Oxadiazole compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses an oxadiazole compound as well as a preparation method, a pharmaceutical composition and application thereof, relates to the fields of medicinal chemistry and pharmacotherapeutics, and in particular relates to a compound as shown in a general formula I, a raceme, an R-isomer, an S-isomer, medicinal salt and a mixture of the raceme, the R-isomer, the S-isomer and the medicinal salt, the invention also relates to a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound as an S1P receptor agonist. The oxadiazole compound provided by the invention can be used for treating S1P receptor excitation related diseases. # imgabs0 #

Description

[0001] This case is a divisional application of the Chinese invention patent application with application number 2021107292886, application date June 29, 2021, and invention name "A class of oxadiazole compounds, preparation methods, pharmaceutical compositions and uses thereof". Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry and pharmacotherapy, and specifically to a class of oxadiazole compounds, a preparation method thereof, a pharmaceutical composition containing such compounds, and use thereof as an S1P receptor agonist, in particular for the preparation of the oxadiazole compounds for the treatment of non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases. Background Art

[0003] Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease.

[0004] Lipid metabolism is one of the core of liver metabolism. More and more evidence shows that triglycerides deposited in hepatocytes are not the main cause of lipotoxicity. Simply lowering triglycerides cannot effectively improve NASH. Therefore, new intervention measures to improve lipid disorders are urgently needed. Triglycerides are the main form of lipids in simple fatty liver. About 25% of patients will progress from simple fatty liver to NASH with a more obvious lipotoxic phenotype. In this process, the reprogramming of lipid metabolism networks may be one of the most important driving factors, but people know very little about this. In the past decade, there have been new breakthroughs in people's understanding of lipid metabolism disorders. Cholesterol, free fatty acids, lysophosphatidylcholine and sphingolipids are considered to be important lipids that cause lipotoxicity. [7]Among them, sphingolipids are a class of lipids containing a sphingosine skeleton, and the metabolites ceramide and sphingosine 1-phosphate (S1P) are the two most studied sphingolipid bioactive molecules. In vivo, ceramide is generally synthesized through three pathways: de novo synthesis, sphingomyelinase hydrolysis, and salvage synthesis. It is then deacetylated to produce sphingosine under the action of ceramidase (CDase), which is further phosphorylated to S1P by sphingosine kinase (SphK). Intracellular S1P can act as a second messenger to exert biological regulatory functions. S1P secreted into the extracellular space activates downstream signaling pathways such as PI3K / Akt, Ras / ERK, Rho, Rac, etc. 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 various tissues. S1PR1, S1PR2, and S1PR3 are widely present in many tissues, including the liver, while S1PR4 is widely expressed in lymphoid tissue and lung tissue, and S1PR5 is expressed in the brain and skin, thus playing different functions. Normal levels of S1P are involved in a variety of vital physiological processes, such as cell growth, survival, and migration, as well as angiogenesis and maturation, but excessive S1P can also induce many pathological changes, including inflammation and fibrosis, two pathological processes closely related to the progression of NASH. Clinical research data found that the content of sphingolipids in the body is positively correlated with the progression of NAFLD, especially the content of ceramide and S1P in the liver, which rises sharply when progressing to NASH, and lowering ceramide levels or regulating the downstream S1P signaling pathway can improve metabolic disorders.

[0005] Innate immune activation is a key factor in initiating and amplifying liver inflammation, and liver inflammation plays a core role in promoting the transition from simple fatty liver to NASH. Kupffer cells (KCs) are macrophages located in the liver sinusoids, accounting for 20–35% of all non-parenchymal cells in the liver. They are the most important type of cells in the liver's innate immunity. The cytokines they release can mediate the inflammatory cascade, induce hepatocyte death and lipid degeneration, and promote the activation of hepatic stellate cells (HSCs). HSCs are the main source of extracellular matrix and play a key role in the formation of liver fibrosis. After activation, HSCs differentiate into myofibroblast-like cells, which have contractility, pro-inflammatory effects, and pro-fibrotic properties. S1P can initiate innate immune responses by acting on S1PR1 and S1PR3 on the surface of liver macrophages, accelerating the progression of NASH. S1P can also directly induce the activation, proliferation and contraction of HSCs by acting on S1PR1-3 on the surface of HSCs, promoting the secretion of extracellular matrix. [8] . Studies have shown that regulating the activity of S1PR1 and S1PR3 in mice through drugs or gene knockout can effectively alleviate the progression of inflammation and fibrosis in various liver disease models. Therefore, S1P receptor is a potential new target for the prevention and treatment of metabolic diseases such as NASH. Especially a new target for type 2 diabetes with a fasting hyperglycemia phenotype.

[0006] In summary, there is an urgent need to develop more S1P receptor modulators in this field. Summary of the invention

[0007] The purpose of the present invention is to provide an S1P receptor agonist.

[0008] The first aspect of the present invention provides a compound as shown in the following formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof:

[0009]

[0010] in,

[0011] M is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted 3-12-membered saturated aliphatic ring, substituted or unsubstituted 3-12-membered unsaturated aliphatic ring, substituted or unsubstituted 3-12-membered aliphatic ring containing 1-8 heteroatoms, substituted or unsubstituted 9-12-membered aromatic condensed ring, substituted or unsubstituted C6-C10 aromatic ring (preferably benzene ring) or substituted or unsubstituted 5-12-membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, in the M group, the substitution refers to the substitution that can be replaced by one or more R 1and

[0012] The various R 1 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aryl ether, substituted or unsubstituted C1-C6 amide, -OSO2R 4 、-OCOR 4 、SO2R 4 ;

[0013] X is selected from the following group: CHR 2 NR 2 , O or S;

[0014] R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted amidino, substituted or unsubstituted guanidino, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C1-C6 amide, -SO2R 5 、-COR 5 ;

[0015] R and R' are independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-12 membered saturated aliphatic ring; or R, R' and the connected N atom together form the following structure:

[0016]

[0017] n is 1, 2, 3, 4, 5, 6, 7;

[0018] R 3Selected from the following group: carboxyl, sulfonic acid (-SO2H), phosphoric acid (-PO3H), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aromatic ether, substituted or unsubstituted C1-C6 amide, -OSO2R 5 、-OCOR 5 、-C(O)R 5 、-C(O)OR 5 、-SO2R 5 、-PO(OR 5 )2;

[0019] Ring B is selected from the following group: a 5-10 membered saturated or unsaturated carbocyclic ring, a 5-10 membered saturated or unsaturated heterocyclic ring; wherein the heterocyclic ring has one or more N atoms as ring atoms;

[0020] R 4 and R 5 Each is independently selected from the following group: hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C1-C6 amide;

[0021] R 6 For One or more groups on the ring are selected from the group consisting of hydrogen, deuterium, tritium, substituted or unsubstituted C1-C6 alkyl;

[0022] The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of halogen, hydroxyl, carboxyl, benzyl, C1-C6 alkoxycarbonyl, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 Aryl, five-membered or six-membered heteroaryl, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl).

[0023] In another preferred embodiment, the compound has a structure shown in the following formula II:

[0024]

[0025] in,

[0026] 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 When CH is present, the CH can be 6 replace.

[0027] In another preferred embodiment, the compound has a structure shown in the following formula III:

[0028]

[0029] Where X is CHR 2 .

[0030] In another preferred embodiment, the M has a structure as shown below:

[0031]

[0032] in,

[0033] The A is selected from the following group: a substituted or unsubstituted 3-12-membered saturated aliphatic ring, a substituted or unsubstituted 3-12-membered unsaturated aliphatic ring, a substituted or unsubstituted 3-12-membered aliphatic ring containing 1-8 heteroatoms, a substituted or unsubstituted 7-12-membered aromatic condensed ring, a substituted or unsubstituted C6-C10 aromatic ring (preferably a benzene ring), or a substituted or unsubstituted 5-12-membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0034] Each R 1 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl (5-7 membered heteroaryl), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aryl ether, substituted or unsubstituted C1-C6 amide, -OSO2R 4 、-OCOR 4 、SO2R 4 ;

[0035] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0036] In another preferred embodiment, the A ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-7 membered saturated aliphatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, a substituted or unsubstituted 5-10 membered partially unsaturated heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0037] Each R 1 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl (5-7 membered heteroaryl), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aryl ether, substituted or unsubstituted C1-C6 amide, -OSO2R 4 、-OCOR 4 、-SO2R 4 ;

[0038] a is 1, 2, 3, 4 or 5.

[0039] In another preferred embodiment, the compound is the compound in each embodiment of the present invention.

[0040] The second aspect of the present invention provides a pharmaceutical composition, which comprises: one or more of the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0041] The third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, and the use of its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, characterized in that it is used for preparing a pharmaceutical composition for treating or preventing diseases associated with S1P agonists.

[0042] In another preferred embodiment, the disease is selected from the following group: non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, and clinically isolated syndrome.

[0043] The fourth aspect of the present invention provides a method for preparing the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, the method comprising the steps of:

[0044]

[0045] (1) reacting the compound of formula Ic with M-COOH, HOBT, EDCI and potassium carbonate in DMF to obtain a compound of formula Ib;

[0046] (2) reacting the compound of formula Ib in acetone / dilute hydrochloric acid to obtain the compound of formula Ia;

[0047] (3) In a methanol / dichloromethane mixed solution, the compound of formula Ia is The hydrochloride of , DIPEA, acetic acid and sodium cyanoborohydride are reacted to obtain a compound of formula I; wherein X is CH.

[0048] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 A1 alleviates the obesity symptoms of GAN diet-induced NASH mouse model, including (A) body weight; (B) food intake; (C) body fat content; (D) fat-to-lean ratio; (E) subcutaneous fat (sWAT), epididymal fat (eWAT) and brown fat (BAT); (F) body temperature; (G) oxygen consumption; (H) carbon dioxide production; (I) energy expenditure. When the LD group was compared with the Model group, #P<0.05, ###P<0.005; when the A1 group was compared with the Model group, *P<0.05, **P<0.05, ***P<0.005.

[0050] Figure 2A1 alleviates the insulin resistance symptoms of the GAN diet-induced NASH mouse model, including (A) fasting blood glucose; (B) fasting insulin; (C) HOMA-IR index; (D) GTT; (E) area under the GTT curve; (F) ITT; (G) area under the ITT curve. When the LD group was compared with the Model group, #P<0.05, ##P<0.01, ###P<0.005; when the A1 group was compared with the Model group, *P<0.05, **P<0.05, ***P<0.005.

[0051] Figure 3 A1 improved the serological and liver biochemical indicators of the GAN diet-induced NASH mouse model, including (A) liver weight; (B) liver weight / body weight; (C) serum ALT; (D) serum AST; (E) serum triglycerides; (F) serum T-CHO; (G) serum HDL-C; (H) serum LDL-C; (I) liver triglycerides; (J) liver total cholesterol. When the LD group was compared with the Model group, ##P<0.01, ###P<0.005; when the A1 group was compared with the Model group, *P<0.05, **P<0.05, ***P<0.005.

[0052] Figure 4 A1 improved liver lipid metabolism disorders, inflammation and fibrosis in the GAN diet-induced NASH mouse model, including (A) mRNA expression of genes related to de novo fatty acid synthesis, transport and β-oxidation metabolism; (B) mRNA expression of genes related to liver inflammation; (C) mRNA expression of genes related to liver fibrosis. *P<0.05, **P<0.05, ***P<0.005.

[0053] Figure 5 A1 improved the histopathological examination of the GAN diet-induced NASH mouse model, including (A) liver H&E staining, Oil Red O staining, and Sirius red staining; (B) NAS score; (C) quantitative results of liver Oil Red O staining; (D) quantitative results of liver Sirius red staining; *P<0.05, **P<0.05, ***P<0.005.

[0054] Figure 6 Compound A1 reduces serum ALT levels in a CCl4-induced liver fibrosis model; (A) body weight; (B) liver weight; (C) spleen weight; (D) serum ALT; (E) liver index; (F) spleen index; *P<0.05, **P<0.05, ***P<0.005;

[0055] Figure 7High-dose A1 down-regulated the mRNA expression of liver fibrosis-related genes (Tgfb, Col1a1) at the gene level; (A) relative expression of Tgfb mRNA; (B) relative expression of Col1a1 mRNA; *P<0.05, **P<0.05, ***P<0.005;

[0056] Figure 8 High-dose A1 alleviated the pathological section analysis of hydroxyproline content in the liver; (A) liver hydroxyproline concentration; (B) area fraction of Sirius red staining; (C) pathological section; *P<0.05, **P<0.05, ***P<0.005;

[0057] Fig. 9 Compound A1 reduced serum ALT and AST levels in the NASH model induced by methionine-choline deficiency combined with high-fat diet (MCD-HFD), and significantly alleviated TG accumulation in the liver; (A) body weight; (B) liver index; (C) spleen weight; (D) serum ALT; (E) serum AST; (F) liver triglycerides; *P<0.05, **P<0.05, ***P<0.005;

[0058] Fig.10 A1 alleviated liver lipid accumulation and inflammatory infiltration at high / medium / low doses; (A) relative gene expression; (B) H&E stained liver pathological sections; *P<0.05, **P<0.05, ***P<0.005;

[0059] Fig.11 High / medium doses of A1 alleviated the hydroxyproline content in the liver and downregulated the expression levels of fibrosis-related genes (Asma, Tgfb, Col1a1) at the gene level; (A) liver hydroxyproline content; (B) relative expression levels of Asma, Tgfb, Col1a1 genes; *P<0.05, **P<0.05, ***P<0.005;

[0060] Fig.12 High / medium / low doses of A1 alleviated the disease progression in the dextran sulfate sodium (DSS)-induced IBD model; (A) body weight change; (B) stool consistency index; (C) rectal bleeding index; (D) disease activity index; *P<0.05, **P<0.05, ***P<0.005;

[0061] Fig.13 Effects of high / medium / low doses of A1 in the IBD model induced by dextran sulfate sodium (DSS); (A) lesioned colon location; (B) colon length; (C) rectal weight; (D) colon pathological section; *P<0.05, **P<0.05, ***P<0.005. DETAILED DESCRIPTION

[0062] After long-term and in-depth research, the inventors have discovered an oxadiazole compound represented by general formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof. The compound is an S1P receptor agonist, and thus can be used to prepare a pharmaceutical composition for treating indications related to S1P receptor agonists (e.g., non-alcoholic fatty liver disease, 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 disorders, wet 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.

[0063] the term

[0064] In the present invention, the halogen is F, Cl, Br or I.

[0065] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0066] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0067] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0068] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0069] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0070] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0071] In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecyl, etc. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0072] In the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C10 aryl" has a similar meaning.

[0073] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0074] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc. The term "3-7 membered heterocyclic group" has a similar meaning.

[0075] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spiro bicyclic system, for example, two rings having a common carbon atom. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, alkoxy, C1-10 sulfonyl, etc.

[0076] Oxadiazoles as S1P receptor agonists

[0077] Based on the purpose of the present invention, the present invention provides an oxadiazole compound having the following general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

[0078] Formula I

[0079]

[0080] in:

[0081] A is selected from the following group: a substituted or unsubstituted 3-12-membered saturated aliphatic ring, a substituted or unsubstituted 3-12-membered unsaturated aliphatic ring, a substituted or unsubstituted 3-12-membered aliphatic ring containing 1-8 heteroatoms, a substituted or unsubstituted aromatic condensed ring, a substituted or unsubstituted aromatic ring (preferably a benzene ring), or a substituted or unsubstituted 5-12-membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the substituted naphthalene ring, substituted benzene ring or substituted aromatic heterocycle has 1-7 substituents on each ring;

[0082] R 1Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1~C6 alkyl (including trifluoromethyl), C1~C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1~C6 alkoxy (including cyclic and chain alkoxy), substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1~C6 alkylphenyl, substituted or unsubstituted C1~C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3~C12 cycloalkyl, substituted or unsubstituted C2~C10 acyl, substituted or unsubstituted C2~C10 ester, substituted or unsubstituted C2~C10 aryl ether, substituted or unsubstituted C1~C6 amide, -OSO2R4, -OCOR4, SO2R4;

[0083] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; (naphthyl, cyclohexyl, etc. may be multi-substituted)

[0084] R 2 Selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted amidino, substituted or unsubstituted guanidino, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C1-C6 amide, -SO2R5, -COR5;

[0085] n is 1, 2, 3, 4, 5, 6, 7

[0086] R 3 is carboxylic acid, sulfonic acid, phosphoric acid, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aromatic ether, substituted or unsubstituted C1-C6 amide, -OSO2R 5 、-OCOR 5 、SO2R 5 ;

[0087] In a more preferred embodiment of the present invention, the compound of the general formula I of the present invention is preferably the following specific compound:

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] The compounds of the present invention have asymmetric centers, chiral axes and chiral planes, and may exist in the form of racemates, R-isomers or S-isomers. Those skilled in the art can obtain R-isomers and / or S-isomers by resolving the racemates using conventional techniques.

[0094] The present invention provides pharmaceutically acceptable salts of the compounds of general formula I, specifically, conventional pharmaceutically acceptable salts formed by reacting the compounds of general formula I with inorganic acids or organic acids. For example, conventional pharmaceutically acceptable salts can be prepared by reacting a compound of formula I with an inorganic acid or an organic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic 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 and isethionic acid, or a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by a compound of formula I and an inorganic base; or a methylamine salt, ethylamine salt or ethanolamine salt formed by a compound of formula I and an organic base.

[0095] The compound of the present invention can be used to prepare a pharmaceutical composition, which comprises a therapeutically effective amount of one or more selected from the oxadiazole compounds represented by the above general formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof. The pharmaceutical composition can be used to treat non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases associated with S1P receptor agonists.

[0096] The compounds of the present invention can also be used to prepare S1P receptor agonists, which include one or more selected from the oxadiazole compounds represented by the above formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof.

[0097] Preparation of oxadiazole compounds

[0098] Another aspect of the present invention provides a method for preparing the compound represented by general formula I, and the preparation method is carried out according to the following scheme.

[0099] The compound of formula (I) can be prepared by the method shown in the following scheme

[0100] plan:

[0101]

[0102] Step a: Dissolve 1-1 (1 eq) in an appropriate amount of acetonitrile, add NBS (1.1 eq) in batches, and stir at 40°C for 4 hours;

[0103] Step b: Dissolve 1-2 (1 eq) 1-2 in an appropriate amount of dimethylformamide, add cuprous cyanide (3 eq), and stir at 130°C for overnight reaction;

[0104] Step c: Dissolve 1-3 (1 eq) in an appropriate amount of carbon tetrachloride, add NBS (1.2 eq) and BPO (0.1 eq), and heat under reflux overnight;

[0105] Step d: 1-4 (1 eq) was dissolved in an appropriate amount of 50% acetic acid aqueous solution, and hexamethylenetetramine (2 eq) was added in batches under stirring. After heating under reflux for 6 hours, 3 mL of concentrated hydrochloric acid was added dropwise, and heating under reflux was continued for half an hour;

[0106] Step e: Dissolve the intermediate 1-5 (1 eq) in an appropriate amount of toluene, add ethylene glycol (3 eq) and p-toluenesulfonic acid (0.1 eq) in sequence, install a water separator, and heat under reflux for 4 hours;

[0107] Step f: Dissolve the intermediate 1-6 (1 eq) 4-(1,3-dioxolane-2-yl)-1-naphthalenecarbonitrile, hydroxylamine hydrochloride (1.05 eq) and triethylamine (1.05 eq) in an appropriate amount of ethanol and heat under reflux overnight;

[0108] Step g: Dissolve the intermediate 1-7 (1 eq) in an appropriate amount of DMF, add benzoic acid (1.1 eq), HOBT (1 eq), EDCI (1 eq) and potassium carbonate (1.5 eq) in sequence, and heat at 90° C. to react overnight;

[0109] Step h: Dissolve the intermediate 1-8 in an appropriate amount of acetone / dilute hydrochloric acid (1:1), heat and stir at 45°C for 4 hours;

[0110] Step i: Dissolve intermediate 1-9 (1 eq) in a suitable amount of a methanol / dichloromethane (1:1) mixed solution, add 1.1 eq of the corresponding amine hydrochloride, DIPEA (1.1 eq), acetic acid (2 eq) and sodium cyanoborohydride (1 eq) in sequence, and stir at room temperature overnight;

[0111] Step k: Dissolve the intermediate 1-10 (1 eq) in an appropriate amount of a methanol / water mixed solution, add lithium hydroxide (10 eq), and stir at room temperature overnight.

[0112] Pharmaceutical composition and preparation thereof

[0113] Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of one or more selected from the compounds of the above-mentioned general formula I, their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners, etc.

[0114] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1-99%, and the preferred ratio is that the compound of general formula I as the active ingredient accounts for 65wt% to 99wt% of the total weight, and the rest is a pharmaceutically acceptable carrier, diluent or solution or saline solution.

[0115] The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

[0116] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula contains 1 mg-700 mg of the compound of formula I, preferably, the unit dosage of the preparation formula contains 25 mg-300 mg of the compound of formula I.

[0117] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung or gastrointestinal tract routes. Oral administration is most preferred. The most preferred daily dose is 50-1400 mg / kg body weight, taken at one time, or 25-700 mg / kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Usually, a small dose is started and the dose is gradually increased until the most suitable dose is found.

[0118] The present invention also provides an S1P agonist, which comprises one or more selected from the compound represented by the above general formula I, its pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0119] The compounds and compositions of the present invention are used to treat and prevent diseases such as non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc., which are associated with S1P agonists. The diseases include, but are not limited to, various types of diabetes, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis, etc.

[0120] Therefore, another aspect of the present invention provides the use of the compound represented by the above-mentioned general formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof in the preparation of a medicament for treating diseases associated with S1P agonists such as non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, such as various types of diabetes, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis and the like.

[0121] Another aspect of the present invention provides a method for treating metabolic diseases and autoimmune diseases associated with non-alcoholic fatty liver disease, 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 disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, and the like, such as various types of diabetes, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis, and the like, which comprises administering to a patient in need of such treatment one or more of the compounds represented by the above-mentioned general formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers, or mixtures thereof.

[0122] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0123] Example 1 Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A1)

[0124]

[0125] Synthesis of 1-Bromo-4-methylnaphthalene

[0126]

[0127] 1-Methylnaphthalene (28.44 g, 200.00 mmol) was dissolved in 300 mL of acetonitrile, and NBS (39.16 g, 220.00 mmol) was added in batches, and stirred at 40°C for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (43.20 g) with a yield of 98%. 1 H NMR (500MHz, CDCl3) δ8.24–8.17(m,1H),7.94–7.86(m,1H),7.63(d,J=8.4Hz,1H),7.57–7.47(m,2H),7.20–7.14(m,1H),2.70(d,J=1.1Hz,3H).

[0128] Synthesis of 4-Methyl-1-naphthonitrile

[0129]

[0130] The intermediate 1-bromo-4-methylnaphthalene (44.00 g, 199.01 mmol) was dissolved in 400 mL of dimethylformamide, and cuprous cyanide (53.47 g, 597.02 mmol) was added, and the mixture was stirred at 130°C overnight. After the reaction was complete by TLC, the mixture was cooled to room temperature, 300 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 hour, and the mixture was filtered under reduced pressure. The filtrate was washed with water three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (18.21 g) with a yield of 55%. 1 H NMR (500MHz, CDCl3) δ8.21–8.15(m,1H),7.98–7.89(m,1H),7.78(d,J=8.4Hz ,1H),7.64–7.54(m,2H),7.43(dq,J=8.3,1.1Hz,1H),2.69(d,J=1.1Hz,3H).

[0131] Synthesis of 4-(Bromomethyl)-1-naphthocarbonitrile

[0132]

[0133] The intermediate 4-methyl-1-naphthonitrile (16.00 g, 95.69 mmol) was dissolved in 200 mL of carbon tetrachloride, and NBS (20.44 g, 114.82 mmol) and BPO (2.16 g, 9.57 mmol) were added, and heated under reflux overnight. After the reaction was complete by TLC detection, it was cooled to room temperature, filtered under reduced pressure, and the filtrate was washed with saturated sodium bicarbonate solution, water and saturated brine in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (13.00 g) with a yield of 55%. 1 H NMR (500MHz, CDCl3) δ8.23–8.17(m,1H),8.09–8.03(m,1H),7.82(d,J=8.4Hz,1H),7.62–7.53(m,2H),7.48(d,J=8.4Hz,1H),4.55(s,2H).

[0134] Synthesis of 4-Formyl-1-naphthocarbonitrile

[0135]

[0136] The intermediate 4-(bromomethyl)-1-naphthocarbonitrile (13.00 g, 52.82 mmol) was dissolved in 50% acetic acid aqueous solution (200 mL), and hexamethylenetetramine (14.81 g, 105.65 mmol) was added in batches under stirring. After heating and reflux for 6 hours, 3 mL of concentrated hydrochloric acid was added dropwise, and heating and reflux were continued for half an hour. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove excess acetic acid, extracted with ethyl acetate three times, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (5.5 g) with a yield of 57%. 1 H NMR (500MHz, CDCl3) δ9.99 (s, 1H), 8.28–8.22 (m, 1H), 8.12 (dd, J = 8.4, 1.4Hz, 1 H),7.97–7.89(m,2H),7.67(td,J=7.8,1.4Hz,1H),7.61(td,J=8.0,1.3Hz,1H).

[0137] Synthesis of 4-(1,3-dioxolane-2-yl)-1-naphthocarbonitrile

[0138]

[0139] The intermediate 4-formyl-1-naphthocarbonitrile (3.00 g, 16.56 mmol) was dissolved in 50 mL of toluene, and 2.8 mL of ethylene glycol and p-toluenesulfonic acid (0.29 g, 1.66 mmol) were added in sequence. After installing a water separator, the mixture was heated under reflux for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound (3.51 g) with a yield of 91%. 1 H NMR(500MHz, CDCl3)δ8.25–8.19(m,1H),8.03–7.97(m,1H),7.84(d,J=8.4Hz, 1H),7.77(d,J=8.4Hz,1H),7.65–7.55(m,2H),6.09(s,1H),4.16–4.02(m,4H).

[0140] Synthesis of (Z)-4-(1,3-dioxolane-2-yl)-N'-hydroxy-1-naphthoimidamide

[0141]

[0142] The intermediate 4-(1,3-dioxolane-2-yl)-1-naphthocarbonitrile (3.55 g, 15.76 mmol), hydroxylamine hydrochloride (1.15 g, 16.55 mmol) and triethylamine (2.29 mL, 16.55 mmol) were dissolved in 40 mL of ethanol and heated under reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and used directly in the next step without purification. ESI-MS m / z: 259.1 [M+H] + .

[0143] Synthesis of 5-(5-(4-(1,3-dioxolane-2-yl)naphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile

[0144]

[0145] The intermediate (Z)-4-(1,3-dioxolane-2-yl)-N'-hydroxy-1-naphthoimidamide obtained in the previous step was dissolved in 50 mL of DMF, and 1.1 equivalents of benzoic acid, 1 equivalent of HOBT, 1 equivalent of EDCI and 1.5 equivalents of potassium carbonate were added in sequence, and the mixture was heated at 90°C for overnight reaction. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of distilled water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound. 1H NMR (500MHz, CDCl3) δ8.02–7.90(m,4H),7.89–7.80(m,6H),7.68(dd,J=8.4,1.8Hz,2H),7.52–7.43(m,5H) ),7.42(s,1H),5.97(s,2H),4.54(hept,J=6.2Hz,2H),4.17–4.03(m,8H),1.36(d,J=6.2Hz,11H).ESI-MS m / z:428.1[M+H] + .、

[0146] Synthesis of 5-(5-(4-formylnaphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile

[0147]

[0148] The intermediate 5-(5-(4-(1,3-dioxolane-2-yl)naphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (2.07 g, 4.84 mmol) was dissolved in 20 mL of acetone, and 20 mL of dilute hydrochloric acid was added, and the mixture was heated and stirred at 45°C for 4 hours. After the reaction was completed, 40 mL of distilled water was added, and the mixture was filtered under reduced pressure. The residue was washed with distilled water several times and dried to obtain the target compound (1.77 g) with a yield of 95%. 1 H NMR (500MHz, CDCl3) δ8.13(d,J=8.4Hz,1H),8.04–7.94(m,3H),7.88(d,J=1.9Hz,1H),7.69(dd,J=8.4,2.0 Hz,1H),7.60–7.49(m,2H),7.42(d,J=8.4Hz,1H),4.57(hept,J=6.2Hz,1H),1.35(d,J=6.2Hz,6H).ESI-MS m / z:384.1[M+H] + .

[0149] Synthesis of Methyl 1-((4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylate

[0150]

[0151] The intermediate 5-(5-(4-formylnaphthalene-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.40 g, 1.04 mmol) was dissolved in 20 mL of a methanol / dichloromethane (1:1) mixed solution, and 1.1 equivalents of the corresponding amine hydrochloride, 1.1 equivalents of DIPEA, 2 equivalents of acetic acid and 1 equivalent of sodium cyanoborohydride were added in sequence, and stirred at room temperature overnight. After the reaction was completed, an appropriate amount of saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound. 1 H NMR (500MHz, CDCl3) δ7.96–7.85(m,3H),7.73–7.64(m,2H),7.51(d,J=8.4Hz,1H),7.48–7.40(m,3H),4.56(hept,J=6.2Hz,1H),3.7 5(s,2H),3.66(s,3H),3.49(dd,J=9.0,5.8Hz,2H),3.19(dd,J=9.0,5.8Hz,2H),3.03(p,J=5.8Hz,1H),1.35(d,J=6.2Hz,6H).ESI-MS m / z:483.1[M+H] + .

[0152] Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride

[0153]

[0154] The intermediate methyl 1-((4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylate (200 mg, 0.41 mmol) was dissolved in 10 mL of a methanol / water mixed solution, lithium hydroxide (99 mg, 4.14 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, 10 mL of distilled water was added, and the pH was adjusted to 3 with 1 M hydrochloric acid to precipitate a white solid. The solid was filtered off with suction, and the residue was washed several times with distilled water and dried to obtain the target compound A1 (152 mg) with a yield of 73%. 1HNMR(400MHz,MeOD)δ9.11–8.99(m,1H),8.57–8.47(m,2H),8.44–8.30(m,2H),7.90–7.76(m,3H),7.50(d, J=9.0Hz,1H),5.10(s,2H),5.04–4.96(m,1H),4.53–4.42(m,4H),3.82–3.73(m,1H),1.52–1.45(m,6H).13C NMR (125MHz, DMSO-d6) δ173.2,168.4,162.6,134.7,133.9,131.4,130.2,128.7,128.1 ,127.5,126.3,124.6,115.9,115.3,115.0,102.5,72.6,55.4,54.0,32.3,21.5.ESI-MS m / z:469.1[M+H]+.

[0155] Example 2 Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride (A2)

[0156]

[0157] The synthesis method of compound A2 is similar to that of compound A1, and the yield is 77%. 1H NMR(400MHz,MeOD)δ8.07(dd,J=8.4,2.0Hz,1H),7.97–7.88(m,2H),7.87–7.81(m,1H),7. 70(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),7.50–7.39(m,2H),7.32(d,J=8.4Hz,1H),4.60– 4.50(m,1H),4.00(s,2H),3.45(dd,J=10.2,5.8Hz,1H),3.04–2.92(m,2H),2.86–2.77(m,1 H),2.57–2.48(m,1H),2.09–1.99(m,1H),1.90–1.80(m,1H),1.35(d,J=6.2Hz,6H).ESI-MS m / z:483.1[M+H] + .

[0158] Example 3 Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)proline hydrochloride) (A3)

[0159]

[0160] The synthesis method of compound A3 is similar to that of compound A1, and the yield is 65%. 1 H NMR(400MHz,MeOD)δ9.03(d,J=8.4Hz,1H),8.67(d,J=8.4Hz,1H),8.52–8.44(m,2H),8.3 7(d,J=7.5Hz,1H),7.91(d,J=7.5Hz,1H),7.87–7.72(m,2H),7.47(d,J=8.9Hz,1H),5.34( d,J=13.2Hz,1H),5.05–4.96(m,1H),4.65(d,J=13.2Hz,1H),4.25–4.16(m,1H),3.48–3.3 5(m,2H),2.68–2.48(m,1H),2.25–2.08(m,2H),2.06–1.88(m,1H),1.49(d,J=6.0Hz,6H). 13C NMR (125MHz, DMSO-d6) δ173.1,168.6,162.6,134.7,133.9,132.3,130.2,128.8,127.6,126. 7,126.0,125.6,116.0,115.3,114.9,102.5,72.6,65.9,56.0,53.2,28.5,22.4,21.5.ESI-MS m / z:483.1[M+H] + .

[0161] 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 hydrochloric acid (A4)

[0162]

[0163] The synthesis method of compound A4 is similar to that of compound A1, and the yield is 71%. 1 H NMR (400MHz, MeOD) δ9.06(d,J=8.2Hz,1H),8.58–8.47(m,2H),8.40(d,J=7.4Hz,1H),8.34–8.26(m,1H),7.90–7.76(m,3H),7.49(d,J=8. 9Hz,1H),5.02–4.97(m,1H),4.76(s,2H),4.02–3.88(m,1H),3.11–2.97(m,1H),2.78–2.62(m,2H),2.52–2.38(m,2H),1.53–1.45(m,6H). 13 C NMR (125MHz, DMSO-d6) δ174.9,173.2,168.5,162.6,134.7,134.0,131.5,130.1,128.7,127.9,127.4 ,127.2,126.3,124.7,123.9,116.0,115.3,114.9,102.5,72.6,47.8,45.5,30.7,30.5,21.5.ESI-MS m / z:483.1[M+H] + .

[0164] 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)

[0165]

[0166] The synthesis method of compound A5 is similar to that of compound A1, and the yield is 63%. 1 H NMR(400MHz,MeOD)δ9.03(d,J=8.4Hz,1H),8.77(d,J=8.3Hz,1H),8.56–8.45(m,2H),8.39(d,J=7.5Hz,1H),7.91(d,J=7 .5Hz,1H),7.87–7.74(m,2H),7.48(d,J=9.0Hz,1H),5.03–4.96(m,3H),3.88(s,2H),2.80(s,3H),1.49(d,J=6.0Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ173.5,169.2,163.0,135.2,134.4,132.8,130.7,129.2,128.0,127.5 ,126.9,126.4,126.2,123.5,116.5,115.8,115.4,103.0,73.0,58.7,57.9,42.1,22.0.ESI-MS m / z:457.1[M+H] + .

[0167] Example 6 Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)alanine hydrochloride (A6)

[0168]

[0169] The synthesis method of compound A6 is similar to that of compound A1, and the yield is 70%. 1 H NMR(400MHz,MeOD)δ8.08(dd,J=8.4,1.8Hz,1H),8.04–7.93(m,2H),7.90(d, J=1.9Hz,1H),7.70(d,J=8.4Hz,1H),7.56(d,J=8.4Hz,1H),7.52–7.46(m,1H ),7.46–7.39(m,1H),7.32(d,J=8.4Hz,1H),4.59–4.50(m,1H),4.21(d,J=5. 4Hz,2H),3.66–3.54(m,2H),1.37(d,J=6.2Hz,3H),1.35–1.27(m,6H).ESI-MS m / z:457.1[M+H] + .

[0170] Example 7 Synthesis of ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)glycine hydrochloride (A7)

[0171]

[0172] The synthesis method of compound A7 is similar to that of compound A1, and the yield is 79%. 1 H NMR (400MHz, MeOD) δ9.05(d,J=8.1Hz,1H),8.56(d,J=2.3Hz,1H),8.54–8.45(m,2H),8.41(d,J=7.4Hz,1H),7.88(d,J=7.6Hz, 1H),7.86–7.78(m,2H),7.50(d,J=9.0Hz,1H),4.98(d,J=6.9Hz,1H),4.89(s,3H),3.98(s,2H),1.49(d,J=6.0Hz,6H).ESI-MS m / z:443.1[M+H] + .

[0173] 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)

[0174]

[0175] The synthesis method of compound A8 is similar to that of compound A1, and the yield is 66%. 1 H NMR (400MHz, MeOD) δ9.07–9.01(m,1H),8.53–8.45(m,2H),8.38(d,J=7.5Hz,1H),8.34–8.30(m,1H),7.86(d,J=7.5Hz,1H),7.84–7.7 5(m,2H),7.48(d,J=9.0Hz,1H),5.02–4.96(m,1H),4.86(s,2H),3.45(t,J=6.5Hz,2H),2.73(t,J=6.5Hz,2H),1.49(d,J=6.0Hz,6H). 13CNMR(125MHz,DMSO-d6)δ172.5,172.1,168.0,162.0,134.1,133.4,131.0,129.6,128.2,127.2,12 6.5,126.1,125.7,124.1,122.9,115.4,114.7,114.4,102.0,72.0,47.9,43.3,31.5,21.0.ESI-MS m / z:457.1[M+H] + .

[0176] 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)

[0177]

[0178] The synthesis method of compound A9 is similar to that of compound A1, and the yield is 58%. 1 H NMR(400MHz,MeOD)δ9.04(d,J=8.4Hz,1H),8.58–8.49(m,3H),8.40(d,J=7.4Hz,1H),7.87(d,J=7.5Hz,1H),7.85 –7.75(m,2H),7.50(d,J=9.0Hz,1H),5.06–4.96(m,1H),4.87(s,2H),3.71(s,1H),1.49(d,J=6.0Hz,6H).ESI-MS m / z:487.1[M+H] + .

[0179] Example 10 Synthesis of 1-((4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A10)

[0180]

[0181] The synthesis method of compound A10 is similar to that of compound A1, and the yield is 65%. 1H NMR(400MHz,MeOD)δ9.08–8.99(m,1H),8.40–8.32(m,2H),8.28(d,J=2.1Hz,1H),8.22–8.15(m,1H),7.87–7.76(m,3H), 7.36(d,J=8.8Hz,1H),5.01(s,2H),4.90–4.82(m,1H),4.41–4.27(m,4H),3.57(p,J=8.4Hz,1H),1.45(d,J=6.0Hz,6H). 13 C NMR(125MHz,DMSO-d6)δ173.7,173.4,168.6,156.8,131.7,130.2,129.5,128.9,128 .7,127.6,126.7,126.1,124.9,123.0,116.1,115.4,71.8,56.5,33.3,21.6.ESI-MS m / z:478.1[M+H] + .

[0182] Example 11 Synthesis of 1-((4-(5-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A11)

[0183]

[0184] The synthesis method of compound A11 is similar to that of compound A1, and the yield is 72%. 1 H NMR (400MHz, MeOD) δ9.06–9.01(m,1H),8.44(d,J=2.1Hz,1H),8.36(dd,J=10.5,7.6Hz,2H),8.22(dd,J=8.7,2.1Hz,1H),7.87–7 .77(m,3H),7.31(d,J=8.7Hz,1H),5.05(s,2H),4.90–4.80(m,1H),4.49–4.33(m,4H),3.74–3.62(m,1H),1.45(d,J=6.0Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ173.9,168.9,158.3,133.1,132.0,130.7,129.8,129.3, 128.4,127.7,126.7,125.2,117.0,115.6,113.1,72.3,56.4,33.2,22.1.ESI-MS m / z:522.1[M+H] + .

[0185] Example 12 Synthesis of 1-((4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A12)

[0186]

[0187] The synthesis method of compound A12 is similar to that of compound A1, and the yield is 81%. 1 H NMR(400MHz,MeOD)δ9.05(dd,J=7.6,2.0Hz,1H),8.47(d,J=7.4Hz,2H),8.38(dd,J=14.9,8.1Hz,2H),7.89–7.77(m,3H ),7.49(d,J=9.0Hz,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=6.0Hz,6H). 13 C NMR(150MHz,DMSO-d6)δ174.0,168.9,159.7,134.6,132.0,130.7,129.3,128.4,127.7,127 .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] + .

[0188] Example 13 Synthesis of 1-((4-(5-(4-isopropoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A13)

[0189]

[0190] The synthesis method of compound A13 is similar to that of compound A1, and the yield is 64%. 1 H NMR(400MHz,MeOD)δ9.06–8.99(m,1H),8.38(d,J=7.8Hz,2H),7.93–7.75(m,5H),7.22(d,J=8.5Hz,1H),5.12 (s,2H),4.83–4.75(m,1H),4.52–4.42(m,4H),3.99(s,3H),3.87–3.74(m,1H),1.41(d,J=6.0Hz,6H).ESI-MS m / z:474.1[M+H]+ .

[0191] Example 14 Synthesis of 1-((4-(5-(4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A14)

[0192]

[0193] The synthesis method of compound A14 is similar to that of compound A1, and the yield is 66%. 1 H NMR (400MHz, MeOD) δ9.08–9.00(m,1H),8.36(t,J=7.2Hz,2H),8.22(d,J=8.7Hz,2H),7.89–7.75(m,3H),7.16( d,J=8.8Hz,2H),5.08(s,2H),4.86–4.74(m,1H),4.50–4.39(m,4H),3.79–3.67(m,1H),1.41(d,J=6.0Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ174.1,167.7,161.1,130.9,129.7,129.6,128.1,127.4,126.7,125.8,124.0,115.7,114.6,69.4,55.2,31.9,21.1.ESI-MS m / z:444.1[M+H] + .

[0194] Example 15 Synthesis of 1-((4-(5-(4-(tert-butyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A15)

[0195]

[0196] The synthesis method of compound A15 is similar to that of compound A1, and the yield is 77%. 1 H NMR(400MHz,MeOD)δ9.08–8.99(m,1H),8.41–8.32(m,2H),8.26–8.18(m,2H),7.89–7.76( m,3H),7.32–7.22(m,2H),5.08(s,2H),4.50–4.37(m,4H),3.79–3.67(m,1H),1.50(s,9H). 13CNMR(125MHz,DMSO-d6)δ174.6,168.4,160.1,131.5,130.3,129.6,128.6,128.0,127.3,126.3,124.6,122.7,117.1,79.7,55.7,32.5,28.5.ESI-MS m / z:458.1[M+H] + .

[0197] Example 16 Synthesis of 1-((4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A16)

[0198]

[0199] The synthesis method of compound A16 is similar to that of compound A1, and the yield is 72%. 1 H NMR(400MHz,MeOD)δ9.03(d,J=8.3Hz,1H),8.39–8.33(m,2H),8.25(d,J=8.7Hz,2H),7.88–7.76 (m,3H),7.21(d,J=8.7Hz,2H),5.03(s,2H),4.43–4.28(m,4H),3.95(s,3H),3.64–3.56(m,1H). 13 C NMR (125MHz, DMSO-d6) δ174.1,167.8,162.7,131.0,129.7,129.5,128.1,127.3,126.6,125.8,124.1,115.1,114.5,55.3,55.2,32.1.ESI-MS m / z:416.1[M+H] + .

[0200] Example 17 Synthesis of 1-((4-(5-(4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A17)

[0201]

[0202] The synthesis method of compound A17 is similar to that of compound A1, and the yield is 68%. 1H NMR(400MHz,MeOD)δ9.06–9.01(m,1H),8.41–8.32(m,2H),8.26–8.20(m,2H),7.88–7.76(m,3H),7.21–7.15(m,2H), 5.08(s,2H),4.50–4.38(m,4H),4.10(t,J=6.4Hz,2H),3.78–3.70(m,1H),1.95–1.82(m,2H),1.11(t,J=7.4Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ175.1,168.7,163.2,131.9,130.7,130.5,129.0,128.5 ,127.9,126.8,125.4,125.0,115.9,115.9,70.0,55.9,32.8,22.4,10.8.ESI-MS m / z:444.1[M+H] + .

[0203] Example 18 Synthesis of 1-((4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A18)

[0204]

[0205] The synthesis method of compound A18 is similar to that of compound A1, and the yield is 65%. 1 H NMR(400MHz,MeOD)δ9.04(d,J=8.2Hz,1H),8.40–8.32(m,2H),8.25(d,J=8.6Hz,2H),7.87–7.77(m,3H),7.51(d,J=7.5Hz,2H),7 .46–7.40(m,2H),7.37(d,J=7.1Hz,1H),7.28(d,J=8.7Hz,2H),5.26(s,2H),5.06(s,2H),4.47–4.35(m,4H),3.74–3.64(m,1H). 13 C NMR(125MHz,DMSO-d6)δ175.1,168.8,162.8,136.8,131.9,130.8,130.6,129 .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] + .

[0206] Example 19 Synthesis of 1-((4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A19)

[0207]

[0208] The synthesis method of compound A19 is similar to that of compound A1, and the yield is 67%. 1 H NMR(400MHz,MeOD)δ9.10–9.03(m,1H),8.46–8.39(m,3H),8.36(d,J=8.1Hz,1H),7.89– 7.78(m,3H),7.61(d,J=8.4Hz,2H),5.09(s,2H),4.52–4.38(m,4H),3.79–3.67(m,1H). 13 C NMR (125MHz, DMSO-d6) δ173.2,168.0,151.1,130.9,130.1,129.7,128.2,127.5,126.9,125.8,124.0,121.9,121.3,55.1,31.8.ESI-MS m / z:470.1[M+H] + .

[0209] Example 20 Synthesis of 1-((4-(5-(4-isopropylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A20)

[0210]

[0211] The synthesis method of compound A20 is similar to that of compound A1, and the yield is 61%. 1 H NMR (400MHz, MeOD) δ9.10–9.00(m,1H),8.41–8.34(m,2H),8.23(d,J=8.1Hz,2H),7.89–7.76(m,3H),7.56(d ,J=8.0Hz,2H),5.08(s,2H),4.55–4.37(m,4H),3.79–3.67(m,1H),3.14–2.98(m,1H),1.35(d,J=6.9Hz,6H). 13C NMR (150MHz, DMSO-d6) δ175.3,168.9,154.9,132.0,130.7,129.2,128.7,128.4,128.1,127.8,126.8,125.1,121.5,56.2,34.1,33.0,24.0.ESI-MS m / z:428.1[M+H] + .

[0212] Example 21 Synthesis of 1-((4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A21)

[0213]

[0214] The synthesis method of compound A21 is similar to that of compound A1, and the yield is 69%. 1 H NMR (400MHz, MeOD) δ9.07–9.03(m,1H),8.42–8.33(m,2H),8.22(d,J=8.0Hz,2H),7.90–7.77(m,3H),7.51(d,J=8.0Hz,2 H),5.09(s,2H),4.51–4.39(m,4H),3.80–3.67(m,1H),2.76(t,J=7.6Hz,2H),1.84–1.65(m,2H),1.02(t,J=7.4Hz,3H). 13 C NMR (150MHz, DMSO-d6) δ175.3,168.8,148.9,131.9,130.7,130.1,129.2,128.5,127.9,126.8,125.1,121.3,56.1,37.7,32.9,24.2,14.1.ESI-MS m / z:428.1[M+H] + .

[0215] Example 22 Synthesis of 1-((4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A22)

[0216]

[0217] The synthesis method of compound A22 is similar to that of compound A1, and the yield is 65%. 1H NMR(500MHz,MeOD)δ7.97–7.89(m,2H),7.83–7.76(m,2H),7.73–7.65(m,3H),7.55–7.47(m,2H),7.47–7.40 (m,1H),3.74(s,2H),3.48(dd,J=9.0,5.8Hz,2H),3.16(dd,J=9.0,5.8Hz,2H),2.98(p,J=5.8Hz,1H).ESI-MS m / z:411.1[M+H] + .

[0218] Example 23 Synthesis of 1-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A23)

[0219]

[0220] The synthesis method of compound A23 is similar to that of compound A1, and the yield is 66%. 1 H NMR(400MHz,MeOD)δ9.07–9.01(m,1H),8.41–8.32(m,4H),7.88–7.75(m,3 H),7.48–7.37(m,2H),5.03(s,2H),4.44–4.30(m,4H),3.68–3.57(m,1H). 13 C NMR (125MHz, DMSO-d6) δ174.3,169.1,167.3,164.5,132.1,131.5,131.4,130.7,129.3,129.1,128 .3,128.2,127.7,127.4,126.8,126.6,125.3,125.0,120.6,117.5,117.3,56.8,48.1,33.5.ESI-MS m / z:404.1[M+H] + .

[0221] Example 24 Synthesis of 1-((4-(5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A24)

[0222]

[0223] The synthesis method of compound A24 is similar to that of compound A1, and the yield is 74%. 1H NMR (500MHz, MeOD) δ7.97–7.90(m,3H),7.85(t,J=1.9Hz,1H),7.78(ddd,J=7.9,1.9,1.2Hz,1H),7.71(d,J=8.6Hz,1H),7.56(d,J= 7.8Hz,1H),7.54–7.40(m,3H),3.74(s,2H),3.48(dd,J=9.0,5.8Hz,2H),3.16(dd,J=9.0,5.8Hz,2H),2.98(p,J=5.8Hz,1H).ESI-MS m / z:411.1[M+H] + .

[0224] Example 25 Synthesis of 1-((4-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A25)

[0225]

[0226] The synthesis method of compound A25 is similar to that of compound A1, and the yield is 78%. 1 H NMR (400MHz, MeOD) δ9.08–9.03(m,1H),8.41(d,J=7.4Hz,1H),8.38–8.34(m,1H),8.15(ddd,J=7.8,1.6,0.9Hz,1H),8.04(ddd,J=9.1,2.6,1.5Hz,1 H),7.88–7.78(m,3H),7.72(td,J=8.1,5.5Hz,1H),7.51(tdd,J=8.5,2.7, 0.9Hz,1H),5.06(s,2H),4.50–4.33(m,4H),3.67(p,J=8.5Hz,1H).ESI-MS m / z:404.1[M+H] + .

[0227] Example 26 Synthesis of 1-((4-(5-phenyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A26)

[0228]

[0229] The synthesis method of compound A26 is similar to that of compound A1, and the yield is 71%. 1H NMR (400MHz, MeOD) δ9.08–9.01(m,1H),8.39(d,J=7.4Hz,1H),8.36(d,J=8.3Hz,1H),8.33–8.28(m ,2H),7.86–7.71(m,4H),7.70–7.65(m,2H),5.00(s,2H),4.37–4.25(m,4H),3.53(p,J=8.1Hz,1H). 13 CNMR(150MHz,DMSO-d6)δ175.1,174.3,169.1,133.9,132.2,130.6,130.1, 129.4,128.5,128.0,127.1,126.6,126.3,125.4,123.9,57.0,33.9.ESI-MS m / z:386.1[M+H] + .

[0230] Example 27 Synthesis of 1-((4-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A27)

[0231]

[0232] The synthesis method of compound A27 is similar to that of compound A1, and the yield is 66%. 1 H NMR(400MHz,MeOD)δ9.09–9.02(m,1H),8.94–8.88(m,2H),8.43(d,J=7.5Hz,1H),8.39–8.34(m ,1H),8.29–8.24(m,2H),7.90–7.78(m,3H),5.05(s,2H),4.44–4.33(m,4H),3.72–3.58(m,1H). 13 C NMR (125MHz, DMSO-d6) δ173.7,169.3,151.7,132.1,130.9,130.6,129.4,128.3,127.5,126.6,125.3,121.9,56.7,33.4.ESI-MS m / z:387.1[M+H] + .

[0233] Example 28 Synthesis of 1-((4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A28)

[0234]

[0235] The synthesis method of compound A28 is similar to that of compound A1, and the yield is 68%. 1 H NMR(400MHz,MeOD)δ9.45(dd,J=2.2,0.9Hz,1H),9.08–9.03(m,1H),8.88(dd,J=4.9,1.7Hz,1H),8.70(ddd,J=8.0,2.3,1.6Hz,1H), 8.42(d,J=7.5Hz,1H),8.38–8.34(m,1H),7.88–7.80(m,3H),7.77–7.73(m,1H),5.03(s,2H),4.42–4.31(m,4H),3.68–3.55(m,1H). 13 CNMR(150MHz,DMSO-d6)δ173.5,169.1,154.2,149.1,136.2,132.1,130.6,129.4,129 .2,128.2,127.7,127.4,126.8,126.6,125.3,125.0,120.5,56.8,48.1,33.6.ESI-MS m / z:387.1[M+H] + .

[0236] Example 29 Synthesis of 1-((4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A29)

[0237]

[0238] The synthesis method of compound A29 is similar to that of compound A1, and the yield is 69%. 1 H NMR(400MHz,MeOD)δ9.13–9.06(m,1H),8.90–8.85(m,1H),8.51–8.43(m,2H),8.40–8.35(m,1 H),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 C NMR (150MHz, DMSO-d6) δ174.3,169.0,151.2,143.3,138.7,131.9,130.7,129.2,128.6,128.1,128.0,126.8,125.2,125.1,56.0,32.8.ESI-MS m / z:387.1[M+H] + .

[0239] Example 30 Synthesis of 1-((4-(5-(5-methylisothiazol-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A30)

[0240]

[0241] The synthesis method of compound A30 is similar to that of compound A1, and the yield is 71%. 1 H NMR(400MHz,MeOD)δ9.08–9.00(m,1H),8.44–8.33(m,2H),7.90–7.76(m,3H),6.95(t,J= 0.9Hz, 1H), 5.06 (s, 2H), 4.48–4.33 (m, 4H), 3.68 (p, J = 8.4Hz, 1H), 2.64 (d, J = 0.9Hz, 3H). 13 CNMR(125MHz,DMSO-d6)δ187.4,172.4,168.0,166.7,149.9,140.1,131.0, 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] + .

[0242] Example 31 Synthesis of 1-((4-(5-(Benzo[d][1,3]dioxazol-5-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A31)

[0243]

[0244] The synthesis method of compound A31 is similar to that of compound A1, and the yield is 71%. 1 H NMR (500MHz, MeOD) δ8.00–7.91(m,2H),7.77(dd,J=8.4,1.8Hz,1H),7.71(d,J=8.4Hz,1H),7.53(d,J=8.4Hz,1H),7.51–7.39(m,2H),7.33(d,J=1. 8Hz,1H),6.91(d,J=8.4Hz,1H),6.09(s,2H),3.74(s,2H),3.49(dd,J=9.0,5.8Hz,2H),3.16(dd,J=9.0,5.8Hz,2H),2.98(p,J=5.8Hz,1H).ESI-MS m / z:430.1[M+H] + .

[0245] 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-3-carboxylic acid hydrochloride (A32)

[0246]

[0247] The synthesis method of compound A32 is similar to that of compound A1, and the yield is 64%. 1 H NMR(400MHz,MeOD)δ9.03(dd,J=7.6,2.0Hz,1H),8.40–8.31(m,2H),7.87–7.75( m,5H),7.11(d,J=8.4Hz,1H),5.09(s,2H),4.50–4.34(m,8H),3.81–3.70(m,1H). 13 C NMR(125MHz,DMSO-d6)δ174.9,168.7,148.5,144.4,131.9,130.7,129.1,128.5, 127.9,126.9,125.0,122.3,118.8,117.1,116.6,65.1,64.6,56.1,32.8.ESI-MS m / z:444.1[M+H] + .

[0248] Example 33 Synthesis of 1-((4-(5-(quinolin-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A33)

[0249]

[0250] The synthesis method of compound A33 is similar to that of compound A1, and the yield is 74%. 1 H NMR(400MHz,MeOD)δ9.15–9.09(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). 13C NMR (125MHz, DMSO-d6) δ174.2,169.2,147.8,143.4,138.9,132.0,131.7,130.7,130. 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] + .

[0251] Example 34 Synthesis of 1-((4-(5-(quinoxalin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A34)

[0252]

[0253] The synthesis method of compound A34 is similar to that of compound A1, and the yield is 69%. 1 H NMR(400MHz,MeOD)δ9.82(s,1H),9.19–9.09(m,1H),8.51(d,J=7.3Hz,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 CNMR(125MHz,DMSO-d6)δ171.7,168.2,166.1,144.0,142.2,140.4,138.0,132.4,131.4,131.1,131.0,129.6,129.6 ,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] + .

[0254] Example 35 Synthesis of 1-((4-(5-(1H-indol-5-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A35)

[0255]

[0256] The synthesis method of compound A35 is similar to that of compound A1, and the yield is 62%. 1H NMR(400MHz,MeOD)δ9.04(dd,J=7.3,2.3Hz,1H),8.57(dd,J=1.7,0.7Hz,1H),8.40–8.31(m,2H),8.04(dd,J=8.6,1.7Hz,1H),7.88–7.7 6(m,3H),7.66–7.59(m,1H),7.44(d,J=3.2Hz,1H),6.70(dd,J=3.2,0.9Hz,1H),5.03(s,2H),4.46–4.24(m,4H),3.60(p,J=8.4Hz,1H). 13 C NMR (125MHz, DMSO-d6) δ176.6,168.9,138.9,132.1,130.7,129.1,128.3,128. 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] + .

[0257] 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)

[0258]

[0259] The synthesis method of compound A6 is similar to that of compound A1, and the yield is 55%. 1 H NMR (400MHz, MeOD) δ9.09–9.03(m,1H),8.41(d,J=7.4Hz,1H),8.37(dd,J=6.9,2.7Hz,1H),8.02(d,J=1.0Hz,1H),7.92–7 .80(m,4H),7.78–7.73(m,1H),7.63–7.56(m,1H),7.49–7.41(m,1H),5.03(s,2H),4.44–4.28(m,4H),3.64–3.54(m,1H). 13 C NMR(125MHz,DMSO-d6)δ168.0,166.5,154.9,139.8,131.1,129.6,128.5,127.7,1 27.1,126.4,126.3,125.5,124.3,124.0,122.7,113.1,111.7,55.9,32.7.ESI-MS m / z:425.1[M+H] + .

[0260] 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)

[0261]

[0262] The synthesis method of compound A37 is similar to that of compound A1, and the yield is 61%. 1 H NMR (400MHz, MeOD) δ9.12–9.06(m,1H),8.43(d,J=7.4Hz,1H),8.36(dd,J=6.8,2.4Hz,1H),7.88–7.80(m,3H),7.77(d,J=8.1Hz,1H ),7.61(d,J=8.7Hz,2H),7.47–7.40(m,1H),7.25–7.19(m,1H),5.04(s,2H),4.43–4.35(m,4H),4.33(s,3H),3.64(p,J=8.4Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ168.6,167.6,139.0,131.1,129.7,128.4,127.3,126.5, 125.6,124.8,124.2,122.0,121.6,120.4,110.6,108.3,55.6,32.3,31.5.ESI-MS m / z:439.1[M+H] + .

[0263] Example 38 Synthesis of (E)-1-((4-(5-phenylvinyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A38)

[0264]

[0265] The synthesis method of compound A38 is similar to that of compound A1, and the yield is 66%. 1 H NMR(400MHz,MeOD)δ9.04–8.96(m,1H),8.40–8.27(m,2H),8.04(d,J=16.5Hz,1H),7.86–7.73(m,5H ),7.53–7.44(m,3H),7.36(d,J=16.4Hz,1H),5.03(s,2H),4.45–4.31(m,3H),3.64(p,J=8.5Hz,1H). 13C NMR(125MHz,DMSO-d6)δ175.1,173.6,168.8,167.4,143.5,134.7,132.1,131.2,130.6, 129.5,129.1,128.9,128.1,127.3,126.8,126.6,125.2,110.7,56.7,48.1,33.6.ESI-MS m / z:412.1[M+H] + .

[0266] Example 39 Synthesis of 1-((4-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A39)

[0267]

[0268] The synthesis method of compound A39 is similar to that of compound A1, and the yield is 81%. 1 H NMR (400MHz, MeOD) δ8.98–8.92(m,1H),8.34(dd,J=8.0,1.5Hz,1H),8.27(d,J=7.4Hz,1H),7.86–7.73(m,3H),5.06(s,2H),4.51–4.33(m,4H ),3.72(p,J=8.5Hz,1H),3.26–3.07(m,1H),2.28–2.16(m,2H),1.96–1.85(m,2H),1.85–1.71(m,3H),1.61–1.47(m,2H),1.49–1.35(m,1H). 13 C NMR (125MHz, DMSO-d6) δ182.7,168.0,131.9,130.6,129.0,128.4,127.7,126.7,125.0,56.2,35.7,32.9,30.2,25.6,25.2.ESI-MS m / z:392.1[M+H] + .

[0269] 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)

[0270]

[0271] The synthesis method of compound A40 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.24(dd,J=7.3,1.6Hz,1H),7.64(d,J=7.5Hz,2H),7 .56–7.43(m,3H),7.35(d,J=2.0Hz,1H),7.16(dd,J=7.5,2.0Hz,1H),4.43(m,1H),3 .39(s,2H),3.16(dt,J=12.4,7.0Hz,2H),2.88(p,J=7.0Hz,1H),2.33(dt,J=12.5, 7.1Hz,2H),1.98(dq,J=14.1,7.1Hz,2H),1.72–1.61(m,2H),1.36(d,J=6.8Hz,6H). 13 C NMR(125MHz,DMSO-d6)δ178.14,172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57,128.91, 127.75,127.03,125.31,124.41,115.46,113.72,105.66,72.86,58.88,50.85,40.41,28.26,21.93.ESI-MS m / z:497.2[M+H] + .

[0272] 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)

[0273]

[0274] The synthesis method of compound A41 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.6Hz,1H),7.98(dd,J=7.4,1.5Hz,1H),7.64(dd,J=7.5,1.1Hz ,2H),7.56–7.43(m,3H),7.34(d,J=2.0Hz,1H),7.16(dd,J=7.5,2.0Hz,1H),4.49–4.41(m,1H),4.38(t,J=12. 8Hz,1H),3.78(d,J=12.3Hz,1H),3.15(dq,J=12.3,7.0Hz,2H),2.65(dd,J=12.4,7.0Hz,1H),2.53(p,J=6.9Hz ,1H),2.27(ddt,J=29.0,12.4,7.0Hz,2H),1.75–1.63(m,1H),1.63–1.46(m,2H),1.36(dd,J=24.9,6.8Hz,6H). 13 C NMR((125MHz,DMSO-d6)δ174.94,172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.62,129.52,128.91,127.81 ,127.68,127.03,125.31,124.41,115.46,113.72,105.66,72.86,58.90,55.40,49.52,41.86,25.14,22.81,21.93.ESI-MS m / z:497.2[M+H] + .

[0275] Example 42 Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-3,4-carboxylic acid hydrochloride (A42)

[0276]

[0277] The synthesis method of compound A42 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.26(dd,J=7.5,1.5Hz,1H),7.87(dd,J=7.4,1.5Hz,1H),7.65(dd,J=7.5,1.3H z,2H),7.59–7.49(m,2H),7.46(td,J=7.5,1.7Hz,1H),7.34(d,J=2.2Hz,1H),7.16(dd,J=7.5,2.0Hz,1H),4.4 4(dq,J=13.6,6.8Hz,1H),4.38(d,J=12.4Hz,1H),3.76(d,J=12.2Hz,1H),3.47–3.37(m,1H),3.21–3.11(m,1 H),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=25.1,6.8Hz,6H). 13 C NMR (125 MHz, DMSO-d6)δ

[0278] 178.27,176.57,172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91,127.75(d,J =16.2Hz),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] + .

[0279] 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)

[0280]

[0281] The synthesis method of compound A43 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.6Hz,1H),7.99(dd,J=7.3,1.6Hz,1H),7.79(s,1H),7.64(dd,J=7 .5,2.8Hz,2H),7.56–7.43(m,3H),7.34(d,J=2.0Hz,1H),7.15(dd,J=7.5,2.0Hz,1H),4.49–4.35(m,2H),3.76(d, J=12.4Hz,1H),3.40(dd,J=9.5,7.0Hz,1H),3.10(ddt,J=16.9,14.0,7.0Hz,2H),2.67(dd,J=9.5,7.0Hz,1H),2.4 6(dq,J=12.8,7.0Hz,1H),2.35(dt,J=9.5,7.1Hz,1H),2.15(dq,J=12.9,7.0Hz,1H),1.36(dd,J=25.1,6.8Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91,127.75( d, J=16.2Hz),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] + .

[0282] Example 44 Synthesis of methyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylate (A44)

[0283]

[0284] The synthesis method of compound A44 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.6Hz,1H),8.00(dd,J=7.4,1.6Hz,1H ),7.64(dd,J=7.5,4.4Hz,2H),7.56–7.43(m,3H),7.34(d,J=2.0Hz,1H),7.15(dd,J= 7.5,1.8Hz,1H),4.43(h,J=6.8Hz,1H),3.81(dd,J=11.1,6.9Hz,2H),3.67(s,3H),3. 39(s,2H),3.23(dd,J=11.1,6.9Hz,2H),3.14(p,J=6.8Hz,1H),1.36(d,J=6.8Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ173.55,172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91,1 27.75(d,J=16.2Hz),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] + .

[0285] Example 45 Synthesis of ethyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylate (A45)

[0286]

[0287] The synthesis method of compound A45 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.3,1.6Hz,1H),7.98(dd,J=7.4,1.6Hz,1H),7.64 (dd,J=7.5,4.4Hz,2H),7.53(dd,J=7.4,1.6Hz,1H),7.52–7.43(m,2H),7.34(d,J=2.0Hz,1H) ,7.15(dd,J=7.5,2.0Hz,1H),4.43(hept,J=6.8Hz,1H),4.17(q,J=5.9Hz,2H),3.82(dd,J=10 .8,6.7Hz,2H),3.39(s,2H),3.26–3.11(m,3H),1.36(d,J=6.8Hz,6H),1.23(t,J=5.9Hz,3H). 13 C NMR (125MHz, DMSO-d6) δ172.69,172.53,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91,127 .75(d,J=16.2Hz),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] + .

[0288] Example 46 Synthesis of isopropyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylate (A46)

[0289]

[0290] The synthesis method of compound A46 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.5,1.6Hz,1H),7.99(dd,J=7.4,1.5Hz,1H) ,7.65(dd,J=9.6,7.4Hz,2H),7.56–7.43(m,3H),7.32(d,J=2.0Hz,1H),7.15(dd,J=7.5 ,2.0Hz,1H),5.04(hept,J=6.8Hz,1H),4.43(hept,J=6.9Hz,1H),3.82(dd,J=10.8,6. 7Hz,2H),3.39(s,2H),3.27–3.12(m,3H),1.36(d,J=6.8Hz,6H),1.23(d,J=6.9Hz,6H). 13 C NMR (125 MHz, DMSO-d6)δ

[0291] 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] + .

[0292] 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)

[0293]

[0294] The synthesis method of compound A47 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.5Hz,1H),8.01(dd,J=7.4,1.6Hz,1H) ,7.73(d,J=7.5Hz,1H),7.63(d,J=7.5Hz,1H),7.56–7.43(m,3H),7.23(d,J=2.0Hz,1H ),7.09(dd,J=7.5,2.0Hz,1H),5.68(s,2H),4.43(hept,J=6.9Hz,1H),3.77(dd,J=11. 1,6.9Hz,2H),3.48–3.39(m,2H),3.24(dd,J=11.1,7.0Hz,2H),1.36(d,J=6.8Hz,6H). 13 C NMR(125MHz,DMSO-d6)δ172.67(d,J=4.7Hz),166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),12 8.91,127.75(d,J=16.2Hz),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] + .

[0295] 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)

[0296]

[0297] The synthesis method of compound A48 is similar to that of compound A1. 1H NMR (500MHz, Chloroform-d) δ8.25 (dd, J=7.4, 1.5Hz, 1H), 8.01 (dd, J=7.4, 1.6Hz, 1H), 7.64 (dd, J= 7.5,5.5Hz,2H),7.52(td,J=7.7,7.2,1.8Hz,2H),7.46(td,J=7.5,1.6Hz,1H),7.34(d,J=2.0Hz,1H) ,7.15(dd,J=7.5,2.0Hz,1H),5.98(s,1H),4.43(hept,J=6.8Hz,1H),3.76(dd,J=11.1,7.0Hz,2H),3 .44(p,J=7.0Hz,2H),3.39(s,1H),3.24(dd,J=11.1,7.0Hz,2H),2.80(s,3H),1.36(d,J=6.8Hz,6H). 13 C NMR(125MHz,DMSO-d6)δ172.69,172.45,166.15,159.05,134.27,132.00,131.29,131.05,129.62,129.52,128.91,1 27.81,127.68,127.03,125.31,124.41,115.46,113.72,105.66,72.86,57.90,46.88,41.89,26.32,21.93..ESI-MS m / z:482.2

[0298] [M+H] + .

[0299] 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)

[0300]

[0301] The synthesis method of compound A49 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.5Hz,1H),7.99(dd,J=7.4,1.5Hz,1H),7.6 5(d,J=7.5Hz,2H),7.56–7.49(m,2H),7.46(td,J=7.4,1.6Hz,1H),7.34(d,J=2.0Hz,1H),7. 16(dd,J=7.5,2.0Hz,1H),4.44(hept,J=6.8Hz,1H),3.80(dd,J=11.1,7.0Hz,2H),3.61(p,J =6.9Hz,1H),3.39(s,2H),3.22(dd,J=11.1,6.9Hz,2H),3.04(s,6H),1.36(d,J=6.8Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ173.60,172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91, 127.75(d,J=16.2Hz),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] + .

[0302] Example 50 Synthesis of 5-(3-(4-((3-(1H-tetrazolyl-1-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (A50)

[0303]

[0304] The synthesis method of compound A50 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.26(dd,J=7.5,1.6Hz,1H),8.02(dd,J=7.4,1.6Hz,1H),7 .65(dd,J=7.4,1.9Hz,2H),7.56–7.49(m,2H),7.47(td,J=7.4,1.7Hz,1H),7.35(d,J=2.0 Hz,1H),7.16(dd,J=7.4,1.9Hz,1H),4.43(h,J=6.8Hz,1H),3.93(dd,J=11.2,7.0Hz,2H) ,3.78(p,J=7.0Hz,1H),3.39(s,2H),3.20(dd,J=11.1,6.9Hz,2H),1.36(d,J=6.8Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ172.69,166.15,159.05,144.67,134.27,132.00,131.29,131.05,129.62,129.52,128. 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] + .

[0305] Example 51 Synthesis of 3-(4-((3-(1H-tetrazolyl-5-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (A51)

[0306]

[0307] The synthesis method of compound A51 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.27(dd,J=7.3,1.6Hz,1H),8.02(dd,J=7.4,1.6Hz ,1H),7.65(d,J=7.5Hz,1H),7.56–7.43(m,4H),7.24(dd,J=2.0,1.0Hz,1H),6.98( dd,J=7.5,2.0Hz,1H),4.43(h,J=6.9Hz,1H),3.93(dd,J=11.2,7.0Hz,2H),3.78( p,J=7.0Hz,1H),3.39(s,2H),3.20(dd,J=11.2,6.9Hz,2H),1.35(d,J=6.9Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ172.69,166.15,154.72,144.67,132.69,132.00,131.05,129.62,129.52,128.91,127.81,127.68,127.03,126. 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] + .

[0308] Example 52 Synthesis of 3-(4-((3-(1H-tetrazolyl-5-yl)azelaton-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole (A52)

[0309]

[0310] The synthesis method of compound A52 is similar to that of compound A1. 1H NMR (500MHz, Chloroform-d) δ9.83 (s, 1H), 8.31 (dd, J = 7.4, 1.6Hz, 1H), 8.23 ​​(s, 1H), 7. 99(dd,J=7.4,1.6Hz,1H),7.66(d,J=7.5Hz,1H),7.60(t,J=1.6Hz,1H),7.57–7.48(m,3 H),7.46(dd,J=7.5,1.5Hz,1H),7.23–7.15(m,2H),6.66(dd,J=7.4,1.5Hz,1H),5.47(p ,J=7.0Hz,1H),4.02(dd,J=11.2,7.0Hz,2H),3.39(s,2H),3.27(dd,J=11.2,7.0Hz,2H). 13 C NMR (125 MHz, DMSO-d6)δ

[0311] 172.69,166.15,142.71,139.91,132.00,131.05,129.57(d,J=12.4Hz),128.91,127.99–127.58(m),127 .00(d,J=7.6Hz),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] + .

[0312] Example 53 Synthesis of 3-(4-((3-(1H-tetrazolyl-1-yl)azelaton-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-6-yl)-1,2,4-oxadiazole (A53)

[0313]

[0314] The synthesis method of compound A53 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ9.83(s,1H),8.30(dd,J=7.4,1.6Hz,1H),8.03–7.98(m,2H ),7.80(dd,J=7.4,1.5Hz,1H),7.66(d,J=7.5Hz,1H),7.57–7.49(m,2H),7.47(td,J=7.5, 1.7Hz,1H),7.34–7.26(m,2H),7.18(d,J=7.5Hz,1H),6.56(dd,J=7.5,1.6Hz,1H),5.48( p,J=7.0Hz,1H),4.02(dd,J=11.2,7.0Hz,2H),3.39(s,2H),3.28(dd,J=11.2,7.0Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ172.69, 166.15, 142.71, 135.24, 132.00, 131.05, 129.57 (d, J = 12.4Hz), 128.91, 128.65, 127. 74(d,J=15.3Hz),127.03,125.31,125.04,124.41,121.84(d,J=7.7Hz),112.61,102.70,57.90,53.88,50.83.ESI-MS m / z:449.2[M+H] + .

[0315] Example 54 Synthesis of 3-(4-((3-(1H-tetrazolyl-1-yl)azelaton-1-yl)methyl)naphthalen-1-yl)-5-(1H-indol-2-yl)-1,2,4-oxadiazole (A54)

[0316]

[0317] The synthesis method of compound A54 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ9.83(s,1H),9.34(s,1H),8.30(dd,J=7.4,1.6Hz,1H),8.01 (dd,J=7.4,1.6Hz,1H),7.74(dt,J=7.5,1.6Hz,1H),7.67(dd,J=7.4,2.2Hz,2H),7.58–7.5 0(m,2H),7.47(td,J=7.4,1.6Hz,1H),7.19–7.08(m,2H),7.00(td,J=7.4,1.5Hz,1H),5.48 (p,J=7.1Hz,1H),4.02(dd,J=11.2,7.0Hz,2H),3.39(s,2H),3.28(dd,J=11.2,7.0Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ167.59,166.52,142.71,136.46,132.00,131.05,129.57(d,J=12.4Hz),128.91,128.46,127.75(d ,J=16.2Hz),127.03,125.31,124.41,122.50,121.37(d,J=13.3Hz),116.68,111.94,107.96,57.90,53.88,50.83.ESI-MS m / z:449.2[M+H] + .

[0318] Example 55 Synthesis of diethyl (1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-yl)phosphonate (A55)

[0319]

[0320] The synthesis method of compound A55 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.5Hz,1H),7.89(dd,J=7.4,1.5Hz,1H),7.74(dd ,J=9.3,7.5Hz,2H),7.64(d,J=7.5Hz,1H),7.52(td,J=7.4,1.7Hz,1H),7.46(td,J=7.5,1.6Hz,1 H),7.23(d,J=2.1Hz,1H),7.09(dd,J=7.5,2.0Hz,1H),4.43(hept,J=6.8Hz,1H),4.24–4.10(m,6 H),3.39(s,2H),3.19(dd,J=11.2,7.0Hz,2H),2.52(dp,J=11.4,7.0Hz,1H),1.39–1.28(m,12H). 13 C NMR (125MHz, DMSO-d6) δ172.69,166.15,159.05,134.27,132.00,131.29,131.05,129.57(d,J=12.4Hz),128.91,127.75(d,J=16.2Hz),127.03, 125.31,124.41,115.46,113.72,105.66,72.86,62.14(d,J=5.7Hz),57.90(d,J=3.8Hz),47.33(d,J=6.7Hz),21.93,16.52(d,J=5.7Hz).ESI-MS m / z:561.2[M+H] + .

[0321] Example 56 Synthesis of 1-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinolin-8-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A56)

[0322]

[0323] The synthesis method of compound A56 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ9.00(dd,J=7.4,1.6Hz,1H),8.32(dd,J=7.4,1.5Hz,1H) ,7.72(d,J=7.5Hz,1H),7.66–7.60(m,2H),7.56(t,J=7.5Hz,1H),7.46(dd,J=7.5,2.0H z,1H),7.22(d,J=7.4Hz,1H),4.43(hept,J=6.8Hz,1H),3.78(dd,J=11.1,6.9Hz,2H),3 .69(s,2H),3.25(dd,J=11.1,6.9Hz,2H),3.14(p,J=6.9Hz,1H),1.36(d,J=6.8Hz,6H). 13 C NMR (125 MHz, DMSO-d6)δ

[0324] 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] + .

[0325] Example 57 Synthesis of 1-((5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)isoquinolin-8-yl)methyl)azelaic acid-3-carboxylic acid hydrochloric acid (A57)

[0326]

[0327] The synthesis method of compound A57 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.61(d,J=7.5Hz,1H),7.93(d,J=7.5Hz,1H),7.76(d,J=7.5Hz,1H),7.62(d,J=2.1Hz,1H),7.54(d,J=7.5Hz, 1H),7.46(dd,J=7.5,2.0Hz,1H),7.22(d,J=7.5Hz,1H),4.42(h,J=6.9Hz,1H ),3.86–3.76(m,2H),3.23–3.10(m,3H),2.95(s,2H),1.36(d,J=6.8Hz,6H).13 C NMR(125MHz,DMSO-d6)δ177.47,172.69,166.15,159.05,147.57,146.61,134.27,131.73,131.41,131.29,1 30.22,130.09,128.35,123.60,118.14,115.46,113.72,105.66,72.86,57.90,42.88,42.82,21.93.ESI-MS m / z:470.2[M+H] + .

[0328] Example 58 Synthesis of 1-((8-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinoxalin-5-yl)methyl)azepine-3-carboxylic acid hydrochloride (A58)

[0329]

[0330] The synthesis method of compound A58 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ9.06–8.98(m,2H),7.85(d,J=7.5Hz,1H),7.78(d,J=7.5Hz,1H),7.62(d,J=2.0Hz,1H),7.44(dd,J=7.5,2.0Hz ,1H),7.16(d,J=7.4Hz,1H),4.43(hept,J=6.8Hz,1H),3.80(dd,J=10.8,6.6Hz,2H),3.69(s,2H),3.26–3.12(m,3H),1.36(d,J=6.8Hz,6H). 13 C NMR (125MHz, DMSO-d6) δ177.47,172.69,168.74,159.05,139.75,139.30,137.09,134.27,131.29,131. 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] +

[0331] Example 59 Synthesis of 1-((4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A59)

[0332]

[0333] The synthesis method of compound A59 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.3,1.6Hz,1H),7.97(dd,J=7.4,1.6Hz,1H),7.71(dd,J=7.5,1.5Hz,1H), 7.64(d,J=7.5Hz,1H),7.57–7.41(m,4H),7.26(t,J=7.5Hz,1H),3.87–3.76(m,2H),3.39(s,2H),3.23–3.10(m,3H). 13 C NMR(125MHz,DMSO-d6)δ177.47,166.52,166.11,133.15,132.00,131.57,131.05,129.62,129.5 2,128.95,128.91,127.81,127.73,127.68,127.03,125.31,124.41,57.90,42.88,42.82.ESI-MS m / z:392.1[M+H] + .

[0334] Example 60 Synthesis of 1-(4-(5-(4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A60)

[0335]

[0336] The synthesis method of compound A60 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.5Hz,1H),7.98(dd,J=7.4,1.6Hz,1H),7.64(d,J=7.5Hz,1H ),7.55–7.41(m,4H),7.17(d,J=1.5Hz,1H),3.87–3.76(m,2H),3.39(s,2H),3.23–3.10(m,3H),2.29(s,3H). 13C NMR(125MHz,DMSO-d6)δ177.47,166.52,166.13,138.12,133.54,132.00,131.05,129.79,129.62,1 29.52,128.91,127.81,127.68,127.03,125.31,124.41,115.40,57.90,42.88,42.82,15.39.ESI-MS m / z:406.1[M+H] + .

[0337] Example 61 Synthesis of 1-(4-(5-(5-methoxy-4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A61)

[0338]

[0339] The synthesis method of compound A61 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.25(dd,J=7.4,1.5Hz,1H),7.95(dd,J=7.4,1.6Hz,1H),7.64(d,J=7.5Hz,1H),7.55–7.47(m,2H), 7.45(td,J=7.4,1.6Hz,1H),7.23(s,1H),3.87–3.77(m,5H),3.39(s,2H),3.20(d,J=6.9Hz,1H),3.21–3.10(m,2H),2.21(s,3H). 13 C NMR (125MHz, DMSO-d6) δ177.47,166.52,166.20,164.76,136.28,132.00,131.05,129.62,129.52,128. 91,127.81,127.68,127.03,125.31,124.41,105.79,100.40,58.07,57.90,42.88,42.82,12.45.ESI-MS m / z:436.1[M+H] + .

[0340] Example 62 Synthesis of 1-((4-(5-(furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A62)

[0341]

[0342] The synthesis method of compound A62 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.24(dd,J=7.3,1.5Hz,1H),7.98(dd,J=7.3,1.6Hz,1H),7.66–7.59(m,2H),7.54–7 .41(m,3H),6.93(dd,J=7.5,1.5Hz,1H),6.54(t,J=7.5Hz,1H),3.87–3.76(m,2H),3.39(s,2H),3.23–3.10(m,3H). 13 C NMR(125MHz,DMSO-d6)δ177.47,167.71,166.52,147.75,141.74,132.00,131.05,129.62,129.5 2,128.91,127.81,127.68,127.03,125.31,124.41,117.03,112.90,57.90,42.88,42.82.ESI-MS m / z:376.1[M+H] + .

[0343] Example 63 Synthesis of 1-(4-(5-(4-(trifluoromethyl)furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A63)

[0344]

[0345] The synthesis method of compound A63 is similar to that of compound A1. 1 H NMR (500 MHz, Chloroform-d) δ8.23 (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). 13C NMR(125 MHz, DMSO-d6)δ177.47,167.83,166.52,140.16,140.14,137.23,137.20,132.00,131.05,129.62,129.52,128.91,12 7.81,127.68,127.03,125.31,125.14,124.89,124.41,122.84,122.81,119.53,117.39,57.90,42.88,42.82.ESI-MS m / z:444.1[M+H] + .

[0346] Example 64 Synthesis of 1-(4-(5-(4-cyanofuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A64)

[0347]

[0348] The synthesis method of compound A64 is similar to that of compound A1. 1 H NMR (500 MHz, Chloroform-d) δ8.25–8.17(m,2H),7.95(dd,J=7.4,1.6 Hz,1H),7.63(d,J=7.5 Hz,1H),7.51(td,J=7.5,2.0Hz,2H),7.45(td,J=7.4,1.7 Hz,1H),7.07(d,J=1.7 Hz,1H),3.87–3.75(m,2H),3.39(s,2H),3.23–3.10(m,3H). 13 C NMR(125 MHz, DMSO-d6)δ177.47,167.83,166.52,147.02,142.97,132.00,131.05,129.62,129.52,128.9 1,127.81,127.68,127.03,125.31,124.49,124.41,113.54,96.69,57.90,42.88,42.82.ESI-MS m / z:401.1[M+H] + .

[0349] Example 65 Synthesis of 1-(4-(5-(4-isopropoxyfuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A65)

[0350]

[0351] The synthesis method of compound A65 is similar to that of compound A1. 1 H NMR (500 MHz, Chloroform-d) δ8.24 (dd, J = 7.4, 1.5 Hz, 1H), 7.92 (dd, J = 7.3, 1.6 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.50 (td, J = 7.4, 1.5 Hz,2H),7.44(td,J=7.4,1.7 Hz,1H),6.73(d,J=1.5 Hz,1H),6.37(d,J=1.5 Hz,1H),4.45(hept,J=6.9 Hz,1H),3.86–3.74(m,2H),3.39(s,2H),3.23–3.10(m,3H),1.34(d,J=6.9 Hz,6H). 13 C NMR(125 MHz, DMSO-d6)δ177.47,167.83,166.52,152.80,137.02,132.00,131.05,129.62,129.52,128.91,1 27.81,127.68,127.03,125.31,124.41,119.72,112.38,70.83,57.90,42.88,42.82,22.03.ESI-MS m / z:434.2[M+H] + .

[0352] Example 66 Synthesis of 1-((4-(5-([1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloride (A66)

[0353]

[0354] The synthesis method of compound A66 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.29(dd,J=7.4,1.6Hz,1H),7.98(dd,J=7.4,1.6Hz,1H),7.65(d,J=7.5Hz,1H),7.62–7.56(m,2H),7.5 7(s,4H),7.57–7.47(m,2H),7.50–7.40(m,3H),7.33(ddt,J=7.4,5.9,2.0Hz,1H),3.86–3.75(m,2H),3.39(s,2H),3.23–3.10(m,3H). 13C NMR(125MHz,DMSO-d6)δ177.47,173.12,166.15,144.42,139.22,132.00,131.05,129.62,129.52,128.91,12 8.86,127.81,127.71,127.68,127.03,126.99,126.35,125.67,125.31,124.41,57.90,42.88,42.82.ESI-MS m / z:462.2[M+H] + .

[0355] Example 67 Synthesis of 1-(4-(5-(4-(thiophen-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A67)

[0356]

[0357] The synthesis method of compound A67 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.29(dd,J=7.5,1.5Hz,1H),7.97(dd,J=7.4,1.5Hz,1H),7.66(dd,J=7.5,2.6Hz,3H),7.61–7.54(m,2H),7.53(td,J=7.5,1 .6Hz,3H),7.46(td,J=7.4,1.5Hz,1H),7.36(dd,J=7.5,1.7Hz,1H),7.17(t, J=7.5Hz,1H),3.93(dd,J=10.9,6.6Hz,2H),3.39(s,2H),3.44–3.30(m,3H). 13 C NMR(125MHz,DMSO-d6)δ177.47,173.12,166.15,143.09,137.84,132.00,131.05,129.62,129.52,128.91 ,127.81,127.68,127.03,126.75,126.64,125.91,125.42,125.31,124.62,124.41,57.90,42.88.ESI-MS m / z:468.1[M+H] + .

[0358] Example 68 Synthesis of 1-(4-(5-(4-(1H-pyrrol-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A68)

[0359]

[0360] The synthesis method of compound A68 is similar to that of compound A1. 1 H NMR(500MHz,Chloroform-d)δ8.64(s,1H),8.29(dd,J=7.4,1.5Hz,1H),8.00(dd,J=7.4,1.6Hz,1H),7.73–7.67(m,2H),7.65(d,J=7.5Hz,1H),7.60–7.54(m ,2H),7.56–7.43(m,3H),6.90(dd,J=7.4,1.6Hz,1H),6.55(dd,J=7.4,1.6Hz, 1H), 6.33 (t, J = 7.5Hz, 1H), 3.89–3.78 (m, 2H), 3.39 (s, 2H), 3.24–3.12 (m, 3H). 13 C NMR(125MHz,DMSO-d6)δ177.47,173.12,166.15,132.92,132.00,130.34,129.62,129.52,128.91,127.81,12 7.68,127.03,126.97,125.83,125.31,124.41,124.18,120.05,111.35,107.64,57.90,42.88,42.82.ESI-MS m / z:451.2[M+H] + .

[0361] Example 69 Synthesis of 1-(4-(5-(4-(furan-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A69)

[0362]

[0363] The synthesis method of compound A69 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.29(dd,J=7.4,1.5Hz,1H),7.98(dd,J=7.4,1.7Hz,1H),7. 77(dd,J=7.5,1.5Hz,1H),7.66(dd,J=8.8,7.3Hz,3H),7.61–7.55(m,2H),7.56–7.49(m,2 H),7.46(td,J=7.4,1.6Hz,1H),6.89(dd,J=7.5,1.5Hz,1H),6.61(t,J=7.5Hz,1H),3.92( dd,J=11.0,6.8Hz,2H),3.39(s,2H),3.38(dd,J=11.1,6.9Hz,2H),3.31(p,J=6.8Hz,1H). 13 C NMR(125MHz,DMSO-d6)δ177.47,173.12,166.15,152.87,142.41,134.11,132.00,131.05,129.62,129.52,12 8.91,127.81,127.68,127.03,126.79,125.37,125.31,125.23,124.41,109.76,107.76,57.90,42.88.ESI-MS m / z:452.2[M+H] + .

[0364] Example 70 Synthesis of 1-(4-(5-(3-cyano-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azepine-3-carboxylic acid hydrochloric acid (A70)

[0365]

[0366] The synthesis method of compound A70 is similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ8.26(dd,J=7.5,1.6Hz,1H),8.00(dd,J=7.4,1.6Hz,1H),7 .71(d,J=7.5Hz,1H),7.64(d,J=7.5Hz,1H),7.53(td,J=7.4,1.5Hz,1H),7.52–7.43(m,2H ),7.22(d,J=2.1Hz,1H),7.08(dd,J=7.5,2.0Hz,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=11.0,5.2,1.9Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ177.47,172.69,166.15,159.08,134.08,132.00,131.11,131.05,129.62,129.52,128.91,1 27.81,127.68,127.03,125.31,124.41,123.28,115.46,114.09,105.53,81.35,57.90,42.88,32.83,23.82.ESI-MS m / z:495.2[M+H] + .

[0367] Pharmacological Activity Experiment Example

[0368] Experimental Example 1: Testing of Compounds for S1P Receptor Agonist Activity

[0369] Instrument: FLIPR TM TETRA (Molecular Device).

[0370] Experimental materials: CHO-K1 / Gα15 / EDG1 cells independently constructed by GenScript.

[0371] Sample processing: Before the experiment, dilute with GPCR dilution buffer to prepare working solution of corresponding concentration.

[0372] Experimental method: CHO-K1 / Gα15 / EDG1 cells stably expressing EDG1 receptors were cultured in 10 cm culture dishes in a 37°C / 5% CO2 incubator. When the cell confluence reached 80%-85%, digestion was performed, and the collected cell suspension was inoculated into a 384 microplate at an appropriate density, and then placed in a 37°C / 5% CO2 incubator for at least 18 hours for use in the experiment. After 18-20 hours, the cell culture plate was removed, the dye working solution was added, and the cell plate was placed in a 37°C / 5% CO2 incubator for 1 hour, and finally equilibrated at room temperature for 15 minutes. The positive agonist working solution was added during the detection, and the RFU value was detected and recorded. The 384 microplate, cell plate and tip box containing the positive agonist working solution were placed in the FLIPRTM TETRA, and the agonist mode detection program was run. The overall detection time of the instrument was 120 seconds, and the positive agonist working solution was added to the cell culture plate at the 21st second. Place the 384-well microplate, cell plate and pipette tip box containing the positive antagonist working solution into the FLIPRTM TETRA, run the antagonist mode detection program, the overall detection time of the instrument is 120 seconds, and add the positive antagonist working solution into the cell culture plate at the 21st second.

[0373] Data processing: Raw data were obtained by ScreenWorks (version 3.1) and saved in the GenScript computer network system as *FMD files. Data acquisition and analysis were performed using Excel and GraphPad Prism 6 software programs. For each test well, the average fluorescence intensity value from 1 to 20 seconds was used as the baseline, and the maximum fluorescence intensity value from 21 to 120 seconds minus the minimum fluorescence intensity value from 21 to 120 seconds was the relative fluorescence intensity value (△RFU). Based on this value and the following equation, the activation or inhibition percentage can be calculated.

[0374] %Activation rate = (△RFUCompound-△RFUBackground) / (△RFUAgonist control-△RFUBackground) x 100%

[0375] The data were analyzed using a four-parameter equation using GraphPad Prism 6 to calculate EC50 and IC50 values. The four-parameter equation is as follows: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC50 / IC50-X)*HillSlope)), where X is the Log value of the concentration and Y is the inhibition rate.

[0376] Experimental results:

[0377]

[0378]

[0379] Experimental Example 2: Study on subtype selectivity of compound A1

[0380] The selectivity of different subtypes of S1P receptors was tested using the method described in Experimental Example 1. The results showed that compound A1 had good selectivity for different subtypes, especially for S1P1 and S1P5 subtypes, as shown in the following table.

[0381]

[0382] Experimental Example 3: Preliminary evaluation of the pharmacokinetics of Compound A1 in mice

[0383] Dosage regimen

[0384] Nine CD-1 mice, male, weighing 20-26 g, were randomly divided into three groups, with three mice in each group. The test compounds were administered orally, intravenously, and intraperitoneally according to the following scheme.

[0385] The animals were fasted for 12 hours before the experiment and allowed to drink water freely. They were fed 2 hours after the administration.

[0386] There were 3 animals at each time point, and the groups and blood collection time points are shown in the table below.

[0387]

[0388] The solution for oral administration was prepared with DMSO / 0.5% HPMC (5 / 95, v / v) to the final concentration. For intravenous and intraperitoneal administration, it was prepared with DMSO / PEG300 / EtOH / NaCl (5 / 40 / 5 / 50, v / v / v). Samples of the administration solution were kept (50 μL of the drug solution was mixed with 50 μL of DMSO before and after administration) for testing.

[0389] Administer the drug according to the above dosage, record the administration time, and collect 20 μL of blood from the femoral plexus of the mouse at the above set time point and place it in a heparinized test tube. Immediately centrifuge at 11000 rpm for 5 minutes. Immediately accurately draw 10 μL of plasma into a centrifuge tube pre-added with 100 μL of PK-IS solution (prepared with methanol: acetonitrile (1:1, v / v)), mix well, and freeze at -20°C for testing.

[0390] We conducted a pharmacokinetic study on compound A1. The oral exposure of compound A1 was 5071h*ng / mL, the intravenous exposure was 806h*ng / mL, and the intraperitoneal exposure was 7975h*ng / mL. The main pharmacokinetic data are shown in the table below.

[0391] Plasma concentration of A1 in mice after intraperitoneal administration of 20 mg / kg A1 (ng / mL)

[0392]

[0393] BLQ:Below LLOQ(LLOQ=0.3ng / mL)

[0394] Plasma concentration of A1 in mice after oral administration of 2 mg / kg A1 (ng / mL)

[0395]

[0396] BLQ:Below LLOQ(LLOQ=0.3ng / mL)

[0397] Plasma concentration of A1 in mice after intraperitoneal injection of 20 mg / kg A1 (ng / mL)

[0398]

[0399] BLQ:Below LLOQ(LLOQ=0.3ng / mL)

[0400] Experimental Example 4: Preliminary evaluation of the pharmacokinetics of compound A1 (DC411151) in rats

[0401] Experimental Design - Rats

[0402]

[0403]

[0404] The animals were fasted for 12 hours before the experiment and allowed to drink water freely. They were fed 4 hours after the administration.

[0405] Drug preparation:

[0406] The drug was first dissolved with DMSO and Tween80, and then normal saline was added, with the final concentration being 1% DMSO, 2% Tween, and 97% normal saline.

[0407] The intravenous administration was prepared with DMSO / HS15 / normal saline (10 / 10 / 80, v / v / v).

[0408] Sample collection: rat

[0409] Before and after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 (5-minute sampling point was added for the intravenous administration group); 0.2 ml of blood was collected from the posterior ocular venous plexus at the above set time points, placed in an EDTA-K2 test tube, centrifuged at 11,000 rpm for 5 minutes, and the plasma was separated and frozen in a -20°C refrigerator.

[0410] Sample testing: The concentration of DC411151 in plasma was determined by LC-MS / MS.

[0411] Data processing: The pharmacokinetic parameters after drug administration were calculated using the non-compartmental model using WinNonlin 7.0 software (Pharsight, USA).

[0412] Peak time T max and peak concentration C max Use measured values;

[0413] Area under the drug-time curve (AUC) 0-t Value: Calculated using the trapezoidal method; AUC 0-∞ =AUC 0-t +C t / k e , C t is the blood drug concentration at the last measurable time point, k e is the elimination rate constant;

[0414] Elimination half-life 1 / 2 =0.693 / k e ;

[0415] Mean residence time MRT = AUMC / AUC.

[0416] Clearance CL = D / AUC 0-∞ ;

[0417] Steady state volume of distribution V ss =CL×MRT

[0418] Absolute bioavailability F = (AUC 灌胃 ×D 静脉 ) / (AUC 静脉 ×D 灌胃 )×100%

[0419] Test results

[0420] Pharmacokinetic results in rats

[0421] The plasma concentration of the drug after a single intravenous injection of 2 mg / kg DC411151 in rats is shown in Table 1, and the blood concentration-time curve is shown in Figure 1 The corresponding pharmacokinetic parameters are shown in Table 2.

[0422] After intravenous administration to rats, the plasma clearance rate CL of DC411151 in rats was 8.66 mL / min / kg, which was equivalent to 15.7% of the rat liver blood flow (about 55 mL / min / kg), and was a low-clearance drug. The steady-state apparent distribution volume V ss The plasma elimination half-life is 0.758 L / kg, which is equivalent to the total body fluid of rats (about 0.67 L / kg). 1 / 2 The average is 3.04h.

[0423] The plasma concentration of the drug after oral administration of 20 mg / kg DC411151 to rats is shown in Table 3, and the blood drug concentration-time curve is shown in Figure 2 The corresponding pharmacokinetic parameters are shown in Table 4.

[0424] After rats were intragastrically administered with 20 mg / kg DC411151, the peak was reached rapidly, with a peak time of T max 0.5~1h, peak concentration C max The area under the drug concentration-time curve AUC is 2760 ng / mL. 0-t The dose-corrected AUC was 8780 ng·h / mL. 0-t The average value was calculated, and the absolute bioavailability of DC411151 administered orally to rats at a dose of 20 mg / kg was 22.8%.

[0425] Table 1 Plasma drug concentrations after intravenous administration of 2 mg / kg DC411151 in rats

[0426]

[0427]

[0428] Table 2 Pharmacokinetic parameters of DC411151 in rats after intravenous administration of 2 mg / kg

[0429]

[0430] Table 3 Plasma drug concentrations after oral administration of 20 mg / kg DC411151 in rats

[0431]

[0432] Table 4 Pharmacokinetic parameters of rats after oral administration of 20 mg / kg DC411151

[0433]

[0434]

[0435] Experimental Example 5: Preliminary evaluation of the pharmacokinetics of Compound A1 in beagle dogs

[0436] Experimental Design - Beagle Dogs

[0437]

[0438] The animals were fasted for 12 hours before the experiment and allowed to drink water freely. They were fed 4 hours after the administration.

[0439] Drug preparation: The drug was first dissolved in DMSO and Tween80, and then normal saline was added to obtain a final concentration of 1% DMSO, 2% Tween, and 97% normal saline.

[0440] The intravenous administration was prepared with DMSO / HS15 / normal saline (10 / 10 / 80, v / v / v).

[0441] Sample collection: before and 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24 h after administration to dogs (the intravenous and subcutaneous administration groups added a 5-min sampling point); 1 ml of blood was collected from the vein at the above-set time points, placed in an EDTA-K2 test tube, centrifuged at 3500 rpm for 10 min, and the plasma was separated and frozen in a -20°C refrigerator.

[0442] Sample testing: The concentration of DC411151 in plasma was determined by LC-MS / MS.

[0443] Data processing: The pharmacokinetic parameters after drug administration were calculated using the non-compartmental model using WinNonlin 7.0 software (Pharsight, USA).

[0444] Peak time T max and peak concentration C max Use measured values;

[0445] Area under the drug-time curve (AUC) 0-t Value: Calculated using the trapezoidal method; AUC 0-∞ =AUC 0-t +C t / k e , C t is the blood drug concentration at the last measurable time point, k e is the elimination rate constant;

[0446] Elimination half-life 1 / 2 =0.693 / k e ;

[0447] Mean residence time MRT = AUMC / AUC.

[0448] Clearance CL = D / AUC 0-∞;

[0449] Steady state volume of distribution V ss =CL×MRT

[0450] Absolute bioavailability F = (AUC 灌胃 ×D 静脉 ) / (AUC 静脉 ×D 灌胃 )×100%

[0451] Test results

[0452] The plasma concentration of the drug after a single intravenous injection of 0.5 mg / kg DC411151 in beagle dogs is shown in Table 5, and the blood concentration-time curve is shown in Figure 3 The corresponding pharmacokinetic parameters are shown in Table 6.

[0453] After intravenous administration to beagle dogs, the plasma clearance rate CL of DC411151 in dogs was 23.3 mL / min / kg, which is equivalent to 75.2% of the dog liver blood flow (about 31 mL / min / kg), and is a high-clearance drug; the steady-state apparent distribution volume V ss It is 1.28L / kg, which is higher than the total body fluid of dogs (0.6L / kg); the elimination half-life t 1 / 2 It is 0.984h.

[0454] The plasma concentration of the drug after oral administration of 3 mg / kg DC411151 to beagle dogs is shown in Table 7, and the blood drug concentration-time curve is shown in Figure 4 The corresponding pharmacokinetic parameters are shown in Table 8.

[0455] After beagle dogs were gavaged with 3 mg / kg DC411151, the peak time T max 0.25-2h, peak concentration C max The area under the drug concentration-time curve AUC is 366 ng / mL. 0-t The dose-corrected AUC was 1160 ng·h / mL. 0-t The average value was calculated, and the absolute bioavailability of DC411151 was 54.0% after oral administration of 3 mg / kg to beagle dogs.

[0456] Table 5 Plasma drug concentrations in beagle dogs after intravenous administration of 0.5 mg / kg DC411151

[0457]

[0458] Table 6 Pharmacokinetic parameters of DC411151 after intravenous administration of 0.5 mg / kg in beagle dogs

[0459]

[0460] Table 7 Plasma drug concentrations in beagle dogs after oral administration of 3 mg / kg DC411151

[0461]

[0462] Table 8 Pharmacokinetic parameters of beagle dogs after oral administration of 3 mg / kg DC411151

[0463]

[0464] Experimental Example 6 In vivo anti-obesity, insulin resistance, NASH pharmacological activity test

[0465] The non-alcoholic steatohepatitis (NASH) model mice induced by high fat, high cholesterol and high fructose (Gubra amylin, GAN) have a triple phenotype of obesity, insulin resistance and NASH. This experiment used this model to investigate the effects of long-term oral administration of compound A1 on obesity, insulin resistance, hepatic lipid accumulation, inflammation and fibrosis in the NASH state of the mice.

[0466] Animal experiment: Male C57BL / 6 mice were fed with GAN diet to induce NASH model. After 12 weeks of modeling, the mice were randomly divided into 3 groups, namely low-fat diet control group (LFD, n=6), model control group (Model, n=10), and A1 group (10 mg / kg, n=10). The mice were gavaged with a dose of 10 mg / kg and a volume of 10 mL / kg once a day. The food intake and body weight of the animals were monitored during the administration period; after 10 weeks of administration, glucose tolerance test (GTT) and insulin tolerance test (ITT) experiments were performed; after 11 weeks of administration, fasting blood glucose and insulin were measured; after 12 weeks of administration, core body temperature and energy metabolism level were measured; after 15 weeks of administration, the body composition of mice was measured, and the mice were killed by dislocation after blood was taken from the retro-ocular venous plexus. The liver, subcutaneous fat, epididymal fat and brown fat were taken and weighed, and part of the liver was fixed with 4% paraformaldehyde, and all tissues and serum were stored at -80°C. The experiment evaluated whether the compound had a weight-loss effect by detecting the energy metabolism, body composition, and fat weight of mice; evaluated whether the compound had a role in improving insulin resistance by detecting random blood glucose, fasting blood glucose, and fasting insulin through GTT, ITT, and calculating the HOMA-IR index; and evaluated whether the compound had a role in improving insulin resistance by detecting the levels of serum liver function indicators ALT, AST, triglycerides, total cholesterol (T-CHO), LDL-C, and HDL-C, the content of triglycerides, T-CHO, and hydroxyproline (a characteristic amino acid of collagen) in the liver, and the genes related to de novo synthesis and transport of fatty acids in the liver (Srebp1c, Scd1, Fasn, Acaca, Cd36 ), 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) mRNA expression levels and liver pathological changes (H&E staining, Oil Red O staining and Sirius Red staining) were used to evaluate whether the compound has the effect of alleviating lipid metabolism disorders, inflammation and fibrosis under the pathological state of NASH.

[0467] The results of the study showed that the compound A1 of the present invention significantly slowed down the weight gain and reduced the body fat content of mice by improving the energy metabolism and promoting thermogenesis without affecting the food intake of mice. Figure 1 ); A1 significantly reduced fasting blood glucose, insulin and HOMA-IR index, and significantly improved the glucose tolerance and insulin sensitivity of mice ( Figure 2); A1 significantly reduced the liver weight, liver-to-body ratio, serum ALT, AST, triglyceride, T-CHO, LDL-C, HDL-C and liver triglyceride, T-CHO, hydroxyproline levels in NASH mice ( Figure 3 ); at the gene level, A1 significantly upregulated the mRNA expression of fatty acid oxidation-related genes (Ppara, Cyp4A1, Acot1, Acox1), and downregulated the mRNA expression of inflammation-related genes (Tnfa, Il1b, Casp1, Pycard, Ccl2, Ccl3) and fibrosis-related genes (Asma, Tgfb, Col1A1, Col3A1, Col5a2) ( Figure 4 ); in the quantitative analysis of H&E-stained liver pathological sections, A1 significantly reduced NAS scores, significantly alleviated liver ballooning and inflammation, and had an improvement effect on lipid accumulation in the liver, but not significantly ( Figure 5 ); In the quantitative analysis of Oil Red O-stained liver pathological sections, A1 significantly reduced liver lipid accumulation, mainly manifested by a reduction in lipid droplet size ( Figure 5 ); In the quantitative analysis of liver pathological sections stained with Sirius red, A1 significantly reduced liver collagen deposition ( Figure 5 ).

[0468] In summary, long-term administration of test substance A1 can significantly alleviate GAN diet-induced obesity and insulin resistance in mice, improve energy metabolism and insulin sensitivity, improve liver function, promote liver fatty acid oxidation, reduce inflammation and fibrosis, and have a significant alleviating effect on NASH.

[0469] Experimental Example 7 Pharmacological Activity Test of Carbon Tetrachloride (CCl4)-Induced Liver Fibrosis Model

[0470] Male C57BL / 6 mice were intraperitoneally injected with 5mL / kg, 5% CCl4 (dissolved in corn oil) twice a week to induce liver fibrosis model. Three weeks after modeling, the mice were randomly divided into 5 groups, namely model control group (Model, n = 12), positive compound FTY720 group (2mg / kg, n = 9), positive compound OCA group (30mg / kg, n = 10), low-dose group (3mg / kg), and high-dose group (10mg / kg). FTY720 was administered by intraperitoneal injection, and the other groups were administered orally by gavage once a day. After 5 weeks of administration, the mice were killed by dislocation after blood was taken from the retroorbital venous plexus, and the liver and spleen were taken and weighed. Part of the liver was fixed with 4% paraformaldehyde, and part of the liver and serum were stored at -80°C. During the entire experiment, 10 mice from the same litter were intraperitoneally injected with the same dose of corn oil as a system control.

[0471] In the CCl4-induced liver fibrosis model, compound A1 significantly reduced serum ALT levels without affecting the weight of liver and spleen organs ( Figure 6 ); at the gene level, high-dose A1 significantly downregulated the mRNA expression of liver fibrosis-related genes (Tgfb, Col1a1) ( Figure 7 ); Pathological analysis of liver tissue showed that high doses of A1 significantly reduced the hydroxyproline content in the liver, and pathological section analysis results showed that A1 significantly reduced liver collagen deposition ( Figure 8 ).

[0472] Experimental Example 8 Pharmacological Activity Test of NASH Model Induced by Methionine-Choline Deficiency Combined with High-Fat Model Diet (MCD-HFD)

[0473] Male C57BL / 6 mice were fed with MCD-HFD diet to induce NASH model. After 4 weeks of modeling, the mice were randomly divided into 3 groups, namely normal diet control group (Control, n = 9), model control group (Model, n = 10), positive compound BAF312 group (0.3 mg / kg, n = 10), low-dose group (0.3 mg / kg, n = 10), medium-dose group (3 mg / kg, n = 10), and high-dose group (10 mg / kg, n = 10). The mice were gavaged once a day with a volume of 5 mL / kg. During the administration period, the food intake and body weight of the animals were monitored; after 4 weeks of administration, the mice were killed by dislocation after blood was collected from the retroorbital venous plexus, and the liver and spleen were taken and weighed. Part of the liver was fixed with 4% paraformaldehyde, and all tissues and serum were stored at -80 ° C.

[0474] In the NASH model induced by methionine-choline deficiency combined with high-fat diet (MCD-HFD), compound A1 significantly reduced serum ALT and AST levels in the high-dose group without affecting body weight, and significantly alleviated TG accumulation in the liver ( Fig. 9 ); at the gene level, high / medium / low doses of A1 can significantly downregulate the mRNA expression of liver inflammation-related genes (Tnfa, Il1b, Nlrp3, Ccl2) to varying degrees. Analysis of H&E-stained liver pathological sections showed that high doses of A1 can effectively alleviate liver lipid accumulation and inflammatory infiltration ( Fig.10 ); high / medium doses of A1 can effectively alleviate the hydroxyproline content in the liver to varying degrees, and significantly downregulate the expression levels of fibrosis-related genes (Asma, Tgfb, Col1a1) at the gene level ( Fig.11 ).

[0475] Experimental Example 9 Pharmacological Activity Test of IBD Model Induced by Dextran Sulfate Sodium (DSS)

[0476] The mice were randomly divided into 5 groups, namely normal control group (Control, n = 5), model control group (Model, n = 11), positive compound BAF312 group (0.3 mg / kg, n = 10), low-dose group (0.03 mg / kg, n = 10), medium-dose group (0.3 mg / kg, n = 10), and high-dose group (3 mg / kg, n = 10). Each group was gavaged with a volume of 5 mL / kg, once a day. DSS with an average molecular weight of 36000-50000Da was dissolved in drinking water to prepare a 2% DSS solution. The modeling group mice were allowed to drink freely for 6 days, and the modeling and drug treatment were carried out simultaneously. The weight, feces hardness and occult blood of each group of mice were observed every day, and the scores of each index were added to obtain the disease activity index of each animal. After the modeling was completed and the drug was administered for 6 days, the modeling agent was withdrawn for a 1-day relief period, and the mice were killed by dislocation after blood was drawn from the retroorbital venous plexus. The colon tissue and spleen of the mice were taken and their lengths were measured or weighed. Part of the colon was fixed with 4% paraformaldehyde, and all tissues and serum were stored at -80°C.

[0477] In the IBD model induced by dextran sulfate sodium (DSS), high / medium / low doses of A1 can effectively alleviate the disease progression to varying degrees ( Fig.12 ); Analysis of the diseased colon showed that high / medium / low doses of A1 could effectively alleviate the shortening of colon length in IBD mice to varying degrees without affecting spleen weight; analysis of H&E stained colon pathological sections showed that high / medium doses of A1 could effectively improve crypt damage and inflammatory infiltration in the colon ( Fig.13 ).

[0478] In summary, long-term administration of the test substance A1 can significantly alleviate GAN diet-induced obesity and insulin resistance in mice, improve energy metabolism and insulin sensitivity, improve liver function, promote liver fatty acid oxidation, reduce inflammation and fibrosis, and have a significant alleviating effect on NASH. At the same time, it can play an effective alleviating role in the CCl4-induced liver fibrosis model and the MCD-HFD diet-induced NASH model. In addition, the test molecule A1 can also exert significant anti-inflammatory and pathological improvement effects in the IBD model.

[0479] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound as shown in the following formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound has a structure shown in the following formula II: in, M is a substituted C6-C10 aromatic ring, wherein the substitution refers to the substitution of one or more R 1 ' group is substituted; and each R 1 'Each independently selected from the following group: cyano, substituted or unsubstituted C1-C6 alkoxy, wherein the alkoxy is selected from the following group: methoxy, ethoxy, isopropoxy; or M is a substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the aromatic heterocycle is selected from the following group: furanyl, thienyl; wherein the substitution refers to the substitution of one or more R 1 and each R 1 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; wherein the alkoxy is selected from the following group: methoxy, ethoxy, isopropoxy; X is selected from the following group: CHR 2 ; R 2 Selected from the group consisting of: hydrogen; n is 2; R 3 Selected from the following groups: carboxyl, substituted or unsubstituted C2-C10 ester group, substituted or unsubstituted C1-C6 amide group, -C(O)R 5 、-C(O)OR 5 ; R 5 Each is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl; Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CH; R 6 For One or more groups on the ring are selected from the group consisting of: hydrogen; The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, hydroxyl, carboxyl, amino, nitro, and cyano.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: M is selected from the following group: substituted or unsubstituted furanyl, substituted or unsubstituted thienyl; the substitution means that one or more R 1 and each R 1 Each is independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; wherein the alkoxy is selected from the following group: methoxy, ethoxy, isopropoxy.

3. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound has a structure shown in the following formula III: Wherein, X is CH2; M is a substituted or unsubstituted benzene ring; wherein the substitution refers to being replaced by one or more R 1 and each R 1 Each is independently selected from the following group: hydrogen, halogen, cyano, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy; wherein the alkoxy is selected from the following group: methoxy, ethoxy, isopropoxy.

4. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The M has a structure as shown below: in, The A is a benzene ring; Each R 1 Each independently selected from the group consisting of cyano, methoxy, ethoxy, isopropoxy; a is 1, 2 or 3.

5. The compound of formula I according to claim 4, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The A ring is a benzene ring; Each R 1 Each independently selected from the group consisting of cyano, methoxy, ethoxy, isopropoxy; a is 1 or 2.

6. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound is selected from the following group:

7. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound is selected from:

8. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound is selected from:

9. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: The compound is compound A1:

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: one or more of the compound of formula I according to any one of claims 1 to 8, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

11. The use of the compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, characterized in that: Used for preparing a pharmaceutical composition for treating or preventing diseases associated with S1P agonists.

12. The use according to claim 11, characterized in that The disease is selected from the following group: non-alcoholic fatty liver disease, liver fibrosis, diabetes, hyperlipidemia, multiple sclerosis, psoriasis, ulcerative colitis, lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome.

13. The use according to claim 11, characterized in that The disease is selected from the group consisting of relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, and active secondary progressive multiple sclerosis.

14. A method for preparing the compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, characterized in that: Includes steps: (1) reacting the compound of formula Ic with M-COOH, HOBT, EDCI and potassium carbonate in DMF to obtain a 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 methanol / dichloromethane mixed solution, the compound of formula Ia is The hydrochloride of , DIPEA, acetic acid and sodium cyanoborohydride are reacted to obtain a compound of formula I; wherein X is CH.

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