CN116854762A - Ursodeoxycholic acid compound and preparation method, pharmaceutical composition and application thereof - Google Patents

Ursodeoxycholic acid compound and preparation method, pharmaceutical composition and application thereof Download PDF

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CN116854762A
CN116854762A CN202310629589.0A CN202310629589A CN116854762A CN 116854762 A CN116854762 A CN 116854762A CN 202310629589 A CN202310629589 A CN 202310629589A CN 116854762 A CN116854762 A CN 116854762A
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acid
alkyl
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邹忠梅
尚海
胡玥
李晓雪
李凌宇
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Institute of Medicinal Plant Development of CAMS and PUMC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention discloses ursodeoxycholic acid compounds, a preparation method, a pharmaceutical composition and application thereof. The compound has a structure shown in a formula 1 and also comprises an isostere, a geometric isomer, a tautomer, a deuterated compound, a pharmaceutically acceptable salt or a mixture thereof. The compound has high-efficiency inhibition effect on inflammatory cells, remarkably inhibits inflammatory mediator generation, has no obvious influence on the activity of normal cells, has lower cytotoxicity, and is suitable for preparing anti-inflammatory drugs; the preparation method of the compound has strong universality and is beneficial to structure expansion.

Description

Ursodeoxycholic acid compound and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention relates to ursodeoxycholic acid compounds and a preparation method, a pharmaceutical composition and application thereof, in particular to ursodeoxycholic acid compounds with anti-inflammatory activity and a preparation method, a pharmaceutical composition and application thereof.
Background
Ursodeoxycholic acid (ursodeoxycholic acid, UDCA) is a less hydrophilic, toxic bile acid having the chemical name 3a, 7 b-dihydroxy-5 b-cholestan-24-oic acid and has the formula:
in particular to a steroid compound which consists of a steroid skeleton consisting of 3 six-membered rings and 1 five-membered rings and 1 aliphatic side chain, wherein the total carbon atoms of the steroid skeleton and the aliphatic side chain are 24, and the three-dimensional configuration diagram shows that the ring A and the ring B on the steroid skeleton are cis-fused, the ring B and the ring C are trans-fused, the ring C and the ring D are trans-fused, the hydroxyl at the 3 position is at the alpha position, and the hydroxyl at the 7 position is at the beta position, so that the molecule has hydrophilicity and lipophilicity. The UDCA molecule contains hydroxyl and carboxyl functional groups, so that the UDCA molecule has wide biological activity and potential medicinal value. Despite their anti-inflammatory activity, ursodeoxycholic acid has limited its further application and development due to its own activity strength and bioavailability.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide an acyl ursodeoxycholic acid compound, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition containing the compound, and the fourth object is to provide an application of the compound and the pharmaceutical composition.
The technical scheme is as follows: the ursodeoxycholic acid compound has a structure shown in a formula 1 and also comprises a stereoisomer, a geometric isomer, a tautomer, a deuterated compound, a pharmaceutically acceptable salt or a mixture of the stereoisomers, the geometric isomer, the tautomer, the deuterated compound and the pharmaceutically acceptable salt:
wherein:
r is selected from
X, Y, Z are each independently selected from C, N and are not identical to C, N;
n is selected from 0, 1, 2, 3;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, mercapto, C1-C6 alkoxy, C1-C6 alkylamino, 6-12 membered aryl substituted C1-C6 alkyl, 5-7 membered heteroaryl containing 1-3N, O, S, 5-7 membered heteroaryl substituted C1-C6 alkyl containing 1-3N, O, S, 3-7 membered heterocyclyl containing 1-2N, O, S, 3-7 membered heterocyclyl substituted C1-C6 alkyl containing 1-2N, O, S, 3-7 membered cycloalkyl containing 0-3 double bonds, or 3-7 membered cycloalkyl substituted C1-C6 alkyl containing 0-3 double bonds;
the 6-12 membered aryl, 5-7 membered heteroaryl containing 1-3N, O, S, 3-7 membered heterocyclyl containing 1-2N, O, S contain the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, mercapto, C1-C6 alkoxy, C1-C6 alkylamino.
Preferably, in the structure:
x, Y each independently is C, N, Z is N;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino, phenyl, naphthyl, phenyl or naphthyl substituted C1-C4 alkyl, 5-6 membered heteroaryl containing 1-3N, O, S, 5-6 membered heteroaryl substituted C1-C4 alkyl containing 1-3N, O, S, 3-6 membered heterocyclyl containing 1-2N, O, S, 3-6 membered heterocyclyl substituted C1-C4 alkyl containing 1-2N, O, S, 3-6 membered cycloalkyl containing 0-2 double bonds, or 3-6 membered cycloalkyl substituted C1-C4 alkyl containing 0-2 double bonds;
the phenyl, naphthyl, 5-6 membered heteroaryl containing 1-3N, O, S, 3-6 membered heterocyclyl containing 1-2N, O, S contain the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino.
Further preferably, in the structure:
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, phenyl substituted C1-C4 alkyl;
the phenyl group contains the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino.
Preferably, in the structure:
r is selected from
n is selected from 0 or 1;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from the group consisting of H, hydroxy, cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, phenyl, benzyl;
the phenyl and benzyl contain the following substituents: H. hydroxy, cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy.
Further preferably, in the structure:
r is selected from
In particular when R 1 、R 2 、R 3 、R 4 When each is independently selected from fluorine, chlorine and bromine, the number can be 1 or 2; when monosubstituted, the substituent is in position R 2 、R 3 、R 4 The method comprises the steps of carrying out a first treatment on the surface of the When disubstituted, the substitution position is R 2 、R 3 . When R is 5 When the benzene is phenyl or benzyl, the substituent position on the benzene ring is at the para position.
Still more preferably, in the structure:
r is selected from
Preferably, the biological ursodeoxycholic acid compound is selected from any one of the following compounds:
the invention carries out structural modification and reconstruction on ursodeoxycholic acid to design and obtain the drug molecule with good anti-inflammatory activity and lower toxicity.
Further, the compound forms a pharmaceutically acceptable salt thereof with any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
The preparation method of the compound provided by the invention comprises the following steps:
(1) When R is selected fromWhen in use, the compound and an intermediate in the formula 3 are subjected to Mannich reaction, condensation reaction and alkylation reaction to obtain a compound in the formula 4;
(2) When R is selected fromCarrying out alkylation reaction on the intermediate with the formula 3 to obtain a compound with a formula 5;
(3) When R is selected fromCarrying out alkylation reaction on the intermediate with the formula 3 to obtain a compound with a formula 6;
therein, X, Y, Z, n, R 1 、R 2 、R 3 、R 4 、R 5 Is as defined above;
salifying the corresponding acid with the target compound of the formula 1 or the formula 2 prepared by the method, and obtaining the pharmaceutically acceptable salt of the compound.
Specifically, the preparation method of the key intermediate comprises the following steps:
(1) Intermediates containing R structural fragments
The starting materials are obtained by taking haloalkane, bromobenzyl, iodobenzene and the like as raw materials:
(2) Intermediate of 3
Ursodeoxycholic acid is used as a raw material to obtain an intermediate of the formula 3:
in a specific embodiment, the synthetic route for the target compound is as follows:
the pharmaceutical composition comprises the compound and a pharmaceutically acceptable carrier, and can be specifically added with medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like to prepare medicinal preparations such as tablets, capsules, syrup, suspending agents, injection and the like.
The compound and the pharmaceutical composition thereof are applied to preparing medicines for treating inflammation, and are particularly applied to inhibiting or treating inflammatory diseases such as inflammation of digestive tracts (colon cancer, rectal cancer, colonoma, rectal tumor, colon canceration, rectal canceration, ulcerative colitis, polypoid adenoma, familial polyposis and the like), inflammation of livers (liver diseases, serum biochemical properties of liver functions, bile flow, bile secretion of phospholipids or cholesterol and the like), inflammatory dermatoses or severe pruritus (atopic dermatitis, acne, psoriasis, urticaria, inflammatory dermatoses, seborrheic dermatitis, contact dermatitis and the like), acute inflammation of gall bladder or biliary tract, chronic inflammation of kidneys and the like.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
the compounds have high-efficiency inhibition effect (IC) on inflammatory cells 50 The value is less than 10 mu M), the generation of NO is obviously inhibited (P is less than 0.01), the normal cell activity is not influenced, the cytotoxicity is low, and the preparation of the anti-inflammatory medicament can be realized; the preparation method of the compound is simple and convenient, and the universality is strong.
Drawings
FIG. 1 is a graph showing the effect of compounds on RAW264.7 cell viability;
FIG. 2 is a graph showing the effect of compounds on LPS-induced NO production by RAW264.7 cells;
FIG. 3 is an IC of compound 4f on LPS-induced RAW264.7 cells 50 Values.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
The materials used in the invention are all commercial sources unless specified otherwise.
Example 1: preparation of the Compound 1-benzyl-7-methylindole (1 a)
7-methylindole (200 mg,1.520 mmol) was dissolved in DMF (2 mL), sodium cyanide (91.5 mg,2.287 mmol) was slowly added at 0deg.C, the reaction was allowed to stand at room temperature after 10min, and finally chlorobenzyl (289 mg,2.287 mmol) was added dropwise, and the reaction was completed at room temperature for 1h. TLC monitored completion of the reaction, stopped the reaction, extracted with water (40 mL), ethyl acetate (40 mL. Times.3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography on silica gel, eluent: petroleum ether-ethyl acetate=100:1 (V/V), compound 1a is finally obtained in yield: 92.9%.
Example 2: preparation of the Compound 1-Benzylndole (1 b)
Indole and chlorobenzyl are used as starting materials, the synthesis method of the same compound 1a is operated to obtain a compound 1b, and the yield is: 94.0%.
Example 3: preparation of the Compound 1-phenylindole (1 c)
The synthesis method of the same compound 1a is operated by using indole and methyl iodide as starting materials to obtain a yellow liquid compound 1c, and the yield is: 62.2%.
Example 4: preparation of the Compound 1-methylindole (1 d)
The synthesis method of the same compound 1a is operated by taking indole and p-fluorobenzyl as starting materials to obtain a yellow liquid compound 1d, and the yield is: 90.7%.
Example 5: preparation of the Compound 1-Benzylndole (1 e)
The synthesis method of the same compound 1a is operated by using indole and p-chlorobenzyl chloride as starting materials to obtain a yellow liquid compound 1e, and the yield is: 94.1%.
Example 6: preparation of the Compound 1-Benzylndole (1 f)
The synthesis method of the same compound 1a is operated by taking indole and p-bromobenzyl chloride as starting materials to obtain a yellow liquid compound 1f, and the yield is: 86.8%.
Example 7: preparation of the Compound 1-Benzylndole (1 g)
To a solution of indole (200 mg,1.709 mmol) in DMF (4 ml) was added potassium carbonate (470 mg,3.418 mmol) and cuprous oxide (73.4 mg,0.513 mmol), and finally iodobenzene (697 mg,3.418 mmol) was added and reacted at 130℃for 10h. TLC monitored completion of the reaction, stopped the reaction, extracted with water (40 mL), dichloromethane (40 ml×3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, eluent: petroleum ether-ethyl acetate=100:1 (V/V) to give 1g of compound as yellow liquid, yield: 60.6%.
Example 8: preparation of Compound 2
Piperazine (655.3 mg,7.62 mmol) was dissolved in dichloromethane (40 mL), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.448 g,3.81 mmol) was added, ursodeoxycholic acid (1.0 g,2.54 mmol) was finally added N, N-diisopropylethylamine (983 mg,7.62 mmol), and the reaction was carried out at room temperature for 4h. TLC monitored completion of the reaction, stopped the reaction, extracted with water (100 mL), dichloromethane (60 mL. Times.3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, eluent: dichloromethane-methanol=10:1 (V/V), finally obtaining white compound 2, yield: 90.1%.
Yield:90.1％.mp:121.1-122.8℃； 1 H NMR(600MHz,CD 3 OD)δ3.67-3.53(m,4H),3.52-3.44(m,2H),2.97-2.86(m,2H),2.85-2.75(m,2H),2.45(ddd,J＝14.7Hz,10.9Hz,5.2Hz,1H),2.31(ddd,J＝14.7Hz,10.6Hz,5.8Hz,1H),2.05(ddd,J＝12.6Hz,3.7Hz,2.8Hz,1H),1.95-1.72(m,5H),1.66-1.53(m,4H),1.52-1.42(m,6H),1.38-1.17(m,6H),1.16-1.10(m,1H),1.04(td,J＝14.2Hz,2.9Hz,1H),0.99(d,J＝6.5Hz,3H),0.97(s,3H),0.72(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.1,72.1,71.9,57.5,56.5,47.1,46.4,46.0,44.8,44.5,44.0,42.7,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.1,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 28 H 49 N 2 O 3 [M+H] + :461.3743；found:461.3743.
Example 9: preparation of Compound 3a
To a solution of compound 1 (300 mg,0.652 mmol) in dichloromethane was added HATU (496 mg,1.304 mmol), indole-3-carboxylic acid (116 mg,0.71 mmol), followed by DIEA (252 mg,1.956 mmol) and the reaction was carried out at room temperature for 2h. TLC monitored completion of the reaction, stopped the reaction, extracted with water (100 mL), dichloromethane (60 mL. Times.3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, eluent: dichloromethane-methanol=10:1 (V/V), finally obtaining white compound 3a, yield: 52.3%.
Yield:52.3％.mp:170.6-171.9℃； 1 H NMR(600MHz,CD 3 OD)δ7.70(d,J＝
7.9Hz,1H),7.65(s,1H),7.45(d,J＝8.0Hz,1H),7.24-7.18(m,1H),7.17-7.12(m,1H),3.85-3.69(m,4H),3.68-3.56(m,4H),3.52-3.43(m,2H),2.46(ddd,J＝14.5Hz,10.9Hz,5.0Hz,1H),2.32(ddd,J＝14.4Hz,10.5Hz,5.7Hz,1H),2.02(ddd,J＝12.5Hz,4.0Hz,2.9Hz,1H),1.94-1.73(m,5H),1.66-1.52(m,4H),1.50-1.40(m,6H),1.34-1.14(m,6H),1.13-1.08(m,1H),1.01(td,J＝14.2Hz,2.9Hz,1H),0.98(d,J＝6.5Hz,,3H),0.95(s,3H),0.70(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.9,169.4,137.5,129.4,127.0,123.6,122.0,121.1,113.0,110.6,72.1,71.9,57.4,56.4,46.9,44.8,44.4,44.0,42.9,41.5,40.7,38.6,38.0,37.0,36.1,35.1,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7；
HRMS m/z calcd for C 37 H 54 N 3 O 4 [M+H] + :604.4114；found:604.4114.
Example 10: preparation of Compound 3b
Indole-3-acetic acid is used as a starting material, the synthesis method of the same compound 3a is operated to obtain a compound 3b, and the yield is: 60.3%.
Yield:60.3％.mp:139.5-140.7℃； 1 H NMR(600MHz,CD 3 OD):～50:50mixture of rotamers,*indicates amide rotamerδ7.59(d,J＝7.9Hz,1H),7.35(dd,J＝8.1Hz,3.9Hz,1H),7.15(s,1H),7.13-7.09(m,1H),7.06-6.98(m,1H),3.91(s,2H),3.69-3.54(m,4H),3.53-3.43(m,4H),3.30-3.27(m,1H),3.26-3.23(m,1H),2.42(ddd,J＝14.7Hz,10.9Hz,5.0Hz,0.5H),*2.35(ddd,J＝14.7Hz,10.9Hz,5.0Hz,0.5H),2.27(ddd,J＝14.7Hz,10.5Hz,5.8Hz,0.5H),*2.20(ddd,J＝14.7Hz,10.5Hz,5.8Hz,0.5H),2.08-1.97(m,1H),1.94-1.76(m,4H),1.75-1.52(m,5H),1.51-1.38(m,6H),1.36-1.13(m,6H),1.12-1.06(m,1H),1.03(td,J＝14.2Hz,2.7Hz,1H),0.99-0.90(m,,3H),0.96(s,6H),0.70(s,1.5H)*0.68(s,1.5H)； 13 C NMR(150MHz,CD 3 OD)δ174.9,174.9,173.1,173.1,138.1,128.3,128.2,124.2,124.2,122.8,122.7,120.1,120.0,119.5,119.4,112.4,112.4,108.9,108.8,72.1,71.9,57.5,56.4,56.4,47.3,47.0,46.6,46.4,44.8,44.5,44.0,43.1,42.7,42.6,42.3,41.5,40.7,38.6,38.0,36.9,36.9,36.1,35.2,32.7,32.7,32.5,31.1,31.1,31.0,29.7,28.0,23.9,22.4,19.1,19.1,12.6；
HRMS m/z calcd for C 38 H 56 N 3 O 4 [M+H] + :618.4271；found:618.4275.
Example 11: preparation of Compound 3c
The synthesis method of the same compound 3a is operated by taking 6-methoxyindole-2-formic acid as a starting material to obtain a compound 3c, and the yield is: 77.7%.
Yield:77.7％.mp:144.8-146.1℃； 1 H NMR(600MHz,CD 3 OD)δ7.48(d,J＝
8.8Hz,1H),6.93(d,J＝2.2Hz,1H),6.82(s,1H),6.74(dd,J＝8.8Hz,2.2Hz,1H),4.07-3.82(m,4H),3.83(s,3H),3.72-3.62(m,4H),3.53-3.42(m,2H),2.50(ddd,J＝14.8Hz,10.9Hz,5.1Hz,1H),2.35(ddd,J＝14.8Hz,10.5Hz,5.8Hz,1H),2.04(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.94-1.74(m,5H),1.66-1.53(m,4H),1.52-1.42(m,6H),1.38-1.16(m,6H),1.16-1.09(m,1H),1.03(td,J＝14.2Hz,3.1Hz,1H),1.00(d,J＝6.5Hz,,3H),0.96(s,3H),0.72(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ175.0,165.2,159.6,138.9,128.9,123.5,123.0,112.8,107.2,94.6,72.1,71.9,57.5,56.5,55.8,46.6,44.8,44.5,44.0,42.7,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7；
HRMS m/z calcd for C 38 H 56 N 3 O 5 [M+H] + :634.4220；found:634.4222.
3a-3c are shown below:
example 12: preparation of Compound 4a
To a solution of compound 1 (100 mg,0.217 mmol) in ethanol-water=1:1 (V/V) was added 37% formaldehyde (26.5 mg,0.326 mmol), followed by indole (25.4 mg,0.217 mmol), and the mixture was reacted at 60℃for 2 hours. TLC monitored completion of the reaction, stopped the reaction, extracted with water (100 mL), dichloromethane (60 mL. Times.3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, eluent: dichloromethane-methanol=10:1 (V/V), finally obtaining white compound 4a, yield: 61.7%.
Yield:61.7％.mp:122.4-124.2℃； 1 H NMR(600MHz,CD 3 OD)δ7.65(ddd,J＝
7.9Hz,1.1Hz,0.7Hz,1H),7.35(ddd,J＝8.1Hz,1.1Hz,0.7Hz,1H),7.21(s,1H),7.14-7.07(m,1H),7.06-7.00(m,1H),3.77(s,2H),3.65-3.52(m,4H),3.51-3.44(m,2H),2.59-2.47(m,4H),2.41(ddd,J＝14.5Hz,10.6Hz,5.1Hz,1H),2.27(ddd,J＝14.5Hz,10.3Hz,6.1Hz,1H),2.02(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.93-1.78(m,4H),1.75-1.68(m,1H),1.65-1.54(m,4H),1.51-1.39(m,6H),1.35-1.14(m,6H),1.12-1.06(m,1H),1.03(td,J＝14.2Hz,3.1Hz,1H),0.97(s,3H),0.96(d,J＝6.5Hz,3H),0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,138.0,129.3,126.1,122.5,120.0,119.8,112.3,110.8,72.1,71.9,57.5,56.5,54.0,53.9,53.5,46.8,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 56 N 3 O 3 [M+H] + :590.4322；found:590.4321.
Example 13: preparation of Compound 4b
The synthesis method of the same compound 4a is operated by taking 6-fluoroindole as a starting material to obtain a compound 4b, and the yield is: 63.6%.
Yield:63.6％.mp:134.0-135.8℃； 1 H NMR(600MHz,CD 3 OD)δ7.61(dd,J＝
8.7Hz,5.3Hz,1H),7.19(s,1H),7.05(dd,J＝9.8Hz,2.3Hz,,1H),6.82(ddd,J＝9.8Hz,8.7Hz,2.3Hz,1H),3.74(s,2H),3.61-3.44(m,6H),2.59-2.45(m,4H),2.40(ddd,J＝14.4Hz,10.7Hz,5.2Hz,1H),2.27(ddd,J＝14.4Hz,10.3Hz,6.1Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.6Hz,1H),1.93-1.77(m,4H),1.75-1.68(m,1H),1.65-1.53(m,4H),1.51-1.38(m,6H),1.33-1.14(m,6H),1.11-1.06(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.96(s,3H),0.95-0.92(m,3H),0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,161.1(d,J＝253.3Hz),138.0(d,J＝13.2Hz),126.5(d,J＝3.3Hz),125.9,120.8(d,J＝10.1Hz),111.2,108.5(d,J＝24.6Hz),98.2(d,J＝26.0Hz),72.1,71.9,57.5,56.5,54.0,54.0,53.5,46.8,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 FN 3 O 3 [M+H] + :608.4227；found:608.4229.
Example 14: preparation of Compound 4c
The synthesis method of the same compound 4a is operated by taking 7-fluoroindole as a starting material to obtain a compound 4c, and the yield is: 38.9%.
Yield:38.9％.mp:135.7-137.5℃； 1 H NMR(600MHz,CD 3 OD)δ7.45(d,J＝
7.9Hz,1H),7.26(s,1H),6.97(ddd,J＝7.9Hz,7.7Hz,4.6Hz,1H),6.84(dd,J＝7.7Hz,3.6Hz,1H),3.94(s,3H),3.78(s,2H),3.64-3.44(m,6H),2.59-2.47(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.2Hz,1H),2.27(ddd,J＝14.5Hz,10.3Hz,6.0Hz,1H),2.00(ddd,J＝12.4Hz,3.5Hz,2.8Hz,1H),1.92-1.77(m,4H),1.75-1.68(m,1H),1.65-1.53(m,4H),1.51-1.37(m,6H),1.34-1.12(m,6H),1.10-1.05(m,1H),1.02(td,J＝14.2Hz,2.9Hz,1H),0.96(s,3H),0.95(d,J＝6.6Hz,3H),0.67(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,151.1(d,J＝243.0Hz),133.2(d,J＝5.6Hz),127.1,126.0(d,J＝13.3Hz),120.3(d,J＝5.6Hz),115.9(d,J＝3.0Hz),111.8,107.1,107.0,72.1,71.9,57.4,56.4,53.9,53.8,53.5,46.7,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.1,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 FN 3 O 3 [M+H] + :608.4227；found:608.4226.
Example 15: preparation of Compound 4d
The synthesis method of the same compound 4a is operated by taking 5-chloroindole as a starting material to obtain a compound 4d, and the yield is: 62.0%.
Yield:62.0％.mp:144.8-146.3℃； 1 H NMR(600MHz,CD 3 OD)δ7.65(d,J＝
1.9Hz,1H),7.32(d,J＝8.6Hz,1H),7.23(s,1H),7.07(dd,J＝8.6Hz,1.9Hz,1H),3.69(s,2H),3.59-3.41(m,6H),2.56-2.42(m,4H),2.38(ddd,J＝14.4Hz,10.8Hz,5.1Hz,1H),2.24(ddd,J＝14.4Hz,10.3Hz,6.0Hz,1H),1.98(ddd,J＝12.5Hz,3.7Hz,2.6Hz,1H),1.91-1.76(m,4H),1.74-1.66(m,1H),1.64-1.52(m,4H),1.48-1.36(m,6H),1.30-1.10(m,6H),1.08-1.03(m,1H),1.00(td,J＝14.2Hz,2.9Hz,1H),0.94(s,3H),0.93-0.90(m,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.5,136.4,130.3,127.7,125.8,122.7,119.4,113.6,111.0,72.1,71.9,57.4,56.4,54.0,53.9,53.5,46.8,44.7,44.4,44.0,42.5,41.5,40.6,38.6,38.0,36.9,36.1,35.1,32.9,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7；
HRMS m/z calcd for C 37 H 55 ClN 3 O 3 [M+H] + :624.3932；found:624.3936.
Example 16: preparation of Compound 4e
The synthesis method of the same compound 4a is operated by taking 7-chloroindole as a starting material to obtain a compound 4e, and the yield is: 62.6%.
Yield:62.2％.mp:137.2-138.9℃； 1 H NMR(600MHz,CD 3 OD)δ7.62(dd,J＝
7.9Hz,0.7Hz,1H),7.29(s,1H),7.13(d,J＝7.5Hz,1H),7.01(dd,J＝7.9Hz,7.7Hz,1H),3.78(s,2H),3.64-3.43(m,6H),2.59-2.46(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.2Hz,1H),2.28(ddd,J＝14.5Hz,10.3Hz,6.1Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.8Hz,1H),1.94-1.78(m,4H),1.76-1.68(m,1H),1.66-1.53(m,4H),1.52-1.38(m,6H),1.36-1.13(m,6H),1.10-1.06(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.96(s,3H),0.94(d,J＝6.6Hz,3H),0.67(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,135.0,131.0,127.2,122.0,120.9,118.9,117.7,112.3,72.1,71.9,57.5,56.5,54.0,53.9,53.5,46.8,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.1,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 ClN 3 O 3 [M+H] + :624.3932；found:624.3933.
Example 17: preparation of Compound 4f
The synthesis method of the same compound 4a is operated by taking 5, 6-dichloroindole as a starting material to obtain a compound 4f, and the yield is: 31.8%.
Yield:31.8％.mp:151.8-153.3℃； 1 H NMR(600MHz,CD 3 OD)δ7.81(s,1H),7.51(s,1H),7.28(s,1H),3.70(s,2H),3.64-3.43(m,6H),2.56-2.43(m,4H),2.40(ddd,J＝14.5Hz,11.0Hz,5.1Hz,1H),2.27(ddd,J＝14.5Hz,10.4Hz,6.1Hz,1H),1.99(ddd,J＝12.3Hz,3.5Hz,2.3Hz,1H),1.92-1.77(m,4H),1.75-1.68(m,1H),1.65-1.52(m,4H),1.50-1.37(m,6H),1.31-1.12(m,6H),1.09-1.04(m,1H),1.02(td,J＝14.2Hz,2.9Hz,1H),0.95(s,3H),0.94(d,J＝6.6Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,136.9,129.0,128.5,126.1,123.8,121.2,113.9,111.3,72.1,71.9,57.4,56.4,54.0,53.8,53.5,46.8,44.8,44.5,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.2,31.0,29.8,28.0,24.0,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 Cl 2 N 3 O 3 [M+H] + :658.3542；found:658.3541.
Example 18: preparation of Compound 4g
The synthesis method of the same compound 4a is operated by taking 5-bromoindole as a starting material to obtain compound 4g, and the yield is as follows: 57.2%.
Yield:57.2％.mp:147.5-149.0℃； 1 H NMR(600MHz,CD 3 OD)δ7.81(d,J＝
1.8Hz,1H),7.28(d,J＝8.6Hz,1H),7.24(s,1H),7.20(dd,J＝8.6Hz,1.8Hz,1H),3.72(s,2H),3.65-3.52(m,4H),3.51-3.44(m,2H),2.57-2.45(m,4H),2.41(ddd,J＝14.5Hz,10.6Hz,5.1Hz,1H),2.28(ddd,J＝14.5Hz,10.3Hz,6.1Hz,1H),2.02(ddd,J＝12.5Hz,3.7Hz,2.6Hz,,1H),1.95-1.77(m,4H),1.76-1.68(m,1H),1.66-1.52(m,4H),1.51-1.39(m,6H),1.34-1.14(m,6H),1.13-1.06(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),1.00-0.90(m,6H),0.69(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,136.7,130.9,127.5,125.3,122.5,114.0,113.3,110.9,72.1,71.9,57.5,56.5,54.0,53.9,53.6,46.8,44.8,44.5,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 BrN 3 O 3 [M+H] + :668.3427；found:668.3422.
Example 19: preparation of Compound 4h
The synthesis method of the same compound 4a is operated by taking 6-bromoindole as a starting material to obtain the compound 4h, and the yield is: 43.0%.
Yield:43.0％.mp:148.8-150.6℃； 1 H NMR(600MHz,CD 3 OD)δ7.55(d,J＝
8.5Hz,1H),7.52(d,J＝1.7Hz,1H),7.19(s,1H),7.13(d,J＝8.5Hz,1.7Hz,1H),3.71(s,2H),3.61-3.43(m,6H),2.56-2.41(m,4H),2.37(ddd,J＝14.5Hz,10.7Hz,5.1Hz,1H),2.24(ddd,J＝14.5Hz,10.3Hz,6.0Hz,1H),1.98(ddd,J＝12.5Hz,3.9Hz,2.8Hz,1H),1.91-1.76(m,4H),1.73-1.66(m,1H),1.64-1.52(m,4H),1.49-1.34(m,6H),1.32-1.10(m,6H),1.08-1.03(m,1H),1.00(td,J＝14.4Hz,2.9Hz,1H),0.95(s,3H),0.93(d,J＝6.5Hz,3H),0.65(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.5,138.8,128.2,126.9,123.2,121.4,115.9,115.2,111.4,72.1,71.9,57.4,56.4,53.9,53.8,53.5,46.8,44.7,44.4,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.1,32.9,31.2,31.0,29.8,28.0,24.0,22.4,19.1,12.7；
HRMS m/z calcd for C 37 H 54 BrN 3 O 3 [M+H] + :668.3427；found:668.3425.
Example 20: preparation of Compound 4i
The 7-bromoindole is used as a starting material, and the synthesis method of the same compound 4a is operated to obtain a compound 4i, and the yield is: 59.3%.
Yield:59.3％.mp:138.0-139.9℃； 1 H NMR(600MHz,CD 3 OD)δ7.66(dd,J＝
7.9Hz,0.8Hz,1H),7.29(s,1H),7.28-7.26(m,1H),6.95(dd,J＝7.9Hz,7.7Hz,1H),3.76(s,2H),3.64-3.43(m,6H),2.58-2.46(m,4H),2.40(ddd,J＝14.5Hz,10.6Hz,5.2Hz,1H),2.27(ddd,J＝14.5Hz,10.3Hz,6.1Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.92-1.78(m,4H),1.75-1.68(m,1H),1.65-1.53(m,4H),1.51-1.37(m,6H),1.35-1.13(m,6H),1.10-1.05(m,1H),1.03(td,J＝14.2Hz,3.1Hz,1H),0.96(s,3H),0.95(d,J＝6.5Hz,3H),0.67(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,136.5,130.8,127.1,125.1,121.3,119.4,112.4,105.6,72.1,71.9,57.5,56.5,54.0,54.0,53.6,46.8,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.1,31.0,29.8,28.0,24.0,22.4,19.1,12.6；
HRMS m/z calcd for C 37 H 55 BrN 3 O 3 [M+H] + :668.3427；found:668.3431.
Example 21: preparation of Compound 4j
The synthesis method of the same compound 4a is operated by taking 5-cyanoindole as a starting material to obtain a compound 4j, and the yield is: 49.0%.
Yield:49.0％.mp:158.7-160.5℃； 1 H NMR(600MHz,CD 3 OD)δ8.13(d,J＝
0.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.43-7.29(m,1H),3.76(s,2H),3.62-3.42(m,6H),2.59-2.44(m,4H),2.40(ddd,J＝14.4Hz,10.8Hz,5.1Hz,1H),2.25(ddd,J＝14.4Hz,10.3Hz,5.9Hz,1H),1.97(ddd,J＝12.5Hz,3.5Hz,2.6Hz,1H),1.89-1.74(m,4H),1.73-1.67(m,1H),1.64-1.52(m,4H),1.47-1.37(m,6H),1.30-1.09(m,6H),1.07-1.02(m,1H),1.00(td,J＝14.2Hz,2.9Hz,1H),0.94(s,3H),0.93-0.90(m,3H),0.65(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.5,139.9,129.0,128.5,126.0,125.3,121.9,113.6,112.6,102.7,72.1,71.8,57.4,56.4,54.0,53.7,53.5,46.8,44.7,44.4,43.9,42.6,41.5,40.6,38.6,38.0,36.9,36.1,35.1,32.9,31.2,31.0,29.7,27.9,24.0,22.3,19.2,12.7；
HRMS m/z calcd for C 38 H 55 N 4 O 3 [M+H] + :615.4274；found:615.4275.
Example 22: preparation of Compound 4k
The synthesis method of the same compound 4a is operated by taking 7-cyanoindole as a starting material to obtain a compound 4k, and the yield is: 46.6%.
Yield:46.6％.mp:147.3-148.7℃； 1 H NMR(600MHz,CD 3 OD)δ8.01(dd,J＝
8.0Hz,0.8Hz,1H),7.51(d,J＝7.7Hz,1H),7.37(s,1H),7.16(dd,J＝8.0Hz,7.7Hz,1H),3.78(s,2H),3.63-3.43(m,6H),2.57-2.44(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.1Hz,1H),2.26(ddd,J＝14.5Hz,10.5Hz,5.9Hz,1H),2.02-1.99(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.99(m,4H),1.75-1.67(m,1H),1.65-1.52(m,4H),1.50-1.36(m,6H),1.34-1.12(m,6H),1.08-1.03(m,1H),1.01(td,J＝14.2Hz,2.9Hz,1H),0.95(s,3H),0.94(d,J＝6.6Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,137.7,130.2,128.0,127.6,125.8,120.1,118.2,112.9,95.4,72.1,71.9,57.4,56.4,54.0,53.6,53.5,46.8,44.7,44.4,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.1,32.9,31.2,31.0,29.8,27.9,24.0,22.4,19.1,12.6；
HRMS m/z calcd for C 38 H 55 N 4 O 3 [M+H] + :615.4274；found:615.4271.
Example 23: preparation of Compound 4l
The synthesis method of the same compound 4a is operated by taking 7-methoxyindole as a starting material to obtain compound 4l, and the yield is as follows: 71.3%.
Yield:71.3％.mp:131.6-133.2℃； 1 H NMR(600MHz,CD 3 OD)δ7.23(dd,J＝
7.9Hz,0.5Hz,1H),7.16(s,1H),6.96(dd,J＝7.9Hz,7.7Hz,1H),6.64(d,J＝7.7Hz,1H),3.94(s,3H),3.76(s,2H),3.63-3.44(m,6H),2.59-2.47(m,4H),2.41(ddd,J＝14.5Hz,10.7Hz,5.2Hz,1H),2.27(ddd,J＝14.5Hz,10.4Hz,6.1Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.93-1.78(m,4H),1.75-1.68(m,1H),1.65-1.53(m,4H),1.52-1.38(m,6H),1.35-1.13(m,6H),1.11-1.05(m,1H),1.03(td,J＝14.2Hz,3.1Hz,1H),0.96(s,3H),0.95(d,J＝6.6Hz,3H),0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,147.8,130.8,128.2,125.7,120.7,112.6,111.1,102.5,72.1,71.9,57.5,56.5,55.7,54.0,53.9,53.5,46.7,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,36.9,36.1,35.2,32.9,31.1,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 38 H 58 N 3 O 4 [M+H] + :620.4227；found:620.4229.
Example 24: preparation of Compound 4m
The 7-methylindole is used as a starting material, and the synthesis method of the compound 4a is operated to obtain a compound 4m, and the yield is: 77.1%.
Yield:77.1％.mp:119.6-121.3℃； 1 H NMR(600MHz,CD 3 OD)δ7.46(d,J＝
7.9Hz,1H),7.19(s,1H),6.95(dd,J＝7.9Hz,7.0Hz,1H),6.90(d,J＝7.0Hz,1H),3.73(s,2H),3.63-3.43(m,6H),2.55-2.48(m,2H),2.48(s,3H),2.47-2.42(m,2H),2.36(ddd,J＝14.4Hz,10.8Hz,5.2Hz,1H),2.22(ddd,J＝14.4Hz,10.3Hz,5.9Hz,1H),1.98(ddd,J＝12.5Hz,3.7Hz,2.8Hz,1H),1.91-1.75(m,4H),1.73-1.66(m,1H),1.64-1.52(m,4H),1.49-1.35(m,6H),1.30-1.10(m,6H),1.07-1.02(m,1H),1.00(td,J＝14.4Hz,3.0Hz,1H),0.94(s,3H),0.93(d,J＝6.6Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.5,137.4,128.9,125.9,123.0,121.8,120.3,117.5,111.1,72.1,71.9,57.4,56.4,54.1,53.9,53.5,46.7,44.7,44.4,44.0,42.5,41.5,40.6,38.6,38.0,36.9,36.1,35.1,32.9,31.2,31.0,29.8,28.0,24.0,22.4,19.1,17.0,12.7；
HRMS m/z calcd for C 38 H 58 N 3 O 3 [M+H] + :604.4478；found:604.4481.
Example 25: preparation of Compound 4n
The synthesis method of the same compound 4a is operated by taking 1a as a starting material to obtain a compound 4n, and the yield is: 83.7%.
Yield:83.7％.mp:111.9-113.8℃； 1 H NMR(600MHz,CD 3 OD)δ7.60(d,J＝
7.9Hz,1H),7.32-7.26(m,2H),7.25-7.20(m,1H),7.02(dd,J＝7.7Hz,7.4Hz,1H),7.00(s,1H),6.96-6.83(m,3H),5.55(s,2H),3.73(s,2H),3.66-3.53(m,4H),3.50-3.39(m,2H),2.51(s,3H),2.50-2.43(m,4H),2.35(ddd,J＝14.5Hz,11.3Hz,5.0Hz,1H),2.19(ddd,J＝14.5Hz,10.9Hz,5.5Hz,1H),1.99(ddd,J＝12.7Hz,3.7Hz,2.9Hz,1H),1.92-1.87(m,1H),1.85-1.70(m,4H),1.69-1.55(m,4H),1.52-1.38(m,6H),1.35-1.21(m,5H),1.14(td,J＝12.9Hz,3.3Hz,1H),1.10-1.04(m,1H),1.01(td,J＝14.2Hz,2.9Hz,1H),0.94(s,3H),0.93-0.88(m,3H),0.67(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ172.1,139.6,135.5,130.0,129.6,128.9,127.4,125.5,124.9,121.3,119.8,117.7,110.0,71.4,71.4,55.8,55.0,53.4,53.2,52.8,52.1,45.8,43.8,43.8,42.5,41.6,40.2,39.2,37.4,36.9,35.7,35.0,34.2,31.6,30.4,30.4,29.8,28.8,27.0,23.5,21.2,19,6,18.7,12.2；
HRMS m/z calcd for C 45 H 64 N 3 O 3 [M+H] + :694.4948；found:694.4948.
Example 26: preparation of Compound 4o
The synthesis method of the same compound 4a is operated by taking 1b as a starting material to obtain a compound 4o, and the yield is: 87.8%.
Yield:587.8％.mp:237.5-239.0℃； 1 H NMR(600MHz,CDCl 3 )δ7.74(d,J＝
7.9Hz,1H),7.33-7.26(m,4H),7.19(ddd,J＝7.9Hz,7.0Hz,0/9Hz,1H),7.15-7.10(m,3H),7.09-7.03(m,1H),5.30(s,2H),3.73(s,2H),3.66-3.54(m,4H),3.49-3.39(m,2H),2.55-2.42(m,4H),2.35(ddd,J＝14.7Hz,11.2Hz,5.0Hz,1H),2.19(ddd,J＝14.7Hz,10.8Hz,5.5Hz,1H),1.99(ddd,J＝12.7Hz,3.5Hz,2.8Hz,1H),1.94-1.86(m,1H),1.82-1.72(m,4H),1.71-1.61(m,4H),1.52-1.41(m,6H),1.36-1.21(m,5H),1.14(td,J＝12.9Hz,3.7Hz,1H),1.10-1.04(m,1H),1.02(td,J＝14.3Hz,3.1Hz,1H),0.94(s,3H),0.93(d,J＝6.5Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ172.2,137.5,136.8,128.9,128.7,128.0,127.8,126.9,122.1,119.8,119.5,111.2,109.9,71.6,71.5,55.8,55.0,53.6,53.2,52.9,50.1,45.9,43.9,42.5,41.7,40.2,39.3,37.4,36.9,35.7,35.0,34.2,31.6,30.4,29.8,28.8,27.0,23.5,21.3,18.7,12.3；
HRMS m/z calcd for C 44 H 62 N 3 O 3 [M+H] + :680.4791；found:680.4789.
Example 27: preparation of Compound 4p
The synthesis of compound 4a was operated with 1g as starting material to give compound 4p, yield: 55.4%.
Yield:55.4％.mp:121.9-123.7℃； 1 H NMR(600MHz,CD 3 OD)δ7.76(d,J＝
7.9Hz,1H),7.61-7.47(m,5H),7.44(s,1H),7.41-7.34(m,1H),7.23-7.17(m,1H),7.16-7.11(m,1H),3.83(s,2H),3.67-3.43(m,6H),2.69-2.47(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.2Hz,1H),2.28(ddd,J＝14.5Hz,10.3Hz,6.0Hz,1H),2.00(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.93-1.77(m,4H),1.76-1.68(m,1H),1.66-1.52(m,4H),1.51-1.38(m,6H),1.32-1.14(m,6H),1.11-1.05(m,1H),1.02(td,J＝14.2Hz,2.9Hz,1H),0.95(s,3H),0.94-0.91(m,3H),0.67(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,141.0,137.5,130.8,130.7,129.2,127.6,125.2,123.7,121.4,120.7,113.3,114.4,72.1,71.9,57.5,56.5,54.8,54.1,53.7,53.6,46.8,44.8,44.5,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7；
HRMS m/z calcd for C 43 H 60 N 3 O 3 [M+H] + :666.4635；found:666.4633.
Example 28: preparation of Compound 4q
The synthesis method of the same compound 4a is operated by taking 1c as a starting material to obtain a compound 4q, and the yield is: 56.5%.
Yield:56.5％.mp:122.4-124.2℃； 1 H NMR(600MHz,CD 3 OD)δ7.63(d,J＝
7.9Hz,1H),7.30(d,J＝8.3Hz,1H),7.20-7.12(m,1H),7.07(s,1H),7.06-7.03(m,1H),3.73(s,3H),3.70(s,2H),3.59-3.39(m,6H),2.55-2.38(m,4H),2.35(ddd,J＝14.5Hz,10.8Hz,5.1Hz,1H),2.21(ddd,J＝14.5Hz,10.3Hz,5.9Hz,1H),1.98(ddd,J＝12.5Hz,3.9Hz,2.6Hz,1H),1.92-1.74(m,4H),1.72-1.65(m,1H),1.64-1.52(m,4H),1.49-1.34(m,6H),1.29-1.09(m,6H),1.06-1.01(m,1H),0.99(td,J＝14.2Hz,2.9Hz,1H),0.94(s,3H),0.93(d,J＝6.6Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.3,138.5,130.4,129.7,122.6,120.1,120.1,110.3,110.2,72.0,71.8,57.4,56.4,53.9,53.8,53.4,46.7,44.7,44.4,43.9,42.5,41.5,40.6,38.6,38.0,36.9,36.1,35.1,32.9,32.9,31.2,31.1,29.8,28.0,24.0,22.4,19.2,12.7；
HRMS m/z calcd for C 38 H 58 N 3 O 3 [M+H] + :604.4478；found:604.4478.
Example 29: preparation of Compound 4r
The synthesis method of the same compound 4a is operated by taking 1d as a starting material to obtain a compound 4r, and the yield is: 50.5%.
Yield:50.5％.mp:104.5-106.2℃； 1 H NMR(600MHz,CD 3 OD)δ7.73(d,J＝
7.9Hz,1H),7.24(d,J＝8.2Hz,1H),7.19(dd,J＝8.2Hz,7.3Hz,1H),7.13(dd,J＝7.9Hz,7.3Hz,1H),7.09(d,J＝8.5Hz,1H),7.08(d,J＝8.5Hz,1H),7.05(s,1H),6.99(d,J＝8.5Hz,1H),6.97(d,J＝8.5Hz,1H),7.03-6.93(m,2H),5.26(s,2H),3.74(s,2H),3.68-3.51(m,4H),3.50-3.36(m,2H),2.59-2.40(m,4H),2.34(ddd,J＝14.5Hz,11.2Hz,5.0Hz,1H),2.18(ddd,J＝14.5Hz,10.8Hz,5.5Hz,1H),1.98(ddd,J＝12.7Hz,3.7Hz,2.6Hz,1H),1.93-1.85(m,1H),1.82-1.71(m,4H),1.67-1.55(m,4H),1.52-1.37(m,6H),1.36-1.26(m,4H),1.24-1.19(m,1H),1.13(td,J＝12.9Hz,3.6Hz,1H),1.10-1.04(m,1H),1.01(td,J＝14.2Hz,2.9Hz,1H),0.94(s,3H),0.92(d,J＝6.5Hz,3H),0.66(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ172.2,162.3(d,J＝245.8Hz),136.6,133.2(d,J＝3.2Hz),128.7,128.6,128.6,127.9,122.1,119.8,119.6,115.9,115.7,111.1,109.8,71.5,71.4,55.8,55.0,53.4,53.1,52.7,49.4,45.7,43.9,43.8,42.5,41.6,40.2,39.2,37.4,36.9,35.7,35.0,34.2,31.6,30.4,30.4,29.8,28.8,27.0,23.5,21.3,18.7,12.2；
HRMS m/z calcd for C 44 H 61 FN 3 O 3 [M+H] + :698.4697；found:689.4692.
Example 30: preparation of Compound 4s
The synthesis method of the same compound 4a is operated by taking 1e as a starting material, and the compound 4s is obtained, and the yield is: 52.9%.
Yield:52.9％.mp:111.6-113.3℃； 1 H NMR(600MHz,CD 3 OD)δ7.69(d,J＝
7.9Hz,1H),7.38-7.19(m,4H),7.18-6.99(m,4H),5.35(s,2H),3.79(s,2H),3.64-3.43(m,6H),2.65-2.44(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.2Hz,1H),2.27(ddd,J＝14.5Hz,10.4Hz,5.9Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.93-1.77(m,4H),1.75-1.67(m,1H),1.66-1.53(m,4H),1.52-1.39(m,6H),1.33-1.16(m,6H),1.11-1.06(m,1H),1.03(td,J＝14.2Hz,3.2Hz,1H),0.96(s,3H),0.95-0.92(m,3H)0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,138.4,138.0,134.2,130.1,129.9,129.8,129.5,123.0,120.5,120.4,111.1,110.9,72.1,71.9,57.4,56.5,54.0,53.7,53.5,49.9,46.8,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,37.0,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 44 H 61 ClN 3 O 3 [M+H] + :714.4401；found:714.4399.
Example 31: preparation of Compound 4t
The synthesis method of the same compound 4a is operated by taking 1f as a starting material to obtain a compound 4t, and the yield is: 34.9%.
Yield:34.9％.mp:113.9-115.8℃； 1 H NMR(600MHz,CD 3 OD)δ7.69(d,J＝
7.9Hz,1H),7.42(d,J＝8.5Hz,2H),7.28(d,J＝8.3Hz,1H),7.26(s,1H),7.16-7.10(m,1H),7.09-7.05(m,1H),7.03(d,J＝8.5Hz,2H),5.34(s,2H),3.81(s,2H),3.64-3.43(m,6H),2.67-2.46(m,4H),2.40(ddd,J＝14.4Hz,10.7Hz,5.2Hz,1H),2.27(ddd,J＝14.4Hz,10.5Hz,5.9Hz,1H),2.01(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.91-1.78(m,4H),1.74-1.67(m,1H),1.65-1.53(m,4H),1.51-1.38(m,6H),1.33-1.14(m,6H),1.11-1.06(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.96(s,3H),0.95-0.91(m,3H),0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,138.9,138.0,132.8,130.1,130.0,129.8,123.0,122.2,120.6,120.4,110.9,72.1,71.9,57.4,56.5,53.9,53.7,53.4,50.0,46.7,44.8,44.5,44.0,42.5,41.5,40.7,38.6,38.0,37.0,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 44 H 61 BrN 3 O 3 [M+H] + :758.3896；found:758.3899.
The structures of 4a-4t are shown below:
example 32: preparation of Compound 5a
To a solution of compound 1 (100 mg,0.217 mmol) in ethanol was added potassium carbonate (150 mg,1.085 mmol), followed by 3- (chloromethyl) pyridine hydrochloride (0.543 mg,89 mmol), and the mixture was reacted under reflux for 4 hours. TLC monitored completion of the reaction, stopped the reaction, extracted with water (100 mL), dichloromethane (60 mL. Times.3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, eluent: dichloromethane-methanol=10:1 (V/V), finally obtaining white compound 5a, yield: 54.6%.
Yield:54.6％.mp:127.6-129.4℃； 1 H NMR(600MHz,CD 3 OD)δ8.52(d,J＝
1.7Hz,1H),8.46(dd,J＝4.9Hz,1.5Hz,1H),7.86(ddd,J＝7.9Hz,1.7Hz,1.5Hz,1H),7.43(dd,J＝7.9Hz,4.9Hz,1H),3.61(s,2H),3.60-3.53(m,4H),3.53-3.44(m,2H),2.54-2.39(m,5H),2.29(ddd,J＝14.5Hz,10.4Hz,5.9Hz,1H),2.04(ddd,J＝12.7Hz,3.7Hz,2.9Hz,1H),1.95-1.79(m,4H),1.78-1.71(m,1H),1.65-1.53(m,4H),1.52-1.42(m,6H),1.36-1.16(m,6H),1.14-1.08(m,1H),1.03(td,J＝14.2Hz,3.0Hz,1H),0.98(d,J＝6.5Hz,3H),0.97(s,3H),0.71(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,150.8,149.1,139.3,135.4,125.2,72.1,71.9,60.5,57.5,56.5,54.2,53.7,46.9,44.8,44.5,44.0,42.7,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.9,31.1,31.0,29.8,28.0,24.0,22.4,19.1,12.7；
HRMS m/z calcd for C 34 H 54 N 3 O 3 [M+H] + :552.4165；found:552.4167.
Example 33: preparation of Compound 5b
The synthesis method of the compound 5a is operated by taking 2-chloromethyl quinoline hydrochloride as a starting material to obtain a compound 5b, and the yield is: 68.9%.
Yield:68.9％.mp:107.5-109.3℃； 1 H NMR(600MHz,CD 3 OD)δ8.34(d,J＝
8.5Hz,1H),8.02(d,J＝8.5Hz,1H)),7.93(d,J＝8.2Hz,1H),7.76(ddd,J＝8.5Hz,7.0Hz,1.4Hz,1H),7.73(d,J＝8.5Hz,1H),7.60(ddd,J＝8.2Hz,7.0Hz,1.0Hz,1H),3.86(s,2H),3.68-3.56(m,4H),3.53-3.43(m,2H),2.62-2.49(m,4H),2.44(ddd,J＝14.5Hz,10.7Hz,5.1Hz,1H),2.30(ddd,J＝14.5Hz,10.4Hz,5.9Hz,1H),2.02(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.94-1.71(m,5H),1.65-1.53(m,4H),1.51-1.41(m,6H),1.33-1.16(m,6H),1.13-1.06(m,1H),1.02(td,J＝14.2Hz,2.9Hz,1H),0.97(d,J＝6.5Hz,,3H),0.96(s,3H),0.70(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,160.3,148.3,138.7,131.1,129.0,128.9,127.8,122.6,72.1,71.9,65.2,57.5,56.5,54.6,54.2,47.0,44.8,44.5,44.0,42.7,41.5,40.7,38.6,38.0,37.0,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7；
HRMS m/z calcd for C 38 H 56 N 3 O 3 [M+H] + :602.4322；found:602.4322.
Example 34: preparation of Compound 5c
The synthesis method of the same compound 5a is operated by taking 2- (chloromethyl) benzimidazole as a starting material to obtain a compound 5c, and the yield is: 60.1%.
Yield:60.1％.mp:157.5-158.9℃； 1 H NMR(600MHz,CD 3 OD)δ7.54(dd,J＝
5.9Hz,3.2Hz,2H),7.23(dd,J＝5.9Hz,3.2Hz,2H),3.84(s,2H),3.72-3.55(m,4H),3.54-3.42(m,2H),2.67-2.47(m,4H),2.43(ddd,J＝14.5Hz,10.7Hz,5.1Hz,1H),2.30(ddd,J＝14.5Hz,10.4Hz,6.0Hz,1H),2.02(ddd,J＝12.7Hz,3.9Hz,2.4Hz,1H),1.95-1.78(m,4H),1.77-1.70(m,1H),1.66-1.53(m,4H),1.51-1.39(m,6H),1.36-1.14(m,6H),1.13-1.07(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.97(d,J＝6.5Hz,,3H),0.96(s,3H),0.69(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,153.0,123.6,115.7,72.1,71.9,57.5,56.5,56.5,54.4,54.0,46.9,44.8,44.5,44.0,42.7,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.9,31.1,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 35 H 52 N 4 O 3 [M+H] + :591.4274；found:591.4276.
Example 35: preparation of Compound 5d
1-bromomethylnaphthalene is used as a starting material, and the synthesis method of the same compound 5a is operated to obtain a compound 5d, and the yield is: 67.0%.
Yield:67.0％.mp:124.5-126.3℃； 1 H NMR(600MHz,CD 3 OD)δ8.31(d,J＝
8.3Hz,1H),7.86(d,J＝8.3Hz,1H),7.81(d,J＝7.7Hz,1H),7.56-7.46(m,2H),7.45-7.38(m,2H),3.94(s,2H),3.61-3.42(m,6H),2.58-2.46(m,4H),2.42(ddd,J＝14.5Hz,10.9Hz,5.1Hz,1H),2.28(ddd,J＝14.4Hz,10.5Hz,5.9Hz,1H),2.03(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.94-1.78(m,4H),1.77-1.70(m,1H),1.65-1.53(m,4H),1.52-1.40(m,6H),1.36-1.15(m,6H),1.13-1.07(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.97(d,J＝6.5Hz,,3H),0.96(s,3H),0.71(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,135.5,134.6,133.9,129.4,129.4,129.0,126.8,126.8,126.1,125.9,72.1,71.9,61.8,57.5,56.4,54.5,54.1,47.0,44.8,44.5,44.0,42.8,41.5,40.7,38.6,38.0,37.0,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7；
HRMS m/z calcd for C 39 H 57 N 2 O 3 [M+H] + :601.4369；found:601.4371.
Example 36: preparation of Compound 5e
2-bromomethylnaphthalene is used as a starting material, and the synthesis method of the compound 5a is operated to obtain a compound 5e, and the yield is: 62.1%.
Yield:62.1％.mp:117.7-113.2℃； 1 H NMR(600MHz,CD 3 OD)δ7.90-7.80(m,3H),7.78(s,1H),7.52(dd,J＝8.4Hz,1.6Hz,1H),7.50-7.42(m,2H),3.71(s,2H),3.66-3.53(m,4H),3.52-3.43(m,2H),2.59-2.45(m,4H),2.42(ddd,J＝14.5Hz,10.8Hz,5.2Hz,1H),2.29(ddd,J＝14.4Hz,10.4Hz,6.0Hz,1H),2.02(ddd,J＝12.5Hz,3.7Hz,2.9Hz,1H),1.95-1.78(m,4H),1.77-1.70(m,1H),1.66-1.33(m,4H),1.52-1.40(m,6H),1.35-1.14(m,6H),1.13-1.07(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),1.00-0.96(m,3H),0.96(s,3H),0.69(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,136.0,134.8,134.4,129.3,129.1,128.8,128.7,128.5,127.2,126.9,72.1,71.9,63.8,57.5,56.5,54.3,53.9,46.9,44.8,44.5,44.0,42.6,41.5,40.7,38.6,38.0,37.0,36.1,35.2,33.0,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.6；
HRMS m/z calcd for C 39 H 57 N 2 O 3 [M+H] + :601.4369；found:601.4369.
Example 37: preparation of Compound 5f
The synthesis method of the same compound 5a is operated by taking 4-bromomethyl-7-methoxycoumarin as a starting material to obtain a compound 5f, and the yield is: 66.4%.
Yield:66.4％.mp:125.1-126.7℃； 1 H NMR(600MHz,CD 3 OD)δ7.89(d,J＝
8.9Hz,1H),6.94(dd,J＝8.9Hz,2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.39(s,1H),3.89(s,3H),3.72(s,2H),3.68-3.53(m,4H),3.52-3.44(m,2H),2.65-2.49(m,4H),2.45(ddd,J＝14.5Hz,10.9Hz,5.1Hz,1H),2.30(ddd,J＝14.5Hz,10.5Hz,5.8Hz,1H),2.04(ddd,J＝12.7Hz,3.7Hz,2.6Hz,1H),1.94-1.72(m,5H),1.65-1.53(m,4H),1.52-1.42(m,6H),1.36-1.16(m,6H),1.15-1.08(m,1H),1.03(td,J＝14.2Hz,2.9Hz,1H),0.99(d,J＝6.5Hz,3H),0.97(s,3H),0.71(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.7,164.5,163.5,156.9,154.5,127.6,113.5,112.3,101.7,72.1,71.9,59.5,57.5,56.4,54.5,54.1,47.1,44.8,44.5,44.0,42.9,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.9,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7；
HRMS m/z calcd for C 39 H 57 N 2 O 6 [M+H] + :649.4217；found:649.4214.
Example 38: preparation of Compound 5g
The synthesis of compound 5a was operated with 1-benzyl-3- (chloromethyl) -1H-indazole as starting material to afford compound 5g, yield: 43.8%.
Yield:43.8％.mp:104.8-106.3℃； 1 H NMR(600MHz,CD 3 OD)δ7.90(d,J＝
8.2Hz,1H),7.48(d,J＝8.5Hz,1H),7.43-7.33(m,1H),7.30-7.19(m,3H),7.18-7.11(m,3H),5.60(s,2H),3.95(s,2H),3.67-3.40(m,6H),2.69-2.44(m,4H),2.40(ddd,J＝14.5Hz,10.7Hz,5.0Hz,1H),2.26(ddd,J＝14.5Hz,10.3Hz,5.9Hz,1H),2.01(ddd,J＝12.5Hz,3.9Hz,2.8Hz,1H),1.94-1.76(m,4H),1.75-1.67(m,1H),1.66-1.53(m,4H),1.52-1.37(m,6H),1.34-1.13(m,6H),1.10-1.05(m,1H),1.02(td,J＝14.0Hz,2.4Hz,1H),0.96(s,3H),0.95-0.88(m,3H),0.68(s,3H)； 13 C NMR(150MHz,CD 3 OD)δ174.6,142.5,142.1,138.6,129.7,128.7,128.2,128.1,124.8,122.1,121.9,110.8,72.1,71.9,57.4,56.4,55.0,54.2,53.8,53.3,46.8,44.8,44.4,44.0,42.6,41.5,40.7,38.6,38.0,36.9,36.1,35.2,33.0,31.2,31.0,29.8,28.0,24.0,22.4,19.1,12.7；
HRMS m/z calcd for C 43 H 61 N 4 O 3 [M+H] + :681.4744；found:681.4745.
The structures of 5a-5g are shown below:
example 39: anti-inflammatory Activity of Compounds against LPS-induced RAW264.7 cells
1. Effect on RAW264.7 cell viability
Preparation of single cell suspension (2×10) from RAW264.7 cells in logarithmic growth phase 6 cells/mL), inoculation at 100. Mu.L/well100. Mu.L of the compound was added to a 96-well plate so that the final concentrations were 20. Mu. Mol/L, respectively, and an equal volume of complete medium containing DMSO was added to a normal control, and after incubation in an incubator for 24 hours, 20. Mu.L of CCK-8 was added to each well, and after incubation in a cell incubator for 1 hour, the absorbance value of each well was measured at a wavelength of 540 nm. Cell viability (%) = (drug group-blank)/(control group-blank) ×100%. The data are shown in FIG. 1.
In FIG. 1, RAW264.7 cells were seeded in 96-well plates, treated with indicated concentrations of compounds for 24h, and the CCK-8 method was used to determine cell viability. Data are expressed as mean ± standard deviation of three independent experiments. P < 0.001 compared to the control group.
The results show that at a concentration of 20. Mu. Mol/L, the compounds were not cytotoxic or only weakly cytotoxic except for 4a, 4d, 4m and 4 q.
2. Effect on NO content in LPS-induced RAW264.7 cells
The experimental group was set as a normal control group (equivalent volume of complete medium containing DMSO), LPS (10 ng/mL) model group, drug group (20. Mu. Mol/L) administration group, and dexamethasone (DEX, 10. Mu. Mol/L) was used as a positive control. RAW264.7 cells at 2X 10 6 cells/mL density was seeded in 96-well plates followed by DEX, drug group and LPS in CO 2 After 24h incubation in the cell incubator, 50. Mu.L of cell culture supernatant was pipetted into a new 96-well plate, 50. Mu.L of each of Griess I and Griess II was added, and the wells were allowed to react well by shaking on a shaker for 10min, and absorbance values were measured at 540 nm. See fig. 2 and 3 for specific data.
In FIG. 2, RAW264.7 cells were treated with synthetic compound (10. Mu.M) and LPS (10 ng/mL) for 24h, and DEX group (10. Mu.M) was used as positive control. Data are expressed as mean ± standard deviation of three independent experiments. In comparison with the normal control group, ## P＜0.01。
in fig. 3, compared with the normal control group, ## p is less than 0.01; p < 0.05, P < 0.01 compared to the LPS model group.
The experimental results show that at the concentration of 10 mu M, most derivatives show obvious inhibition (inhibition rate is more than 50 percent) and inhibitionThe preparation is stronger than ursodeoxycholic acid. Wherein, the inhibition IC of the compound 4f 50 The value was less than 5. Mu.M.

Claims (10)

1. Ursodeoxycholic acid compound characterized by having the structure of formula 1 and further comprising stereoisomers, geometric isomers, tautomers, deuterated compounds, pharmaceutically acceptable salts or mixtures thereof:
wherein:
r is selected from
X, Y, Z are each independently selected from C, N and are different from C or N;
n is selected from 0, 1, 2, 3;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, mercapto, C1-C6 alkoxy, C1-C6 alkylamino, 6-12 membered aryl substituted C1-C6 alkyl, 5-7 membered heteroaryl containing 1-3N, O, S, 5-7 membered heteroaryl substituted C1-C6 alkyl containing 1-3N, O, S, 3-7 membered heterocyclyl containing 1-2N, O, S, 3-7 membered heterocyclyl substituted C1-C6 alkyl containing 1-2N, O, S, 3-7 membered cycloalkyl containing 0-3 double bonds, or 3-7 membered cycloalkyl substituted C1-C6 alkyl containing 0-3 double bonds;
the 6-12 membered aryl, 5-7 membered heteroaryl containing 1-3N, O, S, 3-7 membered heterocyclyl containing 1-2N, O, S contain the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, mercapto, C1-C6 alkoxy, C1-C6 alkylamino.
2. Ursodeoxycholic acid compound according to claim 1, characterized in that in the structure:
x, Y each independently is C, N, Z is N;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino, phenyl, naphthyl, phenyl or naphthyl substituted C1-C4 alkyl, 5-6 membered heteroaryl containing 1-3N, O, S, 5-6 membered heteroaryl substituted C1-C4 alkyl containing 1-3N, O, S, 3-6 membered heterocyclyl containing 1-2N, O, S, 3-6 membered heterocyclyl substituted C1-C4 alkyl containing 1-2N, O, S, 3-6 membered cycloalkyl containing 0-2 double bonds, or 3-6 membered cycloalkyl substituted C1-C4 alkyl containing 0-2 double bonds;
the phenyl, naphthyl, 5-6 membered heteroaryl containing 1-3N, O, S, 3-6 membered heterocyclyl containing 1-2N, O, S contain the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino.
3. Ursodeoxycholic acid compound according to claim 2, characterized in that in the structure:
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, phenyl substituted C1-C4 alkyl;
the phenyl group contains the following substituents: H. hydroxy, cyano, amino, halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, mercapto, C1-C4 alkoxy, C1-C4 alkylamino.
4. Ursodeoxycholic acid compound according to claim 1, characterized in that in the structure:
r is selected from
n is selected from 0 or 1;
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from the group consisting of H, hydroxy, cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, phenyl, benzyl;
the phenyl and benzyl contain the following substituents: H. hydroxy, cyano, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy.
5. Ursodeoxycholic acid compound according to claim 4, characterized in that in the structure:
r is selected from
6. Ursodeoxycholic acid compound according to claim 1, characterized in that it is selected from any one of the following compounds:
7. ursodeoxycholic acid compound according to claim 1, characterized in that the pharmaceutically acceptable salt is a salt of said compound with any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
8. A process for preparing ursodeoxycholic acid according to claim 1,
(1) When R is selected fromWhen in use, the compound and an intermediate in the formula 3 are subjected to Mannich reaction, condensation reaction and alkylation reaction to obtain a compound in the formula 4;
(2) When R is selected fromWhen it is reacted with an intermediate of formula 3 to give
To a compound of formula 5;
(3) When R is selected fromCarrying out alkylation reaction on the intermediate with the formula 3 to obtain a compound with a formula 6;
therein, X, Y, Z, n, R 1 、R 2 、R 3 、R 4 、R 5 Is defined as in claim 1;
salifying the corresponding acid with the target compound of the formula 1 prepared by the method, and obtaining the pharmaceutically acceptable salt of the compound.
9. A pharmaceutical composition comprising the ursodeoxycholic acid compound of claim 1 and a pharmaceutically acceptable carrier.
10. Use of an ursodeoxycholic acid compound according to claim 1 or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of inflammation.
CN202310629589.0A 2023-05-31 2023-05-31 Ursodeoxycholic acid compound and preparation method, pharmaceutical composition and application thereof Pending CN116854762A (en)

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