阅读说明：本技术 PPARs-FXR多靶点小分子激动剂及其制备方法和用途 (PPARs-FXR multi-target small molecule agonist and preparation method and application thereof ) 是由 徐华强 施晶晶 尤二利 赵关关 刘明亮 赵一爽 杨生生 杨青珍 潘华玲 戴金威 于 2019-11-21 设计创作，主要内容包括：本发明公开了一种PPARs-FXR多靶点小分子激动剂及其制备方法和用途,结构如通式I所示,各取代基的定义如说明书和权利要求书所述。本发明所述的化合物具有PPARs和FXR多靶点激动作用,可潜在的用于治疗或者预防糖尿病、高血脂、非酒精性脂肪肝等糖、脂、胆汁酸相关代谢疾病,具有广阔的开发前景。(The invention discloses a PPARs-FXR multi-target small molecule agonist, a preparation method and application thereof, wherein the structure is shown as a general formula I, and the definition of each substituent is described in the specification and the claims. The compound has PPARs and FXR multi-target excitation effects, can be potentially used for treating or preventing sugar, lipid and bile acid related metabolic diseases such as diabetes, hyperlipidemia, non-alcoholic fatty liver disease and the like, and has wide development prospects.)

1. A compound of formula I, an enantiomer, a diastereomer, a tautomer, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R¹and R²Each independently is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 5-10 membered aromatic ringOr a substituted or unsubstituted 5-8 membered heteroaromatic ring; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkyl mercapto group, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy, nitro;

x, Y are each independently O, S or CH₂；

Is a substituted or unsubstituted 5-10 membered aromatic ring, or a substituted or unsubstituted 5-8 membered heteroaromatic ring; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆A haloalkoxy group;

n, m are each independently 0, 1, 2 or 3;

R³and R⁴Each independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆A haloalkoxy group;

R⁵is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl or hydrogen; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₃Alkyl radical, C₁-C₆Haloalkyl, C₁-C₃Alkyl mercapto group, C₁-C₃An alkoxy group.

2. A compound of claim 1, wherein R is¹And R²Each independently is a substituted or unsubstituted group: methyl, ethyl, cyclopropyl, phenyl or pyridineA group; wherein the substitution is mono-, di-or tri-substituted, each substituent being independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, methylmercapto.

3. The compound of claim 1, wherein n is 0, 1, 2, or 3; m is 0 or 1.

4. The compound of claim 1,selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl; wherein the substitution is mono-, di-or tri-substituted, each substituent being independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl.

5. A compound of claim 1, wherein R is³And R⁴Each independently is hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, cyano, C₁-C₄Haloalkyl, C₁-C₄A haloalkoxy group.

6. The compound of claim 1, wherein the compound is selected from the group consisting of:

7. a pharmaceutical composition comprising a compound selected from any one of claims 1-6, an enantiomer, a diastereomer, a tautomer, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

8. A process for preparing a compound, enantiomer, diastereomer, tautomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, according to claim 1, comprising the steps of:

(i) condensing the compound of formula VI with the compound of formula VII to obtain a compound of formula VIII;

(ii) the compound of formula VIII and the compound of formula V give the compound of formula I,

in the formula, R¹、R²、X、Y、n、m、R³、R⁴And R⁵Is as defined in claim 1.

9. The compound of any one of claims 1 to 6, its enantiomers, diastereomers, tautomers, solvates, prodrugs, or a pharmaceutically acceptable salt thereof,

as agonists of PPARs and FXR targets; or

Is used for preparing medicaments for treating PPARs and FXR related diseases.

10. The use according to claim 9, wherein the related disease is non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, gallstones, non-alcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, diabetes, or obesity.

Technical Field

The invention belongs to the field of medicines, and relates to a compound serving as a PPARs and FXR multi-target agonist, and preparation and application thereof. In particular to organic small molecule compounds which can be used as PPARs and FXR multi-target agonists, enantiomers, diastereomers, tautomers, solvates, prodrugs thereof, or pharmaceutically acceptable salts thereof, a preparation method thereof and application thereof in preparing medicaments for treating PPARs and FXR related diseases.

Background

The nuclear receptor widely exists in organisms, is a nuclear transcription regulating factor activated by a specific ligand, belongs to metabolic nuclear receptors, and regulates substance metabolism, cell proliferation, apoptosis and the like in vivo.

PPARs (peroxisome proliferator-activated receptors) belong to the class II nuclear receptor superfamily members, and are involved in lipid regulation, lipogenesis and glycemic control, for a total of three subtypes: α, δ (β), and γ. The PPAR alpha is mainly responsible for the transcription of free fatty acid oxidation related genes, and can increase the high-density lipoprotein level and the expression of lipoprotein lipase, thereby reducing low-density lipoprotein, triglyceride, blood sugar and cholesterol and reducing the occurrence of steatohepatitis; PPAR δ (β) also plays an important role in lipid metabolism, increasing the consumption of free fatty acids in bone and muscle; PPAR gamma is mainly expressed in adipose tissue, has important effect on fat differentiation, participates in the transcription of genes for lipid acid uptake and fat storage, and has the function of reducing blood sugar.

FXR (farnesoid X receptor) is activated by bile acid in vivo and participates in the metabolism of bile acid, lipid and sugar in vivo. FXR regulates bile acid metabolism and transport mechanisms mainly by regulating the transcription of cholesterol 7 α hydroxylase (CYP 7a1), a bile acid synthesis rate-limiting enzyme. FXR as a potential therapeutic target for NASH is mainly manifested in: (1) after FXR activation, the in vivo balance process of bile acid is regulated, so that lipid and cholesterol metabolism is indirectly regulated; (2) after FXR activation, the composition improves insulin sensitivity, inhibits accumulation of triglyceride, promotes oxidation of fatty acid and further improves liver steatosis and lipid accumulation; (3) inhibiting the expression of related inflammatory factors and the activation of hepatic stellate cells after FXR activation so as to inhibit liver inflammation and hepatic fibrosis; (4) the function regulation of FXR can prevent liver cirrhosis caused by liver injury. Therefore, FXR is a potential therapeutic target of NASH, can reduce the generation of liver fat after being activated, improve the steatosis and the insulin sensitivity, inhibit the inflammation and the fibrosis which can cause cirrhosis, play a liver protection role and the like.

Currently, multi-target design development is carried out on the important target PPARs-FXR of NASH diseases. The FXR agonist obeticholic acid in all NASH medicines for treatment is the fastest drug to be marketed and has the best drug effect at present, but the drug effect is not satisfactory, and meanwhile, more side effects exist. PPAR alpha agonist has already been marketed drugs in clinical use as hypolipidemic drugs, has good hypolipidemic effect, and can reduce body weight, improve inflammatory state and vascular function (transcriptional control of High Density Lipoprotein (HDL) apolipoprotein Apo I and Apo II, reduce synthesis and release of liver LDL to improve blood lipid); PPAR α is also an effective target for treating NASH (PPAR α agonist elafinidor is currently in the clinical phase III study). The PPAR gamma agonist has the effects of enhancing insulin sensitivity and reducing blood sugar, and the PPAR gamma agonist is also clinically used as a blood sugar reducing medicament to be put on the market. As most of NASH patients are also obese or diabetic, the PPARs-FXR multi-target agonist is developed, so that the drug effect can be enhanced, and the toxic and side effects caused by a single-target agonist are reduced.

Disclosure of Invention

It is an object of the present invention to provide small organic molecule compounds, enantiomers, diastereomers, tautomers, solvates, prodrugs thereof, or pharmaceutically acceptable salts thereof, which are PPARs and FXR multi-target agonists.

Another object of the present invention is to provide a process for producing the above compound.

The invention further aims to provide the application of the compound and enantiomers, diastereoisomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof in preparing PPARs-FXR multi-target agonists.

In a first aspect of the invention, there is provided a compound of formula I, an enantiomer, diastereomer, tautomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R¹and R²Each independently is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 5-10 membered aromatic ring, or substituted or unsubstituted 5-8 membered heteroaromatic ring; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkyl mercapto group, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy, nitro;

x, Y are each independently O, S or CH₂；

Is a substituted or unsubstituted 5-10 membered aromatic ring, or a substituted or unsubstituted 5-8 membered heteroaromatic ring; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆A haloalkoxy group;

n, m are each independently 0, 1, 2 or 3;

R³and R⁴Each independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, hydroxy, cyano, C₁-C₆Haloalkyl, C₁-C₆A haloalkoxy group;

R⁵is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl or hydrogen; wherein the substitution is mono-or polysubstitution, and each substituent is independently selected from the following group: halogen, C₁-C₃Alkyl radical, C₁-C₆Haloalkyl, C₁-C₃Alkyl mercapto group, C₁-C₃An alkoxy group.

In another preferred embodiment, R¹And R²Each independently is a substituted or unsubstituted group: methyl, ethyl, cyclopropyl, phenyl or pyridyl; wherein the substitution is mono-, di-or tri-substituted, each substituent being independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethylMethyl mercapto.

In another preferred embodiment, R¹Is a substituted or unsubstituted phenyl, wherein said substitution is mono-or di-substituted, each substituent being independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl. In another preferred embodiment, the above substituents are located in the ortho position.

In another preferred embodiment, R²Is methyl, ethyl, cyclopropyl, phenyl or pyridyl. .

In another preferred embodiment, n is 0, 1, 2 or 3; m is 0 or 1.

In another preferred embodiment, n is 0, 1 or 2.

In another preferred embodiment, m is 0.

In a further preferred embodiment of the method,selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl; wherein the substitution is mono-, di-or tri-substituted, each substituent being independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl.

In a further preferred embodiment of the method,is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl; wherein the substitution is mono-or di-substituted, each substituent is independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy.

In a further preferred embodiment of the method,is a substituted or unsubstituted group: the definition of each substituent is the same as that of the above.

In another preferred embodiment, R³And R⁴Each independently is hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, cyano, C₁-C₄Haloalkyl, C₁-C₄A haloalkoxy group.

In another preferred embodiment, R³Is hydrogen, methyl or ethyl; and R⁴Is ethyl or methyl.

In another preferred embodiment, R⁵Is hydrogen, methyl, ethyl or isopropyl.

In another preferred embodiment, the compound is selected from the group consisting of:

in a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound selected from the group consisting of the compounds of the first aspect, enantiomers, diastereomers, tautomers, solvates, prodrugs thereof, or pharmaceutically acceptable salts thereof; and

a pharmaceutically acceptable carrier.

The present invention provides a novel compound which can be used alone or in admixture with pharmaceutically acceptable adjuvants (e.g., excipients, diluents, etc.) to prepare tablets, capsules, granules, syrups, and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional method in pharmacy.

In another preferred embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, said at least one further therapeutic agent comprised in said pharmaceutical composition is selected from the group consisting of drugs for the treatment of PPARs and FXR related diseases.

In a third aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, its enantiomer, diastereomer, tautomer, solvate, prodrug, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(i) condensing the compound of formula VI with the compound of formula VII to obtain a compound of formula VIII;

(ii) the compound of formula VIII and the compound of formula V give the compound of formula I,

in the formula, R¹、R²、X、Y、n、m、R³、R⁴And R⁵As defined above.

In another preferred embodiment, the compound shown in the general formula VI reacts with VII under the action of alkali to form a compound shown in the general formula VIII; the base is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyllithium and lithium diisopropylamide.

In another preferred embodiment, the compound of formula VIII is reacted directly with the compound of formula V to form the compound of formula I under the action of a base selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyllithium, lithium diisopropylamide.

In a fourth aspect of the invention, there is provided the use of a compound of the first aspect, its enantiomers, diastereomers, tautomers, solvates, prodrugs, or a pharmaceutically acceptable salt thereof, as PPARs and FXR target agonists; or

Is used for preparing medicaments for treating PPARs and FXR related diseases.

In another preferred embodiment, the related diseases are diseases related to processes such as bile acid metabolism, sugar metabolism, lipid metabolism, inflammation, and liver fibrosis.

In another preferred example, the associated disease is nonalcoholic steatohepatitis (NASH), Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), gallstones, nonalcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, diabetes, or obesity.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Not to be reiterated herein, but to the extent of space.

Detailed Description

The inventor of the application researches extensively and deeply to develop an organic small molecule compound serving as a PPARs and FXR multi-target agonist, and test results show that the compound has PPARs-FXR multi-target activation capacity and can be used for treating PPARs and FXR related diseases. On the basis of this, the present invention has been completed.

Term(s) for

In the present invention, the halogen is F, Cl, Br or I.

In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.

In the present invention, the term "C₁-C₆"means having 1, 2, 3, 4, 5, or 6 carbon atoms," C1-C4 "means having 1, 2, 3, or 4 carbon atoms, and so on. "5-10 membered" means having 5-10 ring atoms, and so on.

In the present invention, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.

In the present invention, the term "alkoxy" denotes a-O- (C1-6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

In the present invention, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

In the present invention, the term "aryl" denotes a hydrocarbyl moiety comprising one or more aromatic rings. For example, the terms "5-10 membered aromatic ring", "5-10 membered aryl" refer to an aromatic ring group having 5 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring.

In the present invention, the terms "heteroaromatic ring", "heteroaryl" refer to an aromatic ring group having one or more heteroatoms (selected from N, O, S) in the ring.

Unless otherwise specified, alkyl, alkoxy, cycloalkyl, heteroaromatic, heterocyclic and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on the alkyl, alkoxy, cycloalkyl, heteroaromatic ring, heterocyclic group, and aryl groups include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfamomino, arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, acyl, thioacyl, acyloxy, carboxyl, and carboxylate. In another aspect, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused to each other.

In the invention, the substitution is mono-substitution or multi-substitution, and the multi-substitution is di-substitution, tri-substitution, tetra-substitution or penta-substitution. By disubstituted is meant having two substituents and so on.

The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound in the general formula I and organic base.

Pharmaceutical composition

The invention also provides a pharmaceutical composition comprising a safe and effective amount of the active ingredient, and a pharmaceutically acceptable carrier.

The active ingredient refers to the compound of the formula I.

The active ingredients and the pharmaceutical composition are used for preparing the medicaments for treating PPARs and FXR related diseases. The active ingredients and the pharmaceutical composition can be used as PPARs and FXR target agonists. Said PPARs and FXR associated diseases are selected from: non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, gallstone, non-alcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, diabetes, or obesity.

"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a 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 being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. 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) Wetting agent (such as sodium lauryl sulfate), colorant, and flavoring agentAgents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, 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, especially 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 ingredients, may contain suspending agents as, for example, 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.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

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 2000mg, preferably 20 to 500 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.

Preparation method

The preparation method of the compound shown in the general formula I comprises the following steps:

a) substituted benzaldehyde is used as an initial raw material and reacts with hydroxylamine hydrochloride under the action of alkali to obtain an intermediate, and N-chlorosuccinimide (NCS) is used for chlorination to obtain a compound shown in a general formula III;

b) then reacting the compound shown in the general formula III with corresponding 3-oxo-propionic ester under the alkaline condition to obtain a compound shown in the general formula IV;

c) the ester in the compound shown in the general formula IV is reduced by a reducing agent to generate corresponding alcohol, the alcohol is brominated to generate a compound shown in V,

d) reacting the compound shown in the general formula VI with VII under the action of alkali to obtain a compound shown in a general formula VIII;

e) the compound shown in the general formula VIII directly reacts with the compound shown in the general formula V under the action of alkali to form the compound shown in the general formula I.

Wherein the base in steps a), b), d) and e) is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyllithium, lithium diisopropylamide;

the base in the step b) is selected from triethylamine, diisopropylethylamine, pyridine, DBU, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium ethoxide;

the reducing agent in step c) is selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, diisopropylaluminum hydride, borane.

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 experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Examples

The instruments used and the main experimental materials were as follows:

the reagents and anhydrous solvents used were purchased from commercial companies in China and used as received unless otherwise specified; 1H and 13C NMR were carried out using a nuclear magnetic resonance spectrometer of the BrukeraM-400 type and the Varian Mercury plus-400 type, mass spectrometry using an Agilent 6230 type mass spectrometer, and 200-mesh 300-mesh column chromatography silica gel (Qingdao Seisakusho), HSGF254 TLC plates (Nicotine Seisakusho chemical research institute).

Example 1:

intermediate VI-1 synthesis:

aqueous potassium carbonate (3N, 182mmol) was added dropwise to a stirring solution of hydroxylamine hydrochloride (182mmol) in ethanol (100mL) at 0 deg.C, 2, 6-dichlorobenzaldehyde (20g, 114mmol) was dissolved in 100mL of ethanol and then added to the hydroxylamine solution, the temperature was raisedUp to 90 ℃ for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. Water/ethanol (1000mL/100mL) solution was added and the solid was broken up by stirring, filtered and dried overnight under vacuum at 50 ℃ to give the intermediate compound (18.4 g). This intermediate was dissolved in N, N-dimethylformamide (50mL), and a solution of N-chlorosuccinimide (97mmol) in N, N-dimethylformamide (100mL) was added dropwise at 0 ℃ and stirred overnight. The reaction solution was poured into ice water at 0 ℃ and then extracted with methyl t-butyl ether (200 mL each time, 3 times in total), and the organic phase was washed with saturated brine and concentrated to give a crude product. To a flask containing the crude product was added n-hexane (600mL), stirred with a magneton, filtered, and the solid was dried under vacuum (30 ℃ C.) to give intermediate III-1(18.3g, 73% yield).¹H NMR(400MHz，CDCl₃)δ7.43–7.39(m，2H)，7.39–7.33(m，1H).

Triethylamine (8.2g) was added to methyl 3-cyclopropyl-3-oxopropanoate (82mmol), and the mixture was stirred for 30 minutes. Then, it was cooled to 10 ℃ and a solution of III-1(18.3g, 82mmol) in anhydrous ethanol (80mL) was added dropwise thereto (inner temperature not exceeding 30 ℃ C.), and the reaction was allowed to proceed overnight at room temperature. The reaction was diluted with ethyl acetate (100mL), washed with water, and the aqueous phase was extracted with ethyl acetate (100mL each, 3 times). The organic phases were mixed, washed with saturated brine and concentrated. To the concentrate was added 100mL of ether and stirred, and the solvent was removed in vacuo to give the product IV-1 as a solid (21.6g, 84% yield).¹H NMR(400MHz，CDCl₃)δ7.43–7.39(m，2H)，7.39–7.33(m，1H)，3.72(s，3H)，2.21–2.09(m，1H)，1.35–1.28(m，2H)，1.25–1.18(m，2H).

IV-1(21.6g, 69mmol) was dissolved in tetrahydrofuran (140mL), cooled to 0 deg.C, a toluene solution of diisobutylaluminum hydride (1.5M,102mL) was slowly added dropwise to the solution, and the reaction was stirred at room temperature for 6 h. Slowly pouring the reaction liquid into ice water, adding 1M hydrochloric acid aqueous solution to adjust the pH to be about 2, extracting with ethyl acetate (100mL each time, three times in total), concentrating, and performing column chromatography to obtain intermediate alcohol; this intermediate and triphenylphosphine (59mmol) were dissolved in dichloromethane (60mL), cooled to 0 deg.C, a solution of carbon tetrabromide (62mmol) in dichloromethane (60mL) was added dropwise under nitrogen,the reaction was carried out at room temperature for 4 hours. The solvent was removed from the reaction mixture to give an oil, which was subjected to column chromatography to give intermediate V-1(15.3g, 96% yield).¹H NMR(400MHz，CDCl₃)δ7.49–7.44(m，2H)，7.43–7.37(m，1H)，4.25(d，J＝1.3Hz，2H)，2.21–2.09(m，1H)，1.35–1.28(m，2H)，1.25–1.18(m，2H).

VII-1(11.0g, 100mmol) was dissolved in DMF (150mL), NaH (4g, 100mmol) was added to the solution in portions, the reaction was stirred at room temperature for 1h, and ethyl 2-bromo-2-methylpropionate (19.5g, 100mmol) was slowly added dropwise. Then adding 50mL of water to quench the reaction, adjusting the pH to be about 4 by using 1M hydrochloric acid aqueous solution, extracting by using ethyl acetate, concentrating, and carrying out column chromatography to obtain an intermediate VIII-1(13.6g, yield 61%);¹HNMR(400MHz，CDCL3)δ:6.80-6.74(m，2H)，6.72-6.66(m，2H)，4.22(q，2H)，1.51(s，6H)，1.27(t，3H)；MS(ESI，m/z)：223.1[M-H]^-。

compound VI-1(173mg, 0.5mmol), VIII-1(112mg, 0.5mmol) and potassium carbonate (138mg, 1mmol) were added to acetonitrile (15mL) and reacted at 60 ℃ for 10 hours. After the reaction is finished, filtering and concentrating to obtain a crude product IX-1 which is directly used in the next step; MS (ESI, m/z): 490.1[ M + H]⁺。

Compound IX-1(0.23g, 0.47mmol), and sodium hydroxide (40mg, 1mmol) were added to a mixed solution of ethanol and water (10mL, V/V ═ 9:1), and reacted at 60 degrees for 10 hours. After the reaction is finished, removing the solvent under reduced pressure, adding 10ml of water, adjusting the pH to be about 1 by using 1M hydrochloric acid aqueous solution, extracting by using ethyl acetate, concentrating, and carrying out column chromatography to obtain a product, namely 1(0.18g, the two-step yield is 78%), which is colorless oil;¹H NMR(400MHz，CDCl3)δ:7.41-7.26(m，3H)，6.83(d，2H)，6.68(d，2H)，4.75(s，2H)，2.18-2.07(m，1H)，1.52(s，6H)，1.27-1.20(m，2H)，1.13-1.06(m，2H)；MS(ESI，m/z)：462.1[M+H]⁺。

example 2:

preparation of example 2 by proceeding from intermediate VI-1, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

starting from the starting material II-2, the compound V-2 is synthesized according to the synthesis method for the compound V-1, wherein

Yield of white solid IV-2 was 58%.¹H NMR(400MHz，CDCl₃)δ7.82(d，J＝7.5Hz，1H)，7.74–7.59(m，2H)，7.56(d，J＝7.5Hz，1H)，3.3.73(s，3H)，2.19–2.09(m，1H)，1.33–1.27(m，2H)，1.24–1.15(m，2H)。

Yield of colorless liquid V-2 was 88%.¹H NMR(400MHz，CDCl₃)δ7.84(d，J＝7.4Hz，1H)，7.73–7.61(m，2H)，7.57(d，J＝7.4Hz，1H)，4.23(s，2H)，2.17–2.09(m，1H)，1.32–1.27(m，2H)，1.23–1.17(m，2H).

Synthesizing a compound 2 by starting from a raw material VI-1 according to a synthesis method for synthesizing a compound 1, wherein;

VII-2 as a white solid in 81% yield.¹H NMR(400MHz，CDCl₃)δ6.78–6.68(m，4H)，4.47(t，J＝6.2Hz，1H)，4.23(qd，J＝7.1，1.6Hz，2H)，2.01–1.91(m，2H)，1.26(t，J＝7.1Hz，3H)，1.08(t，J＝7.4Hz，3H)。MS(ESI，m/z)：225.1[M+H]⁺。

Colorless liquid VIII-2, yield 81%.¹H NMR(400MHz，CDCl₃)δ7.82–7.75(m，1H)，7.63–7.53(m，2H)，7.48–7.42(m，1H)，6.83–6.77(m，2H)，6.76–6.70(m，2H)，4.69(s，2H)，4.46(t，J＝6.2Hz，1H)，4.22(q，J＝7.1Hz，2H)，2.17–2.07(m，1H)，2.02–1.92(m，2H)，1.30–1.22(m，5H)，1.15–1.05(m，5H)。MS(ESI，m/z)：490.1[M+H]⁺。

Colorless oil 2, yield 87%.¹H NMR(400MHz，CDCl₃)δ7.82–7.76(m，1H)，7.62–7.53(m，2H)，7.46–7.42(m，1H)，6.84–6.79(m，2H)，6.76–6.72(m，2H)，4.71(s，2H)，4.52–4.46(m，1H)，2.17–2.09(m，1H)，2.03–1.94(m，2H)，1.27–1.22(m，2H)，1.15–1.05(m，5H)。MS(ESI，m/z)：462.1[M+H]⁺。

Example 3:

preparation of example 3 by proceeding from intermediate VI-1, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

compound 3 is synthesized from the raw material VI-1 according to the synthesis method for synthesizing the compound 1, and is colorless oily, and the yield is 49 percent;¹H NMR(400MHz，CDCl3)δ:7.42-7.30(m，3H)，7.01(d，2H)，6.81(d，2H)，4.27(s，2H)，3.50(t，2H)，2.70(t，2H)，2.12-2.04(m，1H)，1.57(s，6H)，1.25-1.19(m，2H)，1.10-1.03(m，2H)；MS(ESI，m/z)：490.1[M+H]⁺。

example 4:

synthesizing a compound 4 by starting from raw materials V-2 and VII-3 according to a synthesis method for synthesizing a compound 1;

VIII-4 as a colorless oil in 88% yield.¹H NMR(400MHz，CDCl3)δ:7.80-7.75(m，1H)，7.60-7.51(m，2H)，7.39-7.33(m，1H)，6.99(d，2H)，6.74(d，2H)，4.23(q，2H)，4.19(s，2H)，3.50(t，2H)，2.71(t，2H)，2.10-2.01(m，1H)，1.57(s，6H)，1.27-1.18(m，5H)，1.10-1.02(m，2H)；MS(ESI，m/z)：518.2[M+H]⁺。

Colorless oil 4, yield 91%.¹H NMR(400MHz，CDCl3)δ:7.79-7.75(m，1H)，7.60-7.51(m，2H)，7.36-7.32(m，1H)，7.03(d，2H)，6.83(d，2H)，4.19(s，2H)，3.51(t，2H)，2.73(t，2H)，2.10-2.01(m，1H)，1.57(s，6H)，1.23-1.18(m，2H)，1.09-1.03(m，2H)；MS(ESI，m/z)：490.2[M+H]⁺。

Example 5:

preparation of example 5 operation of reference example 1; starting from intermediate III-1, the compound is prepared by a synthetic route of compound 1, which is as follows:

yield of white solid IV-5 was 51%.¹H NMR(400MHz，CDCl₃)δ7.45–7.41(m，2H)，7.39–7.34(m，1H)，3.71(s，3H)，2.82(s，3H).

Starting from the raw material IV-5, synthesizing a compound intermediate VIII-5 according to the synthetic method for synthesizing the compound VIII-1. Yield 81% of VIII-5 as a colorless oil.¹H NMR(400MHz，CDCl3)δ:7.42-7.29(m，3H)，6.78-6.73(m，2H)，6.67-6.61(m，2H)，4.67(s，2H)，4.23(q，H)，2.52(s，3H)，1.52(s，6H)，1.27(t，3H)；MS(ESI，m/z)：464.1[M+H]⁺。

Yield of 5 as colorless oil 79%.¹H NMR(400MHz，CDCl3)δ:7.42-7.29(m，3H)，6.84(d，2H)，6.68(d，2H)，4.69(s，2H)，2.53(s，3H)，1.52(s，6H)；MS(ESI，m/z)：436.1[M+H]⁺。

Example 6:

preparation of example 6 operation of reference example 1; starting from intermediate III-1, the compound is prepared by a synthetic route of compound 1, which is as follows:

yield of white solid IV-6 was 67%.¹H NMR(400MHz，CDCl₃)δ8.10(d，J＝7.9Hz，1H)，7.97(d，J＝7.9Hz，1H)，7.58–7.44(m，5H)，7.41–7.36(m，1H)，3.65(s，3H).

Starting from the raw material IV-6, synthesizing a compound intermediate VIII-6 according to the synthetic method for synthesizing the compound VIII-1. White solid VIII-6, yield 66%;¹H NMR(400MHz，CDCl3)δ:7.90-7.84(m，2H)，7.54-7.49(m，3H)，7.44-7.31(m，3H)，6.79-6.73(m，2H)，6.68-6.62(m，2H)，4.81(s，2H)，4.23(q，H)，1.52(s，6H)，1.27(t，3H)；MS(ESI，m/z)：526.1[M+H]⁺。

yield of white solid 6 was 86%.¹H NMR(400MHz，CDCl3)δ:7.90-7.84(m，2H)，7.54-7.48(m，3H)，7.44-7.31(m，3H)，6.86-6.80(m，2H)，6.71-6.65(m，2H)，4.84(s，2H)，1.53(s，6H)；MS(ESI，m/z)：498.1[M+H]⁺。

Example 7:

synthesizing a compound 7 by starting from raw materials V-2 and VII-1 according to a synthesis method for synthesizing a compound 1; colorless oil, yield 51%.

¹H NMR(400MHz，CDCl3)δ:7.81-7.74(m，1H)，7.62-7.53(m，2H)，7.47-7.41(m，1H)，6.88-6.81(m，2H)，6.73-6.66(m，2H)，4.68(s，2H)，2.16-2.07(m，1H)，1.52(s，6H)，1.27-1.22(m，2H)，1.14-1.07(m，2H)；MS(ESI，m/z)：462.1[M+H]⁺。

Example 8:

preparation of example 8 by proceeding from intermediate II-9, prepared by the route of synthesis of compound 1, reference to the procedure of example 1, the synthetic route is as follows:

synthesis of Compound 8 starting from starting materials II-8 according to the Synthesis of Compound 1, in which

Yield of white solid IV-8 was 59%.¹H NMR(400MHz，CDCl₃)δ7.66–7.50(m，2H)，7.49–7.41(m，2H)，3.70(s，2H)，2.18–2.10(m，1H)，1.31–1.26(m，2H)，1.23–1.17(m，2H).

The yield of colorless liquid V-8 was 82%.¹H NMR(400MHz，CDCl₃)δ7.65–7.52(m，2H)，7.49–7.40(m，2H)，4.36(s，2H)，2.18–2.10(m，1H)，1.31–1.26(m，2H)，1.23–1.17(m，2H).

Synthesizing a compound 8 by starting from raw materials V-8 and VII-1 according to a synthesis method for synthesizing a compound 1; colorless oil, yield 58%.¹H NMR(400MHz，CDCl3)δ:7.57-7.46(m，2H)，7.40-7.33(m，2H)，6.89-6.82(m，2H)，6.75-6.68(m，2H)，4.82(s，2H)，2.18-2.09(m，1H)，1.53(s，6H)，1.27-1.21(m，2H)，1.14-1.07(m，2H)。MS(ESI，m/z)：478.1[M+H]⁺。

Example 9:

preparation of example 9 by following the procedure of example 1, starting from intermediate II-9, compound 1 was prepared by the following synthetic route:

yield of white solid IV-9 was 64%.¹H NMR(400MHz，CDCl₃)δ7.43–7.34(m，1H)，7.00–6.91(m，2H)，3.69(s，3H)，2.92–2.83(m，1H)，1.36–1.31(m，2H)，1.25–1.20(m，2H)。

The yield of colorless liquid V-9 was 82%.¹H NMR(400MHz，CDCl₃)δ7.54–7.44(m，1H)，7.11–7.04(m，2H)，4.33(s，2H)，2.20–2.08(m，1H)，1.34–1.17(m，4H)。

Synthesizing a compound 9 by starting from raw materials V-9 and VII-1 according to a synthesis method for synthesizing a compound 1; colorless oil, yield 53%.¹H NMR(400MHz，CDCl3)δ:7.46-7.36(m，1H)，7.04-6.95(m，2H)，6.88-6.82(m，2H)，6.73-6.67(m，2H)，4.83(s，2H)，2.18-2.09(m，1H)，1.52(s，6H)，1.28-1.21(m，2H)，1.14-1.07(m，2H)；MS(ESI，m/z)：429.1[M+H]⁺。

Example 10:

preparation of example 10 by proceeding from intermediate VI-10, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

white solid, yield 33%;¹H NMR(400MHz，CDCl3)δ:7.41-7.28(m，3H)，6.64(d，1H)，6.53(d，1H)，4.74(s，2H)，2.18-2.12(m，1H)，2.12(s，3H)，1.96(s，3H)，1.52(s，6H)，1.30-1.24(m，2H)，1.15-1.09(m，2H)；MS(ESI，m/z)：490.1[M+H]⁺。

example 11:

preparation of example 11 by proceeding from intermediate VI-11, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

white solid, yield 39%;¹H NMR(400MHz，CDCl3)δ:7.42-7.28(m，3H)，6.80(s，1H)，6.51(s，1H)，4.74(s，2H)，2.20-2.09(m，1H)，1.65(s，6H)，1.35(s，9H)，1.32-1.25(m，2H)，1.18(s，9H)，1.14-1.07(m，2H)；MS(ESI，m/z)：574.2[M+H]⁺。

example 12:

preparation of example 12 by proceeding from intermediate VI-12, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

white solid, yield 44%;¹H NMR(400MHz，CDCl3)δ:7.80(d，1H)，7.75(d，1H)，7.38-7.22(m，5H)，6.89(d，1H)，6.80(d，1H)，4.98(s，2H)，2.24-2.15(m，1H)，1.71(s，6H)，1.33-1.26(m，2H)，1.16-1.08(m，2H)；MS(ESI，m/z)：512.1[M+H]⁺。

example 13:

preparation of example 13 by proceeding from intermediate VI-13, prepared by the route for the synthesis of compound 1, reference to the procedure of example 1, the synthetic route is as follows:

white solid 13, yield 32%;¹H NMR(400MHz，CDCl3)δ:7.58(t，2H)，7.41-7.20(m，4H)，7.12(dd，1H)，7.05-6.97(m，2H)，4.90(s，2H)，2.25-2.16(m，1H)，1.62(s，6H)，1.32-1.27(m，2H)，1.17-1.11(m，2H)；MS(ESI，m/z)：512.1[M+H]⁺。

example 14:

preparation of example 14 by proceeding from intermediate II-14, prepared by the route of synthesis of compound 1, reference example 1, the synthetic route is as follows:

starting from the starting material II-14, the compound V-14 is synthesized by the synthesis method for the compound V-1, wherein

Yield of white solid IV-14 was 54%.¹H NMR(400MHz，CDCl₃)δ7.52–7.44(m，2H)，7.32–7.26(m，1H)，7.21(d，J＝8.5Hz，1H)，6.46(t，J＝73.7Hz，1H)，3.72(s，3H)，2.88–2.80(m，1H)，1.37–1.32(m，2H)，1.26–1.22(m，2H)。

Yield of colorless liquid V-14 was 72%.¹H NMR(400MHz，CDCl₃)δ7.60–7.51(m，2H)，7.41–7.32(m，2H)，6.51(t，J＝73.7Hz，1H)，4.38(s，2H)，2.18–2.10(m，1H)，1.32–1.17(m，4H).

The yield of VIII-14 was 54% as a colorless oil.¹H NMR(400MHz，CDCl3)δ:7.55-7.43(m，2H)，7.33-7.22(m，2H)，6.90-6.82(m，2H)，6.76-6.68(m，2H)，6.44(t，1H)，，4.83(s，2H),2.18-2.08(m，1H)，1.53(s，6H)，1.25-1.19(m，2H)，1.13-1.06(m，2H)；MS(ESI，m/z)：444.1[M+H]⁺。

Example 15:

preparation of example 15 by following the procedure of example 1, starting from intermediate VI-15, compound 1 was prepared by the following synthetic route:

oily liquid 15, yield 59%;¹H NMR(400MHz，CDCl3)δ:7.42-7.28(m，3H)，7.10(t，1H)，6.55-6.46(m，2H)，6.41(t，1H)，4.76(s，2H)，2.19-2.10(m，1H)，1.57(s，6H)，1.31-1.23(m，2H)，1.16-1.09(m，2H)；MS(ESI，m/z)：462.1[M+H]⁺。

example 16:

preparation of example 16 by proceeding from intermediate VI-16, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

oily liquid 16, yield 51%;¹H NMR(400MHz，CDCl3)δ:7.43-7.28(m，3H)，7.05(d，2H)，6.81(d，2H)，4.33(s，2H)，4.28(s，2H)，2.15-2.06(m，1H)，1.58(s，6H)，1.27-1.24(m，2H)，1.13-1.06(m，2H)；MS(ESI，m/z)：476.1[M+H]⁺。

example 17:

preparation of example 17 by proceeding from intermediate VI-17, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

oily liquid 17, yield 38%;¹H NMR(400MHz，CDCl3)δ:7.41-7.28(m，3H)，6.80(s，2H)，4.30(s，2H)，4.27(s，2H)，2.17(s，6H)，2.15-2.07(m，1H)，1.47(s，6H)，1.28-1.22(m，2H)，1.13-1.06(m，2H)；MS(ESI，m/z)：504.1[M+H]⁺。

example 18:

preparation of example 18 by proceeding from intermediate VI-18, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

oily liquid 18, yield 47%;¹H NMR(400MHz，CDCl3)δ:7.42-7.30(m，3H)，6.90(d，1H)，6.83(s，1H)，6.71(d，1H)，4.35(s，2H)，4.34(s，2H)，2.17-2.08(m，1H)，1.49(s，6H)，1.30-1.26(m，2H)，1.15-1.09(m，2H)；MS(ESI，m/z)：506.1[M+H]⁺。

example 19:

preparation of example 19 by proceeding from intermediate VI-19, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

oily liquid 19, yield 41%;¹H NMR(400MHz，CDCl3)δ:7.44-7.31(m，3H)，7.20(d，1H)，7.02-6.93(m，2H)，4.31(s，4H)，2.15-2.06(m，1H)，1.61(s，6H)，1.30-1.26(m，2H)，1.16-1.09(m，2H)；MS(ESI，m/z)：510.1[M+H]⁺。

example 20:

preparation of example 20 by proceeding from intermediate VI-20, prepared by the route for the synthesis of compound 1, reference example 1, the synthetic route is as follows:

oily liquid 20, yield 55%;¹H NMR(400MHz，CDCl3)δ:7.42-7.30(m，3H)，7.00(s，1H)，6.89(d，1H)，6.70(d，1H)，4.29(s，4H)，2.19(s，3H)，2.16-2.08(m，1H)，1.59(s，6H)，1.29-1.24(m，2H)，1.14-1.07(m，2H)；MS(ESI，m/z)：490.1[M+H]⁺。

example 21:

PPARs and FXR activity assay:

293T cells at 1 x 10⁴Perwell was plated on 96-well flat bottom microwell cell culture plates and after 24 hours, when the cell fusion was about 80% functional, i.e., in the logarithmic growth phase, GLA4-PPAR α, GLA4-PPAR β/δ, GLA4-PPAR γ, GLA4-FXR expression plasmid (20 ng/well) was co-transfected with 50ng/ml pG5-luc) luciferase reporter plasmid (50 ng/well) and reference TK (5 ng/well), respectively, according to the Lipofectamine 2000(Invitrogen) protocol. Adding the test compound 24 hours after transfectionThe substance and positive control (GFT-505(PPAR alpha, beta), rosiglitazone (PPAR gamma), OCA (FXR)), 1 ‰ DMSO as blank control. After the test compound is reacted for 24h, the test compound is used

The Dual-luciferase Reporter kit (Promega) measures the intensity of fluorescence to reflect the efficiency of activation of the corresponding receptor by the compound. Relative activity of test compound to positive compound (relative activity ═ (test compound signal intensity-blank)/(positive compound signal intensity-blank) × 100%). EC (EC)₅₀The value of (d) was calculated by the software Graphpad Prism 7. The results are shown in Table 1.

Table 1 results of activity test

And (4) conclusion: test results show that the compounds have PPARs-FXR multi-target activation capability and have further development potential.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.