–5.69(m,1H),4.96(d,J＝1.4Hz,1H),4.95–4.91(m,2H),4.90–4.82(m,2H),4.75(d,J＝1.8Hz,1H),3.90(d,J＝13.0Hz,1H),3.50(dt,J＝12.6,4.1Hz,1H),3.47–3.40(m,1H),3.37(ddd,J＝12.4,9.1,3.5Hz,1H),3.32–3.21(m,1H),3.21–3.13(m,1H),3.09–2.98(m,2H),2.80(d,J＝12.5Hz,1H),2.75(d,J＝11.6Hz,1H),2.68(d,J＝11.5Hz,1H),2.64–2.56(m,1H),2.51(dd,J＝12.1,4.4Hz,2H),2.47–2.37(m,2H),2.33(dddd,J＝16.6,9.2,6.0,3.3Hz,2H),2.19–1.95(m,6H),1.88–1.82(m,1H),1.74–1.39(m,11H),1.30(s,1H),1.20(d,J＝10.5Hz,2H),1.03(s,3H).LCMS m/z 511.4[M+H]+。
Example 22: preparation of Compound 22
Figure BDA0003261639710000351
According to the synthesis method of example 1, compound 22f (320mg, yield 65%) was obtained.1H NMR(500MHz,CDCl3)δ6.05(s,1H),5.80(dd,J＝17.5,10.7Hz,1H),5.02(s,1H),4.92(d,J＝1.7Hz,1H),4.90–4.81(m,3H),4.76(s,1H),3.67(s,3H),3.63–3.49(m,2H),3.27(q,J＝6.6Hz,2H),3.22–3.09(m,2H),3.07–2.89(m,3H),2.88–2.69(m,4H),2.67–2.45(m,3H),2.44–2.29(m,4H),2.18(dt,J＝16.0,9.1Hz,3H),2.07(s,3H),1.92(s,1H),1.83(p,J＝7.1Hz,2H),1.74–1.47(m,10H),1.45(s,9H),1.43–1.37(m,2H),0.97(s,3H).LCMS m/z 669.4[M+H]+。
Referring to the synthesis method of example 1, compound 22f (200mg, 0.22mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 22(63.5mg, yield 41%) as a white solid.1H NMR(500MHz,CDCl3)δ7.65(s,1H),5.81(dt,J＝17.6,11.1Hz,1H),5.06–4.66(m,6H),4.08(ddd,J＝30.5,12.1,9.1Hz,1H),3.76(ddd,J＝17.4,10.8,8.7Hz,1H),3.24(tdd,J＝17.4,11.9,7.3Hz,2H),3.08(dd,J＝13.6,5.5Hz,1H),3.01(s,1H),3.00–2.81(m,3H),2.80–2.47(m,7H),2.37(td,J＝9.9,8.8,5.5Hz,3H),2.29–2.02(m,6H),2.02–
1.86(m,2H),1.78–1.69(m,2H),1.68–1.60(m,3H),1.58–1.35(m,7H),1.20(s,1H),1.17–1.08(m,1H),0.98(s,3H).LCMS m/z 537.4[M+H]+。
Example 23: preparation of Compound 23
Figure BDA0003261639710000371
According to the synthesis method of example 1, compound 23c (546mg, yield 86%) was obtained in the first step.1H NMR(500MHz,CDCl3)δ6.26(s,1H),3.99(s,2H),3.60(s,3H),3.21(q,J＝6.9Hz,2H),2.63(t,J＝12.6Hz,2H),2.29(t,J＝7.2Hz,2H),2.01(d,J＝7.1Hz,2H),1.90(ddh,J＝11.0,7.2,3.5Hz,1H),1.76(p,J＝7.1Hz,2H),1.60(d,J＝12.6Hz,2H),1.37(s,9H),1.04(qd,J＝12.4,4.2Hz,2H).LCMS m/z 365.2[M+Na]+。
The second step yielded the hydrochloride salt of compound 23d (150mg, 0.62mmol), LCMS M/z 243.2[ M + H ]]+. The crude product was used in the next reaction without purification.
The third step gave compound 23f (152mg, yield 40%).1H NMR(500MHz,CDCl3)δ6.06(t,J＝5.9Hz,1H),5.80(dd,J＝17.5,10.8Hz,1H),5.04(s,1H),4.92(d,J＝1.6Hz,1H),4.91(s,1H),4.87(dd,J＝10.1,1.4Hz,1H),4.84(q,J＝1.4Hz,1H),4.80(s,1H),3.66(s,3H),3.40(s,4H),3.27(q,J＝6.6Hz,2H),3.04(d,J＝13.0Hz,1H),2.92(s,2H),2.84(s,2H),2.65(d,J＝13.6Hz,1H),2.35(t,J＝7.3Hz,4H),2.32–2.21(m,3H),2.17–2.04(m,3H),2.01(d,J＝7.2Hz,1H),1.82(p,J＝7.1Hz,4H),1.70–1.46(m,7H),1.44(s,10H),1.43–1.38(m,2H),0.98(s,3H).LCMS m/z 629.4[M+H]+。
Referring to the synthesis method of example 1, compound 23f (150mg, 0.21mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 23 as a white solid (50mg, yield 42%).1H NMR(500MHz,CDCl3)δ6.24(d,J＝6.7Hz,1H),5.80(dd,J＝17.5,10.8Hz,1H),4.96(s,1H),4.92–4.81(m,4H),4.71(s,1H),4.20(d,J＝13.0Hz,1H),3.63–3.50(m,2H),3.23(d,J＝11.7Hz,1H),3.14–3.04(m,3H),2.99(q,J＝12.9Hz,2H),2.83–2.73(m,2H),2.70(d,J＝11.6Hz,2H),2.54–2.38(m,3H),2.38–2.32(m,1H),2.31–2.19(m,4H),2.15(td,J＝11.3,2.8Hz,1H),2.07(td,J＝11.2,3.4Hz,2H),2.00–1.92(m,1H),1.86–1.75(m,1H),1.71(ddt,J＝13.3,8.8,4.4Hz,1H),1.58(ddd,J＝36.2,20.2,7.3Hz,6H),1.50–1.37(m,4H),0.99(s,3H).LCMS m/z 497.4[M+H]+。
Example 24: preparation of Compound 24
Figure BDA0003261639710000381
According to the synthesis method of example 1, compound 24f (215mg, yield 53%) was obtained.1H NMR(500MHz,CDCl3)δ6.94(s,1H),5.82(dd,J＝17.5,10.7Hz,1H),5.02(s,1H),4.90(s,1H),4.89–4.80(m,3H),4.73(d,J＝38.1Hz,1H),3.76–3.67(m,1H),3.65(s,3H),3.53(d,J＝28.9Hz,1H),3.26(q,J＝6.6Hz,2H),3.11(d,J＝24.7Hz,3H),3.00(s,2H),2.76(s,4H),2.66–2.38(m,4H),2.35(t,J＝7.4Hz,3H),2.28(s,1H),2.23–1.94(m,5H),1.82(p,J＝7.2Hz,4H),1.71–1.50(m,6H),1.45(s,10H),1.43–1.38(m,2H),0.96(s,3H).LCMS m/z 655.4[M+H]+。
Referring to the synthesis method of example 1, compound 24f (190mg, 0.29mmol) was Boc-deprotected, ester-hydrolyzed, and amide-condensed in this order to finally obtain compound 24 as a white solid (39mg, yield 32%).1H NMR(500MHz,CDCl3)δ7.00(d,J＝6.1Hz,1H),5.98(dd,J＝17.6,10.8Hz,1H),4.93(s,1H),4.90–4.79(m,4H),4.64(s,1H),4.09(dd,J＝11.8,8.9Hz,1H),3.82–3.74(m,1H),3.46–3.37(m,1H),3.34(d,J＝13.1Hz,1H),3.26–3.15(m,2H),3.12–3.05(m,1H),3.05–3.01(m,1H),2.90(d,J＝12.3Hz,1H),2.84(dddd,J＝13.9,10.9,7.2,4.4Hz,1H),2.71(dq,J＝9.5,5.9,3.8Hz,2H),2.68–2.62(m,2H),2.62–2.49(m,3H),2.42(d,J＝13.3Hz,1H),2.33–2.25(m,2H),2.19(dd,J＝9.6,5.9Hz,1H),2.14–2.04(m,3H),1.96(t,J＝11.3Hz,1H),1.82–1.75(m,2H),1.70–1.29(m,12H),0.91(s,3H).LCMS m/z 523.4[M+H]+。
Example 25: preparation of Compound 25
Figure BDA0003261639710000401
Referring to the synthesis method of example 1, compound 25f (299mg, yield 47%) was obtained in the first step.1H NMR(500MHz,CDCl3)δ6.41(t,J＝5.8Hz,1H),5.76(dd,J＝17.2,11.0Hz,1H),4.93(s,1H),4.91(d,J＝1.1Hz,1H),4.90–4.88(m,2H),4.87(s,1H),4.15–4.03(m,1H),3.95(d,J＝11.7Hz,1H),3.65(s,3H),3.39(t,J＝7.6Hz,2H),3.31–3.20(m,4H),3.05(d,J＝5.6Hz,3H),2.35(s,1H),2.30(t,J＝7.4Hz,2H),2.28–2.23(m,1H),2.01(tt,J＝11.7,3.8Hz,1H),1.68–1.56(m,4H),1.56–1.48(m,4H),1.48–1.39(m,2H),1.38–1.30(m,2H),0.96(s,3H).LCMS m/z 465.0[M+H]+。
The second step yielded compound 25h (249mg, yield 64%).1H NMR(500MHz,CDCl3)δ6.30(t,J＝5.8Hz,1H),5.78(dd,J＝17.5,10.8Hz,1H),5.04(s,1H),4.92–4.83(m,4H),4.78(s,1H),3.65(s,3H),3.48(dt,J＝12.2,5.3Hz,2H),3.45–3.34(m,4H),3.28(dq,J＝26.6,6.2Hz,4H),3.13(q,J＝6.5Hz,1H),3.09(s,2H),3.01(d,J＝13.8Hz,1H),2.64(d,J＝13.9Hz,1H),2.35(s,1H),2.30(t,J＝7.4Hz,3H),2.23(d,J＝5.6Hz,1H),2.18(dd,J＝12.8,3.3Hz,1H),2.01(d,J＝5.2Hz,1H),1.96(ddt,J＝11.8,8.8,3.3Hz,1H),1.63(td,J＝13.7,12.3,6.1Hz,3H),1.56–1.46(m,5H),1.44(d,J＝1.5Hz,9H),1.43–1.30(m,4H),0.98(s,3H).LCMS m/z 615.4[M+H]+。
Referring to the synthesis method of example 1, compound 25h (122mg, 0.20mmol) was successively subjected to Boc deprotection, ester hydrolysis, and amide condensation reaction to finally obtain compound 25(40mg, yield 42%) as a white solid.1H NMR(500MHz,CDCl3)δ6.13(t,J＝5.4Hz,1H),5.75(dd,J＝17.5,10.8Hz,1H),4.98–4.80(m,6H),3.70–3.51(m,3H),3.46–3.28(m,6H),3.24–3.16(m,1H),3.16–3.03(m,4H),2.66(d,J＝12.4Hz,1H),2.54–2.43(m,2H),2.39(ddd,J＝18.7,10.3,4.5Hz,3H),2.34–2.20(m,2H),2.12–2.01(m,1H),1.76(dt,J＝13.9,7.1Hz,1H),1.64(dt,J＝13.8,6.8Hz,2H),1.61–1.39(m,7H),1.35–1.28(m,2H),1.01(s,3H).LCMS m/z 483.0[M+H]+。
Example 26: tumor cell proliferation inhibition assay
Evaluation of antitumor Activity in vitro
1. Experimental equipment and reagent
1.1 instruments
Biological safety cabinet (Shanghai Baiji Biotechnology Co., Ltd.), constant temperature carbon dioxide incubator (THERMO), enzyme linked immunoassay analyzer (Spark), inverted microscope (Nikon), pipette set (eppendorf) and centrifuge (beckman coulter).
1.2 reagents
DMEM (Zhejiang Senri Biotechnology, Inc.), RPMI 1640 (Zhejiang Senri Biotechnology, Inc.), McCoy' S5A (Zhejiang Senri Biotechnology, Inc.), fat bone Serum (BI), PBS (Zhejiang Senri Biotechnology, Inc.), Trypsin (Zhejiang Senri Biotechnology, Inc.), DMSO (Coolaber), and CCK-8 (Coolaber).
1.3 cell lines
Human colon cancer cells (HCT116), human lung cancer cells (A549), human prostate cancer cells PC-3, human brain glioma cells U87MG and human brain glioma cells U251.
2. Experimental methods
1) Taking test cells in logarithmic growth phase, digesting with pancreatin, counting, and adding at 5 × 104The cells were inoculated in 96-well empty plates at a concentration of 100. mu.L per well (5X 10 per well)3Individual cells) at 37 ℃, 5% CO2Culturing for 24h in an incubator;
2) the test drug was diluted to different concentrations with 10% FBS/DMEM or RPMI 1640 or McCoy' S5A complete medium. The experimental group was replaced with culture medium containing samples to be tested at different concentrations, the control group was replaced with culture medium containing equal volume of solvent (DMSO), each group had 3 parallel wells, and the culture medium was incubated at 37 deg.C with 5% CO2Continuously culturing for 48h in the incubator;
the PC-3 cells and A549 cells were in RPMI 1640 complete medium, the U87MG cells and U251 cells were in DMEM complete medium, and the HCT116 cells were in McCoy' S5A complete medium.
3) Adding 10 μ L of CCK-8 solution into each well, culturing at 37 deg.C for 1-4h, and measuring absorbance (OD value) of each well at 490nm with microplate reader;
4) the survival and inhibition rates were calculated using the following formulas
(ii) cell survival rate ═ As-Ab)/(Ac-Ab)]×100％
Inhibition rate [ (A)c-As)/(Ac-Ab)]×100％
Sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 7.0 software and IC calculated50The value is obtained.
As: absorbance of test well (cell-containing medium, CCK-8, drug to be tested)
Ac: absorbance of control well (cell-containing Medium, CCK-8, vehicle (DMSO))
Ab: absorbance of blank wells (Medium without cells and test drug, CCK-8)
3. Results of the experiment
The proliferation inhibitory effects of the target compounds on five tumor cells were determined according to the above experimental methods. The results are shown in Table 1.
TABLE 1 Effect of target Compounds on tumor cell inhibitor Rate
Figure BDA0003261639710000421
Figure BDA0003261639710000431
50 μ M of the compound was allowed to act on tumor cells for 48 h.
And (4) conclusion: compared with the positive control beta-elemene, the compounds 1-3, 5-7, 9, 10, 12, 16 and 18 have certain improvement. Wherein, the anti-tumor cell proliferation effect of the compounds 9 and 18 is obviously stronger than that of the positive control beta-elemene.
IC determination for Compounds 9 and 18 according to the above test method50The results are shown in Table 2.
TABLE 2 median inhibitory concentration of target compounds on tumor cells
Figure BDA0003261639710000432
The compounds at different concentrations acted on the tumor cells for 48 h.
The results show that the target compounds 9 and 18 have nearly 10-fold improved inhibitory activity on PC-3, HCT116, a549, U87MG, and U251 tumor cells compared to β -elemene.
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 macrocyclic derivative is characterized in that the beta-elemene macrocyclic derivative has a structure shown in any one of formulas (I) to (III):
Figure FDA0003261639700000011
in the formulae (I), (II):
R1each independently selected from the following structural fragments:
Figure FDA0003261639700000012
Figure FDA0003261639700000013
R2each independently selected from the following structural fragments:
Figure FDA0003261639700000014
Figure FDA0003261639700000015
L1each independently selected from the following structural fragments:
Figure FDA0003261639700000016
Figure FDA0003261639700000017
in the formula (III):
R1selected from the following structural fragments:
Figure FDA0003261639700000018
Figure FDA0003261639700000021
L2selected from the following structural fragments:
Figure FDA0003261639700000022
Figure FDA0003261639700000023
2. the β -elemene macrocycle derivative of claim 1, or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein said β -elemene macrocycle derivative is any one of compounds 1-55 represented by the following structures:
Figure FDA0003261639700000031
Figure FDA0003261639700000041
3. a preparation method of a beta-elemene macrocyclic derivative is characterized by adopting a first synthetic route:
Figure FDA0003261639700000051
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-4;
(3) r is to be2And L1The connected structural fragment A-5 is connected to 14-beta-elemene through selective nucleophilic substitution reaction to obtain an intermediate A-6;
(4) sequentially deprotecting the structural fragments at the 13 and 14 positions of the beta-elemene to obtain an intermediate A-7;
(5) finally, R is1、R2The two unprotected ends are condensed into a ring by intramolecular lactam to obtain the beta-elemene macrocyclic derivative shown in the formula (I);
R1selected from the following structural fragments:
Figure FDA0003261639700000052
Figure FDA0003261639700000053
R2selected from the following structural fragments:
Figure FDA0003261639700000054
Figure FDA0003261639700000055
L1selected from the following structural fragments:
Figure FDA0003261639700000061
Figure FDA0003261639700000062
4. a preparation method of a beta-elemene macrocyclic derivative is characterized by adopting a second synthetic route:
Figure FDA0003261639700000063
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-4;
(3) carrying out Boc deprotection on the intermediate A-4 to obtain an intermediate A-8;
(4) r is to be2And L1The connected structural segment A-9 is connected to R at the 13-position of the beta-elemene through an amide condensation reaction1Ending to obtain an intermediate A-10;
(5) carrying out Boc deprotection on the intermediate A-10 to obtain an intermediate A-11;
(6) finally, the R at the 13 th position on the beta-elemene is put into2The structural fragment is deprotected, and then the tail end is connected to 14-beta-elemene by intramolecular nucleophilic substitution reaction to obtain the beta-elemene macrocyclic derivative shown in the formula (I);
R1selected from the following structural fragments:
Figure FDA0003261639700000064
Figure FDA0003261639700000065
R2selected from the following structural fragments:
Figure FDA0003261639700000066
Figure FDA0003261639700000071
L1selected from the following structural fragments:
Figure FDA0003261639700000072
Figure FDA0003261639700000073
5. a preparation method of a beta-elemene macrocyclic derivative is characterized by adopting a third synthetic route:
Figure FDA0003261639700000074
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r is to be2And L1The connected structural fragment A-5 is connected to the beta-elemene at the 13 position through selective nucleophilic substitution reaction to obtain an intermediate A-12;
(3) r containing nitrogen heteroatom functional group1The structural fragment A-3 is connected to 14-beta-elemene through selective nucleophilic substitution reaction to obtain an intermediate A-13;
(4) sequentially deprotecting the structural fragments at positions 14 and 13 of beta-elemene to obtain intermediate A-14;
(5) finally, R is1、R2The two unprotected ends are condensed into a ring by intramolecular lactam to obtain the beta-elemene macrocyclic derivative shown in the formula (II);
R1each independently selected from the following structural fragments:
Figure FDA0003261639700000075
Figure FDA0003261639700000081
R2each independently selected from the following structural fragments:
Figure FDA0003261639700000082
Figure FDA0003261639700000083
L1each independently selected from the following structural fragments:
Figure FDA0003261639700000084
Figure FDA0003261639700000085
6. a preparation method of a beta-elemene macrocyclic derivative is characterized by adopting a fourth synthetic route:
Figure FDA0003261639700000086
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is subjected to nucleophilic substitution reaction and is connected to the beta-elemene at the 13 and 14 positions to obtain an intermediate A-15;
(3) carrying out Boc deprotection on the intermediate A-15 to obtain an intermediate A-16;
(4) finally, the L is2Structural fragments A-17 and R1The tail ends are connected to form a ring, so as to obtain the beta-elemene macrocyclic derivative shown in the formula (III);
R1selected from the following structural fragments:
Figure FDA0003261639700000087
Figure FDA0003261639700000091
L2selected from the following structural fragments:
Figure FDA0003261639700000092
Figure FDA0003261639700000093
7. a preparation method of a beta-elemene macrocyclic derivative is characterized by adopting a fifth synthetic route:
Figure FDA0003261639700000094
the method specifically comprises the following steps:
(1) carrying out allylic double chlorination reaction on the beta-elemene A-1 to obtain an intermediate A-2;
(2) r containing nitrogen heteroatom functional group1The structural fragment A-3 is subjected to nucleophilic substitution reaction and is connected to the beta-elemene at the 13 and 14 positions to obtain an intermediate A-15;
(3) carrying out Boc deprotection on the intermediate A-12 to obtain an intermediate A-18;
(4) carrying out nucleophilic substitution reaction on two ends of the intermediate A-18 and the intermediate A-19 to obtain an intermediate A-20;
(5) the structural fragments A-21 and R1The tail ends are connected to form a ring, so as to obtain the beta-elemene macrocyclic derivative shown in the formula (III);
R1selected from the following structural fragments:
Figure FDA0003261639700000095
Figure FDA0003261639700000096
L2selected from the following structural fragments:
Figure FDA0003261639700000101
Figure FDA0003261639700000102
8. use of a β -elemene macrocycle derivative according to claim 1 or 2, or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, for the preparation of an anti-tumor medicament.
9. The use of claim 8, wherein the tumor comprises colon cancer, lung cancer, prostate cancer, brain glioma.
10. An antitumor agent comprising a safe and effective amount of the β -elemene macrocycle derivative of 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.
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