Novel substituted heterocyclic compound as apelin receptor modulator

Abstract

Disclosed in the present invention is a compound having significant Apelin receptor modulation activity, and specifically disclosed is a compound represented by the following formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isotopologue, or isomer thereof.

Description

Novel substituted heterocyclic compounds as apelin receptor modulators Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically including novel heterocyclic compounds with Apelin receptor regulatory function, compositions containing such compounds, and methods for using such compounds to prepare medicaments for treating or preventing diseases related to Apelin receptors or signaling pathways. Background Technology

[0002] With the improvement of living standards, overweight and obesity are becoming increasingly common in modern society. The number of patients suffering from obesity-related complications such as diabetes and fatty liver disease is growing rapidly, creating a huge demand. Reports from the World Health Organization (WHO) and Zhiyan Consulting predict that by 2030, there will be 3.26 billion obese people globally; by 2029, there will be over 500 million people with diabetes globally; and over 1.5 billion people with non-alcoholic fatty liver disease globally. Currently, there are no effective treatments for fatty liver disease; only six drugs have been approved by the FDA for obesity, and most of them are controlled substances with weak efficacy and significant side effects; although many drugs have been approved for type 2 diabetes, the blood sugar control rate of existing hypoglycemic drugs (<7%) remains low, even the most active combination drugs only achieve a target rate of around 45%. Therefore, new drugs are needed for fatty liver disease, obesity, and diabetes to meet the needs of a wider range of patients.

[0003] Glucagon-like peptide-1 (GLP-1) is a long peptide hormone consisting of 30 or 31 amino acids. It is produced and secreted by certain neurons in the intestinal endocrine L cells and the nucleus of the solitary tract in the brainstem during eating. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, decreases appetite, and stimulates β-cell proliferation. In non-clinical studies, GLP-1 promotes the sustained capacity of β-cells by stimulating the transcription of important genes for glucose-dependent insulin secretion and promoting β-cell regeneration (Meier, et al. Biodrugs. 2003; 17(2):93-102). The GLP-1 receptor has been shown to be an ideal target for metabolic diseases such as obesity, diabetes, and fatty liver. Several GLP-1R agonist peptide drugs, such as dulaglutide and semaglutide, have been approved for marketing abroad for the treatment of diabetes and weight loss.

[0004] However, research has found that long-term use of GLP-1 peptides such as semaglutide, while reducing fat, can also lead to muscle loss. Muscle loss may increase the risk of cardiovascular disease, osteoporosis, and other illnesses, especially for the elderly, where muscle loss can mean a significantly increased risk of death.

[0005] Apelin is a polypeptide hormone produced by adipocytes, endothelial cells, and cardiomyocytes, which regulates cellular physiological functions by binding to its receptor APJ (apelin receptor). The apelin / APJ signaling pathway plays a crucial role in various physiological and pathological processes. For example, it is involved in the regulation of the cardiovascular system, including myocardial contractility, myocardial metabolism, vasomotor activity, and blood pressure. Furthermore, the apelin / APJ signaling pathway also plays an important regulatory role in energy metabolism, exercise endurance, inflammatory responses, and immune activity. When apelin binds to the APJ receptor, it activates multiple downstream signaling pathways, such as PI3K / Akt, AMPK, and MAPK, thereby regulating various physiological and pathological processes. Particularly in cardiovascular diseases, the apelin / APJ signaling pathway exerts a protective effect by inhibiting various cardiac injury-induced pathological processes, such as reducing myocardial ischemia-reperfusion injury and decreasing myocardial inflammation. The apelin / APJ signaling pathway also plays an important role in glucose and lipid metabolism. Related studies have shown that apelin can increase insulin sensitivity, promote glucose uptake and utilization, inhibit fatty acid synthesis, and promote fatty acid oxidation, thereby playing a role in regulating energy metabolism.

[0006] Recent studies have found that apelin receptor modulators have a synergistic effect with GLP1-related target peptide drugs, which can reduce muscle loss while decreasing body weight. Although some apelin receptor modulators, such as BGE-105, are currently in clinical trials and have achieved preliminary clinical validation, these compounds generally suffer from drawbacks such as short half-life, rapid metabolism, low bioavailability, and high clinical dosages. Therefore, there is an urgent need to develop new apelin receptor modulators with better drug-like properties to address muscle loss-related diseases.

[0007] Technical effect

[0008] The inventors unexpectedly discovered that some of the heterocyclic novel compounds of formula (I) of this invention not only have significant Apelin receptor regulatory activity, but also have better solubility, bioavailability and exposure, and longer half-life compared to the structurally known reference compound BGE-105. It is expected that they will have better human pharmacokinetic properties and be more suitable as candidate drugs for the prevention or treatment of diseases related to Apelin receptors or signaling pathways, such as muscle loss. Summary of the Invention

[0009] The object of this invention is to provide compounds of formula (I) or pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutes thereof.

[0010] in,

[0011] A and B are arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures;

[0012] Z can be arbitrarily and independently selected from CR1 or N;

[0013] L1 and L2 are independently selected from non-existent, single bond, and -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-,

[0014] X is independently selected as non-existent, single bond, -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-;

[0015] R0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1- 10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic groups;

[0016] Each R1 can be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, pentafluoride sulfide, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3- 10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: Furthermore, the hydrogen on R1 is preferably further selected by one or more groups chosen from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9The substituents can be substituted; or any two adjacent R1 groups together with their attached carbons can form a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1- 6-alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0017] Each R2 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, pentafluoride sulfide, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3- 10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: Furthermore, the hydrogen atom on R2 is preferably further selected by one or more groups chosen from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9The substituents can be substituted; or any two adjacent R2 groups together with their attached atoms can form a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen atoms thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0018] Each R3 can be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH2, -COOH, C 1- 10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: Furthermore, the hydrogen atom on R3 is preferably further selected by one or more groups chosen from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 The substituents can be substituted; or any two adjacent R3 atoms together with their attached atoms can form a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen atoms thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted.

[0019] Each R4 can be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, pentafluoride sulfide, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3- 10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: Furthermore, the hydrogen on R4 is preferably further selected by one or more groups chosen from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 The substituents can be substituted; or any two adjacent R4 atoms together with their attached atoms can form a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen atoms thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0020] Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10 They can be the same or different, and are independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes or -LQ groups; further R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10 The preferred further option is to use one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents; or any two adjacent R groups. d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10Together with the atoms attached thereto, it forms a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1- 6-alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution;

[0021] The L in -LQ is independently selected as non-existent, single bond, -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-, Q is selected from the following structural fragment:

[0022] in "Any" represents a single or double bond; Xa and Xb are arbitrarily and independently selected from CRb or N;

[0023] Each R a R b and Rc They can be the same or different, and are independently selected from hydrogen, deuterium, halogens, -CN, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups, and 3-8 saturated or partially saturated heterocyclic groups; and R a R b and R c The hydrogen atom is optionally preferably replaced by one or more substituents, said substituents being selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d8 R d9 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 The aryl, heteroaryl, 6-10 aryl, and 5-8 heteroaryl groups are saturated or partially saturated; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group is optionally substituted by one or more substituents, wherein the substituents are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group is preferably substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH.

[0024] The term "heteroatom" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P.

[0025] The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes;

[0026] m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0027] n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5;

[0028] r is any integer selected from 0, 1, 2, 3, 4, and 5;

[0029] t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

[0030] u is any integer selected from 0, 1, 2, and 3;

[0031] v is any integer selected from 0, 1, 2, and 3.

[0032] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, an isotope-substituted thereof, an isomer thereof, or a prodrug thereof:

[0033] Among them, R 1 C 1-6 Alkyl, halogen or -OC 1-6 Alkyl group, or any two adjacent R groups 1 Together with the attached carbon, they form "5-6 membered heteroaromatic rings containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N" or "5-7 membered heterocyclic alkenes containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N";

[0034] A1, A2, and A3 are independently CH or N;

[0035] Ring A is C 6-20 Aryl or "5-12 membered heteroaryl groups containing 1-3 heteroatoms, each heteroatom being independently selected from O, S, and N";

[0036] R 2 and R 3 Independently for C 1-6 Alkyl, C 3-8 cycloalkyl, halogen or -OC 1-6 alkyl;

[0037] m, n, and t are independently 0, 1, 2, or 3.

[0038] In one embodiment, the structure of the compound as described above (e.g., Formula I) is shown in Formula II:

[0039] The definitions of each group in the formula are as described above.

[0040] In a certain scheme, when R 1 When the description is "a 5-7 membered heterocyclic olefin containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N", then the "5-7 membered heterocyclic olefin containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N" is a spiroheterocyclic olefin, for example,

[0041] In one of the solutions, for

[0042] In one embodiment, when ring A is defined as "containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N, forming a 5-12 membered heteroaryl group," ring A is either a monocyclic or bicyclic heteroaryl group. The monocyclic heteroaryl group is a 5-6 membered heteroaryl group containing 1-2 heteroatoms, each heteroatom independently selected from N and S. The bicyclic heteroaryl group is an 8-10 membered heteroaryl group containing 1-3 heteroatoms, each heteroatom independently selected from N and S.

[0043] In one of the solutions, for

[0044] In a particular embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, wherein the compound represented by Formula I is any of the following compounds:

[0045] In one embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0046] Compounds with a retention time of 2.257 min under the following conditions Equipment: Waters SFC 80; Column: Column Name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: ACN (+0.1% 7.0mol / L ammonia in methanol solution), A:B=50:50; wavelength: 214nm; flow rate: 70 mL / min; column temperature: room temperature; back pressure: 100 bar.

[0047] Compounds with a retention time of 2.185 min under the following conditions Equipment: Waters SFC 80; Column: Column Name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol / l Ammonia in IPA), A:B = 45:55; wavelength: 214nm; flow rate: 70 mL / min; column temperature: room temperature; back pressure: 100 bar.

[0048] Compounds with a retention time of 2.661 min under the following conditions Equipment: Waters SFC 80; Column: Column Name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: ACN (+0.1% 7.0mol / l ammonia solution), A:B = 50:50; wavelength: 214nm; flow rate: 70 mL / min; column temperature: room temperature; back pressure: 100 bar.

[0049] Compounds with a retention time of 2.677 min under the following conditions Equipment: Waters SFC 80; Column: Column Name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 45:55; wavelength: 214nm; flow rate: 70 mL / min; column temperature: room temperature; back pressure: 100 bar.

[0050] Compounds with a retention time of 2.607 min under the following conditions Equipment: Waters SFC 80; Column: Column Name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 70:30; wavelength: 214nm; flow rate: 50 mL / min; column temperature: room temperature; back pressure: 100 bar.

[0051] In one aspect of the present invention, the compound represented by Formula I as described above is any of the following compounds:

[0052] The present invention also provides a pharmaceutical composition comprising the compound as described above, a pharmaceutically acceptable salt thereof, an isotope substitute thereof, an isomer thereof, or a prodrug thereof.

[0053] This invention also provides the use of the compound as described above in the preparation of a medicament for the prevention and / or treatment of Apelin receptor-related or Apelin receptor-associated diseases. The Apelin receptor-related or Apelin receptor-associated diseases include, but are not limited to, overweight, obesity, diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1B), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), mature juvenile diabetes (MODY), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disease, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including... Weight gain can be caused by various factors, including hypothalamic obesity and monogenic obesity, as well as related comorbidities such as osteoarthritis and urinary incontinence; eating disorders such as binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndrome; weight gain due to the use of other medications (e.g., steroid and antipsychotic use); excessive sugar consumption; dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hyperinsulinemia); and NAFLD (including fatty degeneration and NAS). H. Related diseases such as fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular diseases, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (such as necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipids, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic kidney disease. Prevention or treatment of conditions such as functional failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and addiction treatment (such as alcoholism and / or drug abuse).

[0054] Definitions and explanations:

[0055] C 1-10Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 C 2-10 Selected from C2, C3, C4, C5, C6, C7, C8, C9 and C 10 C 3-10 Selected from C3, C4, C5, C6, C7, C8, C9 and C 10 ;

[0056] As used herein, the term "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl, and hexyl.

[0057] In this invention, C 1-6 Alkyl groups are preferably C 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0058] The term "alkylene" as used in this article refers to the formula -(CH2). n - A straight-chain or branched divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0059] As used herein, the term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group containing at least three carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0060] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0061] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0062] Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0063] The term "pharmaceutically acceptable salt" as used herein refers to derivatives of the compounds of this invention, wherein the parent compound is modified by salting with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of anions such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, etc. Conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, etc. The inorganic and organic bases mentioned above, such as hydroxyethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid, are selected from Na, potassium, magnesium, calcium, etc., or amines, diethylamine, triethylamine, ethanolamine, etc.

[0064] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0065] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0066] Some compounds of the present invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

[0067] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0068] The illustrations of racemic, ambiscalemic and scalemic, or enantiomerically pure compounds in this document are derived from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, wedge-shaped and dashed lines denote the absolute configuration of a stereocenter. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of this invention.

[0069] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0070] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0071] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0072] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0073] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0074] When a substituent can be cross-bonded to two atoms on a ring, it can bond to any atom on that ring. When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, it can bond to any atom of that substituent. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0075] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0076] The present invention is now further described by way of examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many methods known in the field of organic synthesis. The embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by modifications thereof. Preferred methods include, but are not limited to, the methods described below.

[0077] Unless otherwise specified, all solvents used in this invention are commercially available and require no further purification. Reactions are typically carried out in an anhydrous solvent under an inert nitrogen atmosphere. Nuclear magnetic resonance (NMR) spectra were determined using a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in δ (ppm). Mass spectrometry was performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS or a Shimadzu MS (DAD:SPD-M20A(LC)) and a Shimadzu Micromass 2020 detector. The mass spectrometer was equipped with an electrospray ionization (ESI) source operating in both positive and negative modes.

[0078] The abbreviations used are as follows: aq for aqueous solution; TLC for thin-layer chromatography; RT for room temperature; MeOH for methanol; EtOH for ethanol; EtOAc for ethyl acetate; THF for tetrahydrofuran; equivalent (eq); CDI for carbonyl diimidazole; DCM for dichloromethane; PE for petroleum ether; DIAD for diisopropyl azodicarbonate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; CBz for benzyloxycarbonyl; BOC for tert-butylcarbonyl; HOAc for acetic acid; Ms for methanesulfonyl; NMP for N-methylpyrrolidone; DMAP for 4-(dimethylamino)pyridine; Boc2O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine; SOCl2 for thionyl chloride; CS2 for carbon disulfide; TsOH for 4-toluenesulfonic acid; MTBE for tert-butyl methyl ether; i-PrOH for 2-propanol.

[0079] Compounds can be named manually or using... The reaction should be named accordingly; if commercially purchased, the supplier's catalog name can also be used. TLC or LC-MS is typically used to determine whether the reaction is complete. Detailed Implementation

[0080] To illustrate the invention in more detail, the following examples are given, but the scope of the invention is not limited thereto.

[0081] Example 1: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)but-2-sulfonamide (compound 1):

[0082] 1) Synthesis of tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazine-1-carboxylic acid:

[0083] At room temperature, HATU (1850 mg, 4.80 mmol) and DIEA (1256 mg, 9.60 mmol) were added to a solution of 3-fluoro-5-methylbenzoic acid (500 mg, 3.20 mmol) and tert-butyl hydrazide carboxylate (642 mg, 4.80 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, 254 nm) to give tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazide-1-carboxylate (0.66 g, 2.40 mmol, yield: 75.8%), LCMS m / z: 212 [M+H]. +

[0084] 2) Synthesis of 3-fluoro-5-methylbenzoylhydrazide:

[0085] At room temperature, 2,2,2-trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazine-1-carboxylic acid (660 mg, 2.46 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to >7 (8–9) with aqueous NaHCO3 solution, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-fluoro-5-methylbenzoylhydrazine (320 mg, 1.90 mmol, yield: 77.5%), LCMS m / z: 169 [M+H]. + .

[0086] 3) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide:

[0087] A solution of acetonitrile (10 mL) containing 3-fluoro-5-methylbenzoylhydrazine (36 mg, 0.218 mmol) was cooled to 0 °C, and then 2-isothiocyano-1,3-dimethoxybenzene (47 mg, 0.240 mmol) and Cs₂CO₃ (92 mg, 0.283 mmol) were added. The mixture was stirred at 25 °C for 16 hours. LC-MS showed that the reaction was complete. The mixture was cooled to 0 °C, and (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (49 mg, 0.218 mmol) and AgNO₃ (74 mg, 0.436 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LC-MS showed that the reaction was complete. The mixture was diluted with H₂O (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1, 254 nm) to give (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (100 mg, 0.18 mmol, yield: 83%), LCMS m / z: 578 [M+18+H] + .

[0088] 4) Synthesis of ((2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide:

[0089] To a solution of 1,4-dioxane (10 mL) containing (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (120 mg, 0.215 mmol), MeSO3H (41 mg, 0.430 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed the reaction was complete. The reaction was quenched with H2O (30 mL), and the pH was adjusted to 7 with saturated NaHCO3. The mixture was then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (chromatogram: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 52-67%; retention time: 8.9-9.4 min, 17 min) to obtain the product. This product was then purified by critical fluid chromatography (conditions: system: Waters SFC 150; column name: ...). Column size: 250*25mm 10um; Mobile phase A: supercritical CO2; Mobile phase B: MeOH (with 0.1% 7.0mol / L ammonia methanol solution added), A:B = 70:30; Wavelength: 214nm; Flow rate: 120mL / min; Column temperature: room temperature; Back pressure: 100bar; Injection volume: 2.0mL; Cycle time: 10min) was purified to obtain ((2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (16.31mg, 0.03mmol, yield: 14.0%), LCMS m / z: 541 [M+H] +

[0090] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),8.59(s,2H),7.50(t,J=8.4Hz,1H),7.16(d,J=10.4Hz,1H),7.08(s,1H),6.8 4-6.78(s,3H),3.68(s,6H),3.61-3.59(m,1H),2.24(d,J=4.4Hz,6H),1.23(d,J=6.8Hz,4H),1.09(d,J=6.8Hz,3H).

[0091] 19F NMR (377MHz, DMSO-d6) δ 112.72

[0092] Example 2: Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (compound 2):

[0093] 1) Synthesis of 2-chloro-5-cyclopropylpyrimidine:

[0094] At room temperature, Pd(dppf)Cl2 (10.58 g, 12.953 mmol) and H2O (150 mL) were added to a solution of 5-bromo-2-chloropyrimidine (25 g, 129.53 mmol), cyclopropylboronic acid (33.41 g, 388.59 mmol), K2CO3 (89.37 g, 647.65 mmol), and tetrahydrofuran (750 mL). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, 254 nm) to give 2-chloro-5-cyclopropylpyrimidine (10.74 g, 69.29 mmol, yield: 53.51%), LCMS m / z: 155 [M+H]. + .

[0095] 2) Synthesis of (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine:

[0096] At room temperature, 2-chloro-5-cyclopropylpyrimidine (5 g, 32.34 mmol), (E)-but-2-en-2-yltrifluoro-λ was dissolved in water. 4 In a solution of potassium boronide (6.31 g, 38.8 mmol) in dioxane (100 mL), Pd(dppf)Cl2 (2.37 g, 3.234 mmol), water (10 mL), and K2CO3 (13.44 g, 97.02 mmol) were added, and the mixture was heated to 80 °C and stirred for 16 hours. LCMS showed that the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1, 254 nm) to give (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine (4.8 g, 27.54 mmol, yield: 85%), LCMS m / z: 175 [M+H]. + .

[0097] 3) Synthesis of 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine:

[0098] A solution of pyrimidine-2-thiol (3.089 g, 27.58 mmol) in dichloromethane (115 mL) was cooled to 0 °C, and SO2Cl2 (3.7 g, 27.58 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then continued for another hour. After cooling to 0 °C, (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine (4.8 g, 27.58 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 0%-30%) to 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine (4.34 g, 13.52 mmol, yield: 49%), LCMS m / z: 321 [M+H] + .

[0099] 4) Synthesis of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine:

[0100] At room temperature, a solution of 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine (4.34 g, 13.52 mmol), dichloromethane (100 mL), and m-CPBA (10.49 g, 60.84 mmol) was stirred for 16 hours. LCMS showed that the reaction mixture was complete. The mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine (12.36 g, crude). LCMS m / z: 353 [M+H] + .

[0101] 5) Synthesis of potassium (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate:

[0102] At room temperature, a solution of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine (9.73 g, 27.58 mmol), methanol (100 mL), and potassium carbonate (11.42 g, 82.75 mmol) was stirred at 25 °C for 16 hours. LC-MS showed that the reaction mixture was complete. The reaction mixture was concentrated under reduced pressure to obtain (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate potassium (25.45 g, crude product), which was used directly in the next step without further processing.

[0103] 6) Synthesis of (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide:

[0104] Potassium acetate (5.4 g, 55.17 mmol) was added to 100 mL of water containing potassium (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate (25.45 g, 27.58 mmol) and (aminooxy)sulfonic acid (9.35 g, 82.75 mmol), and the mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0%–5%) to give (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide (1.18 g), LCMS m / z: 254 [M+H]. + .

[0105] 7) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide:

[0106] At room temperature, SP-4-PI (9.6 mg, 0.0237 mmol, CAS: 351378-22-8) and 849924-4-3 (17.5 mg, 0.027 mmol) were added to a methanol (10 mL) solution containing (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide (300 mg, 1.185 mmol) and zinc trifluoromethanesulfonate (86 mg, 0.24 mmol). The mixture was stirred at room temperature for 32 hours under a hydrogen atmosphere (3 MPa). LCMS showed complete mixing. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water (0.01 M NH4HCO3); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 0% B-35% B over 20 min; detector: 254 nm). The fraction containing the product was collected at 32% B and concentrated under reduced pressure to give (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (111 mg, 0.44 mmol, yield: 36%), LCMS m / z: 256 [M+H). + .

[0107] 8) Synthesis of (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboximide:

[0108] A solution of acetonitrile (5 mL) containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (111 mg, 0.44 mmol) was cooled to 0 °C, and then 2-isothiocyano-1,3-dimethoxybenzene (107.6 mg, 0.71 mmol) and cesium carbonate (302 mg, 0.93 mmol) were added. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the reaction was complete. The mixture was cooled to 0 °C, and 5-methylnicotinamide (72.3 mg, 0.48 mmol) and AgNO3 (242 mg, 1.42 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0%–5%) to (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazide-1-carboximide (178 mg, 0.32 mmol, yield: 72%), LCMS m / z: 568 [M+H] + .

[0109] 9) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide:

[0110] Add M to a solution containing (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazide-1-carboximide (178 mg, 0.313 mmol) in 5 mL of 1,4-dioxane. SOH (60 mg, 0.626 mmol) was added and heated to 90 °C with stirring for 16 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water (30 mL), and the pH was adjusted to 7 with saturated NaHCO3, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (Chromatography: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 27%–37%; retention time: 10.8–12.8 min (18 min)). The fraction containing the product was collected at 48% B and concentrated under reduced pressure to obtain the product. The product was then passed through a supercritical fluid (conditions: system: Waters SFC 150; column name: AD column size: 250*30mm × 10μm; Mobile phase A: supercritical CO2; Mobile phase B: IPA (+0.1% 7.0mol / L NH3 / MeOH), A:B = 55:45; Wavelength: 214nm; Flow rate: 140mL / min; Column temperature: room temperature; Back pressure: 100bar; Injection volume: 8mL; Cycle time: 7min) The prepared and separated (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (19.81mg, 0.036mmol, yield: 11.49%) was obtained. LCMS m / z: 550 [M+H] + .

[0111] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.50(s,2H),8.46(s,1H),8.19(s,1H),7.61(s,1H),7.49(t,J=8.6Hz,1H),6.82(dd,J=8.5,2.9Hz,2H),3.68 (d,J=1.8Hz,7H),3.60(s,1H),2.25(s,3H),1.96–1.86(m,1H),1.23(d,J =7.1Hz,3H),1.09(d,J=6.9Hz,3H),1.04–0.98(m,2H),0.84–0.78(m,2H).

[0112] Example 3: Synthesis of (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (compound 3):

[0113] 1) Synthesis of 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane]:

[0114] To a solution of 10 mL of dichloromethane containing 150 mg (0.93 mmol) of 2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine, saturated NaHCO3 (3 mL) was added. The mixture was cooled to 0 °C, and triphosgene (321 mg, 2.80 mmol) was added. The mixture was allowed to rise to room temperature and stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 0% to 10%) to obtain the compound 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (110 mg, 0.54 mmol, yield: 58.0%), LC-MS m / z: 221 [M+18]. + .

[0115] 2) Synthesis of (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide:

[0116] The compound (3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide) (90 mg, 0.39 mmol, 1.0 eq) was dissolved in ACN (10 mL), cooled to 0°C, and 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (90 mg, 0.44 mmol) and Cs₂CO₃ (171 mg, 0.51 mmol) were added. The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The mixture was cooled to 0°C, and 5-methylnicotinamide (59 mg, 0.39 mmol) and AgNO₃ (137 mg, 0.78 mmol) were added. The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 0% to 5%) to obtain (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (130 mg, 0.24 mmol, yield: 61.5%), LCMS m / z: 550 [M+H]. + .

[0117] 3) Synthesis of (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide:

[0118] To a solution of 1,4-dioxane (10 mL) containing (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (120 mg, 0.22 mmol), MeSO3H (41 mg, 0.44 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed that the reaction was complete. Water (30 mL) was added to the reaction mixture, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (conditions as follows: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 52-67%, retention time: 8.9-9.4min of 17min) to obtain the crude product. The crude product was then purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column: ...). 250*25mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol), A:B = 80:20; Detection wavelength: 214nm; Flow rate: 140mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 8mL; Cycle time: 11min) to obtain (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (12.67mg, 0.024mmol, yield: 10.9%), LCMS m / z: 532 [M+H] + .

[0119] 1H NMR (400MHz, DMSO-d6) δ8.60-8.56(m,2H),8.32(d,J=2.0Hz,1H),8.18(d,J=1.6Hz,1H),7.59(s,1H),7.25-6.96(m,2H),6.94-6.86(m,2H),4.38(dd ,J=20.4,8.8Hz,1H),4.23(d,J=8.8Hz,1H),4.14-4.01(m,1H),3.82-3.73 (m,1H),2.25-2.21(m,6H),1.30(dd,J=7.2,2.4Hz,3H),1.13-1.00(m,7H).

[0120] Example 4: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (compound 4):

[0121] 1) Synthesis of quinoline-3-formylhydrazide

[0122] At room temperature, hydrazine monohydrate (267 mg, 5.34 mmol) was added to a 5 mL ethanol solution containing methyl quinoline-3-carboxylate (500 mg, 2.67 mmol), and the mixture was heated to 90 °C and stirred for 16 hours. LCMS showed the formation of the target product. The reaction mixture was purified by reversed-phase rapid column chromatography (conditions: column: spherical C18, 20-40 μm, 130 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 20% B-80% B over 25 min; detector: 254 nm). The fraction containing the product was collected under 25% B and concentrated under reduced pressure to give quinoline-3-carboxyhydrazide (300 mg, 1.60 mmol, yield: 60.0%), LCMS m / z: 188 [M+H]. + .

[0123] 2) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazine-1-carboximide

[0124] Add 10 mL of acetonitrile to a solution containing 50 mg (0.22 mmol) of 3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide and cool to 0 °C. oC, add 2-isothiocyano-1,3-dimethoxybenzene (47 mg, 0.24 mmol) and Cs2CO3 (92 mg, 0.28 mmol), and stir at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was cooled to 0°C, and quinoline-3-formylhydrazide (41 mg, 0.218 mmol) and silver nitrate (74 mg, 0.44 mmol) were added. The mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. Water (30 mL) was added to the mixture, and it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0% to 5%) to give (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazide-1-formylimide (100 mg, 0.17 mmol, yield: 77.3%), LCMS m / z: 578 [M+H]. + .

[0125] 3) Preparation of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0126] To a solution of 1,4-dioxane (10 mL) containing (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazine-1-carboximide (100 mg, 0.17 mmol), MeSO3H (33 mg, 0.34 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed that the reaction was complete. Water (30 mL) was added to the reaction mixture, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative column chromatography (under the following conditions: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20ml / min; gradient: 52-67%; retention time: 8.9-9.4min of 17min) to obtain the product. The product was then purified by supercritical fluid chromatography (separation conditions: system: Waters SFC 150; column: ...). 250*25mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: ethanol (with 0.1% 7.0mol / L ammonia methanol), A:B = 70:30; Detection wavelength: 214nm; Flow rate: 120mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 8mL; Cycle time: 6.2min) was purified to obtain (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (5.63mg, 0.01mmol, yield: 5.81%), LCMS m / z: 560 [M+H] + .

[0127] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.81(s,1H),8.60(s,2H),8.22(s,1H),7.99(d,J=8.4Hz,1H),7.89(d,J=7.6Hz,1H),7.82(t,J=7.2Hz,1H),7 .64(t,J=7.2Hz,1H),7.48(t,J=8.4Hz,1H),6.81(dd,J=7.6,4.8Hz,2H), 3.78-3.64(m,7H),2.24(s,3H),1.31-1.22(m,4H),1.09(d,J=6.8Hz,3H).

[0128] Example 5: Synthesis of (2S,3R)-N-(5-(6-ethoxypyridin-2-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A040):

[0129] 1) Synthesis of 6-ethoxypyridinyl hydrazide

[0130] N₂H₄ was added to a 10 mL solution of EtOH containing ethyl 6-ethoxypyridinecarboxylate (1 g, 5.13 mmol). . H₂O (5 mL), heated to 80 °C and stirred for 5 hours. The reaction mixture was concentrated to give 6-ethoxypyridinyl hydrazide (0.92 g, 5.08 mmol, yield: 99.1%), LCMS m / z: 182.0 [M+H]. + .

[0131] 2) Synthesis of (Z)-2-(6-ethoxypyridinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide

[0132] At 0 °C, 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (98 mg, 0.48 mmol, 1.1 eq) and Cs₂CO₃ (185 mg, 0.568 mmol, 1.3 eq) were added to a 10 mL solution of ACN containing (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (100 mg, 0.44 mmol, 1.3 eq) and stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, and 6-ethoxypyridylhydrazine (79 mg, 0.44 mmol, 1.0 eq) and AgNO₃ (148 mg, 0.88 mmol, 2.0 eq) were added and stirred at room temperature for 1 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give (Z)-2-(6-ethoxypyridinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (150 mg, 0.26 mmol, yield: 59.2%), LCMS m / z: 580.2 [M+H]. + .

[0133] 3) Synthesis of (2S,3R)-N-(5-(6-ethoxypyridin-2-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0134] TFA (118 mg, 1.03 mmol, 5.0 eq) was added to a 1,4-dioxane (10 mL) solution containing (Z)-2-(6-ethoxypyridinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (120 mg, 0.21 mmol, 1.0 eq), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was saturated with NaHCO3 solution (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to (2S,3R)-N-(5-(6-ethoxypyridin-2-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (22.29 mg, 0.04 mmol, yield: 19.1%) by preparative grade HPLC (chromatographic conditions: Waters 3767 / Qda, column: XBridge C18, 19*250 mm, 10 μm; A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 38-48%; retention time: 8-10 min of 17 min). + .

[0135] 1 H NMR (400MHz, DMSO-d6) δ13.34 (s, 1H), 8.60-8.54 (m, 2H), 7.91 (t, J = 7.6Hz, 1H) ,7.59(d,J=7.2Hz,1H),7.10-6.98(m,1H),6.92-6.82(m,2H),6.82-6.74(m,1H) ,4.49-4.39(m,1H),4.39-4.32(m,1H),3.76-3.60(m,2H),3.55-3.44(m,1H),3 .38-3.32(m,1H),2.22(d,J=3.2Hz,3H),1.29-1.22(m,3H),1.17-0.96(m,10H).

[0136] Example 6. Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide and its chiral isomers (MRANK-111-A041 and MRANK-111-A041-A):

[0137] 1) Synthesis of (Z)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(5-methylnicotinyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide:

[0138] At 0 °C, 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (188 mg, 0.93 mmol, 1.1 eq) and cesium carbonate (358 mg, 1.09 mmol) were added to a 10 mL solution of ACN containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (215 mg, 0.84 mmol, 1.0 eq) at room temperature and stirred for 16 hours. The mixture was cooled to 0 °C, and 5-methylnicotinamide (126 mg, 0.84 mmol, 1.0 eq) and AgNO3 (267 mg, 1.68 mmol, 2.0 eq) were added, and the mixture was stirred for 1 hour at room temperature. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give (Z)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(5-methylnicotinyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (210 mg, 0.36 mmol, yield: 43.4%), LCMS m / z: 576.2 [M+H] + .

[0139] 2) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide and its axial chiral isomers (MRANK-111-A041 and MRANK-111-A041-A)

[0140] To a solution of 1,4-dioxane (5 mL) containing (Z)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(5-methylnicotinyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (200 mg, 0.35 mmol, 1.0 eq), MsOH (100 mg, 1.04 mmol, 3.0 eq) was added, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give crude product (110 mg). Crude product was separated by SFC (Conditions: System: Waters SFC150; Column name: Column size: 250*30mm x 10μm; Mobile phase A: Supercritical CO2; Mobile phase B: MeOH (+0.1% 7.0mol / L Ammonia in MeOH), A:B = 70:30; Wavelength: 214nm; Flow rate: 140mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 3.0mL; Cycle time: 7.01min) Two isomers were prepared: MRANK-111-A041 and MRANK-111-A041-A:

[0141] MRANK-111-A041: Peak 1: Chiral HPLC: 4.217 min; (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (42.25 mg, 0.076 mmol, yield: 21.12%), LCMS m / z: 558.3 ​​[M+H] + .

[0142] 1H NMR(400MHz,DMSO-d6)δ13.40(s,1H),8.52-8.42(m,3H),8.26(s,1H),7.69(s,1H),7.26-7.11(m,1H),6.99-6.88(m,2H),4.46-4.37(m, 1H),4.36-4.26(m,1H),3.72-3.60(m,2H),2.26(s,3H),1.95-1.85(m,1H),1.25(t,J=7.6Hz,3H),1.18-0.96(m,9H),0.84-0.77(m,2H).

[0143] MRANK-111-A041-A: Peak 2: Chiral HPLC: 2.839 min; (2R, 3S)-3-(5-cyclopropylpyrimidin-2-yl)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide or isomer (4.38 mg, 0.008 mmol, yield: 2.2%), LCMS m / z: 558.3 ​​[M+H] + .

[0144] 1 H NMR(400MHz, DMSO-d6)δ13.40(s,1H),8.53-8.35(m,3H),8.24(s,1H),7.66(s,1H),7.21-7.05(m,1H),6.99-6.86(m,2H),4.46-4.37(m, 1H),4.36-4.26(m,1H),3.80-3.65(m,2H),2.25(s,3H),1.95-1.85(m,1H),1.26(t,J=6.8Hz,3H),1.18-0.96(m,9H),0.84-0.77(m,2H).

[0145] Example 7: Synthesis of (2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(4-methylthiazolyl-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A044):

[0146] 1) Synthesis of methyl 4-methylthiazole-5-carboxylic acid ester

[0147] At room temperature, iodomethane (4.47 g, 31.47 mmol, 1.5 eq.) and cesium carbonate (10.26 g, 31.47 mmol, 1.5 eq.) were added to a DMF (40 mL) solution containing 4-methylthiazol-5-carboxylic acid (3.00 g, 20.98 mmol, 1.0 eq.), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a diatomaceous earth filter, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 4-methylthiazol-5-carboxylic acid (2.80 g, 17.83 mmol, yield: 85.1%), LCMS m / z: 157.9 [M+H]. + .

[0148] 2) Synthesis of 4-methylthiazol-5-carbonylhydrazide

[0149] At room temperature, hydrazine hydrate (8.92 g, 178.30 mmol, 10.0 eq) was added to a 20 mL ethanol solution containing methyl 4-methylthiazolium-5-carboxylic acid ester (2.80 g, 17.83 mmol, 1.0 eq), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether (40 mL) and filtered to give 4-methylthiazolium-5-carbohydrazine (2.50 g, 15.92 mmol, yield: 89.2%), LCMS m / z: 157.9 [M+H]. + .

[0150] 3) Synthesis of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothioformyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0151] At room temperature, 2-isothiocyanate-1,3-dimethoxybenzene (817 mg, 4.19 mmol, 1.2 eq.) and cesium carbonate (1.48 g, 4.54 mmol, 1.3 eq.) were added to a 20 mL solution of acetonitrile containing (2R,3S)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (800 mg, 3.49 mmol, 1.0 eq.), and the mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was used directly in the next step without further purification. LCMS m / z: 425.1 [M+H] + .

[0152] 4) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(4-methylthiazolyl-5-carbonyl)hydrazine-1-carboximide

[0153] At room temperature, 4-methylthiazolyl-5-carbazide (148 mg, 0.94 mmol, 2.0 eq.) and silver nitrate (160 mg, 0.94 mmol, 2.0 eq.) were added to a solution of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (200 mg, 0.47 mmol, 1.0 eq.) in 10 mL of acetonitrile, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was collected and purified under reduced pressure. The residue was subjected to reversed-phase rapid column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; slope: 5% B-80% B within 20 minutes; detector: 214 nm). The fraction containing the product was collected under reduced pressure at 35% B and concentrated to give (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(4-methylthiazolyl-5-carbonyl)hydrazide-1-carboximide (210 mg, 0.38 mmol, yield: 81.3%), LCMS m / z: 548.3 [M+H]. + .

[0154] 5) Synthesis of (2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(4-methylthiazolyl-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0155] At room temperature, 2 mL of TFA was added to a 10 mL solution of (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(4-methylthiazolyl-5-carbonyl)hydrazine-1-carboximide (200 mg, 0.31 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; slope: 5% B-80% B over 20 minutes; detector: 214 nm). The fraction containing the product was collected at 35% B and concentrated under reduced pressure to give (2R,3S)-N-(4-(2,6-dimethoxyphenyl)-5-(4-methylthiazolyl-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (85 mg, 0.16 mmol, yield: 43.9%), LCMS m / z: 530.2 [M+H]. + .

[0156] 1 H NMR (400MHz, MeOH-d4): δ8.87(s,1H),8.55(s,2H),7.51(d,J=8.8Hz,1H),6.78-6.76(m,2H) ,3.79-3.70(m,8H),2.58(s,3H),2.30(m,3H),1.33(d,J=7.2Hz,3H),1.28(d,J=6.8Hz,3H).

[0157] Example 8: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazolyl-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A046):

[0158] 1) Synthesis of thiazole-2-formylhydrazide

[0159] To a 5 mL ethanol solution containing methyl thiazole-2-carboxylate (500 mg, 3.47 mmol, 1.0 eq.), a solution of hydrazine hydrate (98% w / v, 868 mg, 17.35 mmol, 5.0 eq.) was added, and the mixture was heated to 50 °C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue, methyl tert-butyl ether, was pulped three times and filtered to give thiazole-2-formylhydrazine (0.49 g, 3.43 mmol, yield: 98.8%), LCMS m / z: 144.1 [M+H]. + .

[0160] 2) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-2-carbonyl)hydrazine-1-carboximide

[0161] To a solution of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothioformyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (150 mg, 0.35 mmol, 1.0 eq.) in acetonitrile (5 mL), thiazolyl-2-carboxyhydrazide (50 mg, 0.35 mol, 1.0 eq.) and silver nitrate (120 mg, 0.70 mmol, 2.0 eq.) were added, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was filtered and purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: 0.1% aqueous FA; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-45% B, 30 min; detector: 214 nm). The fraction containing the product was collected under 45% B, concentrated under reduced pressure, and lyophilized to give (Z)-N'-(2,6-dimethoxyphenyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-2-carbonyl)hydrazide-1-carboximide (80 mg, 0.15 mmol, yield: 42.8%), LCMS m / z: 534.2 [M+H]. + .

[0162] 3) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazolyl-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A046)

[0163] Potassium hydroxide (10 mg, 0.182 mmol, 1.3 eq.) was added to an aqueous solution containing (Z)-N'-(2,6-dimethoxyphenyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-2-carbonyl)hydrazide-1-carboximide (75 mg, 0.14 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 16 hours. The pH of the reaction mixture was adjusted to 7 with 1 mol / L hydrochloric acid, and purified by reversed-phase rapid chromatography: column: spherical C18, 20-40 μm, 40 g; mobile phase A: 0.1% FA aqueous solution; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-40% B over 30 minutes; detector: 214 nm. The fraction containing the product was collected at 40% B, concentrated under reduced pressure, and lyophilized to give (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazol-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (63.84 mg, 0.12 mmol, yield: 88%), LCMS m / z: 516.3 [M+H] + .

[0164] 1 H NMR (400MHz, DMSO-d6): δ13.47(s,1H),8.59(s,2H),7.90(s,1H),7.83(s,1H),7.48(t,J=8.4Hz,1H),6.81(dd, J=8.4Hz,3.2Hz,2H),3.69-3.66(m,2H),3.64(s,6H),2.23(s,3H),1.24(d,J=7.2Hz,3H),1.10(d,J=6.8Hz,3H).

[0165] Example 9: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazolyl-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A047):

[0166] 1) Synthesis of thiazole-5-formylhydrazide

[0167] To a 5 mL ethanol solution containing methyl thiazole-5-carboxylate (200 mg, 1.4 mmol, 1.0 eq.), hydrazine hydrate (98% w / v, 105 mg, 2.1 mmol, 1.5 eq.) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was slurried three times with methyl tert-butyl ether to obtain thiazole-5-formylhydrazine (105 mg, 0.73 mmol, yield: 52.1%). LCMS m / z: 144.1 [M+H] + .

[0168] 2) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-5-carbonyl)hydrazine-1-carboximide

[0169] To a solution of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (150 mg, 0.35 mmol, 1.0 eq.) in acetonitrile (5 mL), thiazolium-5-carbonylhydrazine (60 mg, 0.42 mmol, 1.2 eq.) and silver nitrate (119 mg, 0.70 mmol, 2.0 eq.) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and purified by reversed-phase rapid chromatography under the following conditions: column: spherical C18, 20-40 μm, 40 g; mobile phase A: 0.1% aqueous FA solution; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-45% B, 30 min; detector: 214 nm. The fraction containing the product was collected under reduced pressure, concentrated, and lyophilized at 45% B to give (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-5-carbonyl)hydrazine-1-carboximide (110 mg, 0.20 mmol, yield: 57.1%), LCMS m / z: 534.2 [M+H] + .

[0170] 3) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazolyl-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A047)

[0171] Potassium hydroxide (15 mg, 0.26 mmol, 1.3 eq.) was added to an aqueous solution containing (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(thiazolyl-5-carbonyl)hydrazide-1-carboximide (110 mg, 0.20 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 16 hours. The pH of the reaction mixture was adjusted to 7 with 1 mol / L hydrochloric acid and purified by reversed-phase rapid chromatography: column: spherical C18, 20-40 μm, 40 g; mobile phase A: 0.1% aqueous FA solution; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-45% B, 30 min; detector: 214 nm. The fraction containing the product was collected at 45% B, concentrated under reduced pressure, and lyophilized to give (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (79.15 mg, 0.15 mmol, yield: 75.0%), LCMS m / z: 516.3 [M+H] + .

[0172] 1 H NMR (400MHz, DMSO-d6): δ8.88(s,1H),7.58(s,2H),7.45(t,J=8.4Hz,1H),7.26(s,1H),6.81(t,J=8.8Hz,2H),4.16- 4.10(m,1H),3.83-3.77(m,1H),3.66(s,3H),3.61(s,3H),2.23(s,3H),1.30(d,J=7.2Hz,3H),1.00(d,J=6.8Hz,3H).

[0173] Example 10: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(isothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A048):

[0174] 1) Synthesis of isothiazole-4-carboxylic acid methyl ester

[0175] At room temperature, sulfinyl chloride (0.5 mL) was added to a solution of isothiazole-4-carboxylic acid (200 mg, 1.55 mmol, 1.0 eq) in anhydrous methanol (5 mL), and the mixture was heated to 65 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 3-isothiazolium-4-carboxylic acid (200 mg, 1.40 mmol, yield: 90.0%), LCMS m / z: 144.0 [M+H]. + .

[0176] 2) Synthesis of isothiazole-4-formylhydrazide

[0177] At room temperature, hydrazine hydrate (700 mg, 14.00 mmol, 10.0 eq) was added to a solution of isothiazole-4-carboxylic acid methyl ester (200 mg, 1.40 mmol, 1.0 eq) in anhydrous ethanol (10 mL), and the mixture was heated to 80 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure. The residue was slurried twice with methyl tert-butyl ether (10 mL) to give isothiazole-4-carboxyhydrazide (175 mg, 1.22 mmol, yield: 87.5%), LCMS m / z: 144.0 [M+H]. + .

[0178] 3) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-2-(isothiazolyl-4-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0179] At room temperature, isothiazol-4-carboxyhydrazide (100 mg, 0.70 mmol, 2.0 eq.) and silver nitrate (119 mg, 0.70 mmol, 2.0 eq.) were added to a solution of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothiocarboxyyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (150 mg, 0.35 mmol, 2.0 eq.) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a diatomaceous earth mat and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 min; detector: 214 nm. The fraction containing the product was collected at 35% B and concentrated under reduced pressure to give (Z)-N'-(2,6-dimethoxyphenyl)-2-(isothiazolyl-4-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (100 mg, 0.19 mmol, yield: 53.1%), LCMS m / z: 534.2 [M+H] + .

[0180] 4) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(isothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A048)

[0181] At room temperature, MsOH (55 mg, 0.57 mmol, 3.0 eq.) was added to a solution of (Z)-N'-(2,6-dimethoxyphenyl)-2-(isothiazolyl-4-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (100 mg, 0.19 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 min; detector: 214 nm. The fraction containing the product was collected under 40% B and concentrated under reduced pressure to give (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(isothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (36.43 mg, 0.071 mmol, yield: 37.5%), LCMS m / z: 516.2 [M+H] + .

[0182] 1 H NMR (400MHz, MeOH-d4): δ8.61(d,J=4.0Hz,2H),8.55(s,2H),7.56(t,J=8.8Hz,1H),6.85- 6.82(m,2H),3.78-3.72(m,8H),2.30(s,3H),1.33(d,J=6.8Hz,3H),1.28(d,J=6.8Hz,3H),

[0183] Example 11: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylisothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A049):

[0184] 1) Synthesis of 4-bromo-5-methylisothiazol

[0185] At -78°C, n-butyllithium (2.5 M, 15.20 mL, 38.10 mmol, 2.5 eq.) was slowly added to a tetrahydrofuran (15 mL) solution containing 4-bromoisothiazolium (2.5 g, 15.24 mmol, 1.0 eq.), and the mixture was stirred at -78°C for 2 hours. Iodomethane (3.24 g, 22.86 mmol, 1.5 eq.) was added to the mixture, and the mixture was stirred at -78°C for another 2 hours. The mixture was quenched with an aqueous solution of ammonium chloride (50 mL) and extracted with petroleum ether (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-bromo-5-methylisothiazolium (900 mg, 5.05 mmol, yield: 33.17%). 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 2.50 (s, 3H).

[0186] 2) Synthesis of methyl 5-methylisothiazol-4-carboxylic acid ester

[0187] A mixed solution of MeOH (4 mL) and DMF (4 mL) containing 4-bromo-5-methylisothiazolium (160 mg, 0.898 mmol, 1.0 eq.), Pd(dppf)Cl2 (65.7 mg, 0.0898 mmol, 0.1 eq.), and triethylamine (272 mg, 1.796 mmol, 3.0 eq.) was heated to 85 °C and stirred for 16 hours under a carbon monoxide atmosphere. An aqueous solution of ammonium chloride (15 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 20:1) to give methyl 5-methylisothiazolium-4-carboxylic acid (80 mg, 0.508 mmol, yield: 56.5%), LCMS m / z: 158.3 [M+H]. +

[0188] 3) Synthesis of 5-methylisothiazol-4-formylhydrazide

[0189] At room temperature, hydrazine hydrate (128 mg, 2.55 mmol, 5.0 eq) was added to a 5 mL ethanol solution containing methyl 5-methylisothiazolium-4-carboxylate (80 mg, 0.51 mmol, 1.0 eq), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was slurried twice with tert-butyl methyl ether (5 mL) to give 5-methylisothiazolium-4-carboxyhydrazide (50 mg, 0.32 mmol, yield: 62.5%), LCMS m / z: 158.1 [M+H]. + .

[0190] 4) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisothiazolyl-4-carbonyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0191] At room temperature, 5-methylisothiazolyl-4-carbamoylhydrazine (69 mg, 0.38 mmol, 2.0 eq.) and AgNO3 (65 mg, 0.38 mmol, 2.0 eq.) were added to a 5 mL solution of ACN containing (2S,3R)-N-(2,6-dimethoxyphenyl)carbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (80 mg, 0.19 mmol, 1.0 eq.), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a diatomaceous earth filter and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 min; detector: 214 nm). The fraction containing the product was collected at 38% B and concentrated under reduced pressure to give (Z)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisothiazolyl-4-carbonyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (37 mg, 0.07 mmol, yield: 35.9%), LCMS m / z: 548.2 [M+H). + .

[0192] 5) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylisothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MRANK-111-A049)

[0193] At room temperature, MsOH (13 mg, 0.14 mmol, 3.0 eq.) was added to a solution of (Z)-N'-(2,6-dimethoxyphenyl)-2-(5-methylisothiazolyl-4-carbonyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (26 mg, 0.047 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 7 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 min; detector: 214 nm). The fraction containing the product was collected at 35% B and concentrated under reduced pressure to give (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylisothiazolyl-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (15.94 mg, 0.03 mmol, yield: 63.7%), LCMS m / z: 530.2 [M+H]. + .

[0194] 1H NMR (400MHz, DMSO-d6): δ13.32(s,1H),8.59(s,2H),7.94(s,1H),7.46(t,J=8.8Hz,1H),6.78(t,J=8.4Hz,2H) ,3.72-3.67(m,7H),3.62-3.59(m,1H),2.57(s,3H),2.24(s,3H),1.25(d,J=7.2Hz,3H),1.11(d,J=7.2Hz,3H),

[0195] Example 12, Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(imidazo[2,1-b]thiazolyl-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)but-2-sulfonamide (MRANK-111-A045):

[0196] 1) Synthesis of methyl imidazo[2,1-b]thiazole-2-carboxylate

[0197] At room temperature, cesium carbonate (3104.1 mg, 9.522 mmol, 2.0 eq.) and methyl iodoformate (1014.2 mg, 7.142 eq., 1.5 eq.) were added to a DMF (30 mL) solution of imidazo[2,1-b]thiazolium-2-carboxylic acid (800 mg, 4.761 mmol, 1.0 eq.), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with NH4Cl aqueous solution (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl imidazo[2,1-b]thiazolium-2-carboxylate (804 mg, 4.41 mmol, yield: 92.6%), LCMS m / z: 183.1 [M+H]. + .

[0198] 2) Synthesis of imidazo[2,1-b]thiazole-2-hydrazide

[0199] At room temperature, hydrazine hydrate (66 mg, 1.32 mmol, 1.2 eq) was added to an ethanol (10 mL) solution containing imidazo[2,1-b]thiazole-2-carboxylic acid methyl ester (200 mg, 1.10 mmol, 1.0 eq), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was slurried twice with methyl tert-butyl ether (10 mL) to give imidazo[2,1-b]thiazole-2-methylhydrazine (130 mg, 0.71 mmol, yield: 65.0%), LCMS m / z: 183.0 [M+H]. + .

[0200] 3) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-2-(imidazo[2,1-b]thiazol-2-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0201] At room temperature, to a solution of (2S,3R)-N-(2,6-dimethoxyphenyl)aminothioformyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (150 mg, 0.35 mmol, 1.0 eq.) in acetonitrile (5 mL), imidazo[2,1-b]thiazolyl-2-carboxyhydrazide (127 mg, 0.70 mmol, 2.0 eq.) and silver nitrate (119 mg, 0.70 mmol, 2.0 eq.) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a diatomaceous earth mat, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; slope: 5% B-80% B over 20 minutes; detector: 214 nm). The fraction containing the product was collected under 30% B and concentrated under reduced pressure to give (Z)-N'-(2,6-dimethoxyphenyl)-2-(imidazo[2,1-b]thiazol-2-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (52 mg, 0.09 mmol, yield: 25.7%), LCMS m / z: 573.2 [M+H). + .

[0202] 4) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(imidazo[2,1-b]thiazolyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)but-2-sulfonamide (MRANK-111-A045)

[0203] At room temperature, MsOH (26 mg, 0.27 mmol, 3.0 eq.) was added to a solution of (Z)-N'-(2,6-dimethoxyphenyl)-2-(imidazo[2,1-b]thiazol-2-carbonyl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (50 mg, 0.09 mmol, 1.0 eq.), and the mixture was heated to 100 °C and stirred for 7 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 min; detector: 214 nm). The fraction containing the product was collected under 35% B and concentrated under reduced pressure to give (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(imidazo[2,1-b]thiazolyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)but-2-sulfonamide (7.74 mg, 0.014 mmol, yield: 16.1%), LCMS m / z: 555.3 [M+H). + .

[0204] 1 H NMR (400MHz, DMSO-d6): δ13.43(s,1H),8.59(s,2H),7.76(s,2H),7.62(t,J=8.4Hz,1H),7.3 4-7.24(m,1H),3.67-3.61(m,8H),2.23(s,3H),1.23(d,J=7.2Hz,3H),1.10(d,J=6.8Hz,3H).

[0205] Example 13: Synthesis of ((2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A002):

[0206] 1) Synthesis of tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazine-1-carboxylic acid

[0207] At room temperature, HATU (1850 mg, 4.80 mmol) and DIEA (1256 mg, 9.60 mmol) were added to a solution of 3-fluoro-5-methylbenzoic acid (500 mg, 3.20 mmol) and tert-butyl hydrazide carboxylate (642 mg, 4.80 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, 254 nm) to give tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazide-1-carboxylate (0.66 g, 2.40 mmol, yield: 75.8%), LCMS m / z: 212 [M+H]. +

[0208] 2) Synthesis of 3-fluoro-5-methylbenzoylhydrazide

[0209] At room temperature, 2,2,2-trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 2-(3-fluoro-5-methylbenzoyl)hydrazine-1-carboxylic acid (660 mg, 2.46 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to >7 (8–9) with aqueous NaHCO3 solution, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-fluoro-5-methylbenzoylhydrazine (320 mg, 1.90 mmol, yield: 77.5%), LCMS m / z: 169 [M+H]. + .

[0210] 3) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0211] A solution of acetonitrile (10 mL) containing 3-fluoro-5-methylbenzoylhydrazine (36 mg, 0.218 mmol) was cooled to 0 °C, and then 2-isothiocyano-1,3-dimethoxybenzene (47 mg, 0.240 mmol) and Cs₂CO₃ (92 mg, 0.283 mmol) were added. The mixture was stirred at 25 °C for 16 hours. LC-MS showed that the reaction was complete. The mixture was cooled to 0 °C, and (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (49 mg, 0.218 mmol) and AgNO₃ (74 mg, 0.436 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LC-MS showed that the reaction was complete. The mixture was diluted with H₂O (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1, 254 nm) to give (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (100 mg, 0.18 mmol, yield: 83%), LCMS m / z: 578 [M+18+H] + .

[0212] 4) Synthesis of ((2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A002)

[0213] To a solution of 1,4-dioxane (10 mL) containing (Z)-N'-(2,6-dimethoxyphenyl)-2-(3-fluoro-5-methylbenzoyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (120 mg, 0.215 mmol), MeSO3H (41 mg, 0.430 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed the reaction was complete. The reaction was quenched with H2O (30 mL), and the pH was adjusted to 7 with saturated NaHCO3. The mixture was then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (chromatogram: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 52-67%; retention time: 8.9-9.4 min, 17 min) to obtain the product. This product was then purified by critical fluid chromatography (conditions: system: Waters SFC 150; column name: ...). AS; Column size: 250*25mm 10um; Mobile phase A: supercritical CO2; Mobile phase B: MeOH (with 0.1% 7.0mol / L ammonia methanol solution added), A:B = 70:30; Wavelength: 214nm; Flow rate: 120mL / min; Column temperature: room temperature; Back pressure: 100bar; Injection volume: 2.0mL; Cycle time: 10min) Purified to obtain

[0214] ((2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(3-fluoro-5-methylphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (16.31 mg, 0.03 mmol, yield: 14.0%), LCMS m / z: 541 [M+H] +

[0215] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),8.59(s,2H),7.50(t,J=8.4Hz,1H),7.16(d,J=10.4Hz,1H),7.08(s,1H),6.8 4-6.78(s,3H),3.68(s,6H),3.61-3.59(m,1H),2.24(d,J=4.4Hz,6H),1.23(d,J=6.8Hz,4H),1.09(d,J=6.8Hz,3H).

[0216] 19 F NMR (377MHz, DMSO-d6) δ 112.72

[0217] Example 14: Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (MDR-001-A003):

[0218] 1) Synthesis of 2-chloro-5-cyclopropylpyrimidine

[0219] At room temperature, Pd(dppf)Cl2 (10.58 g, 12.953 mmol) and H2O (150 mL) were added to a solution of 5-bromo-2-chloropyrimidine (25 g, 129.53 mmol), cyclopropylboronic acid (33.41 g, 388.59 mmol), K2CO3 (89.37 g, 647.65 mmol), and tetrahydrofuran (750 mL). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, 254 nm) to give 2-chloro-5-cyclopropylpyrimidine (10.74 g, 69.29 mmol, yield: 53.51%), LCMS m / z: 155 [M+H]. + .

[0220] 2) Synthesis of (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine

[0221] At room temperature, 2-chloro-5-cyclopropylpyrimidine (5 g, 32.34 mmol), (E)-but-2-en-2-yltrifluoro-λ was dissolved in water. 4 In a solution of potassium boronide (6.31 g, 38.8 mmol) in dioxane (100 mL), Pd(dppf)Cl2 (2.37 g, 3.234 mmol), water (10 mL), and K2CO3 (13.44 g, 97.02 mmol) were added, and the mixture was heated to 80 °C and stirred for 16 hours. LCMS showed that the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1, 254 nm) to give (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine (4.8 g, 27.54 mmol, yield: 85%), LCMS m / z: 175 [M+H]. + .

[0222] 3) Synthesis of 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine

[0223] A solution of pyrimidine-2-thiol (3.089 g, 27.58 mmol) in dichloromethane (115 mL) was cooled to 0 °C, and SO2Cl2 (3.7 g, 27.58 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then continued for another hour. After cooling to 0 °C, (Z)-2-(but-2-en-2-yl)-5-cyclopropylpyrimidine (4.8 g, 27.58 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 0%-30%) to 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine (4.34 g, 13.52 mmol, yield: 49%), LCMS m / z: 321 [M+H] + .

[0224] 4) Synthesis of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine

[0225] At room temperature, a solution of 2-(2-chloro-3-(pyrimidin-2-ylthio)but-2-yl)-5-cyclopropylpyrimidine (4.34 g, 13.52 mmol), dichloromethane (100 mL), and m-CPBA (10.49 g, 60.84 mmol) was stirred for 16 hours. LCMS showed that the reaction mixture was complete. The mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine (12.36 g, crude). LCMS m / z: 353 [M+H] + .

[0226] 5) Synthesis of potassium (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate

[0227] At room temperature, a solution of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)but-2-yl)-5-cyclopropylpyrimidine (9.73 g, 27.58 mmol), methanol (100 mL), and potassium carbonate (11.42 g, 82.75 mmol) was stirred at 25 °C for 16 hours. LC-MS showed that the reaction mixture was complete. The reaction mixture was concentrated under reduced pressure to obtain (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate potassium (25.45 g, crude product), which was used directly in the next step without further processing.

[0228] 6) Synthesis of (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide

[0229] Potassium acetate (5.4 g, 55.17 mmol) was added to 100 mL of water containing potassium (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfinate (25.45 g, 27.58 mmol) and (aminooxy)sulfonic acid (9.35 g, 82.75 mmol), and the mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0%–5%) to give (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide (1.18 g), LCMS m / z: 254 [M+H]. + .

[0230] 7) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide

[0231] At room temperature, SP-4-PI (9.6 mg, 0.0237 mmol, CAS: 351378-22-8) and 849924-4-3 (17.5 mg, 0.027 mmol) were added to a methanol (10 mL) solution containing (E)-3-(5-cyclopropylpyrimidin-2-yl)but-2-ene-2-sulfonamide (300 mg, 1.185 mmol) and zinc trifluoromethanesulfonate (86 mg, 0.24 mmol). The mixture was stirred at room temperature for 32 hours under a hydrogen atmosphere (3 MPa). LCMS showed complete mixing. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: spherical C18, 20-40 μm, 80 g; mobile phase A: water (0.01 M NH4HCO3); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 0% B-35% B over 20 min; detector: 254 nm). The fraction containing the product was collected at 32% B and concentrated under reduced pressure to give (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (111 mg, 0.44 mmol, yield: 36%), LCMS m / z: 256 [M+H). + .

[0232] 8) Synthesis of (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboximide

[0233] A solution of acetonitrile (5 mL) containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (111 mg, 0.44 mmol) was cooled to 0 °C, and then 2-isothiocyano-1,3-dimethoxybenzene (107.6 mg, 0.71 mmol) and cesium carbonate (302 mg, 0.93 mmol) were added. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the reaction was complete. The mixture was cooled to 0 °C, and 5-methylnicotinamide (72.3 mg, 0.48 mmol) and AgNO3 (242 mg, 1.42 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0%–5%) to (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazide-1-carboximide (178 mg, 0.32 mmol, yield: 72%), LCMS m / z: 568 [M+H] + .

[0234] 9) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (MDR-001-A003)

[0235] Add M to a solution containing (Z)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazide-1-carboximide (178 mg, 0.313 mmol) in 5 mL of 1,4-dioxane. SOH (60 mg, 0.626 mmol) was added and heated to 90 °C with stirring for 16 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water (30 mL), and the pH was adjusted to 7 with saturated NaHCO3, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (HPLC) (Chromatography: Waters 3767 / QDA, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 27%–37%; retention time: 10.8–12.8 min (18 min)). The fraction containing the product was collected at 48% B and concentrated under reduced pressure to obtain the product. The product was then passed through a supercritical fluid (conditions: system: Waters SFC 150; column name: Column size: 250*30mm × 10μm; Mobile phase A: supercritical CO2; Mobile phase B: IPA (+0.1% 7.0mol / L NH3 / MeOH), A:B = 55:45; Wavelength: 214nm; Flow rate: 140mL / min; Column temperature: room temperature; Back pressure: 100bar; Injection volume: 8mL; Cycle time: 7min) The prepared and separated (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)but-2-sulfonamide (19.81mg, 0.036mmol, yield: 11.49%) was obtained. LCMS m / z: 550 [M+H] + .

[0236] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.50(s,2H),8.46(s,1H),8.19(s,1H),7.61(s,1H),7.49(t,J=8.6Hz,1H),6.82(dd,J=8.5,2.9Hz,2H),3.68 (d,J=1.8Hz,7H),3.60(s,1H),2.25(s,3H),1.96–1.86(m,1H),1.23(d,J =7.1Hz,3H),1.09(d,J=6.9Hz,3H),1.04–0.98(m,2H),0.84–0.78(m,2H).

[0237] Example 15: Synthesis of (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A004):

[0238] 1) Synthesis of 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane]

[0239] In 10 mL of dichloromethane containing 2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine (150 mg, 0.93 mmol), saturated NaHCO3 (3 mL) was added, the mixture was cooled to 0 °C, and triphosgene (321 mg, 2.80 mmol) was added. The mixture was allowed to rise to room temperature and stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 0% to 10%) to obtain the compound 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (110 mg, 0.54 mmol, yield: 58.0%), LC-MS m / z: 221 [M+18]. + .

[0240] 2) Synthesis of (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide

[0241] The compound (3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide) (90 mg, 0.39 mmol, 1.0 eq) was dissolved in ACN (10 mL), cooled to 0°C, and 7-isothiocyano-2H-spiro[benzofuran-3,1'-cyclopropane] (90 mg, 0.44 mmol) and Cs₂CO₃ (171 mg, 0.51 mmol) were added. The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The mixture was cooled to 0°C, and 5-methylnicotinamide (59 mg, 0.39 mmol) and AgNO₃ (137 mg, 0.78 mmol) were added. The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 0% to 5%) to obtain (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (130 mg, 0.24 mmol, yield: 61.5%), LCMS m / z: 550 [M+H]. + .

[0242] 3) Synthesis of (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A004)

[0243] To a solution of 1,4-dioxane (10 mL) containing (Z)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (120 mg, 0.22 mmol), MeSO3H (41 mg, 0.44 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed that the reaction was complete. Water (30 mL) was added to the reaction mixture, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (conditions as follows: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 52-67%, retention time: 8.9-9.4min of 17min) to obtain the crude product. The crude product was then purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column: ...). 250*25mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol), A:B = 80:20; Detection wavelength: 214nm; Flow rate: 140mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 8mL; Cycle time: 11min) to obtain (2S,3R)-N-(5-(5-methylpyridin-3-yl)-4-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (12.67mg, 0.024mmol, yield: 10.9%), LCMS m / z: 532 [M+H] + .

[0244] 1H NMR (400MHz, DMSO-d6) δ8.60-8.56(m,2H),8.32(d,J=2.0Hz,1H),8.18(d,J=1.6Hz,1H),7.59(s,1H),7.25-6.96(m,2H),6.94-6.86(m,2H),4.38(dd ,J=20.4,8.8Hz,1H),4.23(d,J=8.8Hz,1H),4.14-4.01(m,1H),3.82-3.73 (m,1H),2.25-2.21(m,6H),1.30(dd,J=7.2,2.4Hz,3H),1.13-1.00(m,7H).

[0245] Example 16: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A005):

[0246] 1) Synthesis of quinoline-3-formylhydrazide

[0247] At room temperature, hydrazine monohydrate (267 mg, 5.34 mmol) was added to a 5 mL ethanol solution containing methyl quinoline-3-carboxylate (500 mg, 2.67 mmol), and the mixture was heated to 90 °C and stirred for 16 hours. LCMS showed the formation of the target product. The reaction mixture was purified by reversed-phase rapid column chromatography (conditions: column: spherical C18, 20-40 μm, 130 g; mobile phase A: water (0.1% NH3·H2O); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 20% B-80% B over 25 min; detector: 254 nm). The fraction containing the product was collected under 25% B and concentrated under reduced pressure to give quinoline-3-carboxyhydrazide (300 mg, 1.60 mmol, yield: 60.0%), LCMS m / z: 188 [M+H]. + .

[0248] 2) Synthesis of (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazine-1-carboximide

[0249] Add 10 mL of acetonitrile to a solution containing 50 mg (0.22 mmol) of 3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide and cool to 0 °C. oC, add 2-isothiocyano-1,3-dimethoxybenzene (47 mg, 0.24 mmol) and Cs2CO3 (92 mg, 0.28 mmol), and stir at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was cooled to 0°C, and quinoline-3-formylhydrazide (41 mg, 0.218 mmol) and silver nitrate (74 mg, 0.44 mmol) were added. The mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. Water (30 mL) was added to the mixture, and it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0% to 5%) to give (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazide-1-formylimide (100 mg, 0.17 mmol, yield: 77.3%), LCMS m / z: 578 [M+H]. + .

[0250] 3) Preparation of (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A005)

[0251] To a solution of 1,4-dioxane (10 mL) containing (Z)-N'-(2,6-dimethoxyphenyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)-2-(quinoline-3-carbonyl)hydrazide-1-carboximide (100 mg, 0.17 mmol), MeSO3H (33 mg, 0.34 mmol) was added, and the mixture was heated to 100 °C and stirred for 8 hours. LC-MS showed that the reaction was complete. Water (30 mL) was added to the reaction mixture, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative column chromatography (under the following conditions: Waters 3767 / QDA column: Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; LA: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20ml / min; gradient: 52-67%; retention time: 8.9-9.4min of 17min) to obtain the product. The product was then purified by supercritical fluid chromatography (separation conditions: system: Waters SFC 150; column: ...). 250*25mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: ethanol (with 0.1% 7.0mol / L ammonia methanol), A:B = 70:30; Detection wavelength: 214nm; Flow rate: 120mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 8mL; Cycle time: 6.2min) was purified to obtain (2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-(quinolin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (5.63mg, 0.01mmol, yield: 5.81%), LCMS m / z: 560 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.81(s,1H),8.60(s,2H),8.22(s,1H),7.99(d,J=8.4Hz,1H),7.89(d,J=7.6Hz,1H),7.82(t,J=7.2Hz,1H),7 .64(t,J=7.2Hz,1H),7.48(t,J=8.4Hz,1H),6.81(dd,J=7.6,4.8Hz,2H), 3.78-3.64(m,7H),2.24(s,3H),1.31-1.22(m,4H),1.09(d,J=6.8Hz,3H).

[0253] Example 17: Synthesis of (2S,3R)-N-(4-(2,6-dimethoxybenzyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A006):

[0254] 1) Synthesis of 2-(methyl isothiocyanate)-1,3-dimethoxybenzene

[0255] At 0 °C, sulfur phosgene (2.66 g, 9.00 mmol) was added to a DCM (5 mL) solution containing (2,6-dimethoxyphenyl)methylamine (300 mg, 1.80 mmol) and NaHCO3 (1 mL), and the mixture was stirred at room temperature for 4 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1, R... f=0.6, 254 nm) Purification yielded 2-(methyl isothiocyanate)-1,3-dimethoxybenzene (150 mg, 0.72 mmol, yield: 40.0%).

[0256] 1 H NMR (400MHz, DMSO-d6) δ7.38-7.34 (q, J=8.4Hz, 1H), 6.74-6.72 (d, J=8.8Hz, 2H), 4.70 (s, 2H), 3.84 (s, 6H).

[0257] 2) Synthesis of (E)-N'-(2,6-dimethoxybenzyl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0258] At room temperature, Cs₂CO₃ (302 mg, 0.94 mmol) was added to a solution of acetonitrile (20 mL) containing (methyl isothiocyanate)-1,3-dimethoxybenzene (150 mg, 0.72 mmol) and (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (163 mg, 0.72 mmol), and the mixture was stirred at 25 °C for 16 hours. LCMS showed that the mixture was complete. The mixture was cooled to 0 °C, and 5-methylnicotinamide (107.6 mg, 0.72 mmol) and AgNO₃ (242 mg, 1.42 mmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMS showed that the mixture was complete. The reaction mixture was diluted with H₂O (30 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 0%–10%) to (E)-N'-(2,6-dimethoxybenzyl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (130 mg, 0.23 mmol, yield: 31.9%), LCMS m / z: 556 [M+H] + .

[0259] 3) Synthesis of (2S,3R)-N-(4-(2,6-dimethoxybenzyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (MDR-001-A006)

[0260] To a solution of 1,4-dioxane (5 mL) containing (E)-N'-(2,6-dimethoxybenzyl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazide-1-carboximide (80 mg, 0.14 mmol), NaOH (11.2 mg, 0.28 mmol) was added, and the mixture was heated to 100 °C and stirred for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with H₂O (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters 2767 / QDA, column: XBridge C18, 19*250mm, 10µm; mobile phase A: 10mmol / L NH4HCO3, mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 57%–67%; retention time: 10.3–11.4min (17min)). The crude product was obtained by collecting and concentrating the fractions under a 48% B gradient. The crude product was then purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column: ...). 250*30mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: isopropanol (with 0.1% 7.0mol / L ammonia-methanol), A:B = 55:45; Detection wavelength: 214nm; Flow rate: 140mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 8mL; Cycle time: 7min) purified to obtain (2S,3R)-N-(4-(2,6-dimethoxybenzyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (2.51mg, 0.004mmol, yield: 3.3%), LCSM m / z: 538 [M+H] + .

[0261] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.58(s,2H),8.45-8.40(m,2H),7.64(s,1H),7.05(t,J=8Hz,1H),6.39(d,J=8Hz,2H ),4.93(d,J=4Hz,2H),3.73-3.60(m,2H),3.56(s,6H),2.28(s,3H),2.24(s,3H),1.28(d,J=8Hz,3H),1.12(d,J=4Hz,3H).

[0262] Example 18: Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide (MRANK-111-A011):

[0263] 1) Synthesis of tert-butyl 3-aminosulfonylazine-1-carboxylate

[0264] The solution containing 250 mg (0.98 mmol) of tert-butyl 3-(chlorosulfonyl)azacyclobutane-1-carboxylic acid was stirred in 50 mL of NH₃ / MeOH (7 M) at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 200 mg (0.85 mmol, yield: 86.4%) of tert-butyl 3-aminosulfonylazacyclobutane-1-carboxylic acid, LCMS m / z: 181 [M+H-56]. + .

[0265] 2) Synthesis of aziridine-3-sulfonamide hydrochloride

[0266] A solution of tert-butyl 3-aminosulfonyl aziridine-1-carboxylate (200 mg, 0.85 mmol) in hydrochloric acid / 1,4-dioxane (20 mL, 4 M) was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to obtain aziridine-3-sulfonamide hydrochloride (120 mg, crude product).

[0267] 3) Synthesis of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide

[0268] At room temperature, 2-chloro-5-methylpyrimidine (90 mg, 0.7 mmol) and DIEA (180 mg, 1.39 mmol) were added to a DMSO (10 mL) solution containing aziridine-3-sulfonamide hydrochloride (80 mg, 0.463 mmol), and the mixture was heated to 80 °C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reversed-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: H2O containing 0.1% FA; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B for 5 min, 5-40% B for 30 min; detector: 214 nm). The fraction containing the product was collected under 30% B and concentrated under reduced pressure to give 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide (50 mg, 0.22 mmol, yield: 47.3%), LCMS m / z: 229 [M+H]. + .

[0269] 4) Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide (MRANK-111-A011)

[0270] A 5 mL tube containing 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-12,4-triazol-3-yl)-5-methylpyridine (66 mg, 0.175 mmol), 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide (40 mg, 0.175 mmol), trans-N,N'-dimethyl-1,2-cyclohexyldiamine (50 mg, 0.35 mmol), Cs₂CO₃ (170 mg, 0.525 mmol), and CuI (17 mg, 0.0875 mmol) was sealed and heated to 100 °C under nitrogen atmosphere with stirring for 16 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-50% B over 30 min; detector: 214 nm). The fraction containing the product was collected at 35% B and concentrated under reduced pressure to give N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-sulfonamide (0.78 mg, 0.00149 mmol, yield: 0.85%), LCMS m / z: 523 [M+H]. + .

[0271] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.30(s,1H),8.20(s,2H),7.69(s,1H),7.41(t,J=8.4Hz,1H), 6.70(d,J=8.4Hz,2H),4.30-4.24(m,2H),4.21-4.16(m,3H),3.74(s,6H),2.29(s,3H),2.17(s,3H).

[0272] Example 19. Synthesis of (2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate or its enantiomers (MRANK-111-A012-1 and MRANK-111-A012-2):

[0273] 1) Synthesis of (Z)-2-(but-2-en-2-yl)-5-methylpyrimidine

[0274] At room temperature, a solution of 1,4-dioxane (85 mL) containing 2-chloro-5-methylpyrimidine (2.66 g, 20.62 mmol) and potassium (Z)-but-2-en-2-trifluoroborate (5.0 g, 30.86 mmol) was added to Pd(dppf)Cl2 (1.49 g, 2.038 mmol), H2O (8.0 mL), and K2CO3 (8.51 g, 61.67 mmol). The mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to give (Z)-2-(but-2-en-2-yl)-5-methylpyrimidine (1.3 g, 8.78 mmol, yield: 42.6%), LCMS m / z: 149.5 [M+H]. + .

[0275] 2) Synthesis of 2-(2,3-dimethylethyleneoxy-2-yl)-5-methylpyrimidine

[0276] To a DCM solution (40 mL) containing (Z)-2-(but-2-en-2-yl)-5-methylpyrimidine (1.3 g, 8.78 mmol), m-CPBA (2.27 g, 13.17 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with H₂O (20 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 1:1) to give 2-(2,3-dimethylethyleneoxy-2-yl)-5-methylpyrimidine (1.2 g, 7.3 mmol, yield: 83.1%), LCMS m / z: 165.2 [M+H]. + .

[0277] 3) Synthesis of 3-(5-methylpyrimidin-2-yl)but-2-ol

[0278] At room temperature, Pd / C (400 mg, 10% carbon, approximately 55% water) was added to a 20 mL ethanol solution containing 1.2 g (7.3 mmol) of 2-(2,3-dimethylethyleneoxy-2-yl)-5-methylpyrimidine. The mixture was purged with hydrogen three times and stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 3-(5-methylpyrimidine-2-yl)but-2-ol (270 mg, 1.62 mmol, yield: 22.5%). LCMS: m / z: 167.1 [M+H] + .

[0279] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,2H),4.24-4.19(m,1H),4.04-3.99(m,1H),2 .84-2.77(m,1H),2.33(s,3H),1.20(d,J=6.8Hz,3H),0.89(d,J=6.4Hz,3H).

[0280] 4) Synthesis of 3-(4-(2,6-dimethoxyphenyl)-5-isocyanate-4H-1,2,4-triazol-3-yl)-5-methylpyridine

[0281] At room temperature, triethylamine (116 mg, 1.15 mmol) and triphosgene (340 mg, 1.15 mmol) were added to a solution of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (300 mg, 0.96 mmol) in 10 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 20 mL of dichloromethane, washed with 10 mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to reverse-phase rapid-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-50% B within 10 min; detector: 214 nm). The fraction containing the product was collected under 45% B and concentrated under reduced pressure to give 3-(4-(2,6-dimethoxyphenyl)-5-isocyanate-4H-1,2,4-triazol-3-yl)-5-methylpyridine (120 mg, 0.36 mmol, yield: 36.92%), LCMS m / z: 338.1 [M+H] + .

[0282] 5) Synthesis of 3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate

[0283] At 0°C, sodium hydride (34 mg, 0.84 mmol) was added to a solution of 3-(5-methylpyrimidin-2-yl)but-2-ol (70 mg, 0.42 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. Then, 3-(4-(2,6-dimethoxyphenyl)-5-isocyanate-4H-1,2,4-triazol-3-yl)-5-methylpyridine (140 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (1 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 80 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-50% B over 10 min; detector: 214 nm). The residue was collected and concentrated under reduced pressure at 45% B to give 3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate (70 mg, 0.14 mmol, yield: 33.49%). LCMS: m / z: 504.3 [M+H] + .

[0284] 6) Synthesis of (2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate or its enantiomers (MRANK-111-A012-1 and MRANK-111-A012-2)

[0285] Compound 3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate (70 mg, 0.14 mmol) was analyzed by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Column size: 250*30mm x 10μm; Mobile phase A: supercritical CO2; Mobile phase B: isopropanol (+0.1% 7.0mol / L ammonia-methanol), A:B = 75:25; Wavelength: 214nm; Flow rate: 140mL / min; Column temperature: room temperature; Column pressure: 100bar; Injection volume: 8.0mL; Cycle time: 30.0min) Purification yielded two single isomers: MRANK-111-A012-1 and MRANK-111-A012-2.

[0286] MRANK-111-A012-1: Peak 1, Chiral HPLC: 1.049 min; (2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate or enantiomer (7.72 mg, 0.015 mmol, yield: 11.03%), LCMS m / z: 504.2 [M+H] + .

[0287] 1 H NMR (400MHz, DMSO-d6) δ8.58(s,2H),8.44(s,1H),8.22(s,1H),7.66(s,1H),7.46(t,J=8.4Hz,1H),6.81-6.79(m,2H),5 .04-4.98(m,1H),3.65-3.63(m,6H),3.01-2.94(m,1H),2.26-2.24(m,6H),1.09(d,J=7.2Hz,3H),0.89(d,J=6.4Hz,3H).

[0288] MRANK-111-A012-2: Peak 2, Chiral HPLC: 1.787 min; (2R,3S)-3-(5-methylpyrimidin-2-yl)but-2-yl(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate or enantiomer (7.04 mg, 0.014 mmol, yield: 10.06%), LCMS: m / z: 504.4 [M+H] + .

[0289] 1H NMR (400MHz, DMSO-d6) δ8.58(s,2H),8.45(s,1H),8.23(s,1H),7.68(s,1H),7.46(t,J=8.8Hz,1H),6.81-6.79(m,2H),5 .05-4.98(m,1H),3.65-3.63(m,6H),3.01-2.94(m,1H),2.26-2.24(m,6H),1.09(d,J=6.8Hz,3H),0.89(d,J=6.4Hz,3H).

[0290] Example 20: Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxamide (MRANK-111-A014):

[0291] 1) 2-Isothiocyano-1,3-dimethoxybenzene

[0292] To a solution containing 2,6-dimethoxyaniline (25.00 g, 163.40 mmol) in dichloromethane (250 mL) and H₂O (250 mL), NaHCO₃ (27.45 g, 326.80 mmol) and phosgene (28.19 g, 245.10 mmol) were added, and the mixture was stirred at 0 °C for 1 hour. LC-MS showed product formation. The reaction mixture was quenched with saturated NaHCO₃ (800 mL) and extracted with EA (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 8 / 1) to give 2-isothiocyano-1,3-dimethoxybenzene (30.00 g, 153.85 mmol, yield: 94.1%).

[0293] 1 H NMR (400MHz, CDCl3-d) δ7.14 (t, J=8.8Hz, 1H), 6.53 (d, J=8.4Hz, 2.0Hz, 2H).

[0294] 2) Synthesis of N-(tert-butylsulfonyl)-N'-(2,6-dimethoxyphenyl)aminothiocarboxylic acid

[0295] Cs₂CO₃ (17.39 g, 53.34 mmol) was added to an 80 mL solution of ACN containing 2-isothiocyano-1,3-dimethoxybenzene (8.00 g, 41.03 mmol) and 2-methylpropane-2-sulfonamide (5.90 g, 43.08 mmol), and the mixture was stirred at 25 °C for 16 hours. The product was detected by LC-MS. The reaction mixture was used directly in the next step without post-processing. LC-MS m / z: 333 [M+H] + .

[0296] 3) Synthesis of N-(tert-butylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazine-1-carboximide

[0297] To an acetonitrile solution containing N-(tert-butylsulfonyl)-N'-(2,6-dimethoxyphenyl)aminothiocarboxylic acid (41.03 mmol), AgNO3 (13.95 g, 82.06 mmol) and 5-methylnicotinamide (5.90 g, 43.08 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. Product formation was detected by LCMS. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was collected and purified under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give N-(tert-butylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinamide)hydrazide-1-carboximide (21.00 g, 46.66 mmol, yield: >99%), LCMS m / z: 450 [M+H]. + .

[0298] 4) Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide

[0299] At room temperature, TFA (26.35 g, 231.10 mmol) was added to a solution of 1,4-dioxane (210 mL) containing N-(tert-butylsulfonyl)-N'-(2,6-dimethoxyphenyl)-2-(5-methylnicotinyl)hydrazide-1-carboximide (20.80 g, 46.22 mmol), and the mixture was heated to 100 °C and stirred for 4 hours. 83% of the target product was detected by LC-MS. The reaction mixture was quenched with saturated NaHCO3 (500 mL) and treated with EA (300 mL × 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide (12.00 g, 27.78 mmol, yield: 60.1%), LCMS m / z: 432 [M+H] + .

[0300] 5) Synthesis of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine

[0301] At room temperature, anisole (9.00 g, 83.34 mmol) was added to a TFA (60 mL) solution containing N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-methylpropane-2-sulfonamide (12.00 g, 27.78 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was quenched with saturated NaHCO3 (500 mL) and treated with EA (300 mL × 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (10.00 g, 32.15 mmol, yield: >99%), LCMS m / z: 312 [M+H]. + .

[0302] 6) Synthesis of methyl 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylic acid ester

[0303] Under a nitrogen atmosphere, Cs₂CO₃ (6.06 g, 18.60 mmol) and Brettphos Pd G₃ (426 mg, 0.47 mmol) were added to a 1,4-dioxane (10 mL) solution containing methyl 3-carboxylate trifluoroacetate (1.06 g, 4.65 mmol) and 2-chloro-5-methylpyrimidine (600 mg, 4.65 mmol). The mixture was heated to 110 °C and stirred for 16 hours. The desired product was analyzed by LC-MS. The reaction mixture was quenched with saturated NH₄Cl (100 mL) and precipitated with EA (50 mL × 2). The combined organic layers were dried over saturated brine (50 mL × 2) and anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to methyl 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylic acid (600 mg, 2.90 mmol, yield: 62.4%), LCMS m / z: 208 [M+H]. + .

[0304] 7) Synthesis of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylic acid

[0305] At room temperature, NaOH (116 mg, 2.90 mmol) was added to a solution of methyl 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylate (300 mg, 1.45 mmol) in 8 mL of THF and 2 mL of H₂O, and the mixture was stirred at 25 °C for 3 hours. The desired product was detected by LCMS. The mixture was neutralized to pH 4 with HCl (1 M). The mixed reaction solution was processed using a reversed-phase column (conditions as follows: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5% B-60% B for 25 min; detector: 254 nm). The fraction containing the desired product was collected under reduced pressure at 30% B to give 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylic acid (150 mg, 0.78 mmol, yield: 53.6%), LCMS m / z: 194 [M+H]. + .

[0306] 8) Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxamide (MRANK-111-A014)

[0307] To a 2 mL solution of DCM containing 50 mg (0.26 mmol) of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxylic acid, (COCl)₂ (5 mg, 0.04 mmol) and DMF (1 drop) were added, and the mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 1:1) showed the reaction was complete. LCMS detected the desired product. The mixture was concentrated under reduced pressure to obtain a crude product (55 mg, 0.26 mmol). To a 2 mL solution of the crude product in DCM, 81 mg (0.26 mmol) of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (53 mg, 0.52 mmol) and TEA (53 mg, 0.52 mmol) were added. The mixture was stirred at room temperature for 2 hours. LCMS detected the product. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (Waters 3767 / Qda, column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 20%–30%; retention time: 9.3min after 16min) to N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)azacyclobutane-3-carboxamide (8.24 mg, 0.017 mmol, yield: 6.5%), LCMS m / z: 487 [M+H]. + .

[0308] 1 H NMR (400MHz, DMSO-d6) δ10.27 (s, 1H), 8.43 (s, J = 1.2Hz, 1H), 8.22-8.21 (m, 3H), 7. 66(s,1H),7.44(t,J=8.4Hz,1H),6.78(d,J=8.4Hz,2H),4.02(t,J=8.4Hz,2H),3.74 -3.72(m,2H),2.82-3.62(s,6H),3.59 -3.54(m,1H),2.26(s,3H),2.09(s,3H).

[0309] Example 21: Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetamide (MRANK-111-A015):

[0310] 1) Synthesis of methyl 2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetate

[0311] Under a nitrogen atmosphere, Cs₂CO₃ (6.06 g, 18.60 mmol) and Brettphos Pd G₃ (426 mg, 0.47 mmol) were added to a solution of 1,4-dioxane (10 mL) containing methyl 2-(azacyclobutane-3-yl)acetate trifluoroacetate (1.05 g, 4.65 mmol) and 2-chloro-5-methylpyrimidine (600 mg, 4.65 mmol). The mixture was heated to 110 °C and stirred for 16 hours. LC-MS showed the presence of the desired product. The mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with saturated brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to methyl 2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetate (500 mg, 2.26 mmol, yield: 48.6%), LCMS m / z: 222 [M+H] + .

[0312] 2) Synthesis of 2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetic acid

[0313] At room temperature, NaOH (181 mg, 4.52 mmol) was added to a solution of methyl 2-(1-(5-methylpyrimidin-2-yl)azacyclobutan-3-yl)acetate (500 mg, 2.26 mmol) in 8 mL of THF and 2 mL of H₂O, and the mixture was stirred at 25 °C for 3 hours. LC-MS showed the presence of the desired product. The reaction mixture was neutralized to pH 4 with HCl (1 M). The reaction mixture was purified by reversed-phase rapid column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 5% B-60% B for 25 min; detector: 254 nm). The product fraction was collected under 30% B conditions and concentrated under reduced pressure to obtain 2-(1-(5-methylpyrimidin-2-yl)azacyclobutan-3-yl)acetic acid (300 mg, 1.45 mmol, yield: 64.0%). LCMS m / z: 208 [M+H] + .

[0314] 3) Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetamide (MRANK-111-A015)

[0315] To a solution of 2 mL DCM containing 50 mg (50 mg, 0.24 mmol) of 2-(1-(5-methylpyrimidin-2-yl)azacyclobutan-3-yl)acetic acid, 61 mg (0.48 mmol) and 1 drop of DMF were added, and the mixture was stirred at room temperature for 2 hours. TLC (PE:EA = 1:1) showed the reaction was complete. LCMS showed the desired product at 214 nm. The mixture was concentrated under reduced pressure to give a crude product (54 mg). To a solution of 2 mL DCM containing the crude product (54 mg), 75 mg (0.24 mmol) and 48 mg (0.48 mmol) of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (48 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 2 hours. LCMS showed 20% of the target product at 254 nm. The mixture was concentrated under reduced pressure. The residue was purified by TLC (DCM / MeOH = 20 / 1) to obtain a crude product (15 mg). The crude product was further purified by preparative-grade high-performance liquid chromatography (Waters 3767 / Qda, column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 19%–25%; retention time: 9.2–10.5 min, 16 min) to obtain N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-2-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)acetamide (2.84 mg, 0.006 mmol, yield: 2.3%), LCMS m / z: 501 [M+H]. + .

[0316] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.41(d,J=16.4Hz,1H),8.20(d,J=11.6Hz,3H), 7.65(s,1H),7.47(t,J=8.4Hz,1H),6.81(d,J=8.4Hz,2H),3.93(t,J=8.0Hz,2H),3.71 -3.64(m,6H),3.51 -3.46(m,2H),2.73(m,1H),2.55-2.53(m,2H),2.26(s,3H),2.07(s,3H).

[0317] Example 22, Synthesis of 1-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)urea (MRANK-111-A016):

[0318] 1) Synthesis of tert-butyl (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)carbamate

[0319] At room temperature, to a solution of 1,4-dioxane (20 mL) containing 2-bromo-5-methylpyrimidine (1.00 g, 5.78 mmol), tert-butyl aziridine-3-ylcarbamate (1.99 g, 11.56 mmol), cesium carbonate (3.77 g, 11.56 mmol), and Brettphos Pd G3 (525 mg, 0.58 mmol) were added, and the mixture was heated at 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give tert-butyl aziridine (1.10 g, 4.17 mmol, yield: 71.8%), LCMS m / z: 265 [M+H]. + .

[0320] 2) Preparation of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-amine

[0321] At room temperature, TFA (5 mL) was added to a DCM (5 mL) solution containing 1.10 g (4.17 mmol) of tert-butyl carbamate (1.10 g, 4.17 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase rapid chromatography (conditions: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (0.1% TFA); mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-80% B over 20 minutes; detector: 214 nm). The fraction containing the product was collected under 6% B and concentrated under reduced pressure to give 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-amine (550 mg, 3.35 mmol, yield: 80.5%), LC-MS m / z: 165 [M+H]. + .

[0322] 3) Synthesis of (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)carbamate

[0323] At room temperature, phenyl chloroformate (169 mg, 1.08 mmol) was added to a solution of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-ylamine (178 mg, 1.08 mmol) and pyridine (256 mg, 3.24 mmol) in acetonitrile (6 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water (50 mL) and diluted with EA (30 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:2) to give phenyl chloroformate (160 mg, 0.56 mmol, yield: 52%), LCMS m / z: 285 [M+H]. + .

[0324] 4) Synthesis of 1-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)urea (MRANK-111-A016)

[0325] At room temperature, DMAP (66 mg, 0.54 mmol) was added to a solution of 1,4-dioxane (10 mL) containing (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)carbamate (140 mg, 0.49 mmol) and 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (152 mg, 0.49 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by prep-TLC (DCM:MeOH = 20:1) to give 1-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)urea (7.66 mg, 0.02 mmol, yield: 3.1%), LCMS m / z: 502 [M+H] + .

[0326] 1H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.63(d,J=5.6Hz,1H),8.40(d,J=1.2Hz,1H),8.23(m,2H),8.17(d,J=1.6Hz,1H),7.55(s,1H),7.49(t,J=8.8 Hz,8.4Hz,1H),6.81(d,J=8.4Hz,2H),4.60-4.58(m,1H),4.28(t,J=8.4H z,8.0Hz,2H),3.87-3.84(m,2H),3.67(s,6H),2.23(s,3H),2.10(s,3H).

[0327] Example 23: Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methanesulfonamide (MRANK-111-A018):

[0328] 1) Synthesis of 3-((methylsulfonyl)oxy)methyl)azacyclobutane-1-carboxylic acid benzyl ester

[0329] At room temperature, MsCl (620 mg, 5.42 mmol) was added to a solution of 30 mL of dichloromethane containing 1.0 g (4.52 mmol) of 3-(hydroxymethyl)azacyclobutane-1-carboxylic acid benzyl ester and 1.37 g (13.56 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (50 mL), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered under reduced pressure to obtain 1.3 g (crude) of 3-((methanesulfonyl)oxy)methyl)azacyclobutane-1-carboxylic acid benzyl ester, which was used directly in the next step without further purification.

[0330] 2) Synthesis of 3-(acetylthio)methyl)azacyclobutane-1-carboxylic acid benzyl ester

[0331] At room temperature, AcSK (746 mg, 6.51 mmol) was added to a 20 mL solution of DMF containing 1.3 g (4.34 mmol) of benzyl 3-((methanesulfonyl)oxy)methyl)azacyclobutane-1-carboxylate, and the mixture was heated at 70 °C and stirred for 3 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give benzyl 3-(acetylthio)methyl)azacyclobutane-1-carboxylate (1.1 g, 3.94 mmol, yield: 91%), LCMS m / z: 280 [M+H]. + .

[0332] 3) Synthesis of benzyl 3-(chlorosulfonyl)methyl)azacyclobutane-1-carboxylate

[0333] At 0°C, acetonitrile (10 mL) containing 500 mg (1.79 mmol) of benzyl 3-(acetylthio)methyl)azacyclobutane-1-carboxylate was slowly added to a 5 mL solution of 2N HCl containing NCS (950 mg, 7.14 mmol, 4.0 eq) at room temperature, and stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 450 mg (crude) benzyl 3-(chlorosulfonyl)methyl)azacyclobutane-1-carboxylate, which was used directly in the next step without further purification.

[0334] 4) Synthesis of 3-(aminosulfonylmethyl)azacyclobutane-1-carboxylic acid benzyl ester

[0335] The solution of benzyl 3-(chlorosulfonyl)methyl)azacyclobutane-1-carboxylate (450 mg, 1.48 mmol) in NH3 / MeOH (50 mL, 7 M) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 1:1) to give benzyl 3-(aminosulfonyl)methyl)azacyclobutane-1-carboxylate (150 mg, 0.53 mmol, yield: 35.6%), LCMS m / z: 285 [M+H]. + .

[0336] 5) Synthesis of aziridine-3-ylmethanesulfonamide

[0337] A solution containing 150 mg (0.53 mmol) of 3-(aminosulfonylmethyl)azacyclobutane-1-carboxylic acid benzyl ester and 10% Pd / C (10 mg, 55% water) MeOH (10 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain azacyclobutane-3-ylmethanesulfonamide (70 mg, 0.466 mmol, yield: 88.2%), LCMS m / z: 151.1 [M+H]. + .

[0338] 6) Synthesis of (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methanesulfonamide

[0339] To a MeCN (20 mL) solution containing aziridine-3-ylmethanesulfonamide (70 mg, 0.466 mmol), add 2-chloro-5-methylpyrimidine (90 mg, 0.7 mmol) and DIEA (180 mg, 1.4 mmol), heat to 80 °C and stir for 3 hours. The mixed reaction solution was purified by reversed-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 80 g; mobile phase A: H2O containing 0.1% FA; mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B for 5 min, 5-40% B for 30 min; detector: 214 nm). The fraction containing the product was collected under 30% B and concentrated under reduced pressure to give (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methanesulfonamide (70 mg, 0.289 mmol, yield: 62%), LCMS m / z: 243 [M+H]. + .

[0340] 7) Synthesis of N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methanesulfonamide (MRANK-111-A018)

[0341] A solution of 1,4-dioxane (10 mL) containing 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine (100 mg, 0.266 mmol), (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methanesulfonamide (39 mg, 0.16 mmol), trans-N,N'-dimethyl-1,2-cyclohexyldiamine (75 mg, 0.532 mmol), Cs₂CO₃ (260 mg, 0.798 mmol), and CuI (25 mg, 0.133 mmol) was sealed in a tube and heated to 100 °C under nitrogen protection with stirring for 16 hours. The mixed reaction solution was diluted with EtOAc (30 mL), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-50% B over 30 min; detector: 214 nm). The fraction containing the desired product was collected in 40% B, concentrated, and lyophilized to give a white solid MRANK-111-A018 (17.52 mg, 0.032 mmol, yield: 20%), LCMS m / z: 537.2 [M+H). + .

[0342] 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),8.47(s,1H),8.19(s,3H),7.60(s,1H),7.51(t,J=8.8Hz,1H),6.84(d,J=8.4Hz, 2H), 4.00 (t, J = 8.4Hz, 2H), 3.77 (s, 6H), 3.75-3.73 (m, 2H), 3.30 (s, 2H), 3.02-2.98 (m, 1H), 2.25 (s, 3H), 2.07 (s, 3H).

[0343] Example 24: Synthesis of N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)-N'-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)sulfonyldiamine (MRANK-111-A019):

[0344] 1) Synthesis of N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)sulfonyldiamine

[0345] At room temperature, triethylamine (554 mg, 5.49 mmol) was added to 6 mL of DCM containing 300 mg (1.83 mmol) of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-amine (300 mg, 1.83 mmol), and the mixture was stirred at 0 °C for 10 min. Then, aminosulfonyl chloride (637 mg, 5.49 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (conditions: column: spherical C18, 20-40 μm, 25 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-95% B, 30 min; detector: 214 nm). The product fraction was collected under 5% B and concentrated under reduced pressure to give crude product (400 mg). The crude product was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 10). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)sulfonyldiamine (120 mg, 0.49 mmol, yield: 26.8%). LCMS m / z: 244 [M+H] + .

[0346] 2) Synthesis of N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)-N'-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)sulfonyldiamine (MRANK-111-A019)

[0347] At room temperature, Cs₂CO₃ (156 mg, 0.48 mmol), (1R,2R)-N₁,N₂-dimethylcyclohexane-1,2-diamine (11 mg, 0.08 mmol), and CuI (15 mg, 0.08 mmol) were added to a 3 mL solution of 1,4-dioxane containing 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine (60 mg, 0.16 mmol) and N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)sulfonyldiamine (117 mg, 0.48 mmol). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-50% B, 30 min; detector: 214 nm). The fraction containing the product was collected under reduced pressure at 33% B and concentrated to give N-(1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)-N'-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)sulfonyldiamine (19.18 mg, 0.04 mmol, yield: 22.0%), LCMS m / z: 538 [M+H]. + .

[0348] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.19(s,3H),7.59(s,1H),7.49(t,J=8.4Hz,8.8Hz,1H),7.06(s,1 H), 6.83 (d, J = 8.4Hz, 2H), 4.13-4.10 (m, 1H), 4.08-4.02 (m, 2H), 3.78 (s, 8H), 2.24 (s, 3H), 2.07 (s, 3H).

[0349] Example 25: Synthesis of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-N-((1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methyl)-4H-1,2,4-triazol-3-carboxamide (MRANK-111-A020):

[0350] 1) Synthesis of ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-carboxylic acid

[0351] To a solution of 3-(5-bromo-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-5-methylpyridine (180 mg, 0.48 mmol) in EtOH (10 mL), KOAc (141 mg, 1.44 mmol) and Pd(dppf)Cl2 (35 mg, 0.048 mmol) were added. The mixture was heated at 75 °C and stirred for 16 hours under a carbon monoxide atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-carboxylic acid (150 mg, 0.41 mmol, yield: 84.8%), LCMS m / z: 369 [M+H]. + .

[0352] 2) Synthesis of tert-butyl ((1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methyl)carbamate

[0353] To a MeCN (10 mL) solution containing 2-chloro-5-methylpyrimidine (300 mg, 2.33 mmol), tert-butyl (1-(5-methylpyrimidine-2-yl)azacyclobutane-3-yl)methyl)carbamate (650 mg, 3.5 mmol) and DIEA (904 mg, 6.99 mmol) were added, and the mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel (PE:EA = 1:2) to obtain tert-butyl ((1-(5-methylpyrimidine-2-yl)azacyclobutane-3-yl)methyl)carbamate (600 mg, 2.16 mmol, yield: 92.5%), LCMS m / z 279.2 [M+H]. + .

[0354] 3) Synthesis of (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methylamine hydrochloride

[0355] A solution of ((1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methyl)carbamate tert-butyl hydrochloride (600 mg, 2.16 mmol) in 30 mL of hydrochloric acid / 1,4-dioxane (4 M) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain (1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methylamine hydrochloride (450 mg, crude product), LCMS m / z: 179.3 [M+H] + .

[0356] 4) Synthesis of 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-N-((1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methyl)-4H-1,2,4-triazol-3-carboxamide (MRANK-111-A020)

[0357] To a toluene (10 mL) solution containing (100 mg, 0.47 mmol) methylamine hydrochloride, AlMe3 (1 M, 1.18 mL, 1.18 mmol) was slowly added, and the mixture was stirred at room temperature for 15 min. Then, ethyl 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-carboxylic acid (87 mg, 0.235 mmol) was added, and the mixture was heated to 110 °C and stirred for 3 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-95% B over 30 min; detector: 214 nm). The fraction containing the product was collected at 40% B and concentrated under reduced pressure to give 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-N-((1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl)methyl)-4H-1,2,4-triazol-3-carboxamide (23.37 mg, 0.047 mmol, yield: 20%), LCMS m / z: 515.2 [M+H). + .

[0358] 1 H NMR (400MHz, DMSO-d6) δ9.23(t,J=6.0Hz,1H),8.48(d,J=1.6Hz,1H),8.20(d,J=2.0Hz,1H),8.1 8(s,2H),7.62(s,1H),7.43(t,J=8.4Hz,1H),6.78(d,J=8.8Hz,2H),3.99(t,J=8.4Hz,2H),3.73 -3.66(m,2H),3.62(s,6H),3.43(t,J=6.4Hz,2H),2.85-2.82(m,1H),2.25(s,3H),2.07(s,3H).

[0359] Example 26: Synthesis of (4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl ester (MRANK-111-A022):

[0360] 1) Synthesis of 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-ol

[0361] At room temperature, DIEA (600 mg, 4.65 mmol) was added to a 5 mL solution of DMF containing 2-chloro-5-methylpyrimidine (200 mg, 1.55 mmol) and aziridine-3-ol (136 mg, 1.86 mmol), and the mixture was heated to 60 °C and stirred for 16 hours. The mixed reaction solution was subjected to reversed-phase column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 50 mL / min; gradient: 5% B-95% B, 30 min; detector: 214 nm). The fraction containing the product was collected under 12% B and concentrated under reduced pressure to give 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-ol (175 mg, 1.06 mmol, yield: 68.4%), LCMS m / z: 166 [M+H]. + .

[0362] 2) Synthesis of (4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-yl ester (MRANK-111-A022)

[0363] At room temperature, triethylamine (190 mg, 1.88 mmol) was added to a DCM (5 mL) solution containing 1-(5-methylpyrimidin-2-yl)azacyclobutane-3-ol (155 mg, 0.94 mmol) and 4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-amine (292 mg, 0.94 mmol). Triphosgene (336 mg, 1.13 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. The residue was subjected to reversed-phase rapid column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 25 g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-95% B, 30 min; detector: 214 nm). The fraction containing the desired product was collected at a concentration of 27% B and concentrated under reduced pressure to give 1-(5-methylpyridin-2-yl)azacyclobutane-3-yl ester of (4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)carbamate (12.01 mg, 0.02 mmol, yield: 2.1%), LCMS m / z: 503 [M+H]. + .

[0364] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.22-8.15(m,3H),7.62(s,1H),7.45(t,J=8.0Hz,1H),6.79 -6.77(m,2H),5.08-5.05(m,1H),4.23-4.19(m,2H),3.71-3.62(m,8H),2.25(s,3H),2.09(s,3H).

[0365] Example 27. Synthesis of (aS,2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or its enantiomers (MRANK-111-A031-1 and MRANK-111-A031-2):

[0366] 1) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)butane-2-sulfonamide

[0367] At room temperature, 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]7-isothiocyanate (110 mg, 0.47 mmol) and Cs₂CO₃ (192 mg, 0.59 mmol) were added to a 5 mL solution of ACN containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (100 mg, 0.39 mmol). The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was used directly in the next step without purification. LCMS m / z: 489.2 [M+H] + .

[0368] 2) Synthesis of (Z)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-2-(5-methylnicotinyl)hydrazine-1-carboximide

[0369] At room temperature, 5-methylnicotinamide (59 mg, 0.39 mmol, 1.0 eq.) and silver nitrate (133 mg, 0.78 mmol, 2.0 eq.) were added to a solution of acetonitrile (5 mL) containing (191 mg, 0.39 mmol, 1.0 eq.), and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was filtered, the filter cake was washed with EA (50 mL), and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give a white solid compound (Z)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-2-(5-methylnicotinyl)hydrazine-1-formamidin (80 mg, 0.13 mmol, yield 33.3%), LCMS: m / Z: 606.3 [M+H] + .

[0370] 3) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide

[0371] At room temperature, TFA (68 mg, 0.60 mmol) was added to a solution of 1,4-dioxane (3 mL) containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)butane-2-sulfonamide (70 mg, 0.12 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The residue was subjected to reversed-phase rapid column chromatography (column: spherical C18, 20-40 μm, 40 g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5%-95% B for 30 min; detector: 214 nm). The fraction containing the product was collected at 48% B and concentrated under reduced pressure to give (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide (40 mg, 0.07 mmol, yield: 58.3%), LCMS: m / z: 588.4 [M+H). + .

[0372] 4) Synthesis of (aS,2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or its enantiomers (MRANK-111-A031-1 and MRANK-111-A031-2).

[0373] The compound (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide (40 mg, 0.07 mmol) was purified by SFC (conditions: system: Waters SFC 80; column name: Column; dimensions: 250×30mm×10μm; mobile phase A: supercritical CO2; mobile phase B: ACN (+0.1% 7.0mol / L ammonia in methanol solution), A:B = 50:50; wavelength: 214nm; flow rate: 70mL / min; column temperature: room temperature; back pressure: 100bar; injection: 3mL; circulation time: 5.27min) Two isomers were prepared: MRANK-111-A031-1 and MRANK-111-A031-2.

[0374] MRANK-111-A031-1: Peak 1: Chiral HPLC: 2.257 min; (aS, 2S, 3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or enantiomer (4.94 mg, 0.01 mmol, yield: 12.3%), LCMS m / z: 588.5 [M+H] + .

[0375] 1 H NMR(DMSO-d6,400MHz)δ13.37(s,1H),8.51(s,2H),8.47(s,1H),8.26(s,1H ),7.70(s,1H),6.91(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),4.48-4.43(m,2 H),3.72-3.69(m,2H),3.61(s,3H),2.27(s,3H),1.93-1.89(m,1H),1.27(d ,J=6.8Hz,3H),1.12(d,J=6.8Hz,3H),1.06-0.99(m,6H),0.83-0.79(m,2H).

[0376] MRANK-111-A031-2: Peak 2, Chiral HPLC: 3.774 min; (aR, 2S, 3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)butane-2-sulfonamide or enantiomer (8.84 mg, 0.014 mmol, yield: 22.1%), LCMS m / z: 588.5 [M+H] + .

[0377] 1H NMR(DMSO-d6,400MHz)δ13.42(s,1H),8.50(s,2H),8.47(s,1H),8.25(s,1 H),7.70(s,1H),6.91(d,J=8.4Hz,1H),6.56(d,J=8.4Hz,1H),4.52-4.46( m,2H),3.71(s,2H),3.60(s,3H),2.27(s,3H),1.94-1.87(m,1H),1.25(d, J=6.8Hz,3H),1.10(d,J=4.8Hz,3H),1.05-0.98(m,6H),0.83-0.79(m,2H).

[0378] Example 28. Synthesis of (aS, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A032-1 and MRANK-111-A032-2):

[0379] 1) Synthesis of 5-cyclopropylnicotinic acid ethyl ester

[0380] To a solution containing 15 mL of toluene (1.0 g, 4.35 mmol) and 2.0 mL of H₂O, cyclopropylboronic acid (0.56 g, 6.52 mmol), K₃PO₄ (1.84 g, 8.70 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (360 mg, 0.44 mmol) were added. The mixture was heated at 90 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 5-cyclopropylnicotinic acid ethyl ester (0.84 g, 4.40 mmol, yield: >99%), LCMS m / z: 192.0 [M+H]. + .

[0381] 2) Synthesis of 5-cyclopropylnicotinamide

[0382] To a 20 mL ethanol solution containing 0.84 g (4.40 mmol) of ethyl 5-cyclopropylnicotinamide, 1.09 g (1.1 mL, 21.85 mmol) of NH₂NH₂·H₂O was added, and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was diluted with 100 mL of ethyl acetate, washed with saturated brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 0.44 g (crude product) of 5-cyclopropylnicotinamide. LCMS m / z: 178.1 [M+H] + .

[0383] 3) Synthesis of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0384] At room temperature, 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isothiocyanate (110 mg, 0.47 mmol) and Cs₂CO₃ (183 mg, 0.56 mmol) were added to a 5.0 mL solution of acetonitrile containing (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (110 mg, 0.43 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was used directly for the next step without purification. LCMS m / z: 489.2 [M+H] +

[0385] 4) Synthesis of (Z)-2-(5-cyclopropylnicotinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0386] At room temperature, 5-cyclopropylnicotinamide (115 mg, 0.65 mmol) and AgNO3 (221 mg, 1.30 mmol) were added to a solution of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (300 mg, 0.43 mmol) in acetonitrile (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give (Z)-2-(5-cyclopropylnicotinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (170 mg, 0.28 mmol, yield: 43.1%), LCMS m / z: 606.4 [M+H] + .

[0387] 5) Synthesis of (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0388] To a solution of 1,4-dioxane (10 mL) containing (Z)-2-(5-cyclopropylnicotinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (170 mg, 0.28 mmol), 0.5 mL of 2,2,2-trifluoroacetic acid was added, and the mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / MeOH = 95 / 5) to obtain a crude product (90 mg). The crude product was purified by reversed-phase rapid chromatography under the following conditions: column: spherical C18, 20-40 μm, 25 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5%-55% B over 30 minutes; detector: 214 nm. The fraction containing the desired product was collected under 55% B and concentrated under reduced pressure to give (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (40 mg, 0.068 mmol, yield: 24.2%). LCMS m / z: 588.5 [M+H] + .

[0389] 6) Synthesis of (aS,2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A032-1 and MRANK-111-A032-2)

[0390] The compound (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (40 mg, 0.068 mmol) was purified by SFC (conditions: System: Waters SFC 80; column name: Column length: 250*30mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: IPA (+0.1% 7.0mol / l Ammonia in IPA), A:B = 45:55; Detection wavelength: 214nm; Flow rate: 70mL / min; Column temperature: RT; Column pressure: 100bar; Injection volume: 4.0mL; Cycle time: 7.59min) Two isomers, MRANK-111-A032-1 and MRANK-111-A032-2, were prepared.

[0391] MRANK-111-A032-1: Chiral HPLC: Peak 1: 2.185 min; (aS, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or enantiomer (12.03 mg, 0.020 mmol, yield: 30%), LCMS m / z: 588.2 [M+H] + .

[0392] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),8.59(s,2H),8.54(d,J=2.0Hz,1H),8.42(d,J=2. 0Hz,1H),7.18(s,1H),6.94(d,J=8.0Hz,,1H),6.58(d,J=8.4Hz,1H),4.48(s,2H),3.73 -3.63(m,2H),3.59(s,3H),2.24(s,3H),1.97-1.92(m,1H),1.27(d,J=7.2,3H),1.13(d ,J=6.8Hz,3H),,1.04(s,4H),1.00-0.97(m,2H),0.53-0.50(m,1H),0.46-0.42(m,1H).

[0393] MRANK-111-A032-2: Chiral HPLC: Peak 2: 3.147 min; (aR, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-1,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its enantiomer (10.99 mg, 0.0019 mmol, yield: 27.5%), LCMS m / z: 588.2 [M+H] +.

[0394] 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.59(s,2H),8.54(s,1H),8.43(s,1H),7.17(s,1H), 6.94(d,J=8.4Hz,,1H),6.57(d,J=8.4Hz,1H),4.54(d,J=8.8Hz,2H),4.47(d,J=8.8Hz,2H), 3.72-3.65(m,2H),3.59(s,3H),2.23(s,3H),1.97-1.92(m,1H),1.25(d,J=7.2,3H),1.11(d ,J=6.8Hz,3H),1.07-1.05(m,4H),1.00-0.97(m,2H),0.53-0.50(m,1H),0.45-0.41(m,1H).

[0395] Example 29. Synthesis of (aS, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A033-1 and MRANK-111-A033-2):

[0396] 1) Synthesis of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0397] At room temperature, 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isocyanate (355 mg, 1.55 mmol) and cesium carbonate (548 mg, 1.68 mmol) were added to 10 mL of acetonitrile containing (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (300 mg, 1.29 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction mixture was used directly for the next step without further purification. LCMS m / z: 463.2 [M+H] + .

[0398] 2) Synthesis of (Z)-2-(6-cyclopropylpyridinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0399] At room temperature, 6-cyclopropylpyridinyl hydrazide (266 mg, 1.50 mmol) and silver nitrate (510 mg, 3.00 mmol) were added to a solution of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (695 mg, 1.50 mmol) in 10 mL of acetonitrile. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (150 mL). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM; MeOH = 10:1) to obtain (Z)-2-(6-cyclopropylpyridinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (219 mg, 0.36 mmol, yield: 24.0%), LCMS m / z: 606.3 [M+H]+.

[0400] 3) Synthesis of (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0401] At room temperature, TFA (0.9 mL) was added to a 1,4-dioxane (9 mL) solution containing (Z)-2-(6-cyclopropylpyridinyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-N-(((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (219 mg, 0.36 mmol), and the mixture was heated to 100 °C and stirred for 16 hours. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (70 mg, 0.12 mmol, yield: 33.0%), LCMS m / z: 588.5 [M+H] + .

[0402] 4) Synthesis of (aS,2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A033-1 and MRANK-111-A033-2)

[0403] The compound (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (70 mg, 0.12 mmol) was prepared by SFC (conditions: system: Waters SFC 80; column name: Column size: 250*30mm x 10μm; Mobile phase A: supercritical CO2; Mobile phase B: ACN (+0.1% 7.0mol / L ammonia solution), A:B = 50:50; Wavelength: 214nm; Flow rate: 70mL / min; Column temperature: room temperature; Column pressure: 100bar; Injection volume: 4.5mL; Cycle time: 7.73min) Purification yielded two single isomers: MRANK-111-A033-1 and MRANK-111-A033-2.

[0404] MRANK-111-A033-1: Peak: Chiral HPLC: 2.661 min; (aS, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or enantiomer (7.00 mg, 0.012 mmol, yield: 10%), LCMS m / z: 588.2 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d) 6) δ13.27(s,1H),8.58(s,2H),7.75-7.69(m,2H),7.36(t,J=7.2Hz,1H),6.83(d,J=8.4Hz,,1H ),6.51(d,J=8.4Hz,1H),4.45-4.39(m,2H),3.73-3.65(m,,2H),3.53(s,2H),2.23(s,3H),2. 23(s,3H),1.89-1.83(m,1H),1.27-1.24(m,3H),1.11(d,J=7.2Hz,3H),1.08-1.01(m,2H),1. 00-0.97(m,2H),0.72-0.67(m,1H),0.65-0.56(m,1H),0.36-0.30(m,1H),0.09-0.02(m,1H).

[0406] MRANK-111-A033-2: Peak 2: Chiral HPLC: 4.197 min; (aR, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or enantiomer (4.26 mg, 0.007 mmol, yield: 6.0%), LCMS m / z: 588.5 [M+H] + .

[0407] 1H NMR (400MHz, DMSO-d6) δ13.30(s,1H),8.58(s,2H),7.77-7.70(m,2H),7.39(t,J=6.4Hz,1H),6.85(d,J=8.0Hz ,,1H),6.51(d,J=8.4Hz,1H),4.49(d,J=8.4Hz,,1H),4.41(d,J=8.8Hz,,1H),3.72-3.70(m,1H),3.69-3.61(m 1),3.53(s,3H),2.23(s,3H),1.91-1.84(m,1H),1.23(d,J=7.2,3H),1.12-1.05(m,4H),1.03(d,J=7.6Hz ,2H),0.99(t,J=5.6Hz,1H),0.73-0.64(m,1H),0.63-0.57(m,1H),0.38-0.32(m,1H),0.08-0.03(m,1H).

[0408] Example 30: Synthesis of (aS, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A034-1 and MRANK-111-A034-2):

[0409] 1) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)but-2-sulfonamide

[0410] At room temperature, 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isocyanate (110 mg, 0.43 mol) and cesium carbonate (183 mg, 0.56 mmol) were added to a solution of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (100 mg, 0.43 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was used directly in the next step without purification. LCMS m / z: 489.2 [M+H] + .

[0411] 2) Synthesis of (Z)-2-(6-cyclopropylpyridinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide

[0412] At room temperature, 6-cyclopropylpyridinyl hydrazide (76 mg, 0.44 mmol) and silver nitrate (146 mg, 0.86 mmol) were added to an acetonitrile (10 mL) solution containing (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)but-2-sulfonamide (210 mg, 0.43 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate cake was washed with ethyl acetate (150 mL). The mixture was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give (Z)-2-(6-cyclopropylpyridinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (108 mg, 0.17 mmol, yield: 39.8%), LCMS m / z: 632.4 [M+H] + .

[0413] 3) Synthesis of (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide

[0414] At room temperature, TFA (0.9 mL) was added to a solution of 1,4-dioxane (9 mL) containing (Z)-2-(6-cyclopropylpyridinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (90 mg, 0.14 mmol), and the mixture was heated to 100 °C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (37 mg, 0.06 mmol, yield: 42.5%), LCMS m / z: 614.2 [M+H]. + .

[0415] 4) Synthesis of (aS,2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A034-1 and MRANK-111-A034-2)

[0416] The compound (2S,3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (37 mg, 0.06 mmol) was purified by SFC (conditions: system: Waters SFC 80; column name: Column size: 250*30mm x 10μm; Mobile phase A: supercritical CO2; Mobile phase B: MEOH (+0.1% 7.0mol / L ammonia in MEOH), A:B = 40:60; Wavelength: 214nm; Flow rate: 80mL / min; Column temperature: room temperature; Column pressure: 100bar; Injection volume: 4.5mL; Cycle time: 3.0min) MRANK-111-A034-1 and MRANK-111-A034-2 were prepared.

[0417] MRANK-111-A034-1: Peak 1: Chiral HPLC: 3.007 min; (aS, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or enantiomer (2.54 mg, 0.004 mmol, yield: 6.8%), LCMS m / z: 614.3 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.50(s,2H),7.77-7.70(m,2H),7.39(d,J=7.2Hz,1H),6.85(d,J =8.0Hz,1H),6.51(d,J=8.4Hz,1H),4.42(d,J=2.4Hz,2H),3.72-3.66(m,1H),3.62-3.59(m,1H),3.53( s,3H),1.94-1.84(m,2H),1.25(d,J=6.8Hz,3H),1.12(d,J=7.2Hz,3H),1.08-1.04(m,2H),1.02-0.98( m,4H),0.82-0.79(m,2H),0.72-0.67(m,1H),0.64-0.57(m,1H),0.36-0.30(m,1H),0.09-0.02(m,1H).

[0419] MRANK-111-A034-2: Peak 1: Chiral HPLC: 5.121 min; (aR, 2S, 3R)-N-(5-(6-cyclopropylpyridin-2-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or enantiomer (3.18 mg, 0.005 mmol, yield: 8.5%), LCMS m / z: 614.3 [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d) 6)δ13.29(s,1H),8.50(s,2H),7.77-7.69(m,2H),7.38(d,J=7.6Hz,1H),6.85(d,J=8.0Hz,1H),6.50(d, J=11.2Hz,1H),4.49(d,J=8.4Hz,1H),4.41(d,J=8.8Hz,1H),3.72-3.67(m,1H),3.65-3.59(m,1H),3.5 3(s,3H),1.94-1.84(m,2H),1.23-1.21(m,3H),1.10(d,J=14.4Hz,4H),1.06-1.01(m,2H),1.00-0.98( m,3H),0.82-0.78(m,2H),0.72-0.66(m,1H),0.66-0.58(m,1H),0.37-0.31(m,1H),0.08-0.02(m,1H).

[0421] Example 31: Synthesis of (aS, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A035-1 and MRANK-111-A035-2):

[0422] 1) Synthesis of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)thiocarbamoyl)but-2-sulfonamide

[0423] At room temperature, 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isothiocyanate (110 mg, 0.47 mmol) and Cs₂CO₃ (183 mg, 0.56 mmol) were added to a solution of (2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (110 mg, 0.43 mmol) in acetonitrile (5.0 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was used directly for purification in the next step. LCMS m / z: 489.2 [M+H] + .

[0424] 2) Synthesis of (Z)-2-(5-cyclopropylnicotinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-formimide

[0425] At room temperature, 5-cyclopropylnicotinamide (76 mg, 0.44 mmol, 1.0 eq.) and AgNO3 (146 mg, 0.86 mmol, 2.0 eq.) were added to an acetonitrile (5.0 mL) solution containing (E)-N-(((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)carbamoylthioic acid (210 mg, 0.43 mmol, 1.0 eq.). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give (Z)-2-(5-cyclopropylnicotinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (140 mg, 0.22 mmol, yield: 51.1%), LCMS m / z: 632.4 [M+H] + .

[0426] 3) Synthesis of (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide

[0427] To a solution of 1,4-dioxane (6 mL) containing (Z)-2-(5-cyclopropylnicotinyl)-N-((2S,3R)-3-(5-cyclopropylpyrimidin-2-yl)but-2-yl)sulfonyl)-N'-(6-methoxy-2H-spirofuran-3,1'-cyclopropane]-7-yl)hydrazine-1-carboximide (140 mg, 0.22 mmol), add 0.6 mL of trifluoroacetic acid and heat to 100 °C with stirring for 2 hours. The mixed reaction solution was purified by rapid chromatography (conditions as follows: column: spherical C18, 20-40 μm, 25 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5%-45% B, 30 min; detector: 214 nm). The fraction containing the product was collected at 45% B and concentrated under reduced pressure to give (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (80 mg, 0.13 mmol, yield: 59.0%), LCMS m / z: 614.2 [M+H]. + .

[0428] 4) Synthesis of (aS, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-A035-1 and MRANK-111-A035-2)

[0429] The compound (2S,3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide (70 mg, 0.11 mmol) was prepared by SFC separation (conditions: System: Waters SFC 80; column name: IH dimensions: 250*30mm 10μm; Mobile phase A: supercritical CO2; Mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 45:55; Detection wavelength: 214nm; Flow rate: 70mL / min; Column temperature: RT; Back pressure: 100bar; Injection volume: 4.0mL; Cycle time: 10.24min) Two isomers were obtained: MRANK-111-A035-1 and MRANK-111-A035-2.

[0430] MRANK-111-A035-1: Peak 1: Chiral HPLC: 2.677 min; (aS, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its enantiomer (22.67 mg, 0.037 mmol, yield: 33.6%), LCMS m / z: 614.2 [M+H] + .

[0431] 1 H NMR(400MHz,DMSO-d6)δ13.40(s,1H),8.54(s,2H),8.51-8.49(m,1H),8.42(d,J=2.0Hz,1 H),7.17(s,1H),8.93(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),4.48(s,2H),3.70(d,J=7.6H z,1H),3.68-3.62(m,1H),3.59(s,3H),1.96-1.87(m,2H),1.26(d,J=7.2Hz,3H),1.12(d, J=7.2Hz,3H),1.04-0.97(m,8H),0.83-0.79(m,2H),0.54-0.48(m,1H),0.45-0.41(m,1H).

[0432] MRANK-111-A035-2:Peak 2:Chiral HPLC: 3.902 min; (aR, 2S, 3R)-N-(5-(5-cyclopropylpyridin-3-yl)-4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-4H-1,2,4-triazol-3-yl)-3-(5-cyclopropylpyrimidin-2-yl)butane-2-sulfonamide or its enantiomer (18.19 mg, 0.030 mmol, yield: 26.0%), LCMS m / z: 614.5 [M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ13.40(s,1H),8.54(s,2H),8.50(s,1H),8.42(d,J=1.6Hz,1H),7.1 7(s,1H),8.93(d,J=8.4Hz,1H),6.57(d,J=8.0Hz,1H),4.54(d,J=8.8Hz,2H),4.48(d,J=8. 8Hz,1H),3.73-3.64(m,2H),3.59(s,3H),1.98-1.87(m,2H),1.24(d,J=6.8Hz,3H),1.10(d ,J=6.8Hz,3H),1.0-0.97(m,8H),0.83-0.79(m,2H),0.53-0.50(m,1H),0.45-0.41(m,1H).

[0434] Example 32, Synthesis of (aS, 2S, 3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-001-1 and MRANK-111-001-2):

[0435] 1) Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-2-one

[0436] To a DMF (200 mL) solution containing 8.77 g (53.5 mmol) of 6-methoxybenzo-3H-furan-2-one, sulfonium (2-bromoethyl)diphenyltrifluoromethanesulfonate (23.7 g, 5.35 mmol) and TEA (16.21 g, 160.2 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with saturated brine (300 mL × 2), and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-2-one (9.35 g, 49.21 mmol, yield: 92%), LCMS m / z: 191.0 [M+H]. +

[0437] 2) Synthesis of 2-(1-(hydroxymethyl)cyclopropyl)-5-methoxyphenol

[0438] At -10°C, LiAlH4 (3.74 g, 98.42 mmol) was added to a dry tetrahydrofuran (100 mL) solution containing 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-2-one (9.35 g, 49.21 mmol), and the mixture was stirred at 0°C for 1 hour. While stirring, the reaction mixture was slowly added to ice water (300 mL). The pH was adjusted to approximately 4 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(1-(hydroxymethyl)cyclopropyl)-5-methoxyphenol (10.97 g, 56.54 mmol, yield: 100%), LCMS m / z: 195.0 [M+H]. + .

[0439] 3) Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]

[0440] To a solution of anhydrous tetrahydrofuran (200 mL) containing 2-(1-(hydroxymethyl)cyclopropyl)-5-methoxyphenol (10.97 g, 56.54 mmol), PPh3 (22.22 g, 84.81 mmol) was added. The mixture was cooled to -30 °C, and DIAD (17.13 g, 84.81 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 15:1) to give 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (8.37 g, 47.56 mmol, yield 84.6%), LCMS m / z: 177.1 [M+H].+ .

[0441] 4) Synthesis of 7-bromo-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]

[0442] At 0 °C, n-Butyllithium (20.9 mL, 52.32 mmol, 1.1 eq. in 2.5 mol / L hexane solution) was slowly added to a tetrahydrofuran (80 mL) solution containing 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (8.37 g, 47.56 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -70 °C, and a tetrahydrofuran (50 mL) solution containing CBr4 (15.79 g, 47.56 mmol) was slowly added, followed by stirring at room temperature for 1 hour. After quenching the reaction with saturated NH4Cl solution (50 mL), the mixture was diluted with ethyl acetate (200 mL) and washed with brine (200 mL × 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / MeOH = 10:1) to give 7-bromo-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane] (3.9 g, 15.29 mmol, yield: 32.1%). LCMS m / z: 254.9 [M+H] + .

[0443] 5) Synthesis of tert-butyl 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-aminocarboxylic acid

[0444] To a dry 1,4-dioxane (20 mL) solution containing 3.9 g (15.29 mmol) of 7-bromo-6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane], Cs₂CO₃ (14.95 g, 45.87 mmol), tert-butyl carbamate (8.94 g, 76.45 mmol), and Brettphos Pd G₃ (1.38 g, 1.53 mmol) were added, and the mixture was heated at 100 °C and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give tert-butyl 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-aminocarboxylic acid (3.46 g, 11.89 mmol, yield: 77.7%), LCMS m / z: 236.1 [M+H-56]. + .

[0445] 6) Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine

[0446] To a DCM solution (30 mL) containing tert-butyl 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-aminocarboxylic acid (3.46 g, 11.9 mmol), 2,2,2-trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), washed with Na₂CO₃ (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine (1.66 g, 8.69 mmol, yield: 73.0%), LCMS m / z: 192.1 [M+H]. + .

[0447] 7) Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isothiocyanate

[0448] To a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine (1.66 g, 8.69 mmol) in dichloromethane (20 mL), 1,1'-thiocarbonylbispyridin-2-one (2.14 g, 9.22 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PA:EA = 10:1–20:1) to give 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isothiocyanate (1.42 g, 6.09 mmol, yield: 72.7%), LCMS m / z: 234.1 [M+H]. + .

[0449] 8) Synthesis of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)aminothioformyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0450] To a solution of (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (142 mg, 0.62 mmol) in acetonitrile (5 mL), 6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-isothiocyanate (160 mg, 0.68 mmol) and cesium carbonate (264 mg, 0.81 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was used directly in the next step without further purification. LCMS m / z: 463.1 [M+H] + .

[0451] 9) Synthesis of (Z)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide

[0452] To a solution of (2S,3R)-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)aminothioformyl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (287 mg, 0.62 mmol), 5-methylnicotinamide (94 mg, 0.62 mmol) and silver nitrate (210 mg, 1.36 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / MeOH = 10 / 1) to (Z)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazine-1-carboximide (80 mg, 0.14 mmol, yield: 22.6%), LCMS m / z: 580.4 [M+H] + .

[0453] 10) Synthesis of (2S,3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0454] A tube containing 5.0 mL of 1,4-dioxane was sealed with (Z)-N'-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-2-(5-methylnicotinyl)-N-((2S,3R)-3-(5-methylpyrimidin-2-yl)but-2-yl)sulfonyl)hydrazide-1-carboximide (80 mg, 0.14 mmol). 2,2,2-trifluoroacetic acid (0.5 mL) was added, and the mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / MeOH = 97:3) to obtain the crude product. The crude product was further purified by reversed-phase rapid chromatography (chromatographic conditions: column: spherical C18, 20-40 μm, 25 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: 5% B-45% B, 30 min; detector: 214 nm). The fraction containing the product was collected under 45% B and concentrated under reduced pressure to give (2S,3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (40 mg, 0.07 mmol, yield: 51.6%), LCMS m / z: 562.5 [M+H). + .

[0455] 11) Synthesis of (aS, 2S, 3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomers (MRANK-111-001-1 and MRANK-111-001-2)

[0456] The compound (2S,3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (40 mg, 0.07 mmol) was purified by SFC (conditions: System: Waters SFC 80; column name: IC, dimensions: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 70:30; detection wavelength: 214nm; flow rate: 50mL / min; column temperature: RT; column pressure: 100bar; injection volume: 0.8mL;

[0457] Cycle time: 5.62 min) yielded two isomers: MRANK-111-001-1 (20 mg, crude, Chiral HPLC (2.607 min)) and MRANK-111-001-2 (20 mg, crude, Chiral HPLC (3.074 min)).

[0458] MRANK-111-001-1: Crude product (20 mg, Chiral HPLC (2.607 min)) was re-passed through SFC (conditions: System: Waters SFC 80; column name: IH, dimensions: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 45:55; detection wavelength: 214nm; flow rate: 70mL / min; column temperature: RT; column pressure: 100bar; injection volume: 4.0mL; cycle time: 4.67min) to prepare (aS,2S,3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its isomer (15.51mg, 0.027mmol, yield: 75%), LCMS. m / z: 562.4 [M+H] + Chiral HPLC: 2.639 min;

[0459] 1H NMR (400MHz, DMSO-d6): δ13.40(s,1H),8.59(s,2H),8.48(s,1H),8.26(d,J =1.6Hz,1H),7.71(s,1H),6.91(d,J=8.4Hz,1H),6.58(d,J=8.4Hz,1H),4.4 6(q,J=13.2Hz,9.2Hz,2H),3.73-3.69(m,2H),3.61(s,3H),2.27(s,3H),2. 24(s,3H),1.27(d,J=6.8Hz,3H),1.13(d,J=7.2Hz,3H),1.08-0.98(m,4H).

[0460] MRANK-111-001-2: Crude product (20 mg, Chiral HPLC (3.074 min)) was further purified by SFC (conditions: System: Waters SFC 80; column name: AD, dimensions: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 65:35; detection wavelength: 214nm; flow rate: 70mL / min; column temperature: RT; column pressure: 100bar; injection volume: 8.0mL; cycle time: 6.34min) yielded (aR, 2S, 3R)-N-(4-(6-methoxy-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide or its enantiomer (12.14mg, 0.022mmol, yield: 61%), LCMS m / z: 562.4 [M+H] + .

[0461] 1 H NMR(400MHz,DMSO-d6)δ13.42(s,1H),8.59(s,2H),8.49(s,1H),8.26(d,J =1.2Hz,1H),7.71(s,1H),6.92(d,J=8.4Hz,1H),6.57(d,J=8.4Hz,1H),4.4 9(q,J=14.4Hz,8.8Hz,2H),3.72-3.69(m,2H),3.61(s,3H),2.28(s,3H),2. 24(s,3H),1.25(d,J=7.2Hz,3H),1.11(d,J=6.8Hz,3H),1.06-1.01(m,4H).

[0462] Test Example 1: Detection of Apelin Receptor Activation Activity by the Test Substance

[0463] Apelin receptor agonists can induce AMPK activation and phosphorylation in cardiac tissue, and therefore can be used to evaluate the activity of apelin receptor agonists. Mice were euthanized after administration of the test substance, and cardiac tissue was harvested. Tissue samples were digested, proteins extracted, and quantified using T-PER tissue protein extractant (containing EDTA and protease / phosphatase inhibitors) and the Pierce™ BCA protein assay kit. Total protein was transferred to a PVDF membrane via SDS-PAGE. The membrane was blocked and visualized using anti-phospho-AMPKa-Thr172, total AMPKa, anti-phospho-Akt-Ser473, total Akt, anti-phospho-ERK1 / 2-Thr204, and total-ERK-1 / 2. Band intensities were calibrated using anti-APLNR receptor antibody and anti-GAPDH antibody. Immunoreactive proteins were detected and quantified using SuperSignalTW WEST Femto substrate and Lab™ software.

[0464] Test Example 2: HTRF cAMP assay to detect and evaluate the agonistic activity of the representative compound of this invention on the apelin receptor.

[0465] 2.1 Experimental Materials and Equipment

[0466] Cells: APJ-CHO cells, from Beijing Aisiyipu Biotechnology Co., Ltd.

[0467] Reagents: See Table 2-1 for reagent information.

[0468] Instruments: Carbon dioxide cell incubator (CLM-240B-8-TC) was purchased from ESCO Technology Co., Ltd., HTS high-throughput drug screening multi-functional microplate reader (PHERAstar FSX) was purchased from BMG LABTECH Co., Ltd., and microplate low-speed centrifuge (TD5B) was purchased from Changsha Xiangzhi Centrifuge Instrument Co., Ltd.

[0469] Table 2-1 - Reagent Information

[0470] 2.2 Experimental Procedure

[0471] 1) Weigh an appropriate amount of the test substance, calculate the required volume of DMSO according to the formula: DMSO volume = actual amount × purity / (molecular weight × theoretical concentration), and dissolve it in the corresponding volume of DMSO.

[0472] 2) According to Prepare 1×Stimulation Buffer according to the Ultra cAMP Kit instructions;

[0473] 3) Dilute the positive control and test substance to 10 concentrations using DMSO in a serial gradient.

[0474] 4) Culture the stable cell line to 80% confluence, digest with trypsin to collect cells, count them, and seed 10 μL / well into a 384-well plate. Then perform Echo drug addition, 10 nL per well, centrifuge and incubate at 37°C for 10 minutes.

[0475] 5) Transfer 10 nL of 0.6 mM Forskolin to each well using ECHO, centrifuge, and incubate at 37°C for 30 minutes to induce cAMP production.

[0476] 6) Dilute Eu-cAMP to the working concentration with detection buffer, and add 4 μL / well to the corresponding experimental well.

[0477] 7) ULight TM The anti-cAMP antibody was diluted to the working concentration with detection buffer, and 4 μL / well was added to the corresponding experimental well; after centrifugation, it was incubated at room temperature for 1 hour.

[0478] 8) After incubation, use an ELISA reader to detect the readings at 665nm and 620nm under excitation at a wavelength of 330nm.

[0479] 2.3 Data Processing and Result Analysis

[0480] Calculation formula

[0481] 1)Z'=1-3*(SD_H+SD_L) / (Ave_H-Ave_L)

[0482] 2) H = Ave(Apelin-13 TFA)

[0483] 3) L = Ave(DMSO)

[0484] 4) S / B = Ave_H / Ave_L

[0485] 5) Calculate compound EC using GraphPad nonlinear fitting formula. 50 :

[0486] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0487] X:cmpd concentration

[0488] Y:Activation%

[0489] Average of the ratio of all positive control wells.

[0490] Average of the ratio of all negative control wells(DMSO).

[0491] Top and Bottom:Plateaus in same units as Y

[0492] logEC 50 Same log units as X

[0493] HillSlope:Slope factor or Hill slope

[0494] The experimental results are shown in Table 2-2.

[0495] Table 2-2. EC50 of representative compounds of this invention on the agonistic activity of Apelin receptor. 50

[0496] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substitute or isomer thereof; in, A and B are arbitrarily and independently selected from monocyclic or polycyclic structures having 3 to 18 carbon atoms, wherein the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings or bridged ring structures; Z can be arbitrarily and independently selected from CR1 or N; L1 and L2 are independently selected as not existing, single bond, -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-, X is independently selected as non-existent, single bond, -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-; Each of R1, R2, R3, and R4 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, sulfide pentafluoride, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1-10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl group or carboxyl substitute, preferably, the carboxyl substitute is: Furthermore, the hydrogens on R1, R2, R3, and R3 are preferably further selected by one or more groups chosen from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 The substituents may be used to replace the alkyl group; or any two adjacent R1, R2, or R3 may form a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group together with the attached carbon. The saturated or partially saturated cycloalkyl or heterocyclic alkyl group may be monocyclic or bicyclic, bridged or spirocyclic. Preferably, the hydrogen atom thereon may be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C. 1- 6-alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl groups are substituted. Each R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10 They can be the same or different, and are independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH and -NH2, -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocyclic alkyl groups, C 3-10 cycloalkyl or C 3-10 Heterocyclic alkyl-substituted C 1- 10 Alkyl, C 3-10 Cycloalkyl-substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl groups or carboxyl substitutes or -LQ groups; further R d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10 The preferred further option is to use one or more groups selected from H, deuterium, halogen, OCH3, carboxyl, OH, CN, and NR. d8 R d9 Substituents; or any two adjacent R groups. d1 R d2 R d3 R d4 R d5 R d6 R d7 R d8 R d9 and R d10 Together with the atoms attached thereto, it forms a 5-6 membered heteroaryl group, a 3-18 membered saturated or partially saturated cycloalkyl group, or a 3-18 membered saturated or partially saturated heterocyclic group, wherein the saturated or partially saturated cycloalkyl group or heterocyclic group can be monocyclic or bicyclic, bridged or spirocyclic, and preferably optionally the hydrogen thereon can be selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl groups, =O, and saturated or partially saturated C groups 3-6 Cycloalkyl substitution, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further surrounded by one or more carbon atoms selected from hydrogen, deuterium, halogen, oxometalate, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C atoms. 3-6 Cycloalkyl group substitution; The L in -LQ is independently selected as non-existent, single bond, -C(R) d1 (R) d2 )-、-C(R d1 (R) d2 )C(R d1 (R) d2 )-、-C(R d1 )=C(R d1 )-、-OC(R d1 (R) d2 )-、-C(R d1 (R) d2 )O-、-C(=O)N(R d3 )-、-N(R d4 )-、-C(=NR d5 )-、-S(=O)2N(R d6 )-、-N(R d7 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)–, -S(=O)2-, Q is selected from the following structural fragment: in Any can represent a single or double bond; Xa and Xb are arbitrarily and independently selected from CRb or N; each R a R b and R c They can be the same or different, and are independently selected from hydrogen, deuterium, halogens, -CN, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, -NR d8 R d9 6-10 aryl groups, 5-8 heteroaryl groups, 3-8 saturated or partially saturated cycloalkyl groups, and 3-8 saturated or partially saturated heterocyclic groups; and R a R b and R c The hydrogen atom is optionally preferably replaced by one or more substituents, said substituents being selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamine, O=, CN, OH, -NR. d8 R d9 C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 The aryl, heteroaryl, 6-10 aryl, and 5-8 heteroaryl groups are saturated or partially saturated; wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group is optionally substituted by one or more substituents, wherein the substituents are optionally selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group, wherein the C 1-3 Alkyl, C 1-3 The alkoxy, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclic group is preferably substituted with 1 to 3 substituents selected from H, deuterium, halogen, haloalkyl, cyano, OCH3, and OH. The term "hybrid" refers to any heteroatom and its isotopes that are independently selected from O, N, S, and P. The halogens mentioned are arbitrarily and independently selected from F, Cl, Br, I and their isotopes; m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4, and 5; r is any integer selected from 0, 1, 2, 3, 4, and 5; t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; u is any integer selected from 0, 1, 2, and 3; v is any integer selected from 0, 1, 2, and 3.

2. A compound as shown in Formula I, a pharmaceutically acceptable salt thereof, an isotopic substitute thereof, an isomer thereof, or a prodrug thereof, in, R 1 C 1-6 Alkyl, halogen or -OC 1-6 Alkyl group, or any two adjacent R groups 1 Together with the attached carbon, they form "5-6 membered heteroaromatic rings containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N" or "5-7 membered heterocyclic olefins containing 1-3 heteroatoms, each heteroatom independently selected from O, S, and N"; A1, A2, and A3 are independently CH or N; Ring A is C 6-20 Aryl or "containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S and N, 5-12 membered heteroaryl"; R 2 and R 3 Independently for C 1-6 Alkyl, C 3-8 cycloalkyl, halogen or -OC 1-6 alkyl; m, n, and t are independently 0, 1, 2, or 3.

3. The compound of formula I as claimed in claim 2, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, The structure of the compound shown in Formula I as described above is shown in Formula II: The definitions of each group in the formula are as described in claim 2.

4. The compound of formula I as described in claim 2 or 3, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, When R 1 When the term is "a 5-7 membered heterocyclic olefin containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N", then the "5-7 membered heterocyclic olefin containing 1-3 heteroatoms, the heteroatoms being independently selected from O, S, and N" is a spiroheterocyclic olefin.

5. The compound of formula I as described in claim 2 or 3, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, When ring A is "containing 1-3 heteroatoms, the heteroatoms being independently selected from 5-12 membered heteroaryls of O, S and N", ring A is a monocyclic or bicyclic heteroaryl; the monocyclic heteroaryl is preferably a 5-6 membered heteroaryl containing 1-2 heteroatoms, the heteroatoms being independently selected from N and S; the bicyclic heteroaryl is preferably an 8-10 membered heteroaryl containing 1-3 heteroatoms, the heteroatoms being independently selected from N and S.

6. The compound of formula I as claimed in claim 2 or 3, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, for And / or, for 7. The compound of Formula I as described in any one of claims 2-6, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, Among the compounds represented by Formula I, their pharmaceutically acceptable salts, their isotopic substitutes, their isomers, or their prodrugs, the compound represented by Formula I is any one of the following compounds:

8. The compound of formula I as claimed in claim 7, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, The compound represented by Formula I is any one of the following compounds: Compounds with a retention time of 2.257 min under the following conditions Equipment: Waters SFC 80; Chromatographic column: Column name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: ACN (+0.1% 7.0mol / L ammonia in methanol solution), A:B=50:50; Wavelength: 214nm; Flow rate: 70 ml / min; Column temperature: room temperature; Back pressure: 100 bar; Compounds with a retention time of 2.185 min under the following conditions Equipment: Waters SFC 80; Chromatographic column: Column name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol / l Ammonia in IPA), A:B = 45:55; Wavelength: 214nm; Flow rate: 70 ml / min; Column temperature: room temperature; Back pressure: 100 bar; Compounds with a retention time of 2.661 min under the following conditions Equipment: Waters SFC 80; Chromatographic column: Column name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: ACN (+0.1% 7.0mol / l ammonia solution), A:B = 50:50; Wavelength: 214nm; Flow rate: 70 ml / min; Column temperature: room temperature; Back pressure: 100 bar; Compounds with a retention time of 2.677 min under the following conditions Equipment: Waters SFC 80; Chromatographic column: Column name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammoniain MeOH), A:B = 45:55; Wavelength: 214nm; Flow rate: 70 ml / min; Column temperature: room temperature; Back pressure: 100 bar; Compounds with a retention time of 2.607 min under the following conditions Equipment: Waters SFC 80; Chromatographic column: Column name: Column, column size: 250×30mm×10μm; column temperature: room temperature; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MeOH), A:B = 70:30; Wavelength: 214nm; Flow rate: 50 ml / min; Column temperature: room temperature; Back pressure: 100 bar.

9. The compound of formula I as claimed in claim 7, its pharmaceutically acceptable salt, its isotopic substitute, its isomer, or its prodrug, characterized in that, The compound represented by Formula I is any one of the following compounds:

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-9, a pharmaceutically acceptable salt thereof, an isotopic substitute thereof, an isomer thereof, or a prodrug and excipient thereof.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substitute, or isomer thereof, for the preparation of a treatment for the prevention and / or treatment of Apelin receptor-related or Apelin receptor-associated metabolic and related diseases discussed herein, including overweight, obesity, diabetes, and idiopathic T1. Type D (1B), latent autoimmune diabetes in adults, early-onset type 2 diabetes mellitus (T2DM), atypical diabetes mellitus in adolescence (YOAD), mature juvenile diabetes, malnutrition-related diabetes, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disease, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity and related comorbidities, eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndrome), weight gain due to other medication use, excessive sugar consumption, dyslipidemia, cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction. Infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipids, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis Uses in medications for the prevention or treatment of conditions such as narrow-mindedness, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, senile dementia, muscular atrophy, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, addiction treatment, and muscular atrophy.

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