Oxadiazole compound, process for preparation thereof, pharmaceutical composition and use thereof

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to a compound of formula I, a pharmaceutically acceptable salt thereof:wherein the compound has formula IIwhere Y1, Y2, Y3 and Y4 is each independently CH; M is selected from a group consisting of a substituted phenyl ring and a substituted or unsubstituted 5–10 membered aromatic heterocycle containing from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen; where the group substituted in M denotes that the group can be substituted with one or more groups R1; and each R1 is independently selected from a group consisting of hydrogen, halogen, cyano-, unsubstituted or halogenated C1-C6 alkyl, unsubstituted C1-C6 alkoxy group; X is selected from a group consisting of CHR2; R2 is selected from a group consisting of hydrogen; n is 2; R3 is selected from a group consisting of carboxyl, C(O)R5, -C(O)OR5; R5 is selected from the group consisting of an amino group, optionally mono- or disubstituted C1-C6 alkyl, unsubstituted C1-C6 alkyl; R6 is hydrogen, a method for production thereof, a pharmaceutical composition containing said compound, and use thereof as an S1P receptor agonist.EFFECT: obtaining novel compounds which can be used to treat or prevent diseases associated with S1P agonists.9 cl, 13 dwg, 8 tbl, 79 ex

Description

[0001] Technical field

[0002] The invention relates to the field of pharmaceutical chemistry and drug therapy, in particular to a class of oxadiazole compounds, a method for producing them, pharmaceutical compositions containing such compounds as S1P receptor agonists, especially to their use in producing drugs for the treatment of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases.

[0003] Prior Art

[0004] Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that poses a serious public health threat to China. Epidemiological studies show that the prevalence of NAFLD in China has increased sharply from 18% in 2008 to 29.2% in 2018, more than twice the growth rate in Western countries. About 58.9% of patients with biopsy-confirmed NAFLD have non-alcoholic steatohepatitis (NASH). Currently, NAFLD has replaced chronic viral liver disease as the main chronic liver disease in China. By 2030, China is estimated to have the highest incidence growth rate in the world, reaching 314.58 million people. NASH will become a major public health problem in China in the foreseeable future.

[0005] Lipid metabolism is one of the major hepatic metabolic processes. There is growing evidence that triglycerides deposited in hepatocytes are not the primary cause of lipotoxicity and that lowering triglyceride levels alone is ineffective in improving NASH. Therefore, new interventions to improve lipid metabolism abnormalities are urgently needed. Triglycerides are the predominant form of lipid in simple fatty liver disease (SFLD), and approximately 25% of patients with SFLD progress to NASH with a more pronounced lipotoxic phenotype. Reprogramming of the lipid metabolic network may be one of the most important driving factors, but little is known about this. In the past decade, a new understanding of lipid metabolism abnormalities has emerged, and cholesterol, free fatty acids, lysophosphatidylcholine, and sphingolipids have been identified as important lipids causing lipotoxicity.Among them, sphingolipids are a class of lipids containing the sphingosine backbone, and the metabolites ceramide and sphingosine-1-phosphate (S1P) are the two most studied bioactive sphingolipid molecules. In vivo, ceramide is generally synthesized through three pathways: de novo synthesis, hydrolysis by sphingomyelinase, and reductive synthesis, and then acetylated by ceramidase (ceramidase, CDase) to form sphingosine, which is further phosphorylated by sphingosine kinase (sphingosine kinase, SphK) to S1P. Intracellular S1P can function as a second messenger for bioregulation, while S1P secreted extracellularly activates downstream signaling pathways such as PI3K / Akt, Ras / ERK, Rho, Rac, etc. via five cell surface G protein-coupled receptors (GPCRs), S1P receptors 1-5 (S1PR1-5), causing a number of biological effects such as cell survival, proliferation, differentiation and migration.The five isoforms are distributed differently in each tissue. S1PR1, S1PR2, and S1PR3 are widely expressed in many tissues, including the liver, while S1PR4 is widely expressed in lymphoid and lung tissues, and S1PR5 is expressed in the brain and skin, thus performing diverse functions. Normal S1P levels are involved in a variety of vital physiological processes, such as cell growth, survival, and migration, as well as vascular formation and maturation. However, excess S1P can also cause a variety of pathological changes, including inflammation and fibrosis, two pathological processes closely associated with the progression of NASH.Clinical trial data have shown that in vivo sphingolipid levels show a positive correlation with NAFLD progression, particularly with hepatic ceramide and S1P levels, which increase dramatically with NASH progression, and that reducing ceramide levels or modulating downstream S1P signaling pathways may ameliorate metabolic disease.

[0006] Intrinsic immune activation is a key factor in triggering and amplifying liver inflammation, which plays a central role in promoting the transition from simple fatty liver disease to NASH. Kupffer cells (KCs) are macrophages located in the hepatic sinusoids, accounting for 20-35% of all non-parenchymal liver cells and the most important cell class in the liver's intrinsic immune system. Cytokines released by Kupffer cells can mediate an inflammatory cascade response, induce hepatocyte death and lipid degeneration, and promote the activation of hepatic stellate cells (HSCs). HSCs are the primary source of extracellular matrix and play a key role in the development of liver fibrosis. Upon activation, HSCs differentiate into myofibroblast-like cells that exhibit contractile, pro-inflammatory, and pro-fibrotic properties.S1P can accelerate the progression of NASH by targeting S1PR1 and S1PR3 on the surface of liver macrophages, initiating an intrinsic immune response. S1P can also directly induce the activation, proliferation, and contraction of HSCs by targeting S1PR1-3 on the surface of HSCs and promoting extracellular matrix secretion. [8] Studies have shown that regulating S1PR1 and S1PR3 activity in mice using drugs or gene knockouts can effectively alleviate the progression of inflammation and fibrosis in various liver disease models. Thus, S1P receptors represent a promising new target for the treatment of metabolic disorders such as NASH. In particular, they are a new target for the treatment of type 2 diabetes mellitus with a phenotype characterized by fasting hyperglycemia.

[0007] In summary, there is a pressing need in this field to develop more S1P receptor regulators.

[0008] SUMMARY OF THE INVENTION

[0009] The object of the present invention is to provide an S1P receptor agonist.

[0010] The first aspect of the present invention relates to a compound represented by formula I, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixture thereof:

[0011]

[0012] where:

[0013] M is selected from the group consisting of 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 from 1 to 8 heteroatoms, substituted or unsubstituted 9-12-membered aromatic condensed ring, substituted or unsubstituted C6-C10 aromatic ring (preferably benzene ring) and substituted or unsubstituted 5-12-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; where the group substituted in M ​​means that the group may be substituted by one or more R groups 1 ; And

[0014] each R 1independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde group, substituted or unsubstituted guanyl, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), substituted or unsubstituted C1-C6 alkoxy group, 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 ester, substituted or unsubstituted C1-C6 amide, -OSO2R 4 , -OCOR 4 and SO2R 4 ;

[0015] X is selected from the group consisting of: CHR 2 , NR 2 , O and S;

[0016] R 2selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde group, substituted or unsubstituted guanyl, substituted or unsubstituted guanidine, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group, 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 and -COR 5 ;

[0017] R and R' are independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-12-membered saturated aliphatic ring; or R, R' and the N atom to which they are bonded together form the following structure:

[0018]

[0019] n - 1, 2, 3, 4, 5, 6 or 7;

[0020] R 3 selected from the group consisting of: carboxyl, sulfonic acid group (-SO2H), phosphate group (-PO3H), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 aryl ester, substituted or unsubstituted C1-C6 amide, -OSO2R 5 , -OCOR 5 , -C(O)R 5 ,-C(O)OR 5 ,-SO2R 5 and -PO(OR 5 )2;

[0021] ring B is selected from the group consisting of: a 5-10-membered saturated or unsaturated carbon ring, a 5-10-membered saturated or unsaturated heterocycle; wherein the heterocycle has one or more N atoms as a ring member;

[0022] R 4 and R 5 independently selected from the group consisting of: hydrogen, deuterium, tritium, amino, hydroxyl group, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl containing 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 and substituted or unsubstituted C1-C6 amide;

[0023] R 6 represents one or more groups in a ring , and is selected from the group consisting of: hydrogen, deuterium, tritium, substituted or unsubstituted C1-C6 alkyl;

[0024] where substituted means one or more hydrogen atoms in a group substituted by a substituent selected from the group consisting of: halogen, hydroxyl, carboxyl, benzyl, C1-C6 alkoxycarbonyl, amino, C1-C6 amido, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy group, C1-C6 alkylamine, C6-C 10 aryl, five-membered or six-membered heteroaryl, -O-(C6-C 10 aryl) and -O-(five-membered or six-membered heteroaryl).

[0025] In another preferred embodiment, the compound has a structure represented by formula II:

[0026]

[0027] where:

[0028] Y 1 , Y 2 , Y 3 and Y 4 independently selected from N or CH, and when Y 1 , Y 2 , Y3 or Y 4 are CH, CH can be replaced by R 6 .

[0029] In another preferred embodiment, the compound has a structure represented by formula III:

[0030]

[0031] where X is CHR 2 .

[0032] In another preferred embodiment, M has a structure represented by the following formula:

[0033]

[0034] where:

[0035] A is selected from the group consisting of: 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) and a substituted or unsubstituted 5-12-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

[0036] each R 1independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl containing 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 ester, substituted or unsubstituted C1-C6 amide, -OSO2R 4 , -OCOR 4 and SO2R 4 ;

[0037] a - 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0038] In another preferred embodiment, ring A is selected from the group consisting of: 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 from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a substituted or unsubstituted partially unsaturated 5-10-membered heterocycle containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0039] every R 1independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, aldehyde, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl containing 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 ester, substituted or unsubstituted C1-C6 amide, -OSO2R 4 , -OCOR 4 and SO2R 4 ;

[0040] а - 1, 2, 3, 4 or 5.

[0041] In another preferred embodiment, the compound is a compound from the various examples of the present invention.

[0042] The second aspect of the present invention relates to a pharmaceutical composition comprising one or more compounds of formula I according to the first aspect of the present invention, their pharmaceutically acceptable salts, racemate, R-isomers, S-isomers or a mixture thereof and one or more pharmaceutically acceptable carriers, excipients, adjuvants, ingredients and / or diluents.

[0043] The third aspect of the present invention relates to the use of a compound of formula I according to the first aspect of the present invention, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixture thereof, in the preparation of a pharmaceutical composition for the treatment or prevention of diseases associated with S1P agonists.

[0044] In another preferred embodiment, the disease is selected from the group consisting of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease and clinically isolated syndrome.

[0045] The fourth aspect of the present invention relates to a method for producing a compound of formula I according to the first aspect of the present invention, a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, comprising the following steps:

[0046]

[0047] (1) reacting a compound of formula Ic with M-COOH, HOBT, EDCI and potassium carbonate in DMF to obtain a compound of formula Ib;

[0048] (2) reacting a compound of formula Ib in a mixture of acetone / diluted hydrochloric acid to obtain a compound of formula Ia;

[0049] (3) reaction of the compound of formula Ia with the hydrochloride , DIPEA, acetic acid and sodium cyanoborohydride in a methanol / dichloromethane mixture to give a compound of formula I; where X is CH.

[0050] It should be understood that, within the scope of the present invention, the above-mentioned technical characteristics of the present invention and the technical characteristics specifically described below (e.g., embodiments) can be combined with each other to form a new or preferable technical solution. Due to space limitations, this will not be repeated here.

[0051] DESCRIPTION OF DRAWINGS

[0052] Figure 1: Compound A1 alleviated the symptoms of obesity in GAN diet-induced NASH mice model; (A) Body weight; (B) Food intake; (C) Body fat content; (D) Fat to lean mass ratio; (E) Subcutaneous fat mass (sWAT), Epididymal fat mass (eWAT), and Brown fat mass (BAT); (F) Body temperature; (G) Oxygen consumption; (H) Carbon dioxide production; and (I) Energy expenditure. When comparing the LD group with the model group, # P < 0.05, ### P < 0.005; when comparing the A1 group with the model group, * P < 0.05, ** P < 0.05, *** P < 0.005.

[0053] Figure 2: Compound A1 alleviated the symptoms of insulin resistance in GAN diet-induced NASH mouse model; (A) Fasting blood glucose level; (B) Fasting insulin level; (C) HOMA-IR index; (D) GTT; (E) Area under the curve of GTT; (F) ITT; (G) Area under the curve of ITT. When comparing the LD group with the model group, # P < 0.05, ## P < 0.01, ### P < 0.005; when comparing the A1 group with the model group, * P < 0.05, ** P < 0.05, *** P < 0.005.

[0054] Figure 3: Compound A1 improved the serological and liver biochemical indices in the GAN diet-induced NASH model of mice; (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.

[0055] Figure 4: Compound A1 improved liver lipid metabolism abnormalities, inflammation and fibrosis in GAN diet-induced NASH mice model; (A) mRNA expression of genes related to ab initio fatty acid synthesis, transport and β-oxidative 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.

[0056] Figure 5: Histopathological examination for compound A1 showed improvement in GAN diet-induced NASH model in mice; (A) H&E staining, Oil Red O staining and Sirius Scarlet staining of liver tissue; (B) NAS score; (C) quantitative results of Oil Red O staining of liver tissue; (D) quantitative results of Sirius Scarlet staining of liver tissue; *P < 0.05, **P < 0.05, ***P < 0.005.

[0057] Figure 6: Compound A1 decreased the serum ALT level in 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;

[0058] Figure 7: High doses of compound A1 suppressed the mRNA expression of liver fibrosis-related genes (Tgfb, Col1a1) at the gene level; (A) relative mRNA expression of Tgfb; (B) relative mRNA expression of Col1a1; *P < 0.05, **P < 0.05, ***P < 0.005.

[0059] Figure 8: Pathological section analysis of high dose compound A1 reducing liver hydroxyproline content; (A) Liver hydroxyproline concentration; (B) Sirius Red staining area proportion; (C) Pathological section; *P < 0.05, **P < 0.05, ***P < 0.005.

[0060] Figure 9: Compound A1 decreased the serum ALT and AST levels in the methionine-choline-deficient high-fat diet (MCD-HFD)-induced NASH model, while significantly reducing the accumulation of TG 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.

[0061] Figure 10: Compound A1 reduced liver lipid accumulation and inflammatory infiltration at high / medium / low doses; (A) Relative gene expression; (C) H&E-stained pathological liver sections; *P < 0.05, **P < 0.05, ***P < 0.005.

[0062] Figure 11: High / medium doses of compound A1 decreased liver hydroxyproline content and suppressed the expression levels of fibrosis-related genes (Asma, Tgfb, Col1a1) at the gene level; (A) liver hydroxyproline content; (B) relative gene expression of Asma, Tgfb, Col1a1; *P < 0.05, **P < 0.05, ***P < 0.005.

[0063] Figure 12: High / medium / low doses of compound A1 alleviated the pathological process in sodium dextran sulfate (DSS)-induced inflammatory bowel disease (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.

[0064] Figure 13: Effect of high / medium / low doses of compound A1 in sodium dextran sulfate (DSS)-induced inflammatory bowel disease (IBD) model; (A) Colonic lesion; (B) Colon length; (C) Rectal weight; (D) Colonic abnormal section; *P < 0.05, **P < 0.05, ***P < 0.005.

[0065] DETAILED DESCRIPTION OF THE IMPLEMENTATION

[0066] The inventors of the present invention, after long-term and intensive study, have discovered an oxadiazole compound represented by the general formula I, a pharmaceutically acceptable salt thereof, a racemate, an R-isomer, an S-isomer, or a mixture thereof. The compound is an S1P receptor agonist, so it can be used to prepare compositions and treat indications associated with S1P receptor agonists (e.g., non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, etc.). The present invention has been made on this basis.

[0067] Terms

[0068] In the present invention, the halogen is F, Cl, Br or I.

[0069] In the present invention, unless otherwise specified, the terms used have a general meaning well known to those skilled in the art.

[0070] In the present invention, the term "C1-C6 alkyl" refers to a linear or branched alkyl having from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0071] In the present invention, the term “C1-C6 alkoxy group” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, etc.

[0072] In the present invention, the term “C2-C6 alkenyl” refers to a linear or branched alkenyl having 2 to 6 carbon atoms and containing one double bond, including, but not limited to, vinyl, propenyl, butenyl, isobutyl, pentenyl, hexenyl, etc.

[0073] In the present invention, the term “C2-C6 alkynyl” refers to a linear or branched alkynyl having 2 to 6 carbon atoms and a triple bond, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, etc.

[0074] In the present invention, the term “C3-C10 cycloalkyl” refers to a cyclic alkyl having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl. The terms “C3-C8 cycloalkyl”, “C3-C7 cycloalkyl” and “C3-C6 cycloalkyl” have similar meanings.

[0075] In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl having 3 to 10 carbon atoms in a ring, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecylenyl, etc. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0076] In the present invention, the terms “aromatic ring” or “aryl” have the same meaning, and “aryl” preferably means “C6-C12 aryl” or “C6-C10 aryl”. The term “C6-C12 aryl” refers to an aromatic ring group having 6 to 12 carbon atoms and not containing heteroatoms in the ring, such as phenyl, naphthyl, etc. The term “C6-C10 aryl” has a similar meaning.

[0077] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. The heteroatoms mentioned herein include oxygen, sulfur, and nitrogen. For example, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidine, pyrazine, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused with an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring bound to the parent structure is a heteroaryl ring. Heteroaryl can be optionally substituted or unsubstituted.

[0078] In the present invention, the term "3- to 12-membered heterocyclyl" refers to a saturated or unsaturated 3- to 12-membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen in the ring, for example, dioxacyclopentyl. The term "3- to 7-membered heterocyclyl" has a similar meaning.

[0079] In the present invention, the term "substituted" means that one or more hydrogen atoms in a particular group are replaced by a particular substituent. Specific substituents are those described above or substituents that appear in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any of the substituted sites of the group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocycloalkyl, can be attached to another ring, such as cycloalkyl, to form a spirobicyclic system, for example, two rings sharing a carbon atom. Those skilled in the art will understand that the combinations of substituents provided by the present invention are stable or chemically achievable.Substituents are, for example, but not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde group, C2-10 acyl, C2-10 ester, amino, alkoxy group, C1-10 sulfonyl, etc.

[0080] Oxadiazole Compounds as S1P Receptor Agonists

[0081] Based on the objective of the present invention, the present invention relates to an oxadiazole compound represented by formula I, its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or a mixture thereof:

[0082] Formula I

[0083]

[0084] where:

[0085] A is selected from the group consisting of: 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) and a substituted or unsubstituted 5-12-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; wherein the substituted naphthalene ring, the substituted benzene ring or the substituted aromatic heterocycle each include from 1 to 7 substituents;

[0086] every R 1independently selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, aldehyde group, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl containing 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group (including cyclic and chain alkoxy groups), 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 ester, substituted or unsubstituted C1-C6 amide, -OSO2R 4 , -OCOR 4 and SO2R 4 ;

[0087] a - 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 (naphthyl, cyclohexyl, etc. may be polysubstituted);

[0088] R 2 selected from the group consisting of: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, aldehyde group, substituted or unsubstituted guanyl, substituted or unsubstituted guanidine, substituted or unsubstituted C1-C6 alkyl (including trifluoromethyl), C1-C3 alkyl substituted with 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group, 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 and -COR 5 ;

[0089] n - 1, 2, 3, 4, 5, 6 or 7;

[0090] R 3is a carboxyl, a sulfonic acid group, a phosphate, a substituted or unsubstituted C3-C12 cycloalkyl, a substituted or unsubstituted C2-C10 acyl, a substituted or unsubstituted C2-C10 ester, a substituted or unsubstituted C2-C10 aryl ester, a substituted or unsubstituted C1-C6 amide, -OSO2R 5 , -OCOR 5 , -C(O)R 5 ,-C(O)OR 5 ,-SO2R 5 or -PO(OR 5 )2;

[0091] In a more preferred embodiment of the present invention, the compound of formula I of the present invention is preferably the following specific compound:

[0092] № Name Structure A1 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A2 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloride A3 ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)proline hydrochloride A4 (cis)-3-(((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)cyclobutane-1-carboxylic acid hydrochloride A5 N-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N-methylglycine hydrochloride A6 ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)alanine hydrochloride A7 ((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)glycine hydrochloride A8 3-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)propionic acid hydrochloride A9 2-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)amino)malonic acid hydrochloride A10 1-((4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A11 1-((4-(5-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A12 1-((4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A13 1-((4-(5-(4-isopropoxy-3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A14 1-((4-(5-(4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A15 1-((4-(5-(4-(tert-butoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A16 1-((4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A17 1-((4-(5-(4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A18 1-((4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A19 1-((4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A20 1-((4-(5-(4-isopropylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A21 1-((4-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A22 1-((4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A23 1-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A24 1-((4-(5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A25 1-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A26 1-((4-(5-phenyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A27 1-((4-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A28 1-((4-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A29 1-((4-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A30 1-((4-(5-(5-methylisothiazol-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A31 1-((4-(5-(5-(benzo[d][1,3]dioxazol-5-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A32 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 A33 1-((4-(5-(quinolin-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A34 1-((4-(5-(quinoxalin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A35 1-((4-(5-(1H-indol-5-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A36 1-((4-(5-(1H-indol-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A37 1-((4-(5-(1-methyl-1H-indol-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A38 (E)-1-((4-(5-styryl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A39 1-((4-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A40 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-4-carboxylic acid hydrochloride A41 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-3-carboxylic acid hydrochloride A42 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)piperidine-3,4-carboxylic acid hydrochloride A43 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)pyrrolidine-3-sulfonic acid A44 Methyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A45 Ethyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A46 Isopropyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A47 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxamide A48 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N-methylazetidine-3-formamide A49 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N,N-dimethylazetidine-3-formamide A50 -(3-(3-(3-(1H-tetrazol-5-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile A51 3-(4-(3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalen-1-yl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole A52 3-(4-(3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole A53 3-(4-(3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-6-yl)-1,2,4-oxadiazole A54 3-(4-(3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-2-yl)-1,2,4-oxadiazole A55 Diethyl (1-(4-(5-(3-cyano-4-isopropoxyphenyl))-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-yl)phosphonate A56 1-((5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)isoquinolin-8-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A57 1-((5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)isoquinolin-8-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A58 1-((8-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinoxalin-5-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A59 1-((4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A60 1-((4-(5-(4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A61 1-((4-(5-(5-methoxy-4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A62 1-((4-(5-(furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A63 1-((4-(5-(4-(trifluoromethyl)furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A64 1-((4-(5-(4-cyanofuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A65 1-((4-(5-(4-isopropoxyfuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A66 1-((4-(5-([1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A67 1-((4-(5-([1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A68 1-((4-(4-(4-(1H-pyrrol-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A69 1-((4-(5-(4-(furan-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A70 1-((4-(5-(3-cyano-4-(cyclopentyloxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride

[0093] The compounds of the present invention have asymmetric centers, chiral axes, and chiral planes, and can also exist as racemates, R-isomers, or S-isomers. Those skilled in the art can use standard technical means to obtain the R-isomer and / or S-isomer from the racemate.

[0094] The invention provides a pharmaceutically acceptable salt of a compound of general formula I, in particular, the compound of general formula I is reacted with an inorganic or organic acid to form a conventional pharmaceutically acceptable salt. For example, conventional medicinal salts can be obtained by reacting a compound of general formula I with an inorganic acid or an organic acid, wherein inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, etc., and the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid; or may be a sodium salt, a potassium salt, a calcium salt, an aluminum salt or an ammonium salt formed by a compound of general formula I and an inorganic base; or a methylamine salt, an ethylamine salt or an ethanolamine salt formed by a compound of general formula I and an organic base.

[0095] The compounds of the present invention can be used to prepare pharmaceutical compositions containing a therapeutically effective amount of one or more compounds selected from the group consisting of oxadiazole compounds of formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers, or a mixture thereof. The pharmaceutical composition can be used to treat non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome, and other diseases.

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

[0097] Preparation of oxadiazole compounds

[0098] Another aspect of the present invention relates to a method for producing a compound represented by general formula I, which is carried out as follows.

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

[0100] Scheme:

[0101]

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

[0103] Step b: Dissolve compound 1-2 (1 equiv.) in an appropriate amount of dimethylformamide, add copper cyanide (3 equiv.), and stir at 130°C to allow the reaction to proceed overnight;

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

[0105] Step d: Dissolve compound 1-4 (1 equiv.) in an appropriate amount of 50% aqueous acetic acid solution, add hexamethylenetetramine (2 equiv.) portionwise with stirring, heat under reflux for 6 hours, add 3 ml of concentrated hydrochloric acid dropwise, and continue heating under reflux for half an hour;

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

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

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

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

[0110] Step i: Dissolve intermediate 1-9 (1 equiv.) in an appropriate amount of methanol / dichloromethane (1:1) mixture, add 1.1 equiv. of the appropriate amine hydrochloride, DIPEA (1.1 equiv.), acetic acid (2 equiv.) and sodium cyanoborohydride (1 equiv.) sequentially, and stir overnight at room temperature;

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

[0112] Pharmaceutical composition and its preparation

[0113] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I, their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates and, optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, ingredients and / or diluents. Excipients include, for example, fragrances, flavorings, sweeteners, etc.

[0114] The pharmaceutical composition of the present invention preferably contains the active substance in a weight ratio of 1 to 99%, and the preferred ratio is that the compound of formula I as the active substance accounts for 65% (by weight) to 99% (by weight) of the total weight, and the rest is a pharmaceutically acceptable carrier, diluent or solvent, or a salt solution.

[0115] The compounds and pharmaceutical compositions of the present invention can be presented in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and can be in a suitable solid or liquid carrier or diluent and in a suitable sterile injection or instillation device.

[0116] Various dosage forms of the pharmaceutical composition of the present invention can be prepared in accordance with standard pharmaceutical preparation methods. A unit dosage form contains 1-700 mg of the compound of Formula I, preferably 25-300 mg of the compound of Formula I.

[0117] The compounds and pharmaceutical compositions of the present invention can be used in clinical practice in mammals, including humans and animals, and can be administered orally, nasally, through the skin, lungs, gastrointestinal tract, etc. Oral administration is the best choice. The most preferred daily dose is 50-1400 mg / kg body weight in a single dose or 25-700 mg / kg body weight in divided doses. Regardless of the route of administration, the optimal dose for a specific patient should be based on the specific treatment. Typically, it is started with a small dose and gradually increased until the most suitable dose is found.

[0118] The present invention also relates to an S1P receptor agonist comprising one or more compounds selected from the group consisting of compounds of the above formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, ingredients and / or diluents.

[0119] The compounds and compositions of the present invention are used for the treatment and prevention of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases, which include, but are not limited to, various types of diabetes, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis, etc.

[0120] Thus, another aspect of the present invention relates to the use of compounds of general formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof for the treatment of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis) associated with S1P agonists, psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases, for example, the use of drugs for various types of diabetes mellitus, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis and other diseases.

[0121] Another aspect of the present invention relates to the treatment of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis (including relapsing multiple sclerosis, relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis), psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease, clinically isolated syndrome and other diseases associated with metabolic disorders and autoimmune diseases, such as a method for treating various types of diabetes, hyperlipidemia, non-alcoholic fatty liver disease, liver fibrosis, multiple sclerosis and other diseases, comprising administering to a patient in need of such treatment one or more compounds selected from the group consisting of a compound of formula I, pharmaceutically acceptable salts thereof,racemates, R-isomers, S-isomers or mixtures thereof,

[0122] The present invention is further described below, along with specific embodiments. It should be understood that these examples are intended to illustrate the invention only and are not intended to limit its scope. The following embodiments do not specify specific experimental procedure conditions; standard conditions or those recommended by the manufacturer are generally used. Percentages and portions are calculated by weight unless otherwise specified.

[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, NBS (39.16 g, 220.00 mmol) was added portionwise, and the mixture was stirred at 40 °C for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography to give the target compound (43.20 g), yield 98%. 1 H NMR (500 MHz, CDCl3), δ 8.24-8.17 (m, 1H), 7.94-7.86 (m, 1H), 7.63 (d,J= 8.4 Hz, 1H), 7.57-7.47 (m, 2H), 7.20-7.14 (m, 1H), 2.70 (d,J= 1.1 Hz, 3H).

[0128] Synthesis of 4-methyl-1-naphtonitrile

[0129]

[0130] The intermediate product 1-bromo-4-methylnaphthalene (44.00 g, 199.01 mmol) was dissolved in 400 ml of dimethylformamide, copper cyanide (53.47 g, 597.02 mmol) was added, and the mixture was stirred at 130 °C to allow the reaction to proceed overnight. After the reaction was completed according to TLC, the mixture was cooled to room temperature, 300 ml of dichloromethane was added, the mixture was stirred at room temperature for 1 hour, and filtered under reduced pressure. The filtrate was washed three times with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give the title compound (18.21 g), yield 55%. 1 H NMR (500 MHz, CDCl3), δ 8.21-8.15 (m, 1H), 7.98-7.89 (m, 1H), 7.78 (d,J= 8.4 Hz, 1H), 7.64-7.54 (m, 2H), 7.43 (dq,J= 8.3, 1.1 Hz, 1H), 2.69 (d,J= 1.1 Hz, 3H).

[0131] Synthesis of 4-(bromomethyl)-1-naphtonitrile

[0132]

[0133] The intermediate product 4-methyl-1-naphthonitrile (16.00 g, 95.69 mmol) was dissolved in 200 mL of carbon tetrachloride, NBS (20.44 g, 114.82 mmol) and BPO (2.16 g, 9.57 mmol) were added, and the mixture was heated under reflux overnight. After the reaction was complete according to TLC, the mixture was cooled to room temperature and filtered under reduced pressure. The filtrate was washed successively with saturated sodium hydrogen carbonate solution, water, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give the title compound (13.00 g), yield 55%. 1 H NMR (500 MHz, CDCl3), δ 8.23-8.17 (m, 1H), 8.09-8.03 (m, 1H), 7.82 (d,J= 8.4 Hz, 1H), 7.62-7.53 (m, 2H), 7.48 (d,J= 8.4 Hz, 1H), 4.55 (s, 2H).

[0134] Synthesis of 4-formyl-1-naphtonitrile

[0135]

[0136] The intermediate product 4-(bromomethyl)-1-naphthonitrile (13.00 g, 52.82 mmol) was dissolved in 50% aqueous acetic acid solution (200 ml), hexamethylenetetramine (14.81 g, 105.65 mmol) was added portionwise with stirring, heated under reflux for 6 hours, then 3 ml of concentrated hydrochloric acid was added dropwise and heated under reflux for half an hour. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure to remove excess acetic acid, and extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give the title compound (5.5 g), yield 57%. 1 H NMR (500 MHz, CDCl3), δ 9.99 (s, 1H), 8.28-8.22 (m, 1H), 8.12 (dd,J= 8.4, 1.4 Hz, 1H), 7.97-7.89 (m, 2H), 7.67 (td,J= 7.8, 1.4 Hz, 1H), 7.61 (td,J= 8.0, 1.3 Hz, 1H).

[0137] Synthesis of 4-(1,3-dioxolan-2-yl)-1-naphtonitrile

[0138]

[0139] The intermediate product 4-formyl-1-naphthonitrile (3.00 g, 16.56 mmol) was dissolved in 50 ml of toluene, 2.8 ml of ethylene glycol and p-toluenesulfonic acid (0.29 g, 1.66 mmol) were added successively, a water separator was installed, and the mixture was heated under reflux for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and separated by column chromatography to give the target compound (3.51 g), yield 91%. 1 H NMR (500 MHz, CDCl3), δ 8.25-8.19 (m, 1H), 8.03-7.97 (m, 1H), 7.84 (d,J= 8.4 Hz, 1H), 7.77 (d,J= 8.4 Hz, 1H), 7.65-7.55 (m, 2H), 6.09 (s, 1H), 4.16-4.02 (m, 4H).

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

[0141]

[0142] The intermediates 4-(1,3-dioxolan-2-yl)-1-naphthonitrile (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 completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and directly used for the next reaction without purification. Electrospray ionization mass spectrometry, m / z: 259.1 [M+H] + .

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

[0144]

[0145] The intermediate product (Z)-4-(1,3-dioxan-2-yl)-N'-hydroxy-1-naphthamidine obtained in the previous step was dissolved in 50 mL of DMF, 1.1 equivalents of benzoic acid, 1 equivalent of HOBT, 1 equivalent of EDCI, and 1.5 equivalents of potassium carbonate were added successively, and the mixture was heated at 90°C to react overnight. After completion of the reaction, 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 give the target compound. 1 H NMR (500 MHz, CDCl3), δ 8.02-7.90 (m, 4H), 7.89-7.80 (m, 6H), 7.68 (dd, J= 8.4, 1.8 Hz, 2H), 7.52-7.43 (m, 5H), 7.42 (s, 1H), 5.97 (s, 2H), 4.54 (hept, J= 6.2 Hz, 2H), 4.17-4.03 (m, 8H), 1.36 (d, J= 6.2 Hz, 11H). Electrospray ionization mass spectrometry, 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 product 5-(4-(4-(1,3-dioxolan-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, 20 ml of dilute hydrochloric acid was added, and the mixture was heated and stirred at 45 °C for 4 hours. After completion of the reaction, 40 ml of distilled water was added, the filter residue was washed several times with distilled water and dried to give the target compound (1.77 g), yield 95%. 1 H NMR (500 MHz, CDCl3), δ 8.13 (d, J = 8.4 Hz, 1H), 8.04-7.94 (m, 3H), 7.88 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.60-7.49 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 4.57 (hept, J = 6.2 Hz, 1H), 1.35 (d, J = 6.2 Hz, 6H). Electrospray ionization mass spectrometry, m / z: 384.1 [M+H] + .

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

[0150]

[0151] The intermediate product 5-(5-(4-formylnaphthalen-1-yl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.40 g, 1.04 mmol) was dissolved in 20 mL of methanol / dichloromethane (1:1), 1.1 equiv. of the corresponding amine hydrochloride, 1.1 equiv. of DIPEA, 2 equiv. of acetic acid, and 1 equiv. of sodium cyanoborohydride were added sequentially, and stirred overnight at room temperature. After completion of the reaction, an appropriate amount of saturated ammonium chloride solution was added, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3), δ 7.96-7.85 (m, 3H), 7.73-7.64 (m, 2H), 7.51 (d,J=8.4 Hz, 1H), 7.48-7.40 (m, 3H), 4.56 (hept,J=1.2Hz), H 3.75 (s, 2H), 3.66 (s, 3H), 3.49 (dd,J= 9.0, 5.8 Hz, 2H), 3.19 (dd,J= 9.0, 5.8 Hz, 2H), 3.03 (p,J= 5.8 Hz, 1H, 1,35Hz), 6,J= 6.2Hz. Electrospray ionization mass spectrometry,m / z: 483.1 [M+H] + .

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

[0153]

[0154] The intermediate product 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 methanol / water, and lithium hydroxide (99 mg, 4.14 mmol) was added, stirred overnight at room temperature, concentrated under reduced pressure, 10 ml of distilled water was added, the pH was adjusted to 3 with 1 M hydrochloric acid, white solids were precipitated and filtered, the filter cake was washed several times with distilled water and dried to give the target compound A1 (152 mg), yield 73%. 1 H NMR (400 MHz, MeOD), δ 9.11-8.99 (m, 1H), 8.57-8.47 (m, 2H), 8.44-8.30 (m, 2H), 7.90-7.76 (m, 3H), 7.50 (d, J = 9.0 Hz, 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 (125 MHz, DMSO-d6), δ 173.2, 168.4, 162.6, 134.7, 133.9, 131.4, 130.2, 128.7, 128.1, 127.5, 115.3, 115.0, 102.5, 72.6, 55.4, 54.0, 32.3, 21.5. Electrospray ionization mass spectrometry, m / z: 469.1 [M+H] + .

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

[0156]

[0157] The synthesis method of compoundA2is similar to the synthesis method of compoundA1, the yield is 77%. 1H NMR (400 MHz, MeOD), δ 8.07 (dd,J= 8.4, 2.0 Hz, 1H), 7.97-7.88 (m, 2H), 7.87-7.81 (m, 1H), 7.70 (d,J= 8.4 Hz, 1H), 5.49 G, J 1H), 7.50-7.39 (m, 2H), 7.32 (d,J= 8.4 Hz, 1H), 4.60-4.50 (m, 1H), 4.00 (s, 2H), 3.45 (dd,J= 10.2, 5.8 Hz, 1H, 3.9, 2H), 2.86-2.77 (m, 1H), 2.57-2.48 (m, 1H), 2.09-1.99 (m, 1H), 1.90-1.80 (m, 1H), 1.35 (d,J= 6.2 Hz, 6H). Electrospray ionization mass spectrometry,m / z: 483.1 [M+H] + .

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

[0159]

[0160] The synthesis method of compoundA3is similar to the synthesis method of compoundA1, the yield is 65%. 1H NMR (400 MHz, MeOD), δ 9.03 (d,J= 8.4 Hz, 1H), 8.67 (d,J= 8.4 Hz, 1H), 8.52-8.44 (m, 2H), 8.37 (d,J= 7.5 Hz, 1H, 7,9.5 Hz), 1H), 7.87-7.72 (m, 2H), 7.47 (d,J= 8.9 Hz, 1H), 5.34 (d,J= 13.2 Hz, 1H), 5.05-4.96 (m, 1H), 4.65 (d,J= 13.2 Hz, 4.6 Hz), 1H), 3.48-3.35 (m, 2H), 2.68-2.48 (m, 1H), 2.25-2.08 (m, 2H), 2.06-1.88 (m, 1H), 1.49 (d,J= 6.0 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 173.1, 168.6, 162.6, 134.7, 133.9, 132.3, 130.2, 128.8, 127.6, 126.7, 115.3, 114.9, 102.5, 72.6, 65.9, 56.0, 53.2, 28.5, 22.4, 21.5. Electrospray ionization mass spectrometry,m / z: 483.1 [M+H] + .

[0161] Example 4. Synthesis of (cis)-3-(((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)amino)cyclobutane-1-carboxylic acid hydrochloride (A4)

[0162]

[0163] The synthesis method of compoundA4is similar to the synthesis method of compoundA1, the yield is 71%. 1H NMR (400 MHz, MeOD), δ 9.06 (d,J= 8.2 Hz, 1H), 8.58-8.47 (m, 2H), 8.40 (d,J= 7.4 Hz, 1H), 8.34-8.26 (m, 1H), 7.0-7.76 (m, 496 Hz), (d,J= 8.9 Hz, 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), 2-2.8, (m, 2H), 1.53-1.45 (m, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 174.9, 173.2, 168.5, 162.6, 134.7, 134.0, 131.5, 130.1, 128.7, 127.9, 127.4, 127.2, 124.7, 123.9, 116.0, 115.3, 114.9, 102.5, 72.6, 47.8, 45.5, 30.7, 30.5, 21.5. Electrospray ionization mass spectrometry,m / z: 483.1 [M+H] + .

[0164] Example 5. Synthesis ofN-((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)-N-methylglycine hydrochloride (A5)

[0165]

[0166] The synthesis method of compoundA5is similar to the synthesis method of compoundA1, the yield is 63%. 1H NMR (400 MHz, MeOD), δ 9.03 (d,J= 8.4 Hz, 1H), 8.77 (d,J= 8.3 Hz, 1H), 8.56-8.45 (m, 2H), 8.39 (d,J= 7.5 Hz, 1H, 7,9.5 Hz), δ 1H), 7.87-7.74 (m, 2H), 7.48 (d,J= 9.0 Hz, 1H), 5.03-4.96 (m, 3H), 3.88 (s, 2H), 2.80 (s, 3H), 1.49 (d,J= 6.0 Hz, 6.0H). 13 C NMR (150 MHz, DMSO-d6), δ 173.5, 169.2, 163.0, 135.2, 134.4, 132.8, 130.7, 129.2, 128.0, 127.5, 126.9, 126.4, 123.5, 116.5, 115.8, 115.4, 103.0, 73.0, 58.7, 57.9, 42.1, 22.0. Electrospray ionization mass spectrometry,m / z: 457.1 [M+H] + .

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

[0168]

[0169] The synthesis method of compoundA6is similar to the synthesis method of compoundA1, the yield is 70%. 1H NMR (400 MHz, MeOD), δ 8.08 (dd,J= 8.4, 1.8 Hz, 1H), 8.04-7.93 (m, 2H), 7.90 (d,J= 1.9 Hz, 1H), 7.70 (d,J= 8.4 Hz, 1.6 Hz, 1H), δ Hz, 1H), 7.52-7.46 (m, 1H), 7.46-7.39 (m, 1H), 7.32 (d,J= 8.4 Hz, 1H), 4.59-4.50 (m, 1H), 4.21 (d,J= 5.4 Hz, 3.6), 3.6 Hz, 1.37 (d,J= 6.2 Hz, 3H), 1.35-1.27 (m, 6H). Electrospray ionization mass spectrometry,m / z: 457.1 [M+H] + .

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

[0171]

[0172] The synthesis method of compoundA7is similar to the synthesis method of compoundA1, the yield is 79%. 1H NMR (400 MHz, MeOD), δ 9.05 (d,J= 8.1 Hz, 1H), 8.56 (d,J= 2.3 Hz, 1H), 8.54-8.45 (m, 2H), 8.41 (d,J= 7.4 Hz, 1H, 8.8 Hz), 6.7 Hz (d,J= 1H), 7.86-7.78 (m, 2H), 7.50 (d,J= 9.0 Hz, 1H), 4.98 (d,J= 6.9 Hz, 1H), 4.89 (s, 3H), 3.98 (s, 2H), 1.49 (d,J= 6.0 Hz, 6H). Electrospray ionization mass spectrometry,m / z: 443.1 [M+H] + .

[0173] Example 8. Synthesis of 1-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)amino)propionic acid hydrochloride (A8)

[0174]

[0175] The synthesis method of compoundA8is similar to the synthesis method of compoundA1, the yield is 66%. 1 H NMR (400 MHz, MeOD), δ 9.07-9.01 (m, 1H), 8.53-8.45 (m, 2H), 8.38 (d,J= 7.5 Hz, 1H), 8.34-8.30 (m, 1H), 7.86 (d,J= 1.5 G), δ 7.84-7.75 (m, 2H), 7.48 (d,J= 9.0 Hz, 1H), 5.02-4.96 (m, 1H), 4.86 (s, 2H), 3.45 (t,J= 6.5 Hz, 2H), 2.73 (t,J= 6.5 Hz, 2H), (d,J= 6.0 Hz, 6H). 13C NMR (125 MHz, DMSO-d6), δ 172.5, 172.1, 168.0, 162.0, 134.1, 133.4, 131.0, 129.6, 128.2, 127.2, 124.1, 122.9, 115.4, 114.7, 114.4, 102.0, 72.0, 47.9, 43.3, 31.5, 21.0. Electrospray ionization mass spectrometry,m / z: 457.1 [M+H] + .

[0176] Example 9. Synthesis of 2-(((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)amino)malonic acid hydrochloride (A9)

[0177]

[0178] The synthesis method of compoundA9is similar to the synthesis method of compoundA1, the yield is 58%. 1 H NMR (400 MHz, MeOD), δ 9.04 (d,J= 8.4 Hz, 1H), 8.58-8.49 (m, 3H), 8.40 (d,J= 7.4 Hz, 1H), 7.87 (d,J= 7.5 Hz, 1H, 7.7, 7.5 Hz), (7.5 Hz), 7.50 (d,J= 9.0 Hz, 1H), 5.06-4.96 (m, 1H), 4.87 (s, 2H), 3.71 (s, 1H), 1.49 (d,J= 6.0 Hz, 6H). Electrospray ionization mass spectrometry,m / z: 487.1 [M+H] + .

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

[0180]

[0181] The synthesis method of compoundA10is similar to the synthesis method of compoundA1, the yield is 65%. 1 H NMR (400 MHz, MeOD), δ 9.08-8.99 (m, 1H), 8.40-8.32 (m, 2H), 8.28 (d,J= 2.1 Hz, 1H), 8.22-8.15 (m, 1H), 7.87-7.7 m (d,36), (d,36). 8.8 Hz, 1H), 5.01 (s, 2H), 4.90-4.82 (m, 1H), 4.41-4.27 (m, 4H), 3.57 (p,J= 8.4 Hz, 1H), 1.45 (d,J= 6.0 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 173.7, 173.4, 168.6, 156.8, 131.7, 130.2, 129.5, 128.9, 128.7, 127.6, 123.0, 116.1, 115.4, 71.8, 56.5, 33.3, 21.6. Electrospray ionization mass spectrometry,m / z: 478.1 [M+H] + .

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

[0183]

[0184] The synthesis method of compoundA11is similar to the synthesis method of compoundA1, the yield is 72%. 1 H NMR (400 MHz, MeOD), δ 9.06-9.01 (m, 1H), 8.44 (d,J= 2.1 Hz, 1H), 8.36 (dd,J= 10.5, 7.6 Hz, 2H), 8.22 (dd,J= 8.7 Hz, 1H), 7.87-7.77 (m, 3H), 7.31 (d,J= 8.7 Hz, 1H), 5.05 (s, 2H), 4.90-4.80 (m, 1H), 4.49-4.33 (m, 4H), 3.74-3.62 (m, 1Hz), 6H). 13 C NMR (150 MHz, DMSO-d6), δ 173.9, 168.9, 158.3, 133.1, 132.0, 130.7, 129.8, 129.3, 128.4, 127.7, 115.6, 113.1, 72.3, 56.4, 33.2, 22.1. Electrospray ionization mass spectrometry,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)naphthalene-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A12)

[0186]

[0187] The synthesis method of compoundA12is similar to the synthesis method of compoundA1, the yield is 81%. 1 H NMR (400 MHz, MeOD), δ 9.05 (dd,J= 7.6, 2.0 Hz, 1H), 8.47 (d,J= 7.4 Hz, 2H), 8.38 (dd,J= 14.9, 8.1 Hz, 2H), 7.89-7.7 m, 7.49 Hz, (d,J= 9.0 Hz, 1H), 5.06 (s, 2H), 5.00-4.95 (m, 1H), 4.48-4.35 (m, 4H), 3.79-3.61 (m, 1H), 1.45 (d,J= 6.0 Hz, 6H). 13 C NMR (150 MHz, DMSO-d6), δ 174.0, 168.9, 159.7, 134.6, 132.0, 130.7, 129.3, 128.4, 127.7, 127.4, 122.6, 119.2, 119.0, 116.2, 115.5, 72.5, 56.4, 33.1, 22.0. Electrospray ionization mass spectrometry,m / z: 512.1 [M+H] + .

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

[0189]

[0190] The synthesis method of compoundA13is similar to the synthesis method of compoundA1, the yield is 64%. 1H NMR (400 MHz, MeOD), δ 9.06-8.99 (m, 1H), 8.38 (d,J= 7.8 Hz, 2H), 7.93-7.75 (m, 5H), 7.22 (d,J= 8.5 Hz, 1H), 5.12-4.53 H, (s (m, 1H), 4.52-4.42 (m, 4H), 3.99 (s, 3H), 3.87-3.74 (m, 1H), 1.41 (d,J= 6.0 Hz, 6H). Electrospray ionization mass spectrometry,m / z: 474.1 [M+H] + .

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

[0192]

[0193] The synthesis method of compoundA14is similar to the synthesis method of compoundA1, the yield is 66%. 1 H NMR (400 MHz, MeOD), δ 9.08-9.00 (m, 1H), 8.36 (t,J= 7.2 Hz, 2H), 8.22 (d,J= 8.7 Hz, 2H), 7.89-7.75 (m, 3H), 7.16 (GJ= 8.8), H 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= 6.0 Hz, 6H). 13C NMR (125 MHz, DMSO-d6), δ 174.1, 167.7, 161.1, 130.9, 129.7, 129.6, 128.1, 127.4, 126.7, 125.8, 124.0, 115.7, 11.6 69.4, 55.2, 31.9, 21.1. Electrospray ionization mass spectrometry,m / z: 444.1 [M+H] + .

[0194] Example 15. Synthesis of 1-((4-(5-(4-(tert-butoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azetidin-3-carboxylic acid hydrochloride (A15)

[0195]

[0196] The synthesis method of compoundA15is similar to the synthesis method of compoundA1, the yield is 77%. 1 H NMR (400 MHz, MeOD), δ 9.08-8.99 (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), (s), 4.50-4.37 (m, 4H), 3.79-3.67 (m, 1H), 1.50 (s, 9H). 13 C NMR (125 MHz, DMSO-d6), δ 174.6, 168.4, 160.1, 131.5, 130.3, 129.6, 128.6, 128.0, 127.3, 126.3, 79.7, 55.7, 32.5, 28.5. Electrospray ionization mass spectrometry,m / z: 458.1 [M+H] + .

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

[0198]

[0199] The synthesis method of compoundA16is similar to the synthesis method of compoundA1, the yield is 72%. 1 H NMR (400 MHz, MeOD), δ 9.03 (d,J= 8.3 Hz, 1H), 8.39-8.33 (m, 2H), 8.25 (d,J= 8.7 Hz, 2H), 7.88-7.76 (m, 3H), d,2,Hz (27.8 Hz), 5.03 (s, 2H), 4.43-4.28 (m, 4H), 3.95 (s, 3H), 3.64-3.56 (m, 1H). 13 C NMR (125 MHz, DMSO-d6), δ 174.1, 167.8, 162.7, 131.0, 129.7, 129.5, 128.1, 127.3, 126.6, 125.8, 55.3, 55.2, 32.1. Electrospray ionization mass spectrometry,m / z: 416.1 [M+H] + .

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

[0201]

[0202] The synthesis method of compoundA17is similar to the synthesis method of compoundA1, the yield is 68%. 1 H NMR (400 MHz, MeOD), δ 9.06-9.01 (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), (s), 4.50-4.38 (m, 4H), 4.10 (t,J= 6.4 Hz, 2H), 3.78-3.70 (m, 1H), 1.95-1.82 (m, 2H), 1.11 (t,J= 7.4 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 175.1, 168.7, 163.2, 131.9, 130.7, 130.5, 129.0, 128.5, 127.9, 126.8, 115.9, 70.0, 55.9, 32.8, 22.4, 10.8. Electrospray ionization mass spectrometry,m / z: 444.1 [M+H] + .

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

[0204]

[0205] The synthesis method of compoundA18is similar to the synthesis method of compoundA1, the yield is 65%. 1H NMR (400 MHz, MeOD), δ 9.04 (d,J= 8.2 Hz, 1H), 8.40-8.32 (m, 2H), 8.25 (d,J= 8.6 Hz, 2H), 7.87-7.77 (m, 3H), 7.5-7.77 (m, 3H), 7.5 G (7.5 Hz), 7.46-7.40 (m, 2H), 7.37 (d,J= 7.1 Hz, 1H), 7.28 (d,J= 8.7 Hz, 2H), 5.26 (s, 2H), 5.06 (s, 2H), 4.47-4.35 (m, 4.4-m, 3.4H). 13 C NMR (125 MHz, DMSO-d6), δ 175.1, 168.8, 162.8, 136.8, 131.9, 130.8, 130.6, 129.1, 129.0, 128.6, 116.4, 116.3, 70.2, 56.3, 32.9. Electrospray ionization mass spectrometry,m / z: 492.1 [M+H] + .

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

[0207]

[0208] The synthesis method of compoundA19is similar to the synthesis method of compoundA1, the yield is 67%. 1H NMR (400 MHz, MeOD), δ 9.10-9.03 (m, 1H), 8.46-8.39 (m, 3H), 8.36 (d,J= 8.1 Hz, 1H), 7.89-7.78 (m, 3H), 7.61 (d,J= 2.09 G), δ (s, 2H), 4.52–4.38 (m, 4H), 3.79–3.67 (m, 1H). 13 C NMR (125 MHz, DMSO-d6), δ 173.2, 168.0, 151.1, 130.9, 130.1, 129.7, 128.2, 127.5, 126.9, 125.8, 124.0, 121.3, 55.1, 31.8. Electrospray ionization mass spectrometry,m / z: 470.1 [M+H] + .

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

[0210]

[0211] The synthesis method of compoundA20is similar to the synthesis method of compoundA1, the yield is 61%. 1 H NMR (400 MHz, MeOD), δ 9.10-9.00 (m, 1H), 8.41-8.34 (m, 2H), 8.23 ​​(d,J= 8.1 Hz, 2H), 7.89-7.76 (m, 3H), 7.56 (d,J= , 20.8 G), δ (s, 2H), 4.55-4.37 (m, 4H), 3.79-3.67 (m, 1H), 3.14-2.98 (m, 1H), 1.35 (d,J= 6.9 Hz, 6H). 13C NMR (150 MHz, DMSO-d6), δ 175.3, 168.9, 154.9, 132.0, 130.7, 129.2, 128.7, 128.4, 128.1, 127.8, 56.2, 34.1, 33.0, 24.0. Electrospray ionization mass spectrometry,m / z: 428.1 [M+H] + .

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

[0213]

[0214] The synthesis method of compoundA21is similar to the synthesis method of compoundA1, the yield is 69%. 1 H NMR (400 MHz, MeOD), δ 9.07-9.03 (m, 1H), 8.42-8.33 (m, 2H), 8.22 (d,J= 8.0 Hz, 2H), 7.90-7.77 (m, 3H), 7.51 (d,J= , 29.0G), δ (s, 2H), 4.51-4.39 (m, 4H), 3.80-3.67 (m, 1H), 2.76 (t,J= 7.6 Hz, 2H), 1.84-1.65 (m, 2H), 1.02 (t,J= 7.4 Hz, 3H). 13C NMR (150 MHz, DMSO-d6), δ 175.3, 168.8, 148.9, 131.9, 130.7, 130.1, 129.2, 128.5, 127.9, 126.8, 37.7, 32.9, 24.2, 14.1. Electrospray ionization mass spectrometry,m / z: 428.1 [M+H] + .

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

[0216]

[0217] The synthesis method of compoundA22is similar to the synthesis method of compoundA1, the yield is 65%. 1 H NMR (500 MHz, MeOD), δ 7.97-7.89 (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), (s), 3.48 (dd,J= 9.0, 5.8 Hz, 2H), 3.16 (dd,J= 9.0, 5.8 Hz, 2H), 2.98 (p,J= 5.8 Hz, 1H). Electrospray ionization mass spectrometry,m / z: 411.1 [M+H] + .

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

[0219]

[0220] The synthesis method of compoundA23is similar to the synthesis method of compoundA1, the yield is 66%. 1 H NMR (400 MHz, MeOD), δ 9.07-9.01 (m, 1H), 8.41-8.32 (m, 4H), 7.88-7.75 (m, 3H), 7.48-7.37 (m, 2H), 5.03 (s, 2H), 4.4-m, (4H), 3.68-3.57 (m, 1H). 13 C NMR (125 MHz, DMSO-d6), δ 174.3, 169.1, 167.3, 164.5, 132.1, 131.5, 131.4, 130.7, 129.3, 129.1, 127.4, 126.8, 126.6, 125.3, 125.0, 120.6, 117.5, 117.3, 56.8, 48.1, 33.5. Electrospray ionization mass spectrometry,m / z: 404.1 [M+H] + .

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

[0222]

[0223] The synthesis method of compoundA24is similar to the synthesis method of compoundA1, the yield is 74%. 1H NMR (500 MHz, MeOD), δ 7.97-7.90 (m, 3H), 7.85 (t,J= 1.9 Hz, 1H), 7.78 (ddd,J= 7.9, 1.9, 1.2 Hz, 1H), 7.71 (d,J8,6.6 Hz), (d,J= 7.8 Hz, 1H), 7.54-7.40 (m, 3H), 3.74 (s, 2H), 3.48 (dd,J= 9.0, 5.8 Hz, 2H), 3.16 (dd,J= 9.0, 5.8 Hz, 2H, 2H, 9.J= , 5.8 G). Electrospray ionization mass spectrometry,m / z: 411.1 [M+H] + .

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

[0225]

[0226] The synthesis method of compoundA25is similar to the synthesis method of compoundA1, the yield is 78%. 1H NMR (400 MHz, MeOD), δ 9.08-9.03 (m, 1H), 8.41 (d,J= 7.4 Hz, 1H), 8.38-8.34 (m, 1H), 8.15 (ddd,J= 7.8, 1.6, 0.9 Gz, 10,J= dd, 1H). 9.1, 2.6, 1.5 Hz, 1H), 7.88-7.78 (m, 3H), 7.72 (td,J= 8.1, 5.5 Hz, 1H), 7.51 (tdd,J= 8.5, 2.7, 0.9 Hz, 06H), (s), , 2H 4.50-4.33 (m, 4H), 3.67 (p,J= 8.5 Hz, 1H). Electrospray ionization mass spectrometry,m / z: 404.1 [M+H] + .

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

[0228]

[0229] The synthesis method of compoundA26is similar to the synthesis method of compoundA1, the yield is 71%. 1 H NMR (400 MHz, MeOD), δ 9.08-9.01 (m, 1H), 8.39 (d,J= 7.4 Hz, 1H), 8.36 (d,J= 8.3 Hz, 1H), 8.33-8.28 (m, 2H), 7.8-7.41 (m, 1H), 7.70-7.65 (m, 2H), 5.00 (s, 2H), 4.37-4.25 (m, 4H), 3.53 (p,J= 8.1 Hz, 1H). 13C NMR (150 MHz, DMSO-d6), δ 175.1, 174.3, 169.1, 133.9, 132.2, 130.6, 130.1, 129.4, 128.5, 128.0, 127.1, 126.6, 125.4, 123.9, 57.0, 33.9. Electrospray ionization mass spectrometry,m / z: 386.1 [M+H] + .

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

[0231]

[0232] The synthesis method of compoundA27is similar to the synthesis method of compoundA1, the yield is 66%. 1 H NMR (400 MHz, MeOD), δ 9.09-9.02 (m, 1H), 8.94-8.88 (m, 2H), 8.43 (d,J= 7.5 Hz, 1H), 8.39-8.34 (m, 1H), 8.29-8.24 (m, 1H), (m, 3H), 5.05 (s, 2H), 4.44-4.33 (m, 4H), 3.72-3.58 (m, 1H). 13 C NMR (125 MHz, DMSO-d6), δ 173.7, 169.3, 151.7, 132.1, 130.9, 130.6, 129.4, 128.3, 127.5, 126.6, 125.3, 121.7, 56.9 33.4. Electrospray ionization mass spectrometry,m / z: 387.1 [M+H] + .

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

[0234]

[0235] The synthesis method of compoundA28is similar to the synthesis method of compoundA1, the yield is 68%. 1 H NMR (400 MHz, MeOD), δ 9.45 (dd,J= 2.2, 0.9 Hz, 1H), 9.08-9.03 (m, 1H), 8.88 (dd,J= 4.9, 1.7 Hz, 1H), 8.70 (ddd,8,J= , 6.6 Hz 1H), 8.42 (d,J= 7.5 Hz, 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, 3.5H), 1H). 13 C NMR (150 MHz, DMSO-d6), δ 173.5, 169.1, 154.2, 149.1, 136.2, 132.1, 130.6, 129.4, 129.2, 128.2, 126.6, 125.3, 125.0, 120.5, 56.8, 48.1, 33.6. Electrospray ionization mass spectrometry,m / z: 387.1 [M+H] + .

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

[0237]

[0238] The synthesis method of compoundA29is similar to the synthesis method of compoundA1, the yield is 69%. 1 H NMR (400 MHz, MeOD), δ 9.13-9.06 (m, 1H), 8.90-8.85 (m, 1H), 8.51-8.43 (m, 2H), 8.40-8.35 (m, 1H), 8.21-8.15 (m, 1H), 4H), 5.11 (s, 2H), 4.54-4.41 (m, 4H), 3.83-3.71 (m, 1H). 13 C NMR (150 MHz, DMSO-d6), δ 174.3, 169.0, 151.2, 143.3, 138.7, 131.9, 130.7, 129.2, 128.6, 128.1, 128.0, 126.8, 125.1, 56.0, 32.8. Electrospray ionization mass spectrometry,m / z: 387.1 [M+H] + .

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

[0240]

[0241] The synthesis method of compoundA30is similar to the synthesis method of compoundA1, the yield is 71%. 1H NMR (400 MHz, MeOD), δ 9.08-9.00 (m, 1H), 8.44-8.33 (m, 2H), 7.90-7.76 (m, 3H), 6.95 (t,J= 0.9 Hz, 1H), 5.06 (s, 4,4-3H), 4H), 3.68 (p,J= 8.4 Hz, 1H), 2.64 (d,J= 0.9 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 187.4, 172.4, 168.0, 166.7, 149.9, 140.1, 131.0, 129.6, 128.5, 127.5, 101.6, 55.5, 32.2, 11.4. Electrospray ionization mass spectrometry,m / z: 391.1 [M+H] + .

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

[0243]

[0244] The synthesis method of compoundA31is similar to the synthesis method of compoundA1, the yield is 71%. 1H NMR (500 MHz, MeOD), δ 8.00-7.91 (m, 2H), 7.77 (dd,J= 8.4, 1.8 Hz, 1H), 7.71 (d,J= 8.4 Hz, 1H), 7.53 (d,J= 8.4 Hz, 17.5 Hz), 2H), 7.33 (d,J= 1.8 Hz, 1H), 6.91 (d,J= 8.4 Hz, 1H), 6.09 (s, 2H), 3.74 (s, 2H), 3.49 (dd,J= 9.0, 5.8 Hz, 2H, 2H), 3.49 (dd,J= 9.0, 5.8 Hz, 2H, 2H), 2H), 2.98 (p,J= 5.8 Hz, 1H). Electrospray ionization mass spectrometry,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)naphthalene-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A32)

[0246]

[0247] The synthesis method of compoundA32is similar to the synthesis method of compoundA1, the yield is 64%. 1 H NMR (400 MHz, MeOD), δ 9.03 (dd,J= 7.6, 2.0 Hz, 1H), 8.40-8.31 (m, 2H), 7.87-7.75 (m, 5H), 7.11 (d,J= 8.4 Hz, 1H, 29), (s 4.50-4.34 (m, 8H), 3.81-3.70 (m, 1H). 13C NMR (125 MHz, DMSO-d6), δ 174.9, 168.7, 148.5, 144.4, 131.9, 130.7, 129.1, 128.5, 127.9, 126.9, 117.1, 116.6, 65.1, 64.6, 56.1, 32.8. Electrospray ionization mass spectrometry,m / z: 444.1 [M+H] + .

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

[0249]

[0250] The synthesis method of compoundA33is similar to the synthesis method of compoundA1, the yield is 74%. 1 H NMR (400 MHz, MeOD), δ 9.15–9.09 (m, 1H), 8.70–8.66 (m, 1H), 8.53–8.47 (m, 2H), 8.40–8.31 (m, 2H), 8.14–8.10 (m, 19.9), 1H), 7.91-7.79 (m, 4H), 5.09 (s, 2H), 4.55-4.35 (m, 4H), 3.74 (q,J= 8.5 Hz, 1H). 13C NMR (125 MHz, DMSO-d6), δ 174.2, 169.2, 147.8, 143.4, 138.9, 132.0, 131.7, 130.7, 130.1, 129.6, 129.4, 129.8, 128.5, 127.8, 126.8, 125.2, 121.2, 56.4, 33.1. Electrospray ionization mass spectrometry,m / z: 437.1 [M+H] + .

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

[0252]

[0253] The synthesis method of compoundA34is similar to the synthesis method of compoundA1, the yield is 69%. 1 H NMR (400 MHz, MeOD), δ 9.82 (s, 1H), 9.19-9.09 (m, 1H), 8.51 (d,J= 7.3 Hz, 1H), 8.40-8.34 (m, 2H), 8.31-8.25 (m, 1,1H), 2H), 7.95-7.81 (m, 3H), 5.12 (s, 2H), 4.57-4.40 (m, 4H), 3.88-3.72 (m, 1H). 13C NMR (125 MHz, DMSO-d6), δ 171.7, 168.2, 166.1, 144.0, 142.2, 140.4, 138.0, 132.4, 131.4, 131.1, 131.0, 129.6, 129.4, 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, 32.0, 32.0. Electrospray ionization mass spectrometry,m / z: 438.1 [M+H] + .

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

[0255]

[0256] The synthesis method of compoundA35is similar to the synthesis method of compoundA1, the yield is 62%. 1 H NMR (400 MHz, MeOD), δ 9.04 (dd,J= 7.3, 2.3 Hz, 1H), 8.57 (dd,J= 1.7, 0.7 Hz, 1H), 8.40-8.31 (m, 2H), 8.04 (dd,J, 8.7, Hz), 7.88-7.76 (m, 3H), 7.66-7.59 (m, 1H), 7.44 (d,J= 3.2 Hz, 1H), 6.70 (dd,J= 3.2, 0.9 Hz, 1H), 5.03 (s, 2H), 4.4-4.6 (m, 40H), (p,J= 8.4 Hz, 1H). 13C NMR (125 MHz, DMSO-d6), δ 176.6, 168.9, 138.9, 132.1, 130.7, 129.1, 128.3, 128.0, 127.3, 126.7, 114.6, 113.0, 103.2, 56.8, 33.6. Electrospray ionization mass spectrometry,m / z: 425.1 [M+H] + .

[0257] Example 36. Synthesis of 1-((4-(5-(1H-indol-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A36)

[0258]

[0259] The synthesis method of compoundA36is similar to the synthesis method of compoundA1, the yield is 55%. 1 H NMR (400 MHz, MeOD), δ 9.09-9.03 (m, 1H), 8.41 (d,J= 7.4 Hz, 1H), 8.37 (dd,J= 6.9, 2.7 Hz, 1H), 8.02 (d,J= 1.0 Hz, 1.7.7 Hz, 7.8), 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). 13C NMR (125 MHz, DMSO-d6), δ 168.0, 166.5, 154.9, 139.8, 131.1, 129.6, 128.5, 127.7, 127.1, 126.4, 124.0, 122.7, 113.1, 111.7, 55.9, 32.7. Electrospray ionization mass spectrometry,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)naphthalene-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride (A37)

[0261]

[0262] The synthesis method of compoundA37is similar to the synthesis method of compoundA1, the yield is 61%. 1 H NMR (400 MHz, MeOD), δ 9.12-9.06 (m, 1H), 8.43 (d,J= 7.4 Hz, 1H), 8.36 (dd,J= 6.8, 2.4 Hz, 1H), 7.88-7.80 (m, 3Hz, 7.8, 7.8 G), δ 1H), 7.61 (d,J= 8.7 Hz, 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), 3.6 G, p 1H). 13C NMR (125 MHz, DMSO-d6), δ 168.6, 167.6, 139.0, 131.1, 129.7, 128.4, 127.3, 126.5, 125.6, 124.8, 120.4, 110.6, 108.3, 55.6, 32.3, 31.5. Electrospray ionization mass spectrometry,m / z: 439.1 [M+H] + .

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

[0264]

[0265] The synthesis method of compoundA38is similar to the synthesis method of compoundA1, the yield is 66%. 1 H NMR (400 MHz, MeOD), δ 9.04-8.96 (m, 1H), 8.40-8.27 (m, 2H), 8.04 (d,J= 16.5 Hz, 1H), 7.86-7.73 (m, 5H), 7.53-7.73 (m, 3.3H), (d,J= 16.4 Hz, 1H), 5.03 (s, 2H), 4.45-4.31 (m, 3H), 3.64 (p,J= 8.5 Hz, 1H). 13C NMR (125 MHz, DMSO-d6), δ 175.1, 173.6, 168.8, 167.4, 143.5, 134.7, 132.1, 131.2, 130.6, 129.5, 127.3, 126.8, 126.6, 125.2, 110.7, 56.7, 48.1, 33.6. Electrospray ionization mass spectrometry,m / z: 412.1 [M+H] + .

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

[0267]

[0268] The synthesis method of compoundA39is similar to the synthesis method of compoundA1, the yield is 81%. 1 H NMR (400 MHz, MeOD), δ 8.98-8.92 (m, 1H), 8.34 (dd,J= 8.0, 1.5 Hz, 1H), 8.27 (d,J= 7.4 Hz, 1H), 7.86-7.73 (m, 3Hz, 26), (s 4.51-4.33 (m, 4H), 3.72 (p,J= 8.5 Hz, 1H), 3.26-3.07 (m, 1H), 2.28-2.16 (m, 2H), 1.96-1.85 (m, 2H), (m, 2H), 1.49–1.35 (m, 1H). 13C NMR (125 MHz, DMSO-d6), δ 182.7, 168.0, 131.9, 130.6, 129.0, 128.4, 127.7, 126.7, 125.0, 56.2, 35.7, 32.9, 25.2. Electrospray ionization mass spectrometry,m / z: 392.1 [M+H] + .

[0269] Example 40. Synthesis of 1-((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)piperidine-4-carboxylic acid hydrochloride (A40)

[0270]

[0271] The synthesis method of compoundA40is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.24 (dd,J= 7.3, 1.6 Hz, 1H), 7.64 (d,J= 7.5 Hz, 2H), 7.56-7.43 (m, 3H), 7.35 (d,2,J= 1.6 Hz), (dd,J= 7.6, J 7.5, 2.0 Hz, 1H), 4.43 (m, 1H), 3.39 (s, 2H), 3.16 (dt,J= 12.4, 7.0 Hz, 2H), 2.88 (p,J= 7.0 Hz, 1H), 1.98 (dq,J= 14.1, 7.1 Hz, 2H), 1.72-1.61 (m, 2H), 1.36 (d,J= 6.8 Hz, 6H). 13C NMR (125 MHz, DMSO-d6), δ 178.14, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 58.88, 50.85, 40.41, 28.26, 21.93. Electrospray ionization mass spectrometry,m / z: 497.2 [M+H] + .

[0272] Example 41. Synthesis of 1-((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)piperidine-3-carboxylic acid hydrochloride (A41)

[0273]

[0274] The synthesis method of compoundA41is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.6 Hz, 1H), 7.98 (dd,J= 7.4, 1.5 Hz, 1H), 7.64 (dd,J= 7.5, 1.1 Hz, 7.5-Hz), 3.6-m 7.34 (d,J= 2.0, 1H), 7.16 (dd,J= 7.5 Hz, 2.0 Hz, 1H), 4.49-4.41 (m, 1H), 4.38 (t,J= 12.8 Hz, 1H), 3.78 (d,J= 1.2 Hz, 1.1H), (dq,J= 12.3, 7.0 Hz, 2H), 2.65 (dd,J= 12.4, 7.0 Hz, 1H), 2.53 (p,J= 6.9 Hz, 1H), 2.27 (ddt,J= 29.0, 12.4, 7.0 Hz, 29.0, 7.6 Hz), 1H), 1.63-1.46 (m, 2H), 1.36 (dd,J= 24.9, 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 174.94, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.62, 127.81, 127.68, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 58.90, 55.40, 4952, 41.86, 25.14, 22.8 21.93. Electrospray ionization mass spectrometry,m / z: 497.2 [M+H] + .

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

[0276]

[0277] The synthesis method of compoundA42is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.26 (dd,J= 7.5, 1.5 Hz, 1H), 7.87 (dd,J= 7.4, 1.5 Hz, 1H), 7.65 (dd,J= 7.5, 1.3 Hz, 7.9), H 7.46 (td,J= 7.5, 1.7 Hz, 1H), 7.34 (d,J= 2.2 Hz, 1H), 7.16 (dd,J= 7.5, 2.0 Hz, 1H), 4.44 (dq,J= 13.6, 6.8 Hz, 1H), Hz, 1H), 3.76 (d,J= 12.2 Hz, 1H), 3.47-3.37 (m, 1H), 3.21-3.11 (m, 1H), 2.75-2.65 (m, 2H), 2.54-2.44 (m, 1H, 2H), 1.82-1.70 (m, 1H), 1.36 (dd,J= 25.1, 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 178.27, 176.57, 172.69, 166.15, 159.05, 134.27, 132.00 131.29, 131.05, 129.5, (2.4 G), (J 128.91, 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 58.90, 53.78, 53.28, 28.4, 27.7 21.93. Electrospray ionization mass spectrometry,m / z: 541.2 [MH].

[0278] Example 43. Synthesis of 1-((4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)pyrrolidin-3-sulfonic acid (A43)

[0279]

[0280] The synthesis method of compoundA43is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.6 Hz, 1H), 7.99 (dd,J= 7.3, 1.6 Hz, 1H), 7.79 (s, 1H), 7.64 (dd,J= 2.8 G), δ 7.56-7.43 (m, 3H), 7.34 (d,J= 2.0 Hz, 1H), 7.15 (dd,J= 7.5, 2.0 Hz, 1H), 4.49-4.35 (m, 2H), 3.76 (d,J= 12.4 Hz, 3.4 Hz), 7.0 Hz, 1H), 3.10 (ddt,J= 16.9, 14.0, 7.0 Hz, 2H), 2.67 (dd,J= 9.5, 7.0 Hz, 1H), 2.46 (dq,J= 12.8, 7.0 Hz, 1H), d 7.1 Hz, 1H), 2.15 (dq,J= 12.9, 7.0 Hz, 1H), 1.36 (dd,J= 25.1, 6.8 Hz, 6H). 13C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05 129.57 (d,J= 12.4 Hz), 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 67.47, 59.06, 56.90, 52.53, 28.58, 21.93. Electrospray ionization mass spectrometry,m / z: 519.2 [MH].

[0281] Example 44. Synthesis of methyl-1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylate (A44)

[0282]

[0283] The synthesis method of compoundA44is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.6 Hz, 1H), 8.00 (dd,J= 7.4, 1.6 Hz, 1H), 7.64 (dd,J= 7.5, 4.4 Hz, 7.6 Hz), 7.6-m 7.34 (d,J= 2.0 Hz, 1H), 7.15 (dd,J= 7.5, 1.8 Hz, 1H), 4.43 (h,J= 6.8 Hz, 1H), 3.81 (dd,J= 11.1, 6.9 Hz, 2H), 3.67 (s, 3.39), (s 2H), 3.23 (dd,J= 11.1, 6.9 Hz, 2H), 3.14 (p,J= 6.8 Hz, 1H), 1.36 (d,J= 6.8 Hz, 6H). 13C NMR (125 MHz, DMSO-d6), δ 173.55, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29 131.05, 129.57 (d,J= 1.19.1 Hz), 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 51.81, 43.42, 42.29, 21.93. Electrospray ionization mass spectrometry,m / z: 483.2 [MH].

[0284] Example 45. Synthesis of ethyl-1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylate (A45)

[0285]

[0286] The synthesis method of compoundA45is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.3, 1.6 Hz, 1H), 7.98 (dd,J= 7.4, 1.6 Hz, 1H), 7.64 (dd,J= 7.5, 4.4 Hz, 2H), 7.53 (dd,J= 7.4, 1.6 Hz, 1H), 7.52-7.43 (m, 2H), 7.34 (d,J= 2.0 Hz, 1H), 7.15 (dd,J= 7.5, 2.0 Hz, 1H), 4.43 (hept,J= 6.8 Hz, 1H), 4.17 (q,J= 5.9 Hz, 2H), 3.82 (dd,J= 10.8, 6.7 Hz, 2H), 3.39 (s, 2H), 3.26-3.11 (m, 3H), 1.36 (d,J= 6.8 Hz, 6H), 1.23 (t,J= 5.9 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 172.53, 166.15, 159.05, 134.27, 132.00, 131.29 131.05, 129.57 (d,J= 12.4 Hz), 128.91, 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 60.82, 57.90, 43.42, 42.31, 21.93, 14.26. Electrospray ionization mass spectrometry, m / z: 497.2 [MH].

[0287] Example 46. Synthesis of isopropyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate (A46)

[0288]

[0289] The synthesis method of compoundA46is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.5, 1.6 Hz, 1H), 7.99 (dd,J= 7.4, 1.5 Hz, 1H), 7.65 (dd,J= 9.6, 7.4 Hz, 7.4-Hz), 3.6-m 7.32 (d,J= 2.0 Hz, 1H), 7.15 (dd,J= 7.5, 2.0 Hz, 1H), 5.04 (hept,J= 6.8 Hz, 1H), 4.43 (hept,J= 6.9 Hz, 1H), 3.82 (dd,J= 2.8 Hz), 6.8 Hz 3.39 (s, 2H), 3.27-3.12 (m, 3H), 1.36 (d,J= 6.8 Hz, 6H), 1.23 (d,J= 6.9 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 170.80, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.62, 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, 21.90, 21.9. Electrospray ionization mass spectrometry,m / z: 511.2 [MH].

[0290] Example 47. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxamide (A47)

[0291]

[0292] The synthesis method of compoundA47is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 8.01 (dd,J= 7.4, 1.6 Hz, 1H), 7.73 (d,J= 7.5 Hz, 1H), d,63, 7.5 Hz, 7.56-7.43 (m, 3H), 7.23 (d,J= 2.0 Hz, 1H), 7.09 (dd,J= 7.5, 2.0 Hz, 1H), 5.68 (s, 2H), 4.43 (hept,J= 6.9 Hz, 1H, 3,7.6), dd,J= 1,16 Hz, 2H), 3.48-3.39 (m, 2H), 3.24 (dd,J= 11.1, 7.0 Hz, 2H), 1.36 (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 172.67, (d,J= 4.7 Hz), 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d,J=1), 2.4 Hz 128.91, 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 47.45, 41.10, 2.93. Electrospray ionization mass spectrometry,m / z: 468.2 [MH].

[0293] Example 48. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)-N-methylazetidine-3-formamide (A48)

[0294]

[0295] The synthesis method of compoundA48is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 8.01 (dd,J= 7.4, 1.6 Hz, 1H), 7.64 (dd,J= 7.5, 5.5 Hz, 2H), t 7.2, 1.8 Hz, 2H), 7.46 (td,J= 7.5, 1.6 Hz, 1H), 7.34 (d,J= 2.0 Hz, 1H), 7.15 (dd,J= 7.5, 2.0 Hz, 1H), 5.98 (spt, 1.4, J= 6.4), J Hz, 1H), 3.76 (dd,J= 11.1, 7.0 Hz, 2H), 3.44 (p,J= 7.0 Hz, 2H), 3.39 (s, 1H), 3.24 (dd,J= 11.1, 7.0 Hz, 2H), 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 172.45, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.62, 127.81, 127.68, 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 46.88, 41.89, 26.32, 21.39. Electrospray ionization mass spectrometry,m / z: 482.2 [MH].

[0296] Example 49. Synthesis of 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)-N,N-dimethylazetidine-3-formamide (A49)

[0297]

[0298] The synthesis method of compoundA49is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 7.99 (dd,J= 7.4, 1.5 Hz, 1H), 7.65 (d,J= 7.5 Hz, 2H), 7.6-m, 7.49, (td,J= 7.4, 1.6 Hz, 1H), 7.34 (d,J= 2.0 Hz, 1H), 7.16 (dd,J= 7.5, 2.0 Hz, 1H), 4.44 (hept, J = 6.8 Hz, 1H), 3.80 (dd,J= 1.0 Hz, 7.0 Hz), 3.61 (p,J= 6.9 Hz, 1H), 3.39 (s, 2H), 3.22 (dd,J= 11.1, 6.9 Hz, 2H), 3.04 (s, 6H), 1.36 (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 173.60, 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d,J= 1.28.9 G), 2.19. 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 57.90, 46.35, 42.85, 35.93, respectively. Electrospray ionization mass spectrometry,m / z: 496.2 [MH].

[0299] Example 50. Synthesis of 5-(3-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (A50)

[0300]

[0301] The synthesis method of compoundA50is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.26 (dd,J= 7.5, 1.6 Hz, 1H), 8.02 (dd,J= 7.4, 1.6 Hz, 1H), 7.65 (dd,J= 7.4, 1.9 Hz, 7.6), H 7.47 (td,J= 7.4, 1.7 Hz, 1H), 7.35 (d,J= 2.0 Hz, 1H), 7.16 (dd,J= 7.4, 1.9 Hz, 1H), 4.43 (h,J= 6.8 Hz, 1H), 3.9,J= 2H), 3.78 (p,J= 7.0 Hz, 1H), 3.39 (s, 2H), 3.20 (dd,J= 11.1, 6.9 Hz, 2H), 1.36 (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 159.05, 144.67, 134.27, 132.00, 131.29, 131.05, 129.62, 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. Electrospray ionization mass spectrometry,m / z: 493.2 [MH].

[0302] Example 51. Synthesis of 3-(3-(3-(1H-tetrazol-5-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (A51)

[0303]

[0304] The synthesis method of compoundA51is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.27 (dd,J= 7.3, 1.6 Hz, 1H), 8.02 (dd,J= 7.4, 1.6 Hz, 1H), 7.65 (d,J= 7.5 Hz, 1H), 7.5-7.4, (7.4, 1H), (dd,J= 2.0, 1.0 Hz, 1H), 6.98 (dd,J= 7.5, 2.0 Hz, 1H), 4.43 (h,J= 6.9 Hz, 1H), 3.93 (dd,J= 11.2, 7.0 Hz, 2H), 3,78 (p, 7.7 Hz), Hz 3.39 (s, 2H), 3.20 (dd,J= 11.2, 6.9 Hz, 2H), 1.35 (d,J= 6.9 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 154.72, 144.67, 132.69, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 126.67, 126.64, 125.87, 125.40, 125.31, 124.41, 123.72, 121.65, 121.40, 115.12, 10.15.15 72.86, 57.90, 46.90, 37.35, 21.93. Electrospray ionization mass spectrometry,m / z: 536.2 [MH].

[0305] Example 52. Synthesis of 3-(4-((3-(1H-tetrazol-5-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole (A52)

[0306]

[0307] The synthesis method of compoundA52is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.83 (s, 1H), 8.31 (dd,J= 7.4, 1.6 Hz, 1H), 8.23 ​​(s, 1H), 7.99 (dd,J= 7.4, 1.6 Hz, 1H, 7.6), d,J=7.6 Hz 1H), 7.60 (t,J= 1.6 Hz, 1H), 7.57-7.48 (m, 3H), 7.46 (dd,J= 7.5, 1.5 Hz, 1H), 7.23-7.15 (m, 2H), 6.66 (dd,J= 1.45 G, 1.7H), (p,J= 7.0 Hz, 1H), 4.02 (dd,J= 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.27 (dd,J= 11.2, 7.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 142.71, 139.91, 132.00, 131.05, 129.57, (d,J= 12.4 Hz), 127.00 (d,J= 7.6 Hz), 125.80, 125.31, 124.78, 124.41, 122.29, 112.56, 102.91, 57.90, 53.88, 50.83. Electrospray ionization mass spectrometry,m / z: 449.2 [MH].

[0308] Example 53. Synthesis of 3-(4-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-6-yl)-1,2,4-oxadiazole (A53)

[0309]

[0310] The synthesis method of compoundA53is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.83 (s, 1H), 8.30 (dd,J= 7.4, 1.6 Hz, 1H), 8.03-7.98 (m, 2H), 7.80 (dd,J= 7.4, 1.5 Hz, 1.6,7.6), J Hz, 1H), 7.57-7.49 (m, 2H), 7.47 (td,J= 7.5, 1.7 Hz, 1H), 7.34-7.26 (m, 2H), 7.18 (d,J= 7.5 Hz, 1H), 6.56 (dd,J= 15,6 Hz), 5.48 (p,J=7.0 Hz, 1H), 4.02 (dd,J= 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.28 (dd,J= 11.2, 7.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 142.71, 135.24, 132.00, 131.05, 129.57 (d,J= 12.4 Hz), (d,J= 15.3 Hz), 127.03, 125.31, 125.04, 124.41, 121.84 (d,J= 7.7 Hz), 112.61, 102.70, 57.90, 53.88, 50.83. Electrospray ionization mass spectrometry,m / z: 449.2 [MH].

[0311] Example 54. Synthesis of 3-(4-((3-(1H-tetrazol-1-yl)azelaic acid-1-yl)methyl)naphthalene-1-yl)-5-(1H-indol-2-yl)-1,2,4-oxadiazole (A54)

[0312]

[0313] The synthesis method of compoundA54is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.83 (s, 1H), 9.34 (s, 1H), 8.30 (dd,J= 7.4, 1.6 Hz, 1H), 8.01 (dd,J= 7.4, 1.6 Hz, 1H, 7.7), t 1.6 Hz, 1H), 7.67 (dd,J= 7.4, 2.2 Hz, 2H), 7.58-7.50 (m, 2H), 7.47 (td,J= 7.4, 1.6 Hz, 1H), 7.19-7.08 (m, 2H, 7.00), t Hz, 1H), 5.48 (p,J= 7.1 Hz, 1H), 4.02 (dd,J= 11.2, 7.0 Hz, 2H), 3.39 (s, 2H), 3.28 (dd,J= 11.2, 7.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6), δ 167.59, 166.52, 142.71, 136.46, 132.00, 131.05, 129.57 (d,J= 12.4 Hz), (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 122.50, 121.37 (d,J= 13.3 Hz), 116.68, 111.94, 107.96, 57.90, 53.83, Electrospray ionization mass spectrometry,m / z: 449.2 [MH].

[0314] Example 55. Synthesis of diethyl-(1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-yl)phosphonate (A55)

[0315]

[0316] The synthesis method of compound A55 is similar to that of compound A1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 7.89 (dd,J= 7.4, 1.5 Hz, 1H), 7.74 (dd,J= 9.3, 7.5 Hz, 2H), 7.64 (d,J= 7.5 Hz, 1H), 7.52 (td,J= 7.4, 1.7 Hz, 1H), 7.46 (td,J= 7.5, 1.6 Hz, 1H), 7.23 (d,J= 2.1 Hz, 1H), 7.09 (dd,J= 7.5, 2.0 Hz, 1H), 4.43 (hept,J= 6.8 Hz, 1H), 4.24-4.10 (m, 6H), 3.39 (s, 2H), 3.19 (dd,J= 11.2, 7.0 Hz, 2H), 2.52 (dp,J= 11.4, 7.0 Hz, 1H), 1.39-1.28 (m, 12H). 13 C NMR (125 MHz, DMSO-d6), δ 172.69, 166.15, 159.05, 134.27, 132.00, 131.29, 131.05, 129.57 (d,J= 12.4 Hz), 128.91, 127.75 (d,J= 16.2 Hz), 127.03, 125.31, 124.41, 115.46, 113.72, 105.66, 72.86, 62.14 (d,J= 5.7 Hz), 57.90 (d,J= 3.8 Hz), 47.33 (d,J= 6.7 Hz), 21.93, 16.52 (d,J= 5.7 Hz). Electrospray ionization mass spectrometry, m / z: 561.2 [MH].

[0317] Example 56. Synthesis of 1-((5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)isoquinolin-8-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A56)

[0318]

[0319] The synthesis method of compoundA56is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.00 (dd,J= 7.4, 1.6 Hz, 1H), 8.32 (dd,J= 7.4, 1.5 Hz, 1H), 7.72 (d,J= 7.5 Hz, 1H), 7.6-6, (7.6 Hz), (t,J= 7.5 Hz, 1H), 7.46 (dd,J= 7.5, 2.0 Hz, 1H), 7.22 (d,J= 7.4 Hz, 1H), 4.43 (hept,J= 6.8 Hz, 1H), 3.78 (dd,J= 11,J= 6.9 Hz, 3.69 Hz), (s, 2H), 3.25 (dd,J= 11.1, 6.9 Hz, 2H), 3.14 (p,J= 6.9 Hz, 1H), 1.36 (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 172.69, 166.15, 159.05, 149.66, 137.44, 134.27, 133.09, 132.93, 129.17, 128.00, 127.54, 123.60, 122.49, 115.46, 113.72, 105.66, 72.86, 57.07, 42.88, 21.93. Electrospray ionization mass spectrometry,m / z: 470.2 [MH].

[0320] 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 hydrochloride (A57)

[0321]

[0322] The synthesis method of compoundA57is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.27 (s, 1H), 8.61 (d,J= 7.5 Hz, 1H), 7.93 (d,J= 7.5 Hz, 1H), 7.76 (d,J= 7.5 Hz, 1H, 7.2), δ 1H), 7.54 (d,J= 7.5 Hz, 1H), 7.46 (dd,J= 7.5, 2.0 Hz, 1H), 7.22 (d,J= 7.5 Hz, 1H), 4.42 (h,J= 6.9 Hz, 1H), 3.8-3.6 (m, 2H), 3.23-3.10 (m, 3H), 2.95 (s, 2H), 1.36 (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 172.69, 166.15, 159.05, 147.57, 146.61, 134.27, 131.73, 131.41, 130.09, 128.35, 123.60, 118.14, 115.46, 113.72, 105.66, 72.86, 57.90, 42.88, 42.82, 21.93. Electrospray ionization mass spectrometry,m / z: 470.2 [MH].

[0323] Example 58. Synthesis of 1-((8-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)quinoxalin-5-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A58)

[0324]

[0325] The synthesis method of compoundA58is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 9.06-8.98 (m, 2H), 7.85 (d,J= 7.5 Hz, 1H), 7.78 (d,J= 7.5 Hz, 1H), 7.62 (d,J= 2.0 Hz, 1H), 7.4, J 2.0 Hz, 1H), 7.16 (d,J= 7.4 Hz, 1H), 4.43 (hept,J= 6.8 Hz, 1H), 3.80 (dd,J= 10.8, 6.6 Hz, 2H), 3.69 (s, 2H), 3.2-3.6 (m, 36), (d,J= 6.8 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 172.69, 168.74, 159.05, 139.75, 139.30, 137.09, 134.27, 131.29, 131.27, 128.04, 124.57, 123.60, 115.46, 113.72, 105.66, 72.86, 57.07, 42.88, 42.82, 21.93. Electrospray ionization mass spectrometry,m / z: 471.2 [MH].

[0326] Example 59. Synthesis of 1-((4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A59)

[0327]

[0328] The synthesis method of compoundA59is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.3, 1.6 Hz, 1H), 7.97 (dd,J= 7.4, 1.6 Hz, 1H), 7.71 (dd,J= 7.5, 1.5 Hz, 1.5 Hz), 7.5 G, 7.5 G 1H), 7.57-7.41 (m, 4H), 7.26 (t,J= 7.5 Hz, 1H), 3.87-3.76 (m, 2H), 3.39 (s, 2H), 3.23-3.10 (m, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 166.52, 166.11, 133.15, 132.00, 131.57, 131.05, 129.62, 129.52, 127.81, 127.73, 127.68, 127.03, 125.31, 124.41, 57.90, 42.88, 42.82. Electrospray ionization mass spectrometry,m / z: 392.1 [MH].

[0329] Example 60. Synthesis of 1-((4-(5-(4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A60)

[0330]

[0331] The synthesis method of compoundA60is similar to the synthesis method of compoundA1. 1 H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 7.98 (dd,J= 7.4, 1.6 Hz, 1H), 7.64 (d,J= 7.5 Hz, 1H-5), 7.5, 7.4, (7.7 Hz), (d,J= 1.5 Hz, 1H), 3.87-3.76 (m, 2H), 3.39 (s, 2H), 3.23-3.10 (m, 3H), 2.29 (s, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 166.52, 166.13, 138.12, 133.54, 132.00, 131.05, 129.79, 129.62, 127.81, 127.68, 127.03, 125.31, 124.41, 115.40, 57.90, 42.88, 42.82, 15.39. Electrospray ionization mass spectrometry,m / z: 406.1 [MH].

[0332] Example 61. Synthesis of 1-((4-(5-(5-methoxy-4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A61)

[0333]

[0334] The synthesis method of compoundA61is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.25 (dd,J= 7.4, 1.5 Hz, 1H), 7.95 (dd,J= 7.4, 1.6 Hz, 1H), 7.64 (d,J= 7.5 Hz, 1H-5), 7.45, (7.5 Hz), (td,J= 7.4, 1.6 Hz, 1H), 7.23 (s, 1H), 3.87-3.77 (m, 5H), 3.39 (s, 2H), 3.20 (d,J= 6.9 Hz, 1H), 3.21-3.10 (m, 2.2H), (21H), (2H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 166.52, 166.20, 164.76, 136.28, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 125.31, 124.41, 105.79, 100.40, 58.07, 57.90, 42.88, 42.82, 12.45. Electrospray ionization mass spectrometry,m / z: 436.1 [MH].

[0335] Example 62. Synthesis of 1-((4-(5-(furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A62)

[0336]

[0337] The synthesis method of compoundA62is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.24 (dd,J= 7.3, 1.5 Hz, 1H), 7.98 (dd,J= 7.3, 1.6 Hz, 1H), 7.66-7.59 (m, 2H), 7.54-7.59 (m, 3.3H), (dd,J= 7.5, 1.5 Hz, 1H), 6.54 (t,J= 7.5 Hz, 1H), 3.87-3.76 (m, 2H), 3.39 (s, 2H), 3.23-3.10 (m, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 167.71, 166.52, 147.75, 141.74, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 125.31, 124.41, 117.03, 112.90, 57.90, 42.88, 42.82. Electrospray ionization mass spectrometry,m / z: 376.1 [MH].

[0338] Example 63. Synthesis of 1-((4-(5-(4-(trifluoromethyl)furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A63)

[0339]

[0340] The synthesis method of compoundA63is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.23 ​​(dd,J= 7.3, 1.6 Hz, 1H), 7.94 (dd,J= 7.4, 1.5 Hz, 1H), 7.71 (d,J= 1.5 Hz, 1H), d,6,J= 7.7, Hz, 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), 3.2-3.0 (m, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 167.83, 166.52, 140.16, 140.14, 137.23, 137.20, 132.00, 131.05, 128.91, 127.81, 127.68, 127.03, 125.31, 125.14, 124.89, 124.41, 122.84, 122.81, 119.53, 117.39, 5, 4.8, 4.8. Electrospray ionization mass spectrometry,m / z: 444.1 [MH].

[0341] Example 64. Synthesis of 1-((4-(5-(4-cyanofuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A64)

[0342]

[0343] The synthesis method of compoundA64is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.25-8.17 (m, 2H), 7.95 (dd,J= 7.4, 1.6 Hz, 1H), 7.63 (d,J= 7.5 Hz, 1H), 7.51 (td,J= 2,5 Hz), 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), δ 177.47, 167.83, 166.52, 147.02, 142.97, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 125.31, 124.49, 124.41, 113.54, 96.69, 57.90, 42.88, 42.82. Electrospray ionization mass spectrometry,m / z: 401.1 [MH].

[0344] Example 65. Synthesis of 1-((4-(5-(4-isopropoxyfuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A65)

[0345]

[0346] The synthesis method of compoundA65is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.24 (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), t 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, 3,3, 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), δ 177.47, 167.83, 166.52, 152.80, 137.02, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 125.31, 124.41, 119.72, 112.38, 70.83, 57.90, 42.88, 42.82, 22.03. Electrospray ionization mass spectrometry,m / z: 434.2 [MH].

[0347] Example 66. Synthesis of 1-((4-(5-([1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A66)

[0348]

[0349] The synthesis method of compoundA66is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.29 (dd,J= 7.4, 1.6 Hz, 1H), 7.98 (dd,J= 7.4, 1.6 Hz, 1H), 7.65 (d,J= 7.5 Hz, 1H-6), 7.25, (7.26 Hz), (s, 4H), 7.57-7.47 (m, 2H), 7.50-7.40 (m, 3H), 7.33 (ddt,J= 7.4, 5.9, 2.0 Hz, 1H), 3.86-3.75 (m, 2H), 3.39 (s, 2.3H), 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 173.12, 166.15, 144.42, 139.22, 132.00, 131.05, 129.62, 129.52, 127.81, 127.71, 127.68, 127.03, 126.99, 126.35, 125.67, 125.31, 124.41, 57.90, 42.88, 42.82. Electrospray ionization mass spectrometry,m / z: 462.2 [MH].

[0350] Example 67. Synthesis of 1-(4-(5-(4-(thiophen-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A67)

[0351]

[0352] The synthesis method of compoundA67is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.29 (dd,J= 7.5, 1.5 Hz, 1H), 7.97 (dd,J= 7.4, 1.5 Hz, 1H), 7.66 (dd,J= 7.5, 2.6 Hz, 3.6, 7.4), H 7.53 (td,J= 7.5, 1.6 Hz, 3H), 7.46 (td,J= 7.4, 1.5 Hz, 1H), 7.36 (dd,J= 7.5, 1.7 Hz, 1H), 7.17 (t,J= 7.5 Hz, 1.9 Hz), 3.9. 6.6 Hz, 2H), 3.39 (s, 2H), 3.44-3.30 (m, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 173.12, 166.15, 143.09, 137.84, 132.00, 131.05, 129.62, 129.52, 127.68, 127.03, 126.75, 126.64, 125.91, 125.42, 125.31, 124.62, 124.41, 57.90, 42.88. Electrospray ionization mass spectrometry,m / z: 468.1 [MH].

[0353] Example 68. Synthesis of 1-(4-(5-(4-(1H-pyrrol-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A68)

[0354]

[0355] The synthesis method of compoundA68is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.64 (s, 1H), 8.29 (dd,J= 7.4, 1.5 Hz, 1H), 8.00 (dd,J= 7.4, 1.6 Hz, 1H), 7.73-7.67 (m, 2,7.6), J Hz, 1H), 7.60-7.54 (m, 2H), 7.56-7.43 (m, 3H), 6.90 (dd,J= 7.4, 1.6 Hz, 1H), 6.55 (dd,J= 7.4, 1.6 Hz, 1H), 6.33 Hz (1.5H), 3.89–3.78 (m, 2H), 3.39 (s, 2H), 3.24–3.12 (m, 3H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 173.12, 166.15, 132.92, 132.00, 130.34, 129.62, 129.52, 128.91, 127.03, 126.97, 125.83, 125.31, 124.41, 124.18, 120.05, 111.35, 107.64, 57.90, 42.88, 42.82. Electrospray ionization mass spectrometry,m / z: 451.2 [MH].

[0356] Example 69. Synthesis of 1-((4-(5-(4-(furan-2-yl)phenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A69)

[0357]

[0358] The synthesis method of compoundA69is similar to the synthesis method of compoundA1. 1H NMR (500 MHz, chloroform-d), δ 8.29 (dd,J= 7.4, 1.5 Hz, 1H), 7.98 (dd,J= 7.4, 1.7 Hz, 1H), 7.77 (dd,J= 7.5, 1.5 Hz, 1.6 Hz), 7.8 (dd,J= 7.8). 7.3 Hz, 3H), 7.61-7.55 (m, 2H), 7.56-7.49 (m, 2H), 7.46 (td,J= 7.4, 1.6 Hz, 1H), 6.89 (dd,J= 7.5, 1.5 Hz, 1H, 6.5 Hz), ,6J= 17.5Hz 1H), 3.92 (dd,J= 11.0, 6.8 Hz, 2H), 3.39 (s, 2H), 3.38 (dd,J= 11.1, 6.9 Hz, 2H), 3.31 (p,J= 6.8 Hz, 1H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 173.12, 166.15, 152.87, 142.41, 134.11, 132.00, 131.05, 129.62, 127.81, 127.68, 127.03, 126.79, 125.37, 125.31, 125.23, 124.41, 109.76, 107.76, 57.90, 42.88. Electrospray ionization mass spectrometry,m / z: 452.2 [M+H] + .

[0359] Example 70. Synthesis of 1-(4-(5-(3-cyano-4-(cyclopentoxy)phenyl)-1,2,4-oxadiazol-3-yl)naphthalene-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride (A70)

[0360]

[0361] The synthesis method of compoundA70is similar to the synthesis method of compoundA1.1 H NMR (500 MHz, chloroform-d), δ 8.26 (dd,J= 7.5, 1.6 Hz, 1H), 8.00 (dd,J= 7.4, 1.6 Hz, 1H), 7.71 (d,J= 7.5 Hz, 1H), 7.64 (d,J= 7.5 Hz, 1H), 7.53 (td,J= 7.4, 1.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.22 (d,J= 2.1 Hz, 1H), 7.08 (dd,J= 7.5, 2.0 Hz, 1H), 4.70-4.61 (m, 1H), 3.87-3.78 (m, 2H), 3.39 (s, 2H), 3.23-3.10 (m, 3H), 1.96-1.79 (m, 6H), 1.60 (tdd,J= 11.0, 5.2, 1.9 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6), δ 177.47, 172.69, 166.15, 159.08, 134.08, 132.00, 131.11, 131.05, 129.62, 129.52, 128.91, 127.81, 127.68, 127.03, 125.31, 124.41, 123.28, 115.46, 114.09, 105.53, 81.35, 57.90, 42.88, 32.83, 23.82. Electrospray ionization mass spectrometry, m / z: 495.2 [M+H] + .

[0362] Examples of Experiments to Study Pharmacological Activity

[0363] Experiment Example 1: Analysis of the Agonistic Activity of the Compound on S1P Receptors

[0364] Device:FLIPR™ TETRA (Molecular Devices)

[0365] Materials used for the experiment: CHO-K1 / Gα15 / EDG1 cells independently constructed by GenScript.

[0366] Sample preparation: Before the experiment, a working solution of appropriate concentration was prepared by diluting with GPCR dilution buffer.

[0367] Experimental procedure: CHO-K1 / Gα15 / EDG1 cells stably expressing the EDG1 receptor were cultured in a 10cm Petri dish in a 37°C / 5% CO2 incubator and split when the confluence reached 80-85%. The cells in the collected cell suspension were inoculated into 384 microtiter plates at the appropriate density and then placed in a 37°C / 5% CO2 incubator and continued to incubate for at least 18 hours before use in the experiments. After 18-20 hours, the cell culture plate was removed and the working dye solution was added, and then the plate was again placed in a 37°C / 5% CO2 incubator for 1 hour and finally equilibrated at room temperature for 15 minutes. A positive working solution of the agonist was added, RFU values ​​were determined and recorded.A total of 384 microplates, cell plates, and a box of tips containing positive agonist working solution were placed in the FLIPR™ TETRA instrument, and the assay program was run in agonist mode with a total assay time of 120 seconds. Positive agonist working solution was added to the cell culture plate at 21 seconds. A total of 384 microplates, a cell plate, and a box of tips containing positive antagonist working solution were placed in the FLIPR™ TETRA instrument. The detection program was run in antagonist mode with a total instrument detection time of 120 seconds, and positive antagonist working solution was added to the cell culture plate at 21 seconds.

[0368] Data processing: The raw data were obtained using ScreenWorks software (version 3.1) and saved as *FMD files in the Kingsray computer network system. The data were collected and analyzed using Excel and GraphPad Prism 6. For each well, the average fluorescence intensity value from 1 to 20 seconds was used as the baseline value, and the maximum fluorescence intensity value between 21 and 120 seconds minus the minimum fluorescence intensity value between 21 and 120 seconds constituted the relative fluorescence intensity value (ΔRFU), from which the percentage of activation or inhibition can be calculated based on the following equation:

[0369] Activation rate, % = (ΔRFU соединение - ΔRFU фон ) / (ΔRFU контроль с агонистом - ΔRFU фон ) x 100%

[0370] Data were analyzed using the GraphPad Prism 6 software package using a four-parameter equation to calculate EC values 50 and IC 50 The four-parameter equation was: y = Bottom + (Top - Bottom) / (1 + 10^((LogEC50 / IC50 - X) * HillSlope)), where X is the log concentration value and Y is the degree of inhibition.

[0371] Experiment results:

[0372] Compound S1PR 1 EC 50 S1PR 3 EC 50 Siponimod 547.0 nM > 10 μM Ozanimod 222.0 nM > 10 μM FTY720-P 39.3 nM 4.52 μM A1 48.0 nM > 10 μM A10 698.9 nM > 10 μM A11 1366.0 nM > 10 μM A12 358.0 nM > 10 μM A13 1549.0 nM > 10 μM A14 1668.0 nM > 10 μM A15 1231.0 nM > 10 μM A16 1169.0 nM > 10 μM A17 > 10 μM > 10 μM A18 > 10 μM > 10 μM A19 1125.0 nM > 10 μM A20 1049.0 nM > 10 μM A21 1273.0 nM > 10 μM A22 1127.0 nM > 10 μM A23 1960.0 nM > 10 μM A24 684.8 nM > 10 μM A25 1057.0 nM > 10 μM A26 749.2 nM > 10 μM A27 > 10 μM > 10 μM A28 1182.0 nM > 10 μM A29 992.5 nM > 10 μM A30 122.9 nM > 10 μM A31 1300.0 nM > 10 μM A32 617.0 nM > 10 μM A33 932.6 nM > 10 μM A34 739.4 nM > 10 μM A35 1960.0 nM > 10 μM A36 1108.0 nM > 10 μM A37 > 10 μM > 10 μM A38 1425.0 nM > 10 μM A39 830.6 nM > 10 μM

[0373] Experiment Example 2: Study of Compound A1 for Subtype Selectivity

[0374] The selectivity for S1P receptor was examined for various subtypes using the method described in Experiment Example 1. The results showed that compound A1 has good selectivity for various subtypes, especially for S1P1 and S1P5 subtypes, as shown in the table below.

[0375] Compound S1P1 EC50 (nM) S1P2 EC50 (nM) S1P3 EC50 (nM) S1P4 EC50 (nM) S1P5 EC50 (nM) A1 48 > 10000 > 10000 > 10000 120 Siponimod 547 > 10000 > 1000 750 0,98 Ozanimod 222 > 10000 2618 > 10000 10,66

[0376] Experiment Example 3: Preliminary Pharmacokinetic Evaluation of Compound A1 in Mice

[0377] Dosage regimen

[0378] Nine male CD-1 mice weighing 20-26 g were randomly divided into three groups of three mice each. The test compounds were administered intragastrically, intravenously, or intraperitoneally according to the following protocol.

[0379] Mice were fasted for 12 hours before testing and drank water freely. Food was consumed evenly 2 hours after administration.

[0380] Three animals were used at each time point, and the grouping and blood collection times are shown in the table below.

[0381] Group Name of the drug Route of administration Dose (mg / kg) Volume of administration (ml / kg) Time of sampling of test samples (h) 1 A1 intragastrically 20 10 0.25, 0.5, 1, 2.4, 8, 24 h 2 intravenously 2 5 0.05, 0.25, 0.75, 2.4, 8, 24 h 3 intraperitoneally 20 5 0.05, 0.25, 0.75, 2.4, 8, 24 h

[0382] The solution for intragastric administration was prepared in a mixture of DMSO / 0.5% HPMC (5:95, v / v) to the final concentration. The solution for intravenous and intraperitoneal administration was prepared in a mixture of DMSO / PEG300 / ethanol / NaCl (5:40:5:50, v / v / v). A sample of the administration solution (50 μL of the solution was mixed with 50 μL of DMSO before and after administration, respectively) was left for testing.

[0383] The drug was administered at the above dose, the administration time was recorded, and 20 μL of blood was collected from the femoral plexus of mice at the above time points and placed in heparinized tubes. The blood was immediately centrifuged at 11,000 rpm for 5 min. Exactly 10 μL of plasma was immediately aspirated into a centrifuge tube pre-filled with 100 μL of PK-IS solution (prepared in a methanol / acetonitrile mixture (1:1, v / v)), mixed well, and frozen at -20°C for testing.

[0384] Pharmacokinetic studies of compound A1 were conducted. Compound A1 was administered orally at a dose of 5071 h*ng / mL, intravenously at a dose of 806 h*ng / mL, and intraperitoneally at a dose of 7975 h*ng / mL. The main pharmacokinetic data are presented in the table below.

[0385] The concentration of drug A1 in the blood plasma of mice (ng / ml) after intraperitoneal administration of 20 mg / kg A1 (ng / ml)

[0386] Time (h) 1 2 3 Average value SD 0,25 1095 1070 3041 1735 1131 0,50 1574 1388 3514 2159 1177 1,00 1914 1843 4055 2604 1257 2,00 571 1318 1662 1184 558 4,00 146 215 65,0 142 75 8,00 25,8 36,4 11,5 24,6 12,5 24,0 4,80 3,80 3,80 4,13 0,58

[0387] < LOQ: less than the lower limit of LOQ (LLOQ = 0.3 ng / ml)

[0388] The concentration of drug A1 in the blood plasma of mice (ng / ml) after oral administration of 2 mg / kg A1 (ng / ml)

[0389] Time (h) 4 5 6 Average value SD 0,05 1786 1521 2513 1940 514 0,25 1041 572 1021 878 265 0,75 178 113 216 169 52 2,00 49,2 39,5 60,6 49,8 10,6 4,00 8,60 11,5 5,20 8,43 3,15 8,00 8,70 2,10 1,10 3,97 4,13 24,0 0,500 0,800 0,500 0,600 0,173

[0390] < LOQ: less than the lower limit of LOQ (LLOQ = 0.3 ng / ml)

[0391] The concentration of drug A1 in the blood plasma of mice (ng / ml) after intraperitoneal administration of 20 mg / kg A1

[0392] Time (h) 4 5 6 Average value SD 0,05 1105 473 715 764 318 0,25 1168 827 1507 1168 340 0,75 1206 1534 3318 2019 1136 2,00 516 1443 4405 2122 2031 4,00 376 201 535 370 167 8,00 273 78,2 119 157 102 24,0 86,9 26,5 35,0 49,5 32,7

[0393] < LOQ: less than the lower limit of LOQ (LLOQ = 0.3 ng / ml)

[0394] Experiment Example 4: Preliminary evaluation of the in vivo pharmacokinetics of compound A1 (DC411151) in rats

[0395] Experimental Plan - Rats

[0396] Group Animal number Input compound Route of administration Administered dose (mg / kg) Volume of administration (ml / kg) 1 1-3 DC411151 intravenously 2 5 2 4-6 DC411151 intragastrically 20 10

[0397] Mice were fasted for 12 hours before testing and drank water freely. Food was consumed evenly 4 hours after administration.

[0398] Preparation of the medicine:

[0399] The drug was first dissolved in DMSO and Tween 80, then saline was added to make a final concentration of 1% DMSO, 2% Tween, 97% saline.

[0400] The drug for intravenous administration was prepared using a mixture of DMSO / HS15 / saline (10 / 10 / 80, v / v / v).

[0401] Sample collection: rats

[0402] Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration (a 5 min sampling point was added in the intravenous administration group); 0.2 ml of blood was collected from the posterior ophthalmic venous plexus at the indicated time points, placed in an EDTA-K2 tube, centrifuged at 11000 rpm for 5 min, plasma was separated and frozen in a freezer at -20 °C.

[0403] Analysis of test sample: The concentration of DC411151 in plasma was determined by LC-MS / MS.

[0404] Data processing: The pharmacokinetic parameters after drug administration were calculated on a non-atrial model using WinNonlin 7.0 software (Pharsight, USA).

[0405] The time to reach maximum plasma concentration, T, was determined max , and the maximum plasma concentration, C, was measured. max .

[0406] Area under the drug concentration-time curve values, AUC 0-t calculated using the trapezoidal method; AUC 0-∞ = AUC 0-t + C t / k e , where C t - the concentration in blood plasma at the last measured point in time, and k e - elimination rate constant.

[0407] Half-life, t 1 / 2 = 0.693 / k e ;

[0408] Mean retention time, MRT = AUMC / AUC

[0409] Excretion rate, CL = D / AUC 0- ∞;

[0410] Distribution volume at equilibrium, V ss = CL × MRT

[0411] Absolute bioavailability, F = (AUC внутрижелудочно × D внутривенно ) / (AUC внутривенно × D внутрижелудочно ) × 100%

[0412] Test results

[0413] Results of pharmacokinetic study in rats

[0414] The plasma drug concentrations after a single intravenous injection of DC411151 at a dose of 2 mg / kg in rats are shown in Table 1, the plasma concentration-time curve is shown in Figure 1, and the relevant pharmacokinetic parameters are shown in Table 2.

[0415] After intravenous administration, the plasma elimination rate of DC411151 in rats was 8.66 ml / min / kg, equivalent to 15.7% of the hepatic blood flow in rats (about 55 ml / min / kg), indicating a drug with low clearance; the apparent distribution volume at steady state, V ss , amounted to 0.758 l / kg, which is comparable to the total volume of fluid in the body of rats (about 0.67 l / kg); the average half-life from plasma, t 1 / 2 , amounted to 3.04 hours.

[0416] The plasma drug concentrations after intragastric administration of DC411151 at a dose of 20 mg / kg in rats are shown in Table 3, the plasma concentration-time curve is shown in Figure 2, and the corresponding pharmacokinetic parameters are shown in Table 4.

[0417] After gavage administration of 20 mg / kg DC411151 to rats, the maximum plasma concentration was reached rapidly with a T max 0.5-1 h and C max 2760 ng / ml, and the area under the drug concentration-time curve, AUC 0-t , was 8780 ng⋅h / ml, calculated as the mean AUC value 0-t after dose adjustment. The absolute bioavailability of 20 mg / kg DC411151 administered to rats via gavage was 22.8%.

[0418] Table 1. Drug concentrations in rat blood plasma after intravenous administration of 2 mg / kg DC411151 ID number 1 2 3 Average value SD Time Concentration (h) (ng / ml) 0,083 3940 3720 3390 3680 277 0,25 2950 2650 2700 2770 161 0,5 1570 1710 1890 1720 160 1 900 1110 951 987 110 2 419 563 528 503 75,1 4 128 138 172 146 23,1 6 45,8 51,4 47 48,1 2,95 8 11,8 13,6 16,9 14,1 2,59 24 < PKO 1,16 1,94 1,55 0,552

[0419] Table 2. Pharmacokinetic parameters in rats after intravenous administration of 2 mg / kg DC411151 ID number AUC0-t AUC0-∞ MRT0-∞ t1 / 2 CL Vss (ng⋅h / ml) (ng h / ml) (h) (h) (ml / min / kg) (l / kg) 1 3550 3570 1,2 1,15 9,34 0,672 2 4030 4040 1,52 3,67 8,26 0,752 3 3960 3980 1,69 4,3 8,38 0,85 Average value 3850 3860 1,47 3,04 8,66 0,758 SD 261 255 0,249 1,67 0,593 0,0892 CV (%) 6,78 6,6 17 54,8 6,84 11,8

[0420] Table 3. Concentrations of the drug in rat blood plasma after intragastric administration of 20 mg / kg DC411151 ID number 4 5 6 Average value SD Route of administration Time Concentration (h) (ng / ml) PO-20 mg / kg 0,25 1960 696 1150 1270 640 0,5 3130 1570 2600 2430 793 1 2560 2070 3070 2570 500 2 2290 1220 2150 1890 582 4 884 635 841 787 133 6 322 350 289 320 30,5 8 65,1 64,0 57,0 62,0 4,39 24 4,33 2,49 2,92 3,25 0,963

[0421] Table 4. Pharmacokinetic parameters in rats after intragastric administration of 20 mg / kg DC411151 Route of administration ID number Tmax Cmax AUC0-t AUC0-∞ MRT0-∞ t1 / 2 (h) (ng / ml) (ng h / ml) (ng h / ml) (h) (h) PO-20 mg / kg 4 0,5 3130 10100 10100 2,62 2,5 5 1 2070 6710 6720 3,00 2,51 6 1 3070 9590 9600 2,55 2,45 Average value 0,833 2760 8780 8790 2,72 2,49 SD 0,289 595 1810 1810 0,243 0,0325 CV (%) 34,6 21,6 20,6 20,6 8,92 1,31

[0422] Experiment Example 5: Preliminary Pharmacokinetic Evaluation of Compound A1 in Beagle Dogs

[0423] Test Plan - Beagle Dogs

[0424] Group Animal number Input compound Route of administration Administered dose (mg / kg) Volume of administration (ml / kg) 1 1-3 DC411151 intravenously 0,5 1 2 4-6 DC411151 intragastrically 3 2 Beagle dogs were fasted for 12 hours before testing and drank water ad libitum. Food was consumed evenly 4 hours after administration.

[0425] Preparation of drug: The drug was first dissolved in DMSO and Tween 80, then physiological saline was added to make a final concentration of 1% DMSO, 2% Tween and 97% physiological saline.

[0426] The drug for intravenous administration was prepared using a mixture of DMSO / HS15 / saline (10 / 10 / 80, v / v / v).

[0427] Sample collection: Before administration and at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 hours after administration (a 5-minute sampling point was added in the intravenous and subcutaneous administration group); at the specified time points, 1 ml of blood was collected from a vein, placed in an EDTA-K2 tube, centrifuged at 3500 rpm for 10 minutes, plasma was separated and frozen in a -20°C freezer.

[0428] Analysis of test sample: The concentration of DC411151 in plasma was determined by LC-MS / MS.

[0429] Data processing: The pharmacokinetic parameters after drug administration were calculated on a non-atrial model using WinNonlin 7.0 software (Pharsight, USA).

[0430] The time to reach maximum plasma concentration, T, was determined max , and the maximum plasma concentration, C, was measured. max .

[0431] Area under the drug concentration-time curve values, AUC 0-t calculated using the trapezoidal method; AUC 0- ∞ = AUC 0-t + C t / k e , where C t - the concentration in blood plasma at the last measured point in time, and k e - elimination rate constant.

[0432] Half-life, t 1 / 2 = 0.693 / k e ;

[0433] Mean retention time, MRT = AUMC / AUC

[0434] Excretion rate, CL = D / AUC 0- ∞;

[0435] Distribution volume at equilibrium, V ss = CL × MRT

[0436] Absolute bioavailability, F = (AUC внутрижелудочно × D внутривенно ) / (AUC внутривенно × D внутрижелудочно ) × 100%

[0437] Test results

[0438] The plasma drug concentrations after a single intravenous injection of DC411151 at a dose of 0.5 mg / kg in beagle dogs are shown in Table 5, the plasma concentration-time curve is shown in Figure 3, and the corresponding pharmacokinetic parameters are shown in Table 6.

[0439] After intravenous administration, the elimination rate, CL, of DC411151 from plasma in beagle dogs was 23.3 ml / min / kg, which is equivalent to 75.2% of the hepatic blood flow in dogs (about 31 ml / min / kg); the apparent volume of distribution at steady state, V ss , amounted to 1.28 l / kg, which is higher than the total volume of fluid in the body of dogs (0.6 l / kg); half-life, t 1 / 2 , amounted to 0.984 h.

[0440] The plasma drug concentrations after intragastric administration of DC411151 at a dose of 3 mg / kg in beagle dogs are shown in Table 7, the plasma concentration-time curve is shown in Figure 4, and the corresponding pharmacokinetic parameters are shown in Table 8.

[0441] After administration of 3 mg / kg DC411151 to beagle dogs via a gastric tube, the time to reach the maximum concentration in blood plasma, T max , was 0.25-2 hours, the maximum concentration in blood plasma, C max , was 366 ng / ml, and the area under the drug concentration-time curve, AUC 0-t , was 1160 ng h / ml, calculated as the mean AUC value 0-t after dose adjustment. The absolute bioavailability of 3 mg / kg DC411151 was 54.0%.

[0442] Table 5. Concentration of the drug in the blood plasma of beagle dogs after intravenous administration of 0.5 mg / kg DC411151 ID number 1 2 3 Average value SD Time Concentration (h) (ng / ml) 0,083 604 554 537 565 34,8 0,25 237 219 340 265 65,3 0,5 190 138 176 168 26,9 1 98,8 76,9 97,1 90,9 12,2 2 27,5 27,8 35,4 30,2 4,48 3 20,4 12,5 20,3 17,7 4,53 4 9,68 7,88 10,6 9,39 1,38 6 2,51 1,64 2,47 2,21 0,491 8 < PKO 1,05 0,496 0,773 0,392

[0443] Table 6. Pharmacokinetic parameters after intravenous administration of 0.5 mg / kg DC411151 in beagle dogs ID number AUC0-t AUC0-∞ MRT0-∞ t1 / 2 CL Vss (ng h / ml) (ng h / ml) (h) (h) (ml / min / kg) (l / kg) 1 375 379 0,910 0,997 22,0 1,20 2 317 319 0,892 1,05 26,1 1,40 3 382 382 0,952 0,905 21,8 1,24 Average value 358 360 0,918 0,984 23,3 1,28 SD 35,5 35,7 0,0309 0,0728 2,45 0,104 CV (%) 9,92 9,92 3,36 7,39 10,5 8,09

[0444] Table 7. Plasma drug concentrations after intragastric administration of 3 mg / kg DC411151 in beagle dogs ID number 4 5 6 Average value SD Route of administration Time Concentration (h) (ng / ml) PO-3 mg / kg 0,25 539 93,3 11,2 215 284 0,5 444 153 188 262 159 1 333 193 318 281 76,9 2 365 242 266 291 65,2 3 212 143 269 208 63,1 4 151 62,7 118 111 44,6 6 90,3 24,0 64,0 59,4 33,4 8 12,0 4,87 15,6 10,8 5,46 24 < PKO < PKO < PKO N / A N / A

[0445] Table 8. Pharmacokinetic parameters after intragastric administration of 3 mg / kg DC411151 in beagle dogs Route of administration ID number Tmax Cmax AUC0-t AUC0-∞ MRT0-∞ t1 / 2 (h) (ng / ml) (ng h / ml) (ng h / ml) (h) (h) PO-3 mg / kg 4 0,25 539 1550 1570 2,58 1,32 5 2 242 757 765 2,44 1,06 6 1 318 1170 1200 2,93 1,3 Average value 1,08 366 1160 1180 2,65 1,23 SD 0,878 154 395 403 0,251 0,142 CV (%) 81 42,1 34,1 34,2 9,48 11,6

[0446] Experiment Example 6: In vivo Analysis of Pharmacological Activity against Obesity, Insulin Resistance, and NASH

[0447] This experiment investigated the effects of long-term oral administration of compound A1 on obesity, insulin resistance, liver lipid accumulation, inflammation and fibrosis in mice with the triple phenotype of obesity, insulin resistance and NASH induced by a high-fat, high-cholesterol, high-fructose diet (Gubra amylin, GAN).

[0448] Animal experiment: Male C57BL / 6 mice were fed the GAN diet to induce NASH model, and after 12 weeks of modeling, the mice were randomly divided into 3 groups: low-fat diet (LFD) control group, n = 6, model control group (model, n = 10), and A1 group (10mg / kg, n = 10), and administered the drug through gavage at a dose of 10mg / kg and a volume of 10ml / kg once a day. During the administration period, food intake and body weight of animals were monitored; after 10 weeks of administration, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed; after 11 weeks of administration, fasting glucose and insulin levels were measured; after 12 weeks of administration, central body temperature and energy metabolism were measured; After 15 weeks of administration, the composition of the body tissues of the mice was measured, the mice were sacrificed by dislocation after blood was taken through the posterior ophthalmic venous plexus, the liver and subcutaneous fat were weighed,Epididymal fat and brown fat, a portion of the liver were fixed in 4% paraformaldehyde, and all tissues and serum were stored at -80°C. This experiment assessed whether the compounds had an effect on weight loss by determining energy metabolism, body tissue composition, and fat mass in mice; whether the compounds had an effect on improving insulin resistance by using GTT, ITT, random blood glucose, fasting blood glucose and insulin, and HOMA-IR; whether the compounds have an effect on improving insulin resistance by determining the serum liver function parameters ALT, AST, triglycerides, total cholesterol (T-CHO), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) levels in serum, triglycerides, T-CHO and hydroxyproline (a characteristic amino acid of collagen) levels in the liver, as well as by measuring the mRNA expression levels of genes associated with the ab initio synthesis and transport of fatty acids (Srebp1c, Scd1, Fasn,Acaca, Cd36), β-oxidative metabolism pathway genes (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), and liver pathological changes (H&E staining, Oil Red O staining and Sirius Scarlet staining) and other indices were determined to evaluate whether the compounds have an effect on improving lipid metabolism disorder, inflammation and fibrosis in the pathological state of NASH.

[0449] The results showed that Compound A1 of the present invention significantly inhibited body weight gain and reduced body fat content in mice by enhancing energy metabolism and promoting thermogenesis without affecting food intake (Figure 1); Compound A1 significantly reduced fasting glucose, insulin, and HOMA-IR, and significantly improved glucose tolerance and insulin sensitivity in mice (Figure 2); Compound A1 significantly reduced liver weight in NASH mice, liver weight / body weight ratio, and serum ALT, AST, triglyceride, T-CHO, LDL-C, and HDL-C levels, as well as liver triglyceride, T-CHO, and hydroxyproline levels (Figure 3);At the gene level, compound A1 significantly increased the mRNA expression of fatty acid oxidation-related genes (Ppara, Cyp4A1, Acot1, and Acox1), and suppressed the mRNA expression of inflammation-related genes (Tnfa, Il1b, Casp1, Pycard, Ccl2, and Ccl3) and fibrosis-related genes (Asma, Tgfb, Col1A1, Col3A1, and Col5a2) (Figure 4); quantitative analysis of hematoxylin and eosin (H&E)-stained pathological liver sections shows that compound A1 significantly decreased the NAS score, significantly alleviated liver ballooning degeneration and inflammation, and had an ameliorating (but not significant) effect on liver lipid accumulation (Figure 5); Quantitative analysis of pathological liver sections stained with Oil Red O showed that compound A1 significantly reduced lipid accumulation in the liver, mainly by reducing the size of lipid droplets (Figure 5);Quantitative analysis of Sirius Scarlet-stained liver pathological sections showed that compound A1 significantly reduced collagen deposition in the liver (Figure 5).

[0450] Thus, long-term administration of Compound A1 could significantly alleviate the obesity and insulin resistance induced by the GAN diet in mice, improve energy metabolism and insulin sensitivity, improve liver function, promote fatty acid oxidation in the liver, reduce inflammation and fibrosis, and have a significant alleviating effect on the symptoms of NASH.

[0451] Experiment Example 7: Pharmacological Activity Analysis in Carbon Tetrachloride (CCl4)-Induced Liver Fibrosis Model

[0452] Male C57BL / 6 mice were intraperitoneally administered 5% CCl4 (in corn oil) solution at a dose of 5ml / kg twice a week to induce liver fibrosis model. Three weeks after the modeling, the mice were randomly divided into five groups: model control group (model, n=12), positive control group receiving FTY720 compound (2mg / kg, n=9), positive control group receiving OCA compound (30mg / kg, n=10), low dose group (3mg / kg), and high dose group (10mg / kg). FTY720 was administered by intraperitoneal injection, and in the other groups, it was administered by gavage once a day. After 5 weeks of administration, the mice were sacrificed by dislocation after blood collection through the posterior ophthalmic plexus, and the liver and spleen were weighed. Part of the liver was fixed in 4% paraformaldehyde, and part of the liver and blood serum were stored at -80°C.Ten mice from the same litter were injected intraperitoneally with the same dose of corn oil throughout the experiment as a systematic control.

[0453] In the CCl4-induced liver fibrosis model, Compound A1 significantly reduced serum ALT levels without affecting the weight of the liver and spleen (Figure 6); at the gene level, high doses of Compound A1 significantly reduced the mRNA expression of liver fibrosis-related genes (Tgfb, Col1a1) (Figure 7); pathological analysis of liver tissues showed that high doses of Compound A1 significantly reduced the hydroxyproline content in the liver, and pathological section analysis showed that Compound A1 significantly reduced collagen deposition in the liver (Figure 8).

[0454] Experiment Example 8: Pharmacological Activity Analysis in the Methionine Choline Deficient High-Fat Diet (MCD-HFD)-Induced NASH Model

[0455] Male C57BL / 6 mice were fed MCD-HFD diet to induce NASH model, and 4 weeks after the modeling, the mice were randomly divided into 3 groups: normal diet control group (control, n = 9), model control group (model, n = 10), BAF312 compound-treated positive control 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), and were administered the drug by gavage at a dose of 5 mg / kg once a day. During the administration period, food intake and body weight of the animals were monitored; Four weeks after administration, mice were sacrificed by dislocation after blood sampling through the posterior ophthalmic plexus, the liver and spleen were weighed, part of the liver was fixed in 4% paraformaldehyde, all tissues and blood serum were stored at -80°C.

[0456] In the methionine-choline-deficient high-fat diet (MCD-HFD)-induced NASH model, Compound A1 significantly decreased the serum ALT and AST levels in the high-dose group without affecting body weight, while significantly reducing the accumulation of TG in the liver (Figure 9); at the gene level, high / medium / low doses of Compound A1 significantly reduced the mRNA expression of liver inflammation-related genes (Tnfa, Il1b, Nlrp3, Ccl2) to different extents, and the analysis of H&E-stained pathological liver sections showed that high doses of Compound A1 were effective in reducing liver lipid accumulation and inflammatory infiltration (Figure 10); High / medium doses of compound A1 were also variably effective in reducing liver hydroxyproline levels and significantly reduced the expression levels of fibrosis-related genes (Asma, Tgfb, and Col1a1) at the gene level (Figure 11).

[0457] Experiment Example 9: Pharmacological Activity Analysis in Sodium Dextran Sulfate (DSS)-Induced Inflammatory Bowel Disease Models

[0458] The mice were randomly divided into 5 groups: normal control group (control, n = 5), model control group (model, n = 11), BAF312 compound-treated positive control group (0.3 mg / kg, n = 10), low dose group (0.03 mg / kg, n = 10), middle dose group (0.3 mg / kg, n = 10), high dose group (3 mg / kg, n = 10), and each group was administered by gavage at a volume of 5 ml / kg once a day. DSS with an average molecular weight of 36,000-50,000 Da was dissolved in drinking water to prepare a 2% DSS solution, and the mice in the model group were allowed to drink it freely for 6 days while receiving the drug administration treatment. In each group, body weight, fecal hardness, and fecal occult blood testing were determined daily, and the scores were summed to obtain a disease activity index for each animal.Six days after completion of the modeling and drug administration, the modeling reagents were discontinued for a 1-day remission period, and the mice were sacrificed by dislocation after blood was collected through the posterior ophthalmic plexus. Colon and spleen tissues were weighed or their length was measured, a portion of the colon was fixed in 4% paraformaldehyde, and all tissues and serum were stored at -80°C.

[0459] In the sodium dextran sulfate (DSS)-induced inflammatory bowel disease (IBD) model, high / medium / low doses of compound A1 were differently effective in alleviating the pathological process (Figure 12); in the analysis of the colon lesions, high / medium / low doses of compound A1 were differently effective in alleviating the shortening of the colon length in IBD mice without affecting the spleen weight; analysis of the H&E-stained colon pathological sections showed that high / medium doses of compound A1 could effectively improve the damaged crypt and alleviate the inflammatory infiltration in the colon lesions (Figure 13).

[0460] Thus, long-term administration of Compound A1 can significantly alleviate the obesity and insulin resistance induced by the GAN diet in mice, improve energy metabolism and insulin sensitivity, enhance liver function, promote fatty acid oxidation in the liver, reduce inflammation and fibrosis, and have a significant alleviating effect on the symptoms of NASH. It also had an effective alleviating effect in the CCl4-induced liver fibrosis model and the MCD-HFD diet-induced NASH model. In addition, Compound A1 also had significant anti-inflammatory effects and improved the pathological process in the IBD model.

[0461] All documents mentioned in this application are incorporated by reference in the same manner as if each document were individually incorporated by reference. Furthermore, it should be understood that, after reviewing the above description of the present invention, various changes or modifications can be made to the present invention by those skilled in the art, and such equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound represented by formula I, a pharmaceutically acceptable salt thereof: where the compound has the formula II where Y 1 , Y 2 , Y 3 and Y 4 - each independently represents CH; M is selected from the group consisting of a substituted phenyl ring and a substituted or unsubstituted 5-10 membered aromatic heterocycle containing from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; where the group substituted in M ​​means that the group may be substituted by one or more R groups 1 ; And each R 1 independently selected from the group consisting of hydrogen, halogen, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted C1-C6 alkoxy group; X is selected from the group consisting of CHR 2 ; R 2selected from the group consisting of hydrogen; n represents 2; R 3 selected from the group consisting of carboxyl, C(O)R 5 ,-C(O)OR 5 ; R 5 selected from the group consisting of an amino group, possibly mono- or disubstituted by C1-C6 alkyl, unsubstituted C1-C6 alkyl; R 6 is hydrogen.

2. A compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of substituted or unsubstituted furanyl and substituted or unsubstituted thienyl.

3. A compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, where M has the following structure: where A is a phenyl ring; each R 1independently selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxyl, nitro, aldehyde group, unsubstituted C1-C6 alkyl, C1-C3 alkyl containing 1-7 fluorine atoms, substituted or unsubstituted C1-C6 alkoxy group; a represents 1, 2, or 3.

4. A compound of formula I according to claim 3, a pharmaceutically acceptable salt thereof, wherein ring A is a benzene ring; each R 1 independently selected from the group consisting of cyano, substituted or unsubstituted C1-C6 alkoxy group; a represents 1 or 2.

5. A compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: № Name Structure A1 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A30 1-((4-(5-(5-methylisothiazol-3-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azetidine-3-carboxylic acid hydrochloride A44 methyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A45 ethyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A46 isopropyl 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylate A47 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxamide A48 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N-methylazetidine-3-formamide A49 1-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)-N,N-dimethylazetidine-3-formamide A59 1-((4-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A60 1-((4-(5-(4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A61 1-((4-(5-(5-methoxy-4-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A62 1-((4-(5-(furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A63 1-((4-(5-(4-(trifluoromethyl)furan-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A64 1-((4-(5-(4-cyanofuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride A65 1-((4-(5-(4-isopropoxyfuran-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-1-yl)methyl)azelaic acid-3-carboxylic acid hydrochloride 6. A pharmaceutical composition in which the pharmaceutical composition comprises one or more compounds of formula I according to claim 1, their pharmaceutically acceptable salts in a therapeutically effective amount and one or more pharmaceutically acceptable carriers, excipients, adjuvants, ingredients and / or diluents, wherein the pharmaceutical composition is intended for the treatment or prevention of diseases associated with S1P agonists; and the disease is selected from the group consisting of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis, psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease and clinically isolated syndrome.

7. The use of a compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment or prevention of diseases associated with S1P agonists; and the disease is selected from the group consisting of non-alcoholic fatty liver disease, liver fibrosis, diabetes mellitus, hyperlipidemia, multiple sclerosis, psoriasis, ulcerative colitis, systemic lupus erythematosus, Crohn's disease, immune disorders, wet age-related macular degeneration, atopic dermatitis, inflammatory bowel disease and clinically isolated syndrome.

8. The use according to claim 7, wherein the disease is selected from the group consisting of relapsing multiple sclerosis, relapsing-remitting multiple sclerosis and active secondary progressive multiple sclerosis.

9. A method for producing a compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, comprising the following steps: (1) reacting a compound of formula Ic with M-COOH, HOBT, EDCI and potassium carbonate in DMF to give a compound of formula Ib; (2) reacting a compound of formula Ib in a dilute acetone / hydrochloric acid mixture to obtain a compound of formula Ia; (3) reaction of the compound of formula Ia with the hydrochloride , DIPEA, acetic acid and sodium cyanoborohydride in a methanol / dichloromethane mixture to give a compound of formula I, where X is CH2.

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