Oxadiazole compound, method for preparing same, pharmaceutical composition, and use thereof

Abstract

The present invention relates to the fields of medicinal chemistry and therapeutics, specifically to compounds of general formula I, their racemates, R-isomers, S-isomers, pharmaceutically acceptable salts and mixtures thereof, methods for their preparation, pharmaceutical compositions containing such compounds and their use as S1P receptor agonists. The oxadiazole compounds involved in the present invention can be used to treat diseases associated with S1P receptor stimulation. [Formula 1] JPEG2023532971000128.jpg3744

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, and specifically to the preparation of drugs for treating diseases such as non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc., a method for preparing the same, a pharmaceutical composition of such a compound, and use as an S1P receptor agonist.

Background Art

[0002] Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that seriously threatens the health of the Chinese people. According to epidemiological surveys, the prevalence of NAFLD in China has increased rapidly from 18% in 2008 to 29.2% in 2018, and the growth rate is more than twice that of Western countries. Approximately 58.9% of NAFLD patients confirmed by biopsy show the form of non-alcoholic steatohepatitis (NASH). Currently, NAFLD has replaced chronic viral liver disease and ranks first among chronic liver diseases in China. By 2030, the prevalence in China is estimated to be the fastest in the world, reaching 314.58 million people. In the near future, NASH will become a major challenge for public health in China.

[0003] Lipid metabolism is one of the cores of liver metabolism. Evidence is increasingly growing that triglycerides deposited in hepatocytes are not the main cause of the production of lipotoxicity, and simply lowering triglycerides cannot effectively improve NASH. Therefore, new intervention measures for improving lipid disorders are urgently needed. Triglycerides are the main form of lipids in simple fatty liver, and about 25% of patients progress from simple fatty liver to NASH with a more obvious lipotoxic phenotype. In this process, reprogramming of the lipid metabolism network is considered to be one of the most important driving factors, but people know little about it. In the past decade, there have been new breakthroughs in the understanding of lipid metabolism disorders. Cholesterol, free fatty acids, lysophosphatidylcholine, and sphingolipids are considered to be important lipids that cause lipotoxicity. [7] . Here, sphingolipids are lipids containing a sphingosine backbone, and the metabolites ceramide and sphingosine 1-phosphate (S1P) are the two most studied bioactive molecules of sphingolipids. In the body, ceramide is generally synthesized through three pathways: de novo synthesis, sphingomyelinase hydrolysis, and salvage synthesis. Then, it is deacetylated by the action of ceramidase (CDase) to produce sphingosine, which is further phosphorylated to S1P by sphingosine kinase (SphK). Intracellular S1P functions as a second messenger that plays a biological regulatory function, and extracellularly secreted S1P activates downstream signaling pathways such as PI3K / Akt, Ras / ERK, Rho, and Rac through five cell surface G protein-coupled receptors (GPCRs), S1P receptors 1-5 (S1PR1-5), causing a series of biological effects such as cell survival, proliferation, differentiation, and migration. The five subtypes are distributed differently in different tissues. S1PR1, S1PR2, and S1PR3 are widely secreted in many tissues including the liver, and S1PR 4 is widely expressed in lymphoid tissues and lung tissues, and S1PR 5It is expressed in the brain and skin and performs various functions. Normal levels of S1P contribute to various important physiological processes such as cell growth, survival and migration, as well as angiogenesis and maturation. However, excessive S1P can also induce many pharmacological changes, including inflammation and fibrosis, which are two pathological processes closely related to the progression of NASH. Clinical research data indicate that the content of sphingolipids in the body is positively correlated with the process of NAFLD, especially the content of ceramide and S1P in the liver, which increases sharply during the progression to NASH. However, by reducing the ceramide level or regulating the downstream S1P signaling pathway, metabolic disorders can be improved.

[0004] Activation of innate immunity is an important factor in initiating and amplifying liver inflammation, which plays a central role in promoting the conversion from simple fatty liver to NASH. Kupffer cells (KCs) account for 20-35% of all non-parenchymal cells in the liver. They are macrophages located in the sinusoids of the liver and are the most important cells in the innate immunity of the liver. The cytokines released by them mediate the inflammatory cascade reaction, induce hepatocyte death and lipid degeneration, and promote the activation of hepatic stellate cells (HSCs). HSCs are the main source of the extracellular matrix and play an important role in the formation of liver fibrosis. After activation, HSCs differentiate into myofibroblast-like cells, which have characteristics such as contractility, inflammation promotion and fibrosis promotion. S1P can initiate the innate immune response and accelerate the progression of NASH by acting on S1PR1 and S1PR3 on the surface of liver macrophages. S1P can also directly induce the activation, proliferation and contraction of HSCs and promote the secretion of the extracellular matrix by acting on S1PR1-3 on the surface of HSCs. [8]Regulation of the activities of S1PR1 and S1PR3 in the body of mice by drugs or gene knockout has been shown by research to be able to effectively alleviate the progression of inflammation and fibrosis in various liver disease models. Therefore, the S1P receptor is a potential new target for the prevention and treatment of metabolic diseases such as NASH. In particular, it is a new target for type 2 diabetes with a hyperglycemic phenotype in the fasting state.

[0005] In summary, there is an urgent need to develop more S1P receptor regulators in the art.

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide an S1P receptor agonist.

Means for Solving the Problems

[0007] The first aspect of the present invention provides a compound represented by the following formula I, its pharmaceutically acceptable salt, racemic compound, R-isomer, S-isomer or a mixture thereof,

Chemical

[0008] In another preferred example, the compound has a structure as shown in the following formula II, [Chem.] wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N or CH, and when Y 1 , Y 2 , Y 3 or Y 4 is CH, said CH can be substituted by R 6 .

[0009] In another preferred example, the compound has a structure as shown in the following formula III, [Chem.] wherein X is CHR 2 .

[0010] In another preferred example, M has a structure as shown in the following formula: [Chemical Formula] where: A is selected from the group consisting of a substituted or unsubstituted 3- to 12-membered saturated aliphatic ring, a substituted or unsubstituted 3- to 12-membered unsaturated aliphatic ring, a substituted or unsubstituted 3- to 12-membered aliphatic ring containing 1 to 8 heteroatoms, a substituted or unsubstituted 7- to 12-membered aromatic condensed ring, a substituted or unsubstituted C6-C10 aromatic ring (preferably a benzene ring), or a substituted or unsubstituted 5- to 12-membered aromatic heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; Each R 1 is independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, amino group, hydroxyl group, nitro group, aldehyde group, substituted or unsubstituted C1-C6 alkyl group (including trifluoromethyl group), substituted C1-C3 alkyl group containing 1 to 7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5- to 7-membered heterocyclic ring, substituted or unsubstituted C1-C6 alkylphenyl group, substituted or unsubstituted C1-C6 alkyl group (5- to 7-membered heteroaryl group), substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted C2-C10 acyl group, substituted or unsubstituted C2-C10 ester group, substituted or unsubstituted C2-C10 aryl ether group, substituted or unsubstituted C1-C6 amide group, -OSO 2 R 4 , -OCOR 4 , SO 2 R 4 ; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In another preferred example, the A ring is selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5- to 7-membered saturated aliphatic ring, a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and a substituted or unsubstituted 5- to 10-membered partially unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. Each R 1 is independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, amino group, hydroxyl group, nitro group, aldehyde group, substituted or unsubstituted C1-C6 alkyl group (including trifluoromethyl group), substituted C1-C3 alkyl group containing 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5- to 7-membered heterocyclic ring, substituted or unsubstituted C1-C6 alkylphenyl group, substituted or unsubstituted C1-C6 alkyl group (5- to 7-membered heteroaryl group), substituted or unsubstituted C3-C12 cycloalkyl group, substituted or unsubstituted C2-C10 acyl group, substituted or unsubstituted C2-C10 ester group, substituted or unsubstituted C2-C10 aryl ether group, substituted or unsubstituted C1-C6 amide group, -OSO 2 R 4 , -OCOR 4 , -SO 2 R 4 and is selected from the group consisting of. a is 1, 2, 3, 4 or 5.

[0011] In another preferred example, the compound is the compound in each example of the present invention.

[0012] The second aspect of the present invention provides a pharmaceutical composition, which comprises one or more species selected from the group consisting of the compound of formula I described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemic compounds, R-isomers, S-isomers or mixtures thereof, and one or more species of pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary substances and / or diluents.

[0013] The third aspect of the present invention provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a racemic compound, an R-isomer, an S-isomer or a mixture thereof according to the first aspect of the present invention, which is used in the preparation of a pharmaceutical composition for treating or preventing a disease related to an S1P agonist.

[0014] In another preferred example, the disease is selected from the group consisting of non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome.

[0015] The fourth aspect of the present invention provides a method for preparing a compound of formula I, a pharmaceutically acceptable salt thereof, a racemic compound, an R-isomer, an S-isomer according to the first aspect of the present invention, and the method includes the following steps:

Chemical formula

Chemical formula

Advantages of the Invention

[0016] It should be understood that within the scope of the present invention, by combining each of the above technical features of the present invention with each of the technical features specifically described below (for example, in the embodiments), new or preferable technical solutions can be constituted. Due to space limitations, it will not be repeated here.

Brief Description of the Drawings

[0017]

Figure 1

Figure 2

[0018]

Figure 3

Figure 4

[0019]

Figure 5

Figure 6

[0020]

Figure 7

Figure 8

[0021]

Figure 9

Figure 10

[0022]

Figure 11

Figure 12

Figure 13

Mode for Carrying Out the Invention

[0023] As a result of long-term intensive research, the inventors have discovered an oxadiazole compound represented by the general formula I, its pharmaceutically acceptable salts, racemic compounds, R-isomers, S-isomers or mixtures thereof. Since the compound is an S1P receptor agonist, it can be used for the preparation of pharmaceutical compositions for treating indications related to S1P receptor agonists (for example, non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis in relapse, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc.). Based on the above findings, the inventors have completed the present invention.

[0024] Term 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 known to those skilled in the art.

[0025] In the present invention, the term "C1-C6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group and hexyl group, etc., preferably including ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group and t-butyl group.

[0026] In the present invention, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and the like.

[0027] In the present invention, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms containing a double bond, and includes, without limitation, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, a hexenyl group, and the like. In the present invention, the term "C2-C6 alkynyl group" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms containing a triple bond, and includes, without limitation, an ethynyl group, a propynyl group, a butynyl group, an isobutynyl group, a pentynyl group, a hexynyl group, and the like.

[0028] In the present invention, the term "C3-C10 cycloalkyl group" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and the like. The terms "C3-C8 cycloalkyl group", "C3-C7 cycloalkyl group", and "C3-C6 cycloalkyl group" have the same meaning.

[0029] In the present invention, the term "C3-C10 cycloalkenyl group" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, and includes, without limitation, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclodecenyl group, and the like. The term "C3-C7 cycloalkenyl group" has the same meaning.

[0030] In the present invention, the terms "aromatic ring" or "aryl group" have the same meaning, and preferably, the "aryl group" is a "C6-C12 aryl group" or a "C6-C10 aryl group". The term "C6-C12 aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms that does not contain heteroatoms in a ring such as a phenyl group or a naphthyl group. The term "C6-C10 aryl group" has a similar meaning.

[0031] In the present invention, the terms "aromatic heterocyclic ring" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to in this specification include oxygen, sulfur, and nitrogen. For example, a furyl group, a thienyl group, a pyridyl group, a pyrazolyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group, etc. The heteroaryl group ring can be condensed with an aryl group, a heterocyclic group, or a cycloalkyl group ring, where the ring bonded to the parent structure is a heteroaryl group ring. The heteroaryl group may or may not be optionally substituted.

[0032] In the present invention, the term "3- to 12-membered heterocyclic group" refers to a saturated or unsaturated 3- to 12-membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, such as a dioxolane base. The term "3- to 7-membered heterocyclic group" has a similar meaning.

[0033] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms of a particular group by a particular substituent. The particular substituent is the corresponding substituent described above, or the substituent appearing in each example. Unless otherwise specified, a substituent can have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position. A cyclic substituent such as a heterocycloalkyl group can be bonded to another ring such as a cycloalkyl group to form a spiro ring system, for example, two rings having a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are stable or chemically feasible. The substituents are, for example, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-8 cycloalkyl group, a 3- to 12-membered heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C1-8 aldehyde group, a C2-10 acyl group, a C2-10 ester group, an amino group, an alkoxy group, a C1-10 sulfonyl group, etc. (not limited thereto).

[0034] Oxadiazole compound as an S1P receptor agonist Based on the object of the present invention, the present invention provides an oxadiazole compound represented by the following general formula I, and its racemic compound, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof,

Chemical formula

[0035]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

[0036] The compounds of the present invention have asymmetric centers, chiral axes and chiral planes and can exist in the form of racemic compounds, R-isomers or S-isomers. Those skilled in the art can obtain R-isomers and / or S-isomers from racemic compounds by conventional technical means.

[0037] The present invention provides pharmaceutically acceptable salts of the compounds of general formula I. Specifically, the compounds of general formula I react with inorganic acids or organic acids to form conventional pharmaceutically acceptable salts. For example, conventional pharmaceutically acceptable salts can be prepared by reacting the compounds of general formula I with inorganic acids or organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, etc. The organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc., or sodium salts, potassium salts, calcium salts, aluminum salts or ammonium salts formed by the compounds of general formula I and inorganic bases, or methylamine salts, ethylamine salts or ethanolamine salts formed by the compounds of general formula I and organic bases.

[0038] The compounds of the present invention can be used to prepare pharmaceutical compositions comprising one or more species selected from a therapeutically effective amount of the oxadiazole compounds represented by the general formula I above, pharmaceutically acceptable salts thereof, racemic compounds, R-isomers, S-isomers or mixtures thereof. The pharmaceutical compositions can be used to treat diseases such as non-alcoholic fatty liver disease, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis in relapse, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc. related to S1P receptor agonists.

[0039] The compounds of the present invention can also be used to prepare S1P receptor agonists comprising one or more species selected from the oxadiazole compounds represented by the above formula I, pharmaceutically acceptable salts thereof, racemic compounds, R-isomers, S-isomers or mixtures thereof.

[0040] Preparation of Oxadiazole Compounds Another aspect of the present invention provides a method for preparing a compound represented by the general formula I, and the preparation method is carried out according to the following scheme.

[0041] The compound of formula (I) can be prepared by the method shown in the following scheme. Scheme:

Chemical formula

[0042] Pharmaceutical Composition and Its Preparation Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more species selected from the compounds of general formula I above, their pharmaceutically acceptable salts, enantiomers, diastereomers or racemic compounds, and optionally one or more species of pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary substances and / or diluents. The auxiliary substances are, for example, odorants, flavorants, sweeteners and the like.

[0043] The pharmaceutical composition provided by the present invention preferably contains the active ingredient in a weight ratio of 1-99%. The preferred ratio is that the compound of general formula I occupies 65 wt% - 99 wt% of the total weight as the active ingredient, and the remaining part is a pharmaceutically acceptable carrier, diluent or solution or physiological saline.

[0044] The compounds and pharmaceutical compositions provided by the present invention can be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and can be present in suitable solid or liquid carriers or diluents, and suitable sterile devices for injection or infusion.

[0045] The various dosage forms of the pharmaceutical composition of the present invention can be prepared by conventional preparation methods in the pharmaceutical field. The unit dosage of the formulation contains 1 mg - 700 mg of the compound of general formula I, and preferably, the unit dosage of the formulation contains 25 mg - 300 mg of the compound of general formula I.

[0046] The compounds and pharmaceutical compositions of the present invention can be clinically used in mammals including humans and animals, and can be administered via oral, nasal, dermal, pulmonary or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is to take 50 - 1400 mg / kg body weight once, or take 25 - 700 mg / kg body weight in several divided doses. Regardless of the administration method, the individual optimal dose needs to depend on the specific treatment method. Usually, start with a small amount and gradually increase the dose until the optimal dose is found.

[0047] The present invention further provides an S1P agonist comprising one or more species selected from the compounds represented by the above general formula I, pharmaceutically acceptable salts thereof, racemic compounds, R-isomers, S-isomers or mixtures thereof, and optionally one or more species of pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary substances and / or diluents.

[0048] The compounds and compositions of the present invention are used for treating and preventing diseases related to S1P agonists such as non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc. The diseases include, but are not limited to, various diseases such as diabetes, hyperlipidemia, non-alcoholic fatty liver, liver fibrosis, multiple sclerosis, etc.

[0049] Accordingly, another aspect of the present invention is the use of the compounds represented by the above general formula I, pharmaceutically acceptable salts thereof, racemic compounds, R-isomers, S-isomers or mixtures thereof in the preparation of a drug for treating diseases related to S1P agonists such as non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc., for example, various diseases such as diabetes, hyperlipidemia, non-alcoholic fatty liver, liver fibrosis, multiple sclerosis, etc.

[0050] Yet another aspect of the present invention provides a method for treating metabolic and autoimmune diseases associated with diseases such as non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc., for example, various diabetes, hyperlipidemia, non-alcoholic fatty liver, liver fibrosis, multiple sclerosis, etc., which comprises administering to a patient in need of treatment one or more species selected from the compounds represented by the general formula I above, pharmaceutically acceptable salts thereof, racemic compounds, R-isomers, S-isomers or mixtures thereof.

[0051] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used only for the purpose of explaining the present invention and are not intended to limit the scope of the present invention. In the following examples, experimental methods without specific conditions indicated generally follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0052] Example 1. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A1)

Chemical formula

Chemical formula

[0053] Synthesis of 4-Methyl-1-naphthalenecarbonitrile

Chemical Structure

[0054] Synthesis of 4-(Bromomethyl)-1-naphthalenecarbonitrile

Chemical Structure

[0055] Synthesis of 4-formyl-1-naphthalenecarbonitrile

Chemical Structure

[0056] Synthesis of 4-(1,3-dioxolan-2-yl)-1-naphthalenenitrile

Chemical Structure

[0057] (Z)-4-(1,3-Dioxolan-2-yl)-N'-hydroxy-1-naphthaleneamidine synthesis

Chemical Structure

[0058] Synthesis of 5-(5-(4-(1,3-dioxolan-2-yl)naphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile

Chemical Structure

[0059] Synthesis of 5-(5-(4-formylnaphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile

Chemical Structure

[0060] Synthesis of Methyl 1 - ((4 - (3 - (3 - Cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 5 - yl)naphthalen - 1 - yl)methyl)azetidinepyridine - 3 - carboxylate

Chemical Structure

[0061] Synthesis of 1 - ((4 - (5 - (3 - cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) azetidine pyridine - 3 - carboxylate hydrochloride

Chem.

[0062] Example 2. Synthesis of 1 - ((4 - (5 - (3 - cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) pyrrolalkane - 3 - carboxylate hydrochloride (A2)

Chem.

[0063] Example 3. Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)proline hydrochloride) (A3)

Chemical Structure

[0064] Example 4. Synthesis of (cis)-3-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)cyclobutane-1-carboxylic acid hydrochloride (A4)

Chemical formula

[0065] Example 5. Synthesis of N-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N-methylglycine hydrochloride (A5)

Chemical Structure

[0066] Example 6. Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)alanine hydrochloride (A6)

Chemical Structure

[0067] Example 7. Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)glycine hydrochloride (A7)

Chemical formula

[0068] Example 8. Synthesis of 1-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)propionic acid hydrochloride (A8)

Chemical formula

[0069] Example 9. Synthesis of 2-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)malic acid hydrochloride (A9)

Chemical formula

[0070] Example 10. Synthesis of 1-((4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A10)

Chemical formula

[0071] Example 11. Synthesis of 1-((4-(5-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A11)

Chemical formula

[0072] Example 12. Synthesis of 1 - ((4 - (5 - (4 - isopropoxyl - 3 - (trifluoromethyl)phenyl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A12) [Chemical formula] The synthesis method of compound A12 is the same as that of compound A1, and the yield is 81%. 1 1H NMR (400 MHz, MeOD) δ 9.05 (dd, J = 7.6, 2.0 Hz, 1H), 8.47 (d, J = 7.4 Hz, 2H), 8.38 (dd, J = 14.9, 8.1 Hz, 2H), 7.89 - 7.77 (m, 3H), 7.49 (d, J = 9.0 Hz, 1H), 5.06 (s, 2H), 5.00 - 4.95 (m, 1H), 4.48 - 4.35 (m, 4H), 3.79 - 3.61 (m, 1H), 1.45 (d, J = 6.0 Hz, 6H). 13 13C NMR (150 MHz, DMSO-d 6)δ 174.0, 168.9, 159.7, 134.6, 132.0, 130.7, 129.3, 128.4, 127.7, 127.4, 126.7, 125.2, 124.4, 122.6, 119.2, 119.0, 116.2, 115.5, 72.5, 56.4, 33.1, 22.0. ESI-MS m / z: 512.1 [M+H] + 。

[0073] Example 13. Synthesis of 1-((4-(5-(4-Isopropoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A13)

Chemical Structure

[0074] Example 14. Synthesis of 1-((4-(5-(4-Isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A14)

Chemical Structure

[0075] Example 15. Synthesis of 1 - ((4 - (5 - (4 - (t - butoxy)phenyl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A15)

Chemical Structure

[0076] Synthesis of Example 16. 1-((4-(5-(4-Methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A16)

Chemical formula

[0077] Synthesis of Example 17. 1-((4-(5-(4-Propoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A17)

Chemical formula

[0078] Example 18. Synthesis of 1 - ((4 - (5 - (4 - (benzyloxy)phenyl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A18) [Chemical formula] The synthesis method of compound A18 is the same as that of compound A1, and the yield is 65%. 1 1H NMR (400 MHz, MeOD) δ 9.04 (d, J = 8.2 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.25 (d, J = 8.6 Hz, 2H), 7.87 - 7.77 (m, 3H), 7.51 (d, J = 7.5 Hz, 2H), 7.46 - 7.40 (m, 2H), 7.37 (d, J = 7.1 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 5.26 (s, 2H), 5.06 (s, 2H), 4.47 - 4.35 (m, 4H), 3.74 - 3.64 (m, 1H). 13 13C NMR (125 MHz, DMSO-d 6)δ 175.1, 168.8, 162.8, 136.8, 131.9, 130.8, 130.6, 129.1, 129.0, 128.6, 128.3, 126.8, 125.0, 116.4, 116.3, 70.2, 56.3, 32.9. ESI-MS m / z: 492.1 [M+H] + 。

[0079] Example 19. Synthesis of 1-((4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A19)

Chemical formula

[0080] Example 20. Synthesis of 1-((4-(5-(4-isopropylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A20)

Chemical formula

[0081] Example 21. Synthesis of 1-((4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A21)

Chemical Structure

[0082] Example 22. Synthesis of 1-((4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A22)

Chemical formula

[0083] Example 23. Synthesis of 1-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A23)

Chemical formula

[0084] Example 24. Synthesis of 1 - ((4 - (5 - (3 - cyanophenyl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A24)

Chemical formula

[0085] Example 25. Synthesis of 1 - ((4 - (5 - (3 - fluorophenyl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A25)

Chemical formula

[0086] Example 26. Synthesis of 1 - ((4 - (5 - phenyl - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) azetidine pyridine - 3 - carboxylate hydrochloride (A26)

Chemical Structure

[0087] Synthesis of Example 27. 1 - ((4-(5-(Pyridin - 4 - yl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A27)

Chem.

[0088] Synthesis of Example 28. 1 - ((4-(5-(Pyridin - 3 - yl)-1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl)azetidine pyridine - 3 - carboxylate hydrochloride (A28)

Chem.

[0089] Example 29. Synthesis of 1-((4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A29) [Chemical formula] The synthesis method of compound A29 is the same as that of compound A1, and the yield is 69%. 1 1H NMR (400 MHz, MeOD) δ 9.13 - 9.06 (m, 1H), 8.90 - 8.85 (m, 1H), 8.51 - 8.43 (m, 2H), 8.40 - 8.35 (m, 1H), 8.21 - 8.15 (m, 1H), 7.90 - 7.74 (m, 4H), 5.11 (s, 2H), 4.54 - 4.41 (m, 4H), 3.83 - 3.71 (m, 1H). 13 13C NMR (150 MHz, DMSO-d 6 ) δ 174.3, 169.0, 151.2, 143.3, 138.7, 131.9, 130.7, 129.2, 128.6, 128.1, 128.0, 126.8, 125.2, 125.1, 56.0, 32.8. ESI-MS m / z: 387.1 [M+H]+ .

[0090] Example 30. Synthesis of 1-((4-(5-(5-Methylisothiazol-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A30) [Chemical formula] The synthesis method of compound A30 is the same as that of compound A1, and the yield is 71%. 1 H NMR (400 MHz, MeOD) δ 9.08 - 9.00 (m, 1H), 8.44 - 8.33 (m, 2H), 7.90 - 7.76 (m, 3H), 6.95 (t, J = 0.9 Hz, 1H), 5.06 (s, 2H), 4.48 - 4.33 (m, 4H), 3.68 (p, J = 8.4 Hz, 1H), 2.64 (d, J = 0.9 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 187.4, 172.4, 168.0, 166.7, 149.9, 140.1, 131.0, 129.6, 128.5, 127.5, 126.7, 125.6, 124.2, 101.6, 55.5, 32.2, 11.4. ESI-MS m / z: 391.1 [M+H] + .

[0091] Example 31. Synthesis of 1-((4-(5-(Benzo[d][1,3]dioxazol-5-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A31) [Chemical formula] The synthesis method of compound A31 is the same as that of compound A1, and the yield is 71%. 11H NMR (500 MHz, MeOD) δ 8.00 - 7.91 (m, 2H), 7.77 (dd, J = 8.4, 1.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.09 (s, 2H), 3.74 (s, 2H), 3.49 (dd, J = 9.0, 5.8 Hz, 2H), 3.16 (dd, J = 9.0, 5.8 Hz, 2H), 2.98 (p, J = 5.8 Hz, 1H). ESI-MS m / z: 430.1 [M+H] + 。

[0092] Example 32. Synthesis of 1-((4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A32)

Chemical Structure

[0093] Synthesis of Example 33. 1-((4-(5-(quinolin-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A33) [Chemical formula] The synthesis method of compound A33 is the same as that of compound A1, and the yield is 74%. 1 H NMR(400MHz,MeOD)δ 9.15-9.09(m,1H),8.70-8.66(m,1H),8.53-8.47(m,2H),8.40-8.31(m,2H),8.14-8.10(m,1H),7.99-7.93(m,1H),7.91-7.79(m,4H),5.09(s,2H),4.55-4.35(m,4H),3.74(q,J=8.5Hz,1H). 13 C NMR(125MHz,DMSO-d 6 )δ 174.2,169.2,147.8,143.4,138.9,132.0,131.7,130.7,130.1,129.6,129.4,129.3,128.8,128.5,127.8,126.8,125.2,121.2,56.4,33.1.ESI-MS m / z:437.1[M+H] + .

[0094] Synthesis of Example 34. 1-((4-(5-(quinoxalin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A34) [Chemical formula] The synthesis method of compound A34 is the same as that of compound A1, and the yield is 69%. 11H NMR (400 MHz, MeOD) δ 9.82 (s, 1H), 9.19 - 9.09 (m, 1H), 8.51 (d, J = 7.3 Hz, 1H), 8.40 - 8.34 (m, 2H), 8.31 - 8.25 (m, 1H), 8.11 - 8.01 (m, 2H), 7.95 - 7.81 (m, 3H), 5.12 (s, 2H), 4.57 - 4.40 (m, 4H), 3.88 - 3.72 (m, 1H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 171.7, 168.2, 166.1, 144.0, 142.2, 140.4, 138.0, 132.4, 131.4, 131.1, 131.0, 129.6, 129.6, 129.4, 128.7, 128.5, 128.3, 127.7, 127.6, 126.9, 126.8, 125.8, 125.7, 124.2, 124.1, 55.3, 46.8, 46.7, 32.0. ESI-MS m / z: 438.1 [M+H] + .

[0095] Example 35. Synthesis of 1 - ((4 - (5 - (1H - indol - 5 - yl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) azetidine pyridine - 3 - carboxylate hydrochloride (A35) [Chemical formula] The synthesis method of compound A35 is the same as that of compound A1, and the yield is 62%. 1 1H NMR (400 MHz, MeOD) δ 9.04 (dd, J = 7.3, 2.3 Hz, 1H), 8.57 (dd, J = 1.7, 0.7 Hz, 1H), 8.40 - 8.31 (m, 2H), 8.04 (dd, J = 8.6, 1.7 Hz, 1H), 7.88 - 7.76 (m, 3H), 7.66 - 7.59 (m, 1H), 7.44 (d, J = 3.2 Hz, 1H), 6.70 (dd, J = 3.2, 0.9 Hz, 1H), 5.03 (s, 2H), 4.46 - 4.24 (m, 4H), 3.60 (p, J = 8.4 Hz, 1H). 13 13C NMR (125 MHz, DMSO-d 6)δ 176.6, 168.9, 138.9, 132.1, 130.7, 129.1, 128.3, 128.0, 127.3, 126.7, 125.2, 121.8, 121.1, 114.6, 113.0, 103.2, 56.8, 33.6. ESI-MS m / z: 425.1[M+H] + 。

[0096] Example 36. Synthesis of 1-((4-(5-(1H-Indol-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A36)

Chem.

[0097] Example 37. Synthesis of 1-((4-(5-(1-Methyl-1H-indol-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A37)

Chem.

[0098] Example 38. Synthesis of (E)-1-((4-(5-styryl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine pyridine-3-carboxylate hydrochloride (A38)

Chemical formula

[0099] Example 39. Synthesis of 1-((4-(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidinepyridine-3-carboxylic acid hydrochloride (A39)

Chemical Structure

[0100] Example 40. Synthesis of 1-((4-(5-(3-Cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-4-carboxylic acid hydrochloride (A40)

Chemical Structure

[0101] Example 41. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-3-carboxylic acid hydrochloride (A41)

Chemical Structure

[0102] Example 42. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-3,4-dicarboxylic acid hydrochloride (A42) [Chemical formula] The synthesis method of compound A42 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.87 (dd, J = 7.4, 1.5 Hz, 1H), 7.65 (dd, J = 7.5, 1.3 Hz, 2H), 7.59 - 7.49 (m, 2H), 7.46 (td, J = 7.5, 1.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 7.5, 2.0 Hz, 1H), 4.44 (dq, J = 13.6, 6.8 Hz, 1H), 4.38 (d, J = 12.4 Hz, 1H), 3.76 (d, J = 12.2 Hz, 1H), 3.47 - 3.37 (m, 1H), 3.21 - 3.11 (m, 1H), 2.75 - 2.65 (m, 2H), 2.54 - 2.44 (m, 1H), 2.35 - 2.22 (m, 2H), 1.82 - 1.70 (m, 1H), 1.36 (dd, J = 25.1, 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 178.27, 176.57, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 58.90, 53.78, 53.20, 42.81, 27.48, 21.93. ESI-MS m / z: 541.2 [M + H] + .

[0103] Example 43. Synthesis of 1 - ((4 - (5 - (3 - cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) pyrrolidine - 3 - sulfonic acid (A43) [Chemical formula] The synthesis method of compound A43 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.6 Hz, 1H), 7.99 (dd, J = 7.3, 1.6 Hz, 1H), 7.79 (s, 1H), 7.64 (dd, J = 7.5, 2.8 Hz, 2H), 7.56 - 7.43 (m, 3H), 7.34 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.5, 2.0 Hz, 1H), 4.49 - 4.35 (m, 2H), 3.76 (d, J = 12.4 Hz, 1H), 3.40 (dd, J = 9.5, 7.0 Hz, 1H), 3.10 (ddt, J = 16.9, 14.0, 7.0 Hz, 2H), 2.67 (dd, J = 9.5, 7.0 Hz, 1H), 2.46 (dq, J = 12.8, 7.0 Hz, 1H), 2.35 (dt, J = 9.5, 7.1 Hz, 1H), 2.15 (dq, J = 12.9, 7.0 Hz, 1H), 1.36 (dd, J = 25.1, 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 67.47, 59.06, 56.90, 52.53, 28.58, 21.93. ESI-MS m / z: 519.2 [M + H] + .

[0104] Example 44. Synthesis of methyl 1 - ((4 - (5 - (3 - cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl) azelate - 3 - carboxylic acid (A44) [Chemical formula] The synthesis method of compound A44 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.6 Hz, 1H), 8.00 (dd, J = 7.4, 1.6 Hz, 1H), 7.64 (dd, J = 7.5, 4.4 Hz, 2H), 7.56 - 7.43 (m, 3H), 7.34 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.5, 1.8 Hz, 1H), 4.43 (h, J = 6.8 Hz, 1H), 3.81 (dd, J = 11.1, 6.9 Hz, 2H), 3.67 (s, 3H), 3.39 (s, 2H), 3.23 (dd, J = 11.1, 6.9 Hz, 2H), 3.14 (p, J = 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 173.55, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 51.81, 43.42, 42.29, 21.93. ESI-MS m / z: 483.2 [M + H] + .

[0105] Example 45. Synthesis of Ethyl 1 - ((4 - (5 - (3 - Cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl) azelate - 3 - carboxylic acid (A45) [Chemical formula] The synthesis method of compound A45 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.3, 1.6 Hz, 1H), 7.98 (dd, J = 7.4, 1.6 Hz, 1H), 7.64 (dd, J = 7.5, 4.4 Hz, 2H), 7.53 (dd, J = 7.4, 1.6 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.5, 2.0 Hz, 1H), 4.43 (hept, J = 6.8 Hz, 1H), 4.17 (q, J = 5.9 Hz, 2H), 3.82 (dd, J = 10.8, 6.7 Hz, 2H), 3.39 (s, 2H), 3.26 - 3.11 (m, 3H), 1.36 (d, J = 6.8 Hz, 6H), 1.23 (t, J = 5.9 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 172.53, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 60.82, 57.90, 43.42, 42.31, 21.93, 14.26. ESI-MS m / z: 497.2 [M + H] + .

[0106] Example 46. Synthesis of Isopropyl 1 - ((4 - (5 - (3 - Cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl)naphthalen - 1 - yl)methyl) azelate - 3 - carboxylic acid (A46) [Chemical formula] The synthesis method of compound A46 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.5, 1.6 Hz, 1H), 7.99 (dd, J = 7.4, 1.5 Hz, 1H), 7.65 (dd, J = 9.6, 7.4 Hz, 2H), 7.56 - 7.43 (m, 3H), 7.32 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.5, 2.0 Hz, 1H), 5.04 (hept, J = 6.8 Hz, 1H), 4.43 (hept, J = 6.9 Hz, 1H), 3.82 (dd, J = 10.8, 6.7 Hz, 2H), 3.39 (s, 2H), 3.27 - 3.12 (m, 3H), 1.36 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.9 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 170.80, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 67.81, 57.90, 43.42, 42.42, 21.93, 21.90. ESI-MS m / z: 511.2 [M+H] + .

[0107] Example 47. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxamide (A47) [Chemical formula] The synthesis method of compound A47 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.5 Hz, 1H), 8.01 (dd, J = 7.4, 1.6 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.23 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 7.5, 2.0 Hz, 1H), 5.68 (s, 2H), 4.43 (hept, J = 6.9 Hz, 1H), 3.77 (dd, J = 11.1, 6.9 Hz, 2H), 3.48 - 3.39 (m, 2H), 3.24 (dd, J = 11.1, 7.0 Hz, 2H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.67 (d, J = 4.7 Hz), 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 47.45, 41.10, 21.93. ESI-MS m / z: 468.2 [M+H] + .

[0108] Example 48. Synthesis of 1 - ((4 - (5 - (3 - cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) - N - methylazetidine - 3 - carboxamide (A48) [Chemical formula] The synthesis method of compound A48 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.5 Hz, 1H), 8.01 (dd, J = 7.4, 1.6 Hz, 1H), 7.64 (dd, J = 7.5, 5.5 Hz, 2H), 7.52 (td, J = 7.7, 7.2, 1.8 Hz, 2H), 7.46 (td, J = 7.5, 1.6 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 7.5, 2.0 Hz, 1H), 5.98 (s, 1H), 4.43 (hept, J = 6.8 Hz, 1H), 3.76 (dd, J = 11.1, 7.0 Hz, 2H), 3.44 (p, J = 7.0 Hz, 2H), 3.39 (s, 1H), 3.24 (dd, J = 11.1, 7.0 Hz, 2H), 2.80 (s, 3H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 172.45, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 46.88, 41.89, 26.32, 21.93. ESI-MS m / z: 482.2 [M+H] + .

[0109] Example 49. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N,N-dimethylazetidine-3-carboxamide (A49) [Chemical formula] The synthesis method of compound A49 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.5 Hz, 1H), 7.99 (dd, J = 7.4, 1.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.46 (td, J = 7.4, 1.6 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 7.5, 2.0 Hz, 1H), 4.44 (hept, J = 6.8 Hz, 1H), 3.80 (dd, J = 11.1, 7.0 Hz, 2H), 3.61 (p, J = 6.9 Hz, 1H), 3.39 (s, 2H), 3.22 (dd, J = 11.1, 6.9 Hz, 2H), 3.04 (s, 6H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 173.60, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 46.35, 42.85, 35.58, 21.93. ESI-MS m / z: 496.2 [M+H] + .

[0110] Example 50. Synthesis of 5-(3-(4-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (A50) [Chemical formula] The synthesis method of compound A50 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J = 7.5, 1.6 Hz, 1H), 8.02 (dd, J = 7.4, 1.6 Hz, 1H), 7.65 (dd, J = 7.4, 1.9 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.47 (td, J = 7.4, 1.7 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 7.4, 1.9 Hz, 1H), 4.43 (h, J = 6.8 Hz, 1H), 3.93 (dd, J = 11.2, 7.0 Hz, 2H), 3.78 (p, J = 7.0 Hz, 1H), 3.39 (s, 2H), 3.20 (dd, J = 11.1, 6.9 Hz, 2H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 159.05, 144.67, 134.27, 132.00, 131.29, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 46.90, 37.35, 21.93. ESI-MS m / z: 493.2 [M+H] + .

[0111] Example 51. Synthesis of 3-(4-((3-(1H-Tetrazol-5-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (A51) [Chemical formula] The synthesis method of compound A51 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.27 (dd, J = 7.3, 1.6 Hz, 1H), 8.02 (dd, J = 7.4, 1.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.56 - 7.43 (m, 4H), 7.24 (dd, J = 2.0, 1.0 Hz, 1H), 6.98 (dd, J = 7.5, 2.0 Hz, 1H), 4.43 (h, J = 6.9 Hz, 1H), 3.93 (dd, J = 11.2, 7.0 Hz, 2H), 3.78 (p, J = 7.0 Hz, 1H), 3.39 (s, 2H), 3.20 (dd, J = 11.2, 6.9 Hz, 2H), 1.35 (d, J = 6.9 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 154.72, 144.67, 132.69, 132.00, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 126.67, 126.64, 125.87, 125.40, 125.31, 124.41, 123.72, 121.65, 121.40, 115.12, 115.10, 115.09, 72.86, 57.90, 46.90, 37.35, 21.93. ESI-MS m / z: 536.2 [M + H] + .

[0112] Example 52. Synthesis of 3-(4-((3-(1H-tetrazol-5-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole (A52) [Chemical formula] 3- The synthesis method of compound A52 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 9.83 (s, 1H), 8.31 (dd, J = 7.4, 1.6 Hz, 1H), 8.23 (s, 1H), 7.99 (dd, J = 7.4, 1.6 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 1.6 Hz, 1H), 7.57 - 7.48 (m, 3H), 7.46 (dd, J = 7.5, 1.5 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.66 (dd, J = 7.4, 1.5 Hz, 1H), 5.47 (p, J = 7.0 Hz, 1H), 4.02 (dd, J = 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.27 (dd, J = 11.2, 7.0 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 142.71, 139.91, 132.00, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.99 - 127.58 (m), 127.00 (d, J = 7.6 Hz), 125.80, 125.31, 124.78, 124.41, 122.29, 112.56, 102.91, 57.90, 53.88, 50.83. ESI-MS m / z: 449.2 [M + H] + .

[0113] Example 53. Synthesis of 3-(4-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-6-yl)-1,2,4-oxadiazole (A53) [Chemical formula] The synthesis method of compound A53 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 9.83 (s, 1H), 8.30 (dd, J = 7.4, 1.6 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.80 (dd, J = 7.4, 1.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.47 (td, J = 7.5, 1.7 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.56 (dd, J = 7.5, 1.6 Hz, 1H), 5.48 (p, J = 7.0 Hz, 1H), 4.02 (dd, J = 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.28 (dd, J = 11.2, 7.0 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 142.71, 135.24, 132.00, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 128.65, 127.74 (d, J = 15.3 Hz), 127.03, 125.31, 125.04, 124.41, 121.84 (d, J = 7.7 Hz), 112.61, 102.70, 57.90, 53.88, 50.83. ESI-MS m / z: 449.2 [M+H] + .

[0114] Example 54. Synthesis of 3-(4-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-2-yl)-1,2,4-oxadiazole (A54) [Chemical formula] The synthesis method of compound A54 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 9.83 (s, 1H), 9.34 (s, 1H), 8.30 (dd, J = 7.4, 1.6 Hz, 1H), 8.01 (dd, J = 7.4, 1.6 Hz, 1H), 7.74 (dt, J = 7.5, 1.6 Hz, 1H), 7.67 (dd, J = 7.4, 2.2 Hz, 2H), 7.58 - 7.50 (m, 2H), 7.47 (td, J = 7.4, 1.6 Hz, 1H), 7.19 - 7.08 (m, 2H), 7.00 (td, J = 7.4, 1.5 Hz, 1H), 5.48 (p, J = 7.1 Hz, 1H), 4.02 (dd, J = 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.28 (dd, J = 11.2, 7.0 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 167.59, 166.52, 142.71, 136.46, 132.00, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 128.46, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 122.50, 121.37 (d, J = 13.3 Hz), 116.68, 111.94, 107.96, 57.90, 53.88, 50.83. ESI-MS m / z: 449.2 [M + H] + .

[0115] Example 55. Synthesis of Diethyl (1 - ((4 - (5 - (3 - Cyano - 4 - isopropoxyphenyl) - 1,2,4 - oxadiazol - 3 - yl) naphthalen - 1 - yl) methyl) azelate - 3 - yl) phosphonate (A55) [Chemical formula] The synthesis method of compound A55 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.25 (dd, J = 7.4, 1.5 Hz, 1H), 7.89 (dd, J = 7.4, 1.5 Hz, 1H), 7.74 (dd, J = 9.3, 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.52 (td, J = 7.4, 1.7 Hz, 1H), 7.46 (td, J = 7.5, 1.6 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 7.5, 2.0 Hz, 1H), 4.43 (hept, J = 6.8 Hz, 1H), 4.24 - 4.10 (m, 6H), 3.39 (s, 2H), 3.19 (dd, J = 11.2, 7.0 Hz, 2H), 2.52 (dp, J = 11.4, 7.0 Hz, 1H), 1.39 - 1.28 (m, 12H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d, J = 12.4 Hz), 128.91, 127.75 (d, J = 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 62.14 (d, J = 5.7 Hz), 57.90 (d, J = 3.8 Hz), 47.33 (d, J = 6.7 Hz), 21.93, 16.52 (d, J = 5.7 Hz). ESI-MS m / z: 561.2 [M + H] + .

[0116] Example 56. Synthesis of 1-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinolin-8-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A56) [Chemical formula] The synthesis method of compound A56 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 9.00 (dd, J = 7.4, 1.6 Hz, 1H), 8.32 (dd, J = 7.4, 1.5 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.46 (dd, J = 7.5, 2.0 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 4.43 (hept, J = 6.8 Hz, 1H), 3.78 (dd, J = 11.1, 6.9 Hz, 2H), 3.69 (s, 2H), 3.25 (dd, J = 11.1, 6.9 Hz, 2H), 3.14 (p, J = 6.9 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 177.47, 172.69, 166.15, 159.05, 149.66, 137.44, 134.27, 133.09, 132.93, 132.29, 131.29, 129.17, 128.00, 127.54, 123.60, 122.49, 115.46, 113.72, 105.66, 72.86, 57.07, 42.88, 21.93. ESI-MS m / z: 470.2 [M+H] + .

[0117] Example 57. Synthesis of 1-((5-(5-(3-Cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)isoquinolin-8-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A57)

Chemical Structure

[0118] Example 58. Synthesis of 1-((8-(5-(3-Cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinoxalin-5-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A58) [Chemical formula] The synthesis method of compound A58 is the same as that of compound A1. 1 1H NMR (500 MHz, Chloroform-d) δ 9.06 - 8.98 (m, 2H), 7.85 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 7.5, 2.0 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 4.43 (hept, J = 6.8 Hz, 1H), 3.80 (dd, J = 10.8, 6.6 Hz, 2H), 3.69 (s, 2H), 3.26 - 3.12 (m, 3H), 1.36 (d, J = 6.8 Hz, 6H). 1313C NMR (125 MHz, DMSO-d 6 ) δ 177.47, 172.69, 168.74, 159.05, 139.75, 139.30, 137.09, 134.27, 131.29, 131.22, 128.47, 128.04, 124.57, 123.60, 115.46, 113.72, 105.66, 72.86, 57.07, 42.88, 42.82, 21.93. ESI-MS m / z: 471.2 [M+H] +

[0119] Example 59. Synthesis of 1-((4-(5-(Thiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A59)

Chemical Structure

[0120] Synthesis of (4-(5-(4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A60)

Chemical formula

[0121] Synthesis of (4-(5-(5-methoxy-4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A61)

Chemical formula

[0122] Example 62. Synthesis of 1-((4-(5-(Furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A62) [Chemical formula] The synthesis method of compound A62 is the same as that of compound A1. 1 1H NMR (500 MHz, Chloroform-d) δ 8.24 (dd, J = 7.3, 1.5 Hz, 1H), 7.98 (dd, J = 7.3, 1.6 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.54 - 7.41 (m, 3H), 6.93 (dd, J = 7.5, 1.5 Hz, 1H), 6.54 (t, J = 7.5 Hz, 1H), 3.87 - 3.76 (m, 2H), 3.39 (s, 2H), 3.23 - 3.10 (m, 3H). 13 13C NMR (125 MHz, DMSO-d 6)δ 177.47, 167.71, 166.52, 147.75, 141.74, 132.00, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 117.03, 112.90, 57.90, 42.88, 42.82. ESI-MS m / z: 376.1 [M+H] + .

[0123] Example 63. Synthesis of 3-carboxylate hydrochloride of 1-(4-(5-(4-(trifluoromethyl)furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid (A63) [Chemical formula] The synthesis method of compound A63 is the same as that of compound A1. 1 H NMR (500 MHz, Chloroform-d) δ 8.23 (dd, J = 7.3, 1.6 Hz, 1H), 7.94 (dd, J = 7.4, 1.5 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.45 (td, J = 7.5, 1.6 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.39 (s, 2H), 3.23 - 3.10 (m, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 177.47, 167.83, 166.52, 140.16, 140.14, 137.23, 137.20, 132.00, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 125.14, 124.89, 124.41, 122.84, 122.81, 119.53, 117.39, 57.90, 42.88, 42.82. ESI-MS m / z: 444.1 [M+H] + .

[0124] Synthesis of (4-(5-(4-cyanofuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A64)

Chemical Structure

[0125] Synthesis of (4-(5-(4-isopropoxylfuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A65)

Chemical Structure

[0126] Example 66. Synthesis of 1-((4-(5-([1,1'-Biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A66) [Chemical formula] The synthesis method of compound A66 is the same as that of compound A1. 1 1H NMR (500 MHz, Chloroform-d) δ 8.29 (dd, J = 7.4, 1.6 Hz, 1H), 7.98 (dd, J = 7.4, 1.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.57 (s, 4H), 7.57 - 7.47 (m, 2H), 7.50 - 7.40 (m, 3H), 7.33 (ddt, J = 7.4, 5.9, 2.0 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.39 (s, 2H), 3.23 - 3.10 (m, 3H). 13 13C NMR (125 MHz, DMSO-d6 )δ 177.47, 173.12, 166.15, 144.42, 139.22, 132.00, 131.05, 129.62, 129.52, 128.91, 128.86, 127.81, 127.71, 127.68, 127.03, 126.99, 126.35, 125.67, 125.31, 124.41, 57.90, 42.88, 42.82. ESI-MS m / z: 462.2 [M+H] + 。

[0127] Example 67. Synthesis of 3-carboxylate hydrochloride of 1-(4-(5-(4-(thiophen-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid (A67)

Chemical Structure

[0128] Synthesis of (1-(4-(5-(4-(1H-pyrrol-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A68)

Chemical Structure

[0129] Synthesis of (1-(4-(5-(4-(furan-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A69)

Chemical Structure

[0130] Example 70. Synthesis of 1-(4-(5-(3-cyano-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate hydrochloride (A70) [Chemical formula] The synthesis method of compound A70 is the same as that of compound A1. 11H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J = 7.5, 1.6 Hz, 1H), 8.00 (dd, J = 7.4, 1.6 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.53 (td, J = 7.4, 1.5 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.22 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 7.5, 2.0 Hz, 1H), 4.70 - 4.61 (m, 1H), 3.87 - 3.78 (m, 2H), 3.39 (s, 2H), 3.23 - 3.10 (m, 3H), 1.96 - 1.79 (m, 6H), 1.60 (tdd, J = 11.0, 5.2, 1.9 Hz, 2H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 177.47, 172.69, 166.15, 159.08, 134.08, 132.00, 131.11, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 123.28, 115.46, 114.09, 105.53, 81.35, 57.90, 42.88, 32.83, 23.82. ESI-MS m / z: 495.2 [M+H] + .

[0131] Experimental Examples of Pharmacological Activity Experimental Example 1: Agonist Activity Test of the Compound against the S1P Receptor Equipment: FLIPR TM TETRA (Molecular Device). Experimental Materials: CHO-K1 / Gα15 / EDG1 cells constructed by GenScript. Sample Treatment: Before the experiment, dilute with GPCR dilution buffer to prepare a working solution with the corresponding concentration.

[0132] Experimental Method: Culture CHO-K1 / Gα15 / EDG1 cells stably expressing the EDG1 receptor in a 10 cm culture dish at 37 °C / 5% CO 2Cultivate in an incubator. When the cell confluence reaches 80%-85%, perform digestion, inoculate the collected cell suspension into a 384-well plate at an appropriate density, and then place it in an incubator at 37°C / 5% CO 2 Put it in an incubator and culture for at least 18 hours before using in the experiment. Take out the cell culture plate after 18 - 20 hours, add the dye working solution, and then place the cell plate in an incubator at 37°C / 5% CO 2 Put it in an incubator and incubate for 1 hour, and finally equilibrate at room temperature for 15 minutes. When detecting, add the positive agonist working solution and detect and record the RFU value. Put the 384-well plate, cell plate and chip box containing the positive agonist working solution into FLIPRTM TETRA, run the detection program in agonist mode, the total detection time of the instrument is 120 seconds, and add the positive agonist working solution into the cell culture plate at 21 seconds. Put the 384-well plate, cell plate and chip box containing the positive antagonist working solution into FLIPRTM TETRA, run the detection program in antagonist mode, the total detection time of the instrument is 120 seconds, and add the positive antagonist working solution into the cell culture plate at 21 seconds.

[0133] Data processing: The raw data obtained by ScreenWorks (version 3.1) is saved as an *FMD file in GenScript's computer network system. Data collection and analysis are performed using Excel and GraphPad Prism6 software programs. For each detection well, using the average fluorescence intensity value from 1 to 20 seconds as the baseline, the value obtained by subtracting the minimum fluorescence intensity value from 21 to 120 seconds from the maximum fluorescence intensity value from 21 to 120 seconds is the relative fluorescence intensity value (△RFU), and based on this value, the activation or inhibition percentage can be calculated according to the following formula. % Activation rate = (△RFUCompound - △RFUBackground) / (△RFUAgonist control - △RFUBackground) × 100%

[0134] Data was analyzed using GraphPad Prism6 with a four-parameter equation to calculate the EC 50 value and the IC 50 value. The four-parameter equation is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC 50 / IC 50 - X) * HillSlope)), where X is the Log value of the concentration and Y is the inhibition rate.

[0135]

Table 2

[0136] Experimental Example 2: Study on subtype selectivity of Compound A1 Using the method described in Experimental Example 1, the selectivity of different subtypes of S1P receptors was tested. According to the results, Compound A1 has good selectivity for various subtypes, especially for S1P 1 and S1P 5 subtypes, as shown specifically in the following table.

Table 3

[0137] Experimental Example 3: Preliminary evaluation of the in vivo pharmacokinetics of Compound A1 in mice Dosing schedule Nine CD-1 male mice, weighing 20 - 26 g, were randomly divided into three groups of 3 mice each. According to the following scheme, the test compound was administered by forced oral administration, intravenous administration, and intraperitoneal administration, respectively. The mice were fasted for 12 hours before the test and allowed free access to water. They were fed together 2 hours after administration.

[0138] There were 3 animals at each time point. The grouping and blood sampling time points are shown in the following table.

Table 4

[0139] The forced oral administration solution is prepared to the final concentration with DMSO / 0.5% HPMC (5 / 95, v / v). Intravenous administration and intraperitoneal administration are prepared with DMSO / PEG300 / EtOH / NaCl (5 / 40 / 5 / 50, v / v / v). Take the administration solution as a sample for testing (take 50 μL of the drug solution and 50 μL of DMSO before and after administration respectively and mix them).

[0140] Administer the drug according to the above dosage, record the administration time, collect 20 μL of blood from the sciatic nerve plexus of the mouse at the set time point above, and put it into a heparin test tube. Immediately centrifuge at 11000 rpm for 5 minutes. Immediately transfer 10 μL of plasma accurately to a centrifuge tube pre-added with 100 μL of PK-IS solution (prepared with methanol: acetonitrile (1:1, v / v)), mix evenly, and freeze and store at -20 °C for testing.

[0141] Perform a pharmacokinetics study on Compound A1. The oral exposure of Compound A1 is 5071 h*ng / mL, the exposure of intravenous injection is 806 h*ng / mL, and the exposure of intraperitoneal injection is 7975 h*ng / mL. The main pharmacokinetic data are shown in the following table.

Table 5

[0142]

Table 6

[0143]

Table 7

[0144] Experimental Example 4: Preliminary Evaluation of the In Vivo Pharmacokinetics of Compound A1 (DC411151) in Rats Test Plan - Rats

Table 8

[0145] Fast the rats for 12 hours before the experiment and allow them to freely ingest water. Feed them together 4 hours after administration. Drug preparation: First, dissolve the drug in DMSO and Tween 80, add physiological saline, and the final concentration is 1% DMSO, 2% Tween, and 97% physiological saline. Intravenous administration is prepared with DMSO / HS15 / physiological saline (10 / 10 / 80, v / v / v).

[0146] Sample collection: Rats Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24 hours after administration (for the intravenous administration group, increase the sampling points for 5 minutes), collect 0.2 ml of blood from the posterior vena cava of the eye at the above-set time points, put it into an EDTA-K2 test tube, centrifuge at 11000 rpm for 5 minutes to separate the plasma, and freeze it in a refrigerator at -20°C. Sample test: Use the LC-MS / MS method to measure the concentration of DC411151 in plasma.

[0147] Data processing: Use the non-compartment model of WinNonlin 7.0 software (Pharsight Corporation, USA) to calculate the pharmacokinetic parameters after administration. Peak time T max and peak concentration C max are based on the measured values. Area under the drug time curve AUC 0-t Value: Calculated by the trapezoidal method, AUC 0-∞ = AUC 0-t + C t / k e where C t is the blood drug concentration at the last measurable time point, and k e is the elimination rate constant. Elimination half-life t 1 / 2 = 0.693 / k e , Mean residence time MRT = AUMC / AUC. Clearance CL = D / AUC 0-∞ ; Steady-state volume of distribution V ss = CL × MRT Absolute bioavailability F = (AUC 強制経口投与 × D 静脈内 ) / (AUC 静脈内 × D 強制経口投与 ) × 100%

[0148] Test results Results of pharmacokinetics in rats After a single intravenous injection of 2 mg / kg of DC411151 in rats, the drug plasma concentration can be referred to Table 1, the plasma drug concentration-time curve can be referred to Figure 1, and the corresponding pharmacokinetic parameters can be referred to Table 2.

[0149] After intravenous injection into rats, the in vivo plasma clearance CL of DC411151 in rats was 8.66 mL / min / kg, corresponding to 15.7% of the liver blood flow of rats (about 55 mL / min / kg), which is a low-clearance drug, and the steady-state apparent volume of distribution V ss was 0.758 L / kg, corresponding to the total body fluid volume of rats (about 0.67 L / kg), and the plasma elimination half-life t 1 / 2 was on average 3.04 hours.

[0150] After forced oral administration of 20 mg / kg of DC411151 to rats, the drug plasma concentration can be referred to Table 3, the plasma drug concentration-time curve can be referred to Figure 2, and the corresponding pharmacokinetic parameters can be referred to Table 4. After forced oral administration of 20 mg / kg of DC411151 to rats, it rapidly reached the peak, and the peak time T max was 0.5 - 1 hour, the peak concentration C max was 2760 ng / mL, the area under the drug concentration-time curve AUC 0-t was 8780 ng·h / mL, and the AUC 0-t calculated as the average value after dose correction, the absolute bioavailability of 20 mg / kg of DC411151 after forced oral administration in rats was 22.8%.

[0151]

Table 9

[0152]

Table 10

[0153]

Table 11

[0154]

Table 12

[0155] Experimental Example 5: Preliminary Evaluation of the Pharmacokinetics of Compound A1 In Vivo in Beagle Dogs Test Plan - Beagle Dogs

Table 13

[0156] Before the test, fast the dogs for 12 hours and allow them to drink water freely. Feed them together 4 hours after administration. Drug Preparation: First, dissolve the drug in DMSO and Tween 80, and add physiological saline. The final concentration is 1% DMSO, 2% Tween, and 97% physiological saline. Intravenous administration is prepared with DMSO / HS15 / physiological saline (10 / 10 / 80, v / v / v).

[0157] Sample Collection: Dogs Before administration and 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 24 hours after administration (for the intravenous and subcutaneous administration groups, increase the sampling points to 5 minutes), collect 1 ml of blood from the vein at the above set time points, put it into an EDTA-K2 test tube, centrifuge at 3500 rpm for 10 minutes to separate the plasma, and freeze it in a -20°C refrigerator. Sample test: Measure the concentration of DC411151 in plasma using the LC-MS / MS method.

[0158] Data processing: Calculate the pharmacokinetic parameters after administration using the non-compartmental model of WinNonlin 7.0 software (Pharsight Corporation, USA). Peak time T max and peak concentration C max are based on the measured values. Area under the drug time curve AUC 0-t value: Calculated by the trapezoidal method, AUC 0-∞ = AUC 0-t + C t / k e where C t is the blood drug concentration at the last measurable time point, and k e is the elimination rate constant, Elimination half-life t 1 / 2 = 0.693 / k e , Mean residence time MRT = AUMC / AUC. Clearance CL = D / AUC 0-∞ , Steady-state volume of distribution V ss = CL × MRT Absolute bioavailability F = (AUC 強制経口投与 × D 静脈内 ) / (AUC 静脈内 × D 強制経口投与 ) × 100%

[0159] Test results After a single intravenous injection of 0.5 mg / kg of DC411151 in beagle dogs, the plasma drug concentration is shown in Table 5, the blood drug concentration-time curve is shown in Figure 3, and the corresponding pharmacokinetic parameters are shown in Table 6. After intravenous injection into beagle dogs, the in vivo plasma clearance CL of DC411151 in dogs is 23.3 mL / min / kg, which is equivalent to 75.2% of the liver blood flow of dogs (about 31 mL / min / kg), indicating a high-clearance drug, and the steady-state apparent volume of distribution V ssis 1.28 L / kg, which is higher than the total body fluid volume of dogs (0.6 L / kg), and the elimination half-life t 1 / 2 is 0.984 hours.

[0160] After the forced oral administration of 3 mg / kg of DC411151 to beagle dogs, the plasma drug concentration is shown in Table 7, the plasma drug concentration-time curve is shown in Figure 4, and the corresponding pharmacokinetic parameters are shown in Table 8. After the forced oral administration of 3 mg / kg of DC411151 to beagle dogs, the peak time T max is 0.25 - 2 hours, and the peak concentration C max is 366 ng / mL, and the area under the drug concentration-time curve AUC 0-t is 1160 ng·h / mL. The AUC after dose correction 0-t is calculated as the average value, and the absolute bioavailability after the forced oral administration of 3 mg / kg of DC411151 in beagle dogs is 54.0%.

[0161]

Table 14

[0162]

Table 15

[0163]

Table 16

[0164]

Table 17

[0165] Experimental Example 6. In Vivo Anti-Obesity, Insulin Resistance, and NASH Pharmacological Activity Test Non-alcoholic steatohepatitis (NASH) model mice induced by high fat, high cholesterol and high fructose (Gubra amylin, GAN) have three phenotypes of obesity, insulin resistance and NASH at the same time. This experiment uses this model to investigate the effects of long-term oral administration of compound A1 on obesity, insulin resistance, hepatic lipid accumulation, inflammation and fibrosis of the mice under NASH conditions.

[0166] Animal experiment: GAN was administered to male C57BL / 6 mice by gavage to induce a NASH model. After 12 weeks of modeling, the mice were randomly divided into three groups: a low-fat diet control group (LFD, n = 6), a model control group (Model, n = 10), and an A1 group (10 mg / kg, n = 10). The administration was by forced oral gavage, the dosage was 10 mg / kg, the administration volume was 10 mL / kg, and it was administered once a day. During the administration, the food intake and body weight of the animals were monitored. After 10 weeks of administration, a glucose tolerance test (GTT) and an insulin tolerance test (ITT) were performed. After 11 weeks of administration, fasting blood glucose and insulin were measured. After 12 weeks of administration, deep body temperature and energy metabolism levels were measured. After 15 weeks of administration, the body composition of the mice was measured. After blood was collected from the retro-orbital venous plexus, the mice were sacrificed by cervical dislocation. The liver, subcutaneous fat, epididymal fat, and brown fat were collected and weighed. A part of the liver was fixed with 4% paraformaldehyde, and all tissues and sera were stored at -80°C. This experiment evaluated whether the compound had an effect on reducing body weight by detecting the energy metabolism, body composition, and fat weight of the mice. By detecting GTT, ITT, random blood glucose, fasting blood glucose, and fasting insulin, and calculating the HOMA-IR index, it was evaluated whether the compound had an effect on improving insulin resistance. By detecting the levels of liver function indicators ALT, AST, triglyceride, total cholesterol (T-CHO), LDL-C, HDL-C in serum, the contents of triglyceride, T-CHO, hydroxyproline (a characteristic amino acid of collagen) in the liver, the mRNA expression levels of genes related to fatty acid de novo synthesis and transport in the liver (Srebp1c, Scd1, Fasn, Acaca, Cd36), the β-oxidation metabolic pathway (Ppara, Cyp4A1, Cpt1b, Acot1, Acox1), inflammation-related genes (Tnfa, Il1b, Casp1, Nlrp3, Pycard, Panx1, Ccl2, Ccl3), and fibrosis-related genes (Asma, Tgfb, Col1A1, Col3A1, Col4A1, Col4a2, Col5a2), as well as liver pathological changes (H&E staining, Oil Red O staining, and Picrosirius Red staining), it was evaluated whether the compound had an effect on alleviating lipid metabolism disorders, inflammation, and fibrosis under the pathological state of NASH.

[0167] According to the research results, compound A1 of the present invention can improve the energy metabolism of mice, promote heat production, significantly delay the weight gain of mice and reduce the body fat rate without affecting food intake (Figure 1). A1 can significantly reduce fasting blood glucose, insulin and HOMA-IR index, and significantly improve the glucose tolerance and insulin sensitivity of mice (Figure 2). A1 can significantly reduce the liver weight, liver-to-body ratio, levels of ALT, AST, triglyceride, T-CHO, LDL-C, HDL-C in serum and triglyceride, T-CHO, hydroxyproline in the liver of NASH mice (Figure 3). At the gene level, A1 can significantly up-regulate the mRNA expression of fatty acid oxidation-related genes (Ppara, Cyp4A1, Acot1, Acox1), and down-regulate the mRNA expression of inflammation (Tnfa, Il1b, Casp1, Pycard, Ccl2, Ccl3) and fibrosis-related genes (Asma, Tgfb, Col1A1, Col3A1, Col5a2) (Figure 4). In the quantitative analysis of pathological sections of H&E-stained liver, A1 can significantly reduce the NAS score, significantly relieve liver ballooning and inflammation, and improve liver lipid accumulation, but not significantly (Figure 5). In the quantitative analysis of pathological sections of Oil Red O-stained liver, A1 can significantly reduce liver lipid accumulation, and the main manifestation is to reduce the size of lipid droplets (Figure 5). In the quantitative analysis of pathological sections of Sirius Red-stained liver, A1 can significantly reduce liver collagen deposition (Figure 5).

[0168] In summary, long-term administration of the test substance A1 can significantly relieve obesity and insulin resistance in GAN diet-induced mice, improve energy metabolism and insulin sensitivity, improve liver function, promote fatty acid oxidation in the liver, reduce inflammation and fibrosis, and have a significant alleviating effect on NASH.

[0169] Experimental Example 7. Pharmacological Activity Test of Carbon Tetrachloride (CCl 4 )-Induced Liver Fibrosis Model Male C57BL / 6 mice were given 5 mL / kg of 5% CCl 4Induce a liver fibrosis model by intraperitoneal injection twice a week according to (dissolved in corn oil). After 3 weeks of modeling, the mice are randomly divided into five groups: a model control group (Model, n = 12), a positive compound FTY720 group (2 mg / kg, n = 9), a positive compound OCA group (30 mg / kg, n = 10), a low-dose group (3 mg / kg), and a high-dose group (10 mg / kg). The administration method of FTY720 is intraperitoneal injection, and the remaining groups are all forced oral administration, once a day. After 5 weeks of administration, blood is collected from the retro-orbital venous plexus, and then the mice are sacrificed by cervical dislocation. The liver and spleen are collected and weighed. A part of the liver is fixed with 4% paraformaldehyde, and some liver and serum are stored at -80 °C. Throughout the experiment, another 10 littermate mice are intraperitoneally injected with the same dose of corn oil as a systemic control.

[0170] CCl 4 In the induced liver fibrosis model, compound A1 significantly reduces the ALT level in the serum without affecting the weights of the liver and spleen organs (Figure 6). At the gene level, high-dose A1 significantly downregulates the mRNA expression of liver fibrosis-related genes (Tgfb, Col1a1) (Figure 7). Regarding the pathological analysis of liver tissue, high-dose A1 significantly alleviates the hydroxyproline content in the liver, and the results of pathological section analysis indicate that A1 significantly reduces collagen deposition in the liver (Figure 8).

[0171] Experimental Example 8. Pharmacological Activity Test of a Methionine-Choline Deficiency and High-Fat Diet-Induced NASH Model (MCD-HFD) Male C57BL / 6 mice were fed an MCD-HFD to induce a NASH model. After 4 weeks of modeling, the mice were randomly divided into three groups: a normal diet control group (Control, n = 9), a model control group (Model, n = 10), a positive compound BAF312 group (0.3 mg / kg, n = 10), a low-dose group (0.3 mg / kg, n = 10), a medium-dose group (3 mg / kg, n = 10), and a high-dose group (10 mg / kg, n = 10). They were force-fed orally at a volume of 5 mL / kg once a day. During administration, the food intake and body weight of the animals were monitored. After 4 weeks of administration, the mice were sacrificed by cervical dislocation after blood sampling from the retro-orbital venous plexus. The liver and spleen were collected and weighed. A part of the liver was fixed with 4% paraformaldehyde, and all tissues and sera were stored at -80°C.

[0172] In the methionine-choline-deficient and high-fat diet (MCD-HFD)-induced NASH model, compound A1 had no effect on body weight. In the high-dose group, it significantly decreased the levels of ALT and AST in the serum and simultaneously greatly alleviated the TG accumulation in the liver (Figure 9). At the gene level, high / middle / low doses of A1 could significantly down-regulate the mRNA expression of liver inflammation-related genes (Tnfa, Il1b, Nlrp3, Ccl2) to varying degrees. By analyzing the pathological sections of H&E-stained liver, high-dose A1 could effectively reduce the lipid accumulation and inflammatory infiltration in the liver (Figure 10). High / middle doses of A1 could simultaneously and effectively alleviate the hydroxyproline content in the liver to varying degrees and significantly down-regulate the expression levels of fibrosis-related genes (Asma, Tgfb, Col1a1) at the gene level (Figure 11).

[0173] Experimental Example 9. Pharmacological Activity Test of Dextran Sulfate Sodium (DSS)-Induced IBD Model Mice were randomly divided into five groups: a normal control group (Control, n = 5), a model control group (Model, n = 11), a positive compound BAF312 group (0.3 mg / kg, n = 10), a low-dose group (0.03 mg / kg, n = 10), a medium-dose group (0.3 mg / kg, n = 10), and a high-dose group (3 mg / kg, n = 10). All groups were administered by forced oral gavage, with a dosing volume of 5 mL / kg once a day. Dextran sulfate sodium (DSS) with an average molecular weight of 36,000 - 50,000 Da was dissolved in drinking water to prepare a 2% DSS solution, and the mice in the modeling group were allowed to drink water freely for six days. Modeling and dosing treatments were performed simultaneously. The body weight of the mice in each group, the softness and hardness of feces and occult blood, and the occult blood status were observed daily, and the scores of each index were summed to obtain the disease activity index of each animal. Six days after the end of modeling and dosing, the modeling reagent was removed, and after a one-day remission period, blood was collected from the posterior orbital venous plexus, and then the mice were sacrificed by cervical dislocation. The colonic tissue and spleen of the mice were collected to measure the length or weight. A part of the colon was fixed with 4% paraformaldehyde, and all tissues and sera were stored at -80°C.

[0174] In the dextran sulfate sodium (DSS)-induced IBD model, high / medium / low doses of A1 can effectively reduce the disease process to varying degrees (Figure 12). Regarding the analysis of the lesioned colonic site, high / medium / low doses of A1 can effectively reduce the shortening of the colon length in IBD mice to varying degrees without affecting the spleen weight. The analysis of the pathological sections of the H&E-stained colon shows that high / medium doses of A1 can effectively improve the crypt damage and inflammatory infiltration in the colonic site (Figure 13).

[0175] In summary, long-term administration of the test substance A1 significantly alleviates obesity and insulin resistance in GAN diet-induced mice, improves energy metabolism and insulin sensitivity, improves liver function, promotes fatty acid oxidation in the liver, reduces inflammation and fibrosis, and has a significant alleviating effect on NASH. At the same time, CCl 4In an induced liver fibrosis model and an MCD-HFD diet-induced NASH model, it can exert an effective alleviating effect. Furthermore, test molecule A1 can also exert a significant anti-inflammatory and pathological improvement effect in an IBD model.

[0176] All documents referred to in this invention are cited as references in this application as if each document was individually cited as a reference. Further, after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula I below or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein the compound is of formula II, [Chemical 2] wherein, Y １ , Y ２ , Y ３ , and Y ４ are each CH, M is selected from the group consisting of a substituted C6-C10 aromatic ring and a substituted or unsubstituted 5- to 12-membered aromatic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein in the M group, the substitution means that it can be substituted by one or more R １ groups, and moreover Each of the Rs １ is independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, amino group, hydroxyl group, nitro group, aldehyde group, substituted or unsubstituted C1-C6 alkyl group, and substituted or unsubstituted C1-C6 alkoxy group, X is CHR ２ and R ２ is selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, amino group, hydroxyl group, nitro group, and substituted or unsubstituted C1-C6 alkyl group, n is 2, R ３ is selected from the group consisting of a carboxyl group, a substituted or unsubstituted C2-C10 ester group, a substituted or unsubstituted C1-C6 amide group, -C(O)R ５ , -C(O)OR ５ wherein the C2-C10 ester group refers to -COO(C1-9 alkyl), and wherein the C1-C6 amide group refers to -C(O)NH2, -C(O)NH(C1-5 alkyl) or -C(O)N(C1-4 alkyl)(C1-4 alkyl) having 1 to 6 carbon atoms R ５ is selected from the group consisting of hydrogen, deuterium, tritium, an amino group, a hydroxyl group, a substituted or unsubstituted C1-C6 alkyl group, R ６ is hydrogen, and wherein said substitution means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of halogen, hydroxyl group, carboxyl group, amino group, nitro group, cyano group, said compound of formula I or a pharmaceutically acceptable salt thereof.

2. M is selected from the group consisting of substituted or unsubstituted furanyl and substituted or unsubstituted thienyl, The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof.

3. The compound has a structure as shown in the following formula III, 【Chemical Formula 3】 Here, X is CHR ２ is The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof.

4. M has a structure as shown in the following formula, [Chemical Formula 4] wherein, A is a C6 - C10 aromatic ring, Each R １ is independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, amino group, hydroxyl group, nitro group, aldehyde group, substituted or unsubstituted C1-C6 alkyl group, substituted C1-C3 alkyl group containing 1 to 7 fluorine atoms, and substituted or unsubstituted C1-C6 alkoxy group, a is 1, 2, or 3, The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof.

5. Ring A is a benzene ring, Each R １ is independently selected from the group consisting of a cyano group and a substituted or unsubstituted C1-C6 alkoxy group, a is 1 or 2, The compound of formula I according to claim 4, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof.

6. The compound is selected from the group consisting of the following, The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof. 【Table 1】

7. A pharmaceutical composition, One or more species of the compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof, and one or more species of pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary substances and / or diluents, said pharmaceutical composition.

8. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a racemic compound, an R - isomer, an S - isomer or a mixture thereof for use in the preparation of a pharmaceutical composition for treating or preventing a disease associated with an S1P agonist.

9. The compound, pharmaceutically acceptable salt, racemic compound, R-isomer, S-isomer or mixture thereof according to claim 8, wherein the disease is selected from the group consisting of non-alcoholic fatty liver, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis, psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune diseases, exudative age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome.

10. The compound, pharmaceutically acceptable salt, racemic compound, R-isomer, S-isomer or mixture thereof according to claim 8, wherein the disease is selected from the group consisting of relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

11. A method for preparing the compound of formula I, pharmaceutically acceptable salt, racemic compound, R-isomer, S-isomer according to claim 1, comprising: the following steps: [Chemical Formula 5] (1) Reacting the compound of formula Ic with M-COOH, HOBT, EDCI and potassium carbonate in DMF to obtain the compound of formula Ib; (2) Reacting the compound of formula Ib in acetone / dilute hydrochloric acid to obtain the compound of formula Ia; (3) In a mixed solution of methanol / dichloromethane, reacting the compound of formula Ia 【Chemical Formula 6】 with hydrochloride, DIPEA, acetic acid and sodium cyanoborohydride to obtain the compound of formula I, wherein X is CH, said preparation method.

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