Substituted diphenyl derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a substituted diphenyl derivative, a preparation method therefor, and pharmaceutical use of a pharmaceutical composition comprising the derivative. Specifically, the present invention relates to a substituted diphenyl derivative represented by general formula (I), a preparation method therefor, and a pharmaceutically acceptable salt thereof, as well as use thereof in treating or preventing cannabinoid CB1 receptor-related diseases and disorders, wherein the definition of each substituent in general formula (I) is the same as the definition in the description.

Description

Substituted diphenyl derivatives, their preparation methods and uses Technical Field

[0001] This invention relates to a substituted diphenyl derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a CB1 inverse agonist or antagonist. Background Technology

[0002] CB1R, or cannabinoid receptor type 1, is an inhibitory G protein-coupled receptor (Gi / o GPCR) mainly distributed in the central nervous system (CNS). Its main function is to regulate the release of neurotransmitters, which can regulate behaviors such as mood, cognition, and appetite. It is also distributed in small amounts in the periphery, including adipose tissue, myocardium, vascular endothelium, gastrointestinal tract, liver, pancreas, and skeletal muscle, where it is expressed to varying degrees.

[0003] Endocannabinoids have G protein-coupled receptors that couple to Gi / o proteins. Upon activation, these receptors perform a range of functions, including inhibiting adenylate cyclase activity, opening K+ channels, and closing Ca2+ channels. 2+ Cannabinoids mediate cannabinoid-induced effects, including food intake, memory loss, gastrointestinal motility, rigidity, anxiety, and chronic pain, through pathways and activation of protein kinase activity. CB1R plays a crucial role in promoting or inhibiting the pathological processes of peripheral tissues and related diseases, with functions including weight loss, various cardiometabolic diseases, and glaucoma.

[0004] Inhibiting CB1R in the central nervous system can reduce the secretion of ghrelin and neuropeptides, thereby decreasing appetite and achieving weight loss. CB1R, a weight-loss target discovered over many years, saw the drug Rimonabant approved by the EMA in 2006 for the treatment of some obese patients. However, due to its central nervous system side effects (depression and suicidal tendencies), the FDA did not approve the drug in 2007, and it was gradually withdrawn from the European market in 2008. But with in-depth research into the target and the drug, it has been discovered that peripheral CB1R antagonists—that is, peripherally selective CB1R antagonists that do not cross the blood-brain barrier (BBB)—can avoid central nervous system side effects. Simultaneously, they enhance leptin sensitivity, promote mitochondrial formation in adipose tissue to increase energy expenditure and thermogenesis, reduce hepatic lipogenesis, improve β-cell glucose response, and reduce insulin resistance, thus achieving weight loss through multiple approaches.

[0005] Obesity has been recognized as a disease by the WHO. Obesity can trigger a range of health problems, such as increasing the risk of hypertension, diabetes, dyslipidemia, coronary heart disease, myocardial infarction, stroke, and some cancers. Globally, obesity causes up to 2.8 million deaths annually, and there is currently a strong demand for weight-loss drugs. Obesity can also lead to social and psychological problems, increase the cost of healthcare services, and place a heavier burden on healthcare systems. According to WTO statistics, nearly 2 billion people worldwide are overweight or obese; in China alone, the number of obese people reaches 220 million, and the obesity rate is showing an upward trend.

[0006] Currently, obesity treatment primarily includes behavioral / psychological / exercise interventions, clinical nutritional therapy, drug therapy, and surgical treatment. In China, as of June 25, 2024, the NMPA-approved drugs for obesity treatment mainly include lipase inhibitors (orlistat) and GLP-1 receptor agonists (liraglutide generics, benaglutide, semaglutide, and telpoglutide). Some drugs can also be used off-label for obesity treatment. Despite this, the number of drugs available for treating obesity remains relatively small. Considering the competition from more injectable drugs entering the market, and given the large number of obese and overweight individuals, and the common (gastrointestinal) and rare / possible (pancreatitis) side effects of injectable drugs, as well as weight rebound after discontinuation, it is believed that there remains an unmet clinical need for weight loss drugs with other mechanisms of action.

[0007] At least six companies are currently developing peripheral antagonists targeting this target, but only one small molecule antagonist is in the clinical stage: INV-202 from Inversago Pharma, which was acquired by Novo Nordisk, and INV-347, which are currently in Phase II and Phase I clinical trials. In general, CB1R is an important receptor that plays a role in a variety of physiological and pathological processes, and has potential application value, especially in the treatment of weight loss and metabolic diseases. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0009] in:

[0010] Ring A is selected from 5-6-membered heteroaryl, 5-12-membered heterocyclic or 8-12-membered bicyclic fused ring, wherein the 8-12-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl.

[0011] p is between 0 and 2; the condition is that when p is 2, the two R values ​​are equal. aThe same carbon atom bonded to them forms a -C (=O) group. When p is 0, ring A is not selected from the following groups:

[0012] When p is 1, R a Independently selected from halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano, preferably R a Selected from F, methyl, ethyl, isopropyl, cyclopropyl, or cyano; or R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring, arbitrarily, R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring is further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and amide groups; preferably R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring may be a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring; wherein the 5-membered ring, 6-membered ring, 7-membered ring, or 8-membered ring may optionally be further composed of one or more elements selected from deuterium, hydroxyl, halogen, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of halogenated alkoxy groups and amide groups;

[0013] R 1 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Haloalkoxy; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6The haloalkoxy group may optionally be further selected from one or more groups selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups;

[0014] R 2 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0015] Z is selected from S (=O) r Or C (=O) or C (=S) or S (=O)(=N);

[0016] R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may optionally be further influenced by one or more R groups. A Replaced;

[0017] R A Whether the groups are the same or different, they are each independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R7 -S (=O) r R 5 Or C 1-6 Alkyl C 6-10 Aryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0018] And / or, two Rs A The same carbon atom they are connected to forms -C (=O);

[0019] R 4 Selected from C 1-6 Alkyl, -OR 5 -SR 5 -S (=O) r R 5 -S (=O) r NR 6 R 7 -N(R) 6 )C(=O)R 7 -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8Cycloalkyl, 5-12 membered heterocyclic groups, -NH(CH2) m1 CR e R f (CH2) n1 C(=O)NR 6 R 7 -NH-C 3-8 cycloalkyl-C(=O)NR 6 R 7 -NR g (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ; wherein C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic groups optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced;

[0020] Rd Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups optionally further selected from one or more halogens, cyano groups, amino groups, hydroxyl groups, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -(CH2) r C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced;

[0021] R e and R fEach is independently selected from hydrogen, alkyl, and cycloalkyl; wherein the alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, hydroxyl, halogen, cyano, alkyl, and 5-10 heteroaryl groups; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0022] R g Independently selected from hydrogen, alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0023] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more atoms selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0024] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10The substituents are replaced;

[0025] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0026] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0027] m can be 0, 1, 2, 3, or 4;

[0028] n is 0, 1, 2, 3 or 4;

[0029] m1 is independently selected from 0, 1, 2, 3 or 4;

[0030] n1 is independently selected from 0, 1, 2, 3, or 4; and

[0031] r can be 0, 1, or 2 independently.

[0032] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof.

[0033] in:

[0034] Ring A is selected from 5-6-membered heteroaryl, 5-12-membered heterocyclic or 8-12-membered bicyclic fused ring, wherein the 8-12-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl.

[0035] p is between 0 and 2; the condition is that when p is 2, the two R values ​​are equal. a The same carbon atom bonded to them forms a -C (=O) group. When p is 0, ring A is not selected from the following groups:

[0036] When p is 1, R a Independently selected from halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano, preferably R a Selected from F, methyl, ethyl, isopropyl, cyclopropyl, or cyano; or R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring, arbitrarily, R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring is further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and amide groups; preferably R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring may be a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring; wherein the 5-membered ring, 6-membered ring, 7-membered ring, or 8-membered ring may optionally be further composed of one or more elements selected from deuterium, hydroxyl, halogen, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of halogenated alkoxy groups and amide groups;

[0037] R 1 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C1-6 Halogenated alkoxy groups;

[0038] R 2 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0039] Z is selected from S (=O) r Or C (=O) or C (=S) or S (=O)(=N);

[0040] R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may optionally be further influenced by one or more R groups. A Replaced;

[0041] R A Whether the groups are the same or different, they are each independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 -S (=O) r R 5 Or C 1-6 Alkyl C6-10 Aryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0042] And / or, two Rs A The same carbon atom they are connected to forms -C (=O);

[0043] R 4 Selected from C 1-6 Alkyl, -OR 5 -SR 5 -S (=O) r R 5 -S (=O) r NR 6 R 7 -N(R) 6 )C(=O)R 7 -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -NH(CH2) m1 CR e R f(CH2) n1 C(=O)NR 6 R 7 -NR g (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ; wherein C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic groups optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced;

[0044] R d Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 ;

[0045] R e and R f Each is independently selected from hydrogen, alkyl, and cycloalkyl; wherein the alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, hydroxyl, halogen, cyano, and alkyl; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0046] R g Independently selected from hydrogen, alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0047] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more atoms selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0048] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0049] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0050] R 8 R 9 and R 10Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0051] m is 0, 1, 2, 3 or 4

[0052] n is 0, 1, 2, 3 or 4;

[0053] m1 is independently selected from 0, 1, 2, 3 or 4;

[0054] n1 is independently selected from 0, 1, 2, 3, or 4; and

[0055] r can be 0, 1, or 2 independently.

[0056] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein Z is selected from S(=O)2.

[0057] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4 Selected from R d The definition is as described in claim 1.

[0058] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0059] Among them, R 1 R 2 R 3 R d R a The definitions of , p, m and n are as described in general formula (I).

[0060] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, R 1 Selected from halogens, preferably chlorine.

[0061] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 6-10aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic, wherein the C 6-10 Aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be selected by one or more groups chosen from halogen, cyano, C 1-6 Alkyl, -OR 5 C 1-6 Halogenated alkyl, -SF5 or -NR 6 R 7 Replaced;

[0062] R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl.

[0063] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Selected from phenyl, wherein the phenyl group is optionally substituted with one or more substituents selected from halogen, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SF5 or amino.

[0064] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R d Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -NR g C(=O)NR 6 R 7 -N(R) 6 )C(=O)OR 7 or -N(R) 6 )C(=O)R 7 Preferably, R d Selected from C 1-6 Alkyl, 5-6 membered heteroaryl, -NR g C(=O)NR 6 R 7 -N(R) 6 )C(=O)OR 7 or -N(R) 6 )C(=O)R 7 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10aryl or 5-10 heteroaryl groups optionally further selected from one or more halogens, cyano groups, amino groups, hydroxyl groups, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced;

[0065] R 6 Selected from hydrogen atoms or C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1- 6-alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl groups optionally further selected from one or more hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Substituted with an aryl or 5-12 heteroaryl group; preferably, R 6 Selected from hydrogen atoms or C 1-6 alkyl;

[0066] R 7 Selected from hydrogen atom, hydroxyl group, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl groups optionally further selected from one or more hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Substituted with an aryl or 5-12 heteroaryl group; preferably, R 7 Selected from hydrogen atom C 1-6 Alkyl, C 3-8Cycloalkyl or 5-12-membered heteroaryl, wherein the alkyl, cycloalkyl, or heteroaryl group is optionally further selected from one or more hydroxyl, halogen, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups;

[0067] R g Selected from hydrogen or C 1-6 alkyl.

[0068] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R d for

[0069] A preferred embodiment of the present invention is a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heteroaryl or 6-membered heterocyclic.

[0070] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups: Preferably, Selected from the following groups:

[0071] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0072] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0073] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4 Selected from -NH(CH2) m1 CR e R f (CH2) n1 C(=O)NR 6 R 7 -NRg (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ;

[0074] R e and R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl; wherein the C 1-6 Alkyl, C 3-8 cycloalkyl groups may optionally be further divided by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Substituents of alkyl groups; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0075] R g Independently selected from hydrogen and C 1-6 Alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

[0076] m1 is independently selected from 0, 1, 2, 3 or 4;

[0077] n1 is independently selected from 0, 1, 2, 3, or 4; and

[0078] r can be 0, 1, or 2 independently.

[0079] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 4 Selected from

[0080] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0081] Or its stereoisomers, tautomers, or pharmaceutically usable salts. Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0082] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0083] The present invention provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a CB1 inverse agonist or antagonist.

[0084] The present invention also provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating CB1-mediated diseases; preferably, wherein the CB1-mediated diseases are selected from obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, more preferably obesity, metabolic syndrome or diabetic nephropathy.

[0085] The present invention also provides the use of a compound of general formula (I) or (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating the following diseases: obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, more preferably obesity, metabolic syndrome or diabetic nephropathy.

[0086] Detailed description of the invention

[0087] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0088] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0089] "Alkylene" refers to saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably C1-C. 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylenes may be substituted or unsubstituted.

[0090] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C6 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0091] "Alkenyl" refers to an alkylene group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, having two residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms, preferably C2-C. 10 The alkenyl group, more preferably a C2-C6 alkenyl group, is used. Examples of alkenyl groups include, but are not limited to, those described above. Etc. The alkenyl group can be substituted or unsubstituted.

[0092] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0093] "Alynyl group" refers to an alkylene group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, having two residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms, preferably C2-C. 10 The ynyl group, more preferably a C2-C6 ynyl group. Examples of ynyl groups include, but are not limited to, those described above. The ynylene group can be substituted or unsubstituted.

[0094] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0095] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0096] Monocyclic alkyl groups can be substituted or unsubstituted.

[0097] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0098] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0099] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged cycloalkyl groups can be substituted or unsubstituted.

[0100] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having 3 to 8-membered monocyclic or 5 to 18-membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0101] The heterocyclic group can be substituted or unsubstituted.

[0102] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, azabolane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0103] "Spirocyclone" refers to a polycyclic aromatic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0104] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0105] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0106] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0107] "Heteroaryl" refers to an aromatic monocyclic or polycyclic group, wherein the ring skeleton comprises one or more atoms selected from nitrogen, oxygen, and / or sulfur, and the remaining ring atoms are carbon. The heteroaryl is preferably a 5-14 membered heteroaryl, more preferably a 5-10 membered heteroaryl. For example, the heteroaryl is an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazinyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridine , pyridin-2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl,

[0108] The heteroaryl group can be substituted or unsubstituted.

[0109] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r(where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary elements, more preferably 8 to 12 quinary elements, and even more preferably 8 to 10 quinary elements. Examples of "fused rings" include, but are not limited to:

[0110] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0111] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0112] "Nitro" refers to the -NO2 group.

[0113] "Hydroxy" refers to the -OH group.

[0114] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0115] "Amino" refers to -NH2.

[0116] "Hydroxyamino group" refers to -NHOH.

[0117] “Cyano” refers to -CN.

[0118] "Benzyl" refers to -CH2-phenyl.

[0119] "Carboxyl group" refers to -C(=O)OH.

[0120] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0121] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0122] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0123] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0124] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0125] "DMSO" refers to dimethyl sulfoxide.

[0126] “BOC” refers to tert-butoxycarbonyl.

[0127] “Bn” refers to benzyl.

[0128] "THP" refers to 2-tetrahydropyranyl.

[0129] "TFA" refers to trifluoroacetic acid.

[0130] “Ts” refers to p-toluenesulfonyl group.

[0131] “Bn” refers to benzyl.

[0132] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0133] "Formyl group" refers to

[0134] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0135] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0136] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, SF5, =O, -OR5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 or -S(O) r R 5 The substituents are replaced;

[0137] R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more atoms selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0138] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9)C(=O)R 10 The substituents are replaced;

[0139] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0140] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0141] r can be 0, 1, or 2 independently.

[0142] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0143] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0144] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0145] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0146] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0147] Example

[0148] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0149] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0150] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0151] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0152] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0153] CD3OD: Deuterated methanol.

[0154] CDCl3: Deuterated chloroform.

[0155] DMSO-d6: Deuterated dimethyl sulfoxide.

[0156] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0157] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0158] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0159] Example 1

[0160] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0161] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0162] first step

[0163] methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutanoate

[0164] Methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate

[0165] 1-(4-chlorophenyl)-2-phenylethyl-1-one 1a (50.0 g, 217.39 mmol) was dissolved in N,N-dimethylformamide (600 mL), and sodium hydride (13.0 g, 326.09 mmol, 60% purity) was added at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 0.5 hours. Then, methyl 2-bromoacetate 1b (32.82 mL, 346.78 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched at 0°C with saturated ammonium chloride aqueous solution (600 mL), extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (700 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate 1c (51.8 g), with a yield of 78.9%.

[0166] Step 2

[0167] 4-(4-chlorophenyl)-4-oxo-3-phenylbutanoic acid

[0168] 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid

[0169] Methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate 1c (51.8 g, 171.52 mmol) was dissolved in ethanol (250 mL) and water (250 mL), and sodium hydroxide (13.42 g, 335.59 mmol) was added. The reaction mixture was reacted at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated to remove ethanol, the pH was adjusted to 5 with 6M hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (400 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (600 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid 1d (50 g), with a yield of 99.1%.

[0170] MS m / z(ESI): 289.0 [M+H] +

[0171] Step 3

[0172] 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazin-3(2H)-one

[0173] 6-(4-Chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one

[0174] 1d (50 g, 173.61 mmol) of 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid was dissolved in 600 mL of ethanol, and 27.38 g (519.52 mmol) of hydrazine hydrate was added. The mixture was reacted at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filter cake was dried to give 1e (50 g) of 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one, which was used directly in the next reaction.

[0175] MS m / z(ESI): 289.0 [M+H] +

[0176] Step 4

[0177] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine

[0178] 3-(4-Chlorophenyl)-4-phenyl-1,4,5,6-Tetrahydropyridazine

[0179] 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one 1e (20 g, 70.24 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), and lithium aluminum hydride (2.5 M tetrahydrofuran solution, 84.29 mL) was added dropwise under a nitrogen atmosphere at 0 °C. After the addition was complete, the reaction was carried out at 70 °C for 1 hour. After the reaction was complete, water (8 mL), 15% sodium hydroxide aqueous solution (8 mL), and water (34 mL) were added dropwise to the reaction solution at 0 °C. The mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (15 g), with a yield of 78.9%.

[0180] MS m / z(ESI): 271.1 [M+H] +

[0181] Step 5

[0182] 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

[0183] 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

[0184] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (3.5 g, 12.93 mmol) was dissolved in toluene (80 mL), and methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate 1 g (4.03 g, 14.22 mmol, prepared according to published patent "WO2023114366A2") was added under a nitrogen atmosphere at room temperature. The mixture was reacted at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and methanol (20 mL) was added to the resulting mixture. The mixture was stirred for 15 minutes, filtered, and the filter cake was dried to give 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 1h (8 g), with a yield of 100%.

[0185] MS m / z(ESI): 522.1 [M+H] +

[0186] Step 6

[0187] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbimidoyl chloride

[0188] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide chloride

[0189] 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (3 g, 5.75 mmol) was dissolved in chlorobenzene (60 mL), and phosphorus pentachloride (4.79 g, 22.99 mmol) was added under a nitrogen atmosphere at room temperature. The mixture was reacted at 100 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with water (200 mL) in an ice bath, extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (3 g), with a yield of 90.8%.

[0190] MS m / z(ESI): 576.0 [M+H] +

[0191] Step 7

[0192] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0193] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0194] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (3 g, 5.22 mmol) was dissolved in N,N-dimethylformamide (50 mL), and N-(carbamoyl)acetamide 1j (2.11 g, 20.88 mmol) and N,N-diisopropylethylamine (3.37 g, 26.09 mmol) were added under a nitrogen atmosphere at room temperature. The mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B). Then methanol (30 mL) was added, stirred for 15 minutes, filtered, and the filter cake was dried to give N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 1 (737 mg), yield 23.4%.

[0195] 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.28(s,1H),8.03(d,J=8.2Hz,2H),7.84(d,J=8.4Hz,3H),7.29-7.22(m,5 H),7.07(d,J=8.6Hz,2H),6.97(dd,J=7.2,2.3Hz,2H),6.53(t,J=4.6Hz,1H),4.58(d,J=3.8Hz,2H),2.09(s,3H).

[0196] MS m / z (ESI): 603.5 [M+H] +

[0197] Examples 2 and 2A

[0198] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide andN-((E)-N'-((E)-(4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0199] N-((E)-N'-(E)-(4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide and N-((E)-N'-((E)-(4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoamidanyl)acetamide

[0200] first step

[0201] ethyl 2-(2-(4-chlorophenyl)hydrazinyl)-2-oxoacetate

[0202] 2-(2-(4-chlorophenyl)hydrazino)-2-oxoethyl acetate

[0203] 4-Chlorophenylhydrazine 2a (13 g, 91.17 mmol, commercially available) was dissolved in ethanol (200 mL), and diethyl oxalate 2b (13.14 g, 91.17 mmol) was added dropwise under a nitrogen atmosphere at 0 °C. The mixture was reacted at 25 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and dichloromethane (50 mL) was added to the residue. The mixture was stirred for 15 minutes, filtered, and the filter cake was dried to give ethyl 2-(2-(4-chlorophenyl)hydrazyl)-2-oxoethyl acetate 2c (17 g).

[0204] MS m / z(ESI): 243.1 [M+H] +

[0205] Step 2

[0206] ethyl 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate and ethyl 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate

[0207] 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid ethyl ester and 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid ethyl ester

[0208] Ethyl 2-(2-(4-chlorophenyl)hydrazino)-2-oxoethyl acetate 2c (17 g, 70.07 mmol) was dissolved in N,N-dimethylformamide (200 mL), and 1,2-dibromoethylbenzene 2d (18.49 g, 70.07 mmol) and potassium carbonate (19.36 g, 140.11 mmol) were added under a nitrogen atmosphere at room temperature. The mixture was reacted at 80 °C for 12 hours. After the reaction was complete, water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give a mixture (4.7 g) of ethyl 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate 2e and ethyl 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate 2f, with a yield of 19.45%.

[0209] MS m / z (ESI): 345.1 [M+H] +

[0210] Step 3

[0211] 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid and ethyl 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate

[0212] 5-(4-4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid and 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid)

[0213] A mixture (4.7 g, 13.63 mmol) of ethyl 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate 2e and ethyl 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylate 2f was dissolved in methanol (10 mL), tetrahydrofuran (20 mL), and water (10 mL). Potassium hydroxide (1.38 g, 24.54 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the resulting mixture was added to water (100 mL). The pH was then adjusted to 5 with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture (4 g) of 2 g of 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid and 2 h of 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid, which was directly used in the next reaction.

[0214] MS m / z (ESI): 317.1 [M+H] +

[0215] Step 4

[0216] 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide and4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide

[0217] 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide and 4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide

[0218] A mixture of 2 g of 4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid and 2 h of 4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxylic acid (4 g, 12.63 mmol) and 2 i of 4-(trifluoromethyl)benzenesulfonamide (3.41 g, 15.15 mmol) was dissolved in dichloromethane (50 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.63 g, 18.94 mmol) and 4-dimethylaminopyridine (2.31 g, 18.94 mmol) were added, and the mixture was stirred at 25 °C for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with 1 M hydrochloric acid solution (50 mL), then with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give a mixture (2.85 g) of 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide 2j and 4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide 2k, with a yield of 43.1%.

[0219] MS m / z (ESI): 524.1 [M+H] +

[0220] Step 5

[0221] (E)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbimidoyl chloride and(E)-4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbimidoyl chloride

[0222] (E)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboimide acyl chloride and

[0223] (E)-4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboimide chloride

[0224] A mixture (1.45 g, 2.77 mmol) of 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide 2j and 4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carboxamide 2k was dissolved in chlorobenzene (20 mL). Phosphorus pentachloride (1.15 g, 5.54 mmol) was added under a nitrogen atmosphere at room temperature. The mixture was reacted at 100 °C for 0.5 h. TLC showed that the starting material disappeared. The reaction solution was concentrated to obtain a mixture (1.4 g) of (E)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbonimide acyl chloride 2l and (E)-4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbonimide acyl chloride 2m.

[0225] Step 6

[0226] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide and N-((E)-N'-((E)-(4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0227] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide and N-((E)-N'-((E)-(4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoamido)acetamide

[0228] A mixture of (E)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbonimide acyl chloride 2l and (E)-4-(4-chlorophenyl)-6-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydro-4H-1,3,4-oxadiazine-2-carbonimide acyl chloride 2m (1.4 g, 2.58 mmol) was dissolved in dichloromethane (20 mL), and N-ureidoylaminoacetamide 1j (1.04 g, 10.33 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was separated by preparative liquid chromatography (Waters 2767) using a Sunfire C10 column. 18The apparatus was 19*250mm*10μm; mobile phase A: 0.1% formic acid / water, B: acetonitrile; flow rate: 20mL / min; gradient: 62-65%; ) was purified to give N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoamido)acetamide 2 (29.56 mg), yield 3.7%. N-((E)-N'-((E)-(4-(4-chlorophenyl)-6-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoamido)acetamide 2A (35.25 mg), yield 4.5%.

[0229] 2: MS m / z (ESI): 607.4 [M+H] +

[0230] 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.84(s,2H),8.01(d,J=8.2Hz,2H),7.86(d,J=8.2Hz,2H),7.36-7.25(m,3H),7.21(d,J=9.2H z,2H),7.14(d,J=7.2Hz,2H),7.02(d,J=9.2Hz,2H),5.56(s,1H),4.53(d,J=10.4Hz,1H),4.35(dd,J=10.8,2.8Hz,1H),2.12(s,3H).

[0231] 2A:MS m / z(ESI):607.4 [M+H] +

[0232] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.81(s,2H),8.02(d,J=8.1Hz,2H),7.85(d,J=8.4Hz,2H),7.53-7.38(m,5H) ,7.20(dd,J=36.0,9.1Hz,4H),5.31(d,J=5.4Hz,1H),4.33-4.23(m,1H),3.42(dd,J=12.1,8.1Hz,1H),2.05(s,3H).

[0233] Example 3

[0234] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0235] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0236] first step

[0237] methyl(Z)-4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate

[0238] (Z)-4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid methyl ester

[0239] 1-(4-chlorophenyl)ethyl-1-one 3a (20 g, 129.37 mmol) and dimethyl oxalate 3b (15.28 g, 129.37 mmol) were dissolved in methanol (300 mL). Sodium methoxide (5.4 M methanol solution, 47.92 mL) was added dropwise under a nitrogen atmosphere at 0 °C. After the addition was complete, the mixture was reacted at room temperature for 12 hours. After the reaction was complete, the reaction solution was quenched by adding water (200 mL) and hydrochloric acid (70 mL, 1 M) at 0 °C. The mixture was filtered, and the filter cake was collected and dried to obtain (Z)-4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid methyl ester 3c (32 g).

[0240] Step 2

[0241] methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate

[0242] Methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate

[0243] Methyl (Z)-4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate 3c (10 g, 41.56 mmol) was dissolved in methanol (150 mL), and phenylhydrazine 3d (8.99 g, 83.11 mmol) was added under a nitrogen atmosphere at room temperature. The mixture was stirred at 75 °C for 12 hours. After the reaction was complete, the mixture was quenched with water (300 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate 3e (8 g), yield 56.0%.

[0244] Step 3

[0245] 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid

[0246] 5-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid

[0247] Methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid 3e (2 g, 6.39 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (20 mL), and water (10 mL). Potassium hydroxide (538.18 mg, 9.59 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and the resulting mixture was added to water (100 mL). The pH was then adjusted to 5 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid 3f (1.96 g), which was directly used in the next reaction.

[0248] MS m / z(ESI): 299.0 [M+H] +

[0249] Step 4

[0250] 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0251] 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0252] 4-(trifluoromethyl)benzenesulfonamide 2i (500 mg, 2.22 mmol) and 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid 3f (795.93 mg, 2.66 mmol) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (638.47 mg, 3.33 mmol) and 4-dimethylaminopyridine (406.89 mg, 3.33 mmol) were added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added to methanol (10 mL), stirred for 15 minutes, filtered, and the filter cake was dried to give 3 g (880 mg) of 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide, with a yield of 78.3%.

[0253] MS m / z (ESI): 506.1 [M+H] +

[0254] Step 5

[0255] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoyl chloride

[0256] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride

[0257] 3 g (780 mg, 1.54 mmol) of 5-(4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide was dissolved in 20 mL of chlorobenzene. Phosphorus pentachloride (642.14 mg, 3.08 mmol) was added under a nitrogen atmosphere at room temperature, and the mixture was reacted at 100 °C for 0.5 h. After the reaction was complete, the reaction solution was concentrated to give (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride 3 h (800 mg).

[0258] Step 6

[0259] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0260] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0261] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride 3h (800 mg, 1.53 mmol) was dissolved in dichloromethane (20 mL), and N-(carbamoyl)acetamide 1j (617.04 mg, 6.10 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was added to water (10 mL), stirred for 15 minutes, filtered, and dried to give N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide 3 (175 mg), yield 19.4%.

[0262] MS m / z (ESI): 589.1 [M+H] +

[0263] 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.63-8.27(m,2H),8.10-8.01(m,2H),7.9 0-7.83(m,2H),7.47-7.38(m,5H),7.27-7.14(m,4H),7.01(s,1H),2.05(s,3H).

[0264] Example 4

[0265] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0266] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0267] first step

[0268] ethyl 4,5-dibromofuran-2-carboxylate

[0269] Ethyl 4,5-dibromofuran-2-carboxylate

[0270] 10 g (37.05 mmol) of 4,5-dibromofuran-2-carboxylic acid 4a was dissolved in 100 mL of ethanol, and 2 mL (37.05 mmol) of concentrated sulfuric acid was added. The mixture was reacted at 90 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to alkalinity with saturated sodium bicarbonate aqueous solution, filtered, and the filter cake was collected and dried to give 8.2 g (8.2 g) of ethyl 4,5-dibromofuran-2-carboxylic acid, with a yield of 74.2%.

[0271] Step 2

[0272] ethyl 4-bromo-5-phenylfuran-2-carboxylate

[0273] ethyl 4-bromo-5-phenylfuran-2-carboxylate

[0274] Ethyl 4,5-dibromofuran-2-carboxylate 4b (2.55 g, 8.56 mmol) was dissolved in 40 mL of 1,4-dioxane and 10 mL of water. Phenyboronic acid 4c (1.34 g, 8.56 mmol), potassium carbonate (2.37 g, 17.12 mmol), and tetrakis(triphenylphosphine)palladium (989 mg, 0.86 mmol) were added. The reaction mixture was reacted at 70 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to obtain ethyl 4-bromo-5-phenylfuran-2-carboxylate 4d (3 g).

[0275] Step 3

[0276] ethyl 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylate

[0277] Ethyl 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylate

[0278] Ethyl 4-bromo-5-phenylfuran-2-carboxylate 4d (1.8 g, 6.10 mmol) and 4-chlorophenylboronic acid 4e (954 mg, 6.10 mmol) were dissolved in 20 mL of 1,4-dioxane and 5 mL of water. Potassium carbonate (1.69 g, 12.20 mmol) and tetrakis(triphenylphosphine)palladium (705 mg, 609.90 μmol) were added, and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylate 4f (1.8 g), with a yield of 90%.

[0279] MS m / z (ESI): 327.1 [M+H] +

[0280] Step 4

[0281] 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylic acid

[0282] 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylic acid

[0283] Ethyl 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylic acid 4f (2g, 6.12mmol) was dissolved in tetrahydrofuran (10mL), methanol (5mL), and water (5mL). Potassium hydroxide (618mg, 11.02mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated to remove the solvent, the pH was adjusted to 2 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (80mL × 3). The combined organic phases were washed with saturated sodium chloride solution (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4g (2g) of 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylic acid, which was used directly in the next step.

[0284] MS m / z (ESI): 299.0 [M+H] +

[0285] Step 5

[0286] 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide

[0287] 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide

[0288] 4-(trifluoromethyl)benzenesulfonamide 2i (1.16 g, 5.13 mmol) and 4-(4-chlorophenyl)-5-phenylfuran-2-carboxylic acid 4 g (1.84 g, 6.16 mmol) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.92 g, 25.67 mmol) and 4-dimethylaminopyridine (1.88 g, 15.40 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide 4h (1.8 g), yield 69.3%.

[0289] MS m / z (ESI): 506.1 [M+H] +

[0290] Step 6

[0291] (Z)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carbimidoyl chloride

[0292] (Z)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboximide chloride

[0293] 4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide 4h (300 mg, 0.59 mmol) was dissolved in chlorobenzene (6 mL), and phosphorus pentachloride (247 mg, 1.19 mmol) was added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 0.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain (Z)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboximide acyl chloride 4i (300 mg), which was directly used in the next step.

[0294] MS m / z (ESI): 520.1 [M+H] +

[0295] Step 7

[0296] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0297] N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0298] (Z)-4-(4-chlorophenyl)-5-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carbamylimide acyl chloride 4i (300 mg, 0.57 mmol) was dissolved in dichloromethane (8 mL), and N-carbamoylacetamide 1j (231 mg, 2.29 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake was collected, water (15 mL) was added, the mixture was stirred for 15 minutes, filtered again, the filter cake was collected and dried to give N-((E)-N'-((E)-(4-(4-chlorophenyl)-5-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide 4 (52 mg), yield 15.4%.

[0299] MS m / z (ESI): 589.2 [M+H] +

[0300] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.86-8.27(m,2H),8.07(d,J=8.0Hz,2H),7.88(d,J=8.4Hz,2H),7.56-7.31(m,10H),2.09(s,3H).

[0301] Example 5

[0302] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0303] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0304] first step

[0305] ethyl 4-bromo-5-(4-chlorophenyl)furan-2-carboxylate

[0306] Ethyl 4-bromo-5-(4-chlorophenyl)furan-2-carboxylate

[0307] Ethyl 4,5-dibromofuran-2-carboxylate 4b (2.55 g, 8.56 mmol) was dissolved in 1,4-dioxane (40 mL) and water (10 mL). (4-chlorophenyl)boronic acid 4e (1.34 g, 8.56 mmol), potassium carbonate (2.37 g, 17.12 mmol), and tetrakis(triphenylphosphine)palladium (989 mg, 0.86 mmol) were added. The reaction mixture was reacted at 70 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 4-bromo-5-(4-chlorophenyl)furan-2-carboxylate 5a (3 g), with a yield of 88.9%.

[0308] Step 2

[0309] ethyl 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylate

[0310] Ethyl 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylate

[0311] Ethyl 4-bromo-5-(4-chlorophenyl)furan-2-carboxylate 5a (2.5 g, 7.59 mmol) was dissolved in 1,4-dioxane (80 mL) and water (20 mL). Phenyboronic acid 4c (924.90 mg, 7.59 mmol), potassium carbonate (2.10 g, 15.17 mmol), and tetrakis(triphenylphosphine)palladium (876 mg, 0.76 mmol) were added. The mixture was reacted at 80 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylate 5b (1.8 g), with a yield of 60.5%.

[0312] Step 3

[0313] 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylic acid

[0314] 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylic acid

[0315] Ethyl 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylic acid 5b (1.7 g, 5.20 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (20 mL), and water (10 mL). Potassium hydroxide (525.39 mg, 9.36 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent, dissolved in water (100 mL), and the pH was adjusted to 3 with 1 M hydrochloric acid solution. The solution was extracted with ethyl acetate (100 mL × 3 times). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylic acid 5c (1.5 g), with a yield of 91.2%.

[0316] MS m / z(ESI): 299.0 [M+H] +

[0317] Step 4

[0318] 5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide

[0319] 5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide

[0320] 4-(trifluoromethyl)benzenesulfonamide 2i (0.88 g, 3.91 mmol) and 5-(4-chlorophenyl)-4-phenylfuran-2-carboxylic acid 5c (1.40 g, 4.69 mmol) were dissolved in dichloromethane (50 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.75 g, 19.54 mmol) and 4-dimethylaminopyridine (1.43 g, 11.72 mmol) were added. The mixture was stirred and reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide 5d (2.1 g), yield 82.7%.

[0321] MS m / z (ESI): 506.1 [M+H] +

[0322] Step 5

[0323] (Z)-5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carbimidoyl chloride

[0324] (Z)-5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboximide chloride

[0325] 5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboxamide 5d (250 mg, 0.49 mmol) was dissolved in chlorobenzene (6 mL), and phosphorus pentachloride (205.81 mg, 0.99 mmol) was added. The mixture was reacted at 100 °C for 0.5 h. After the reaction was complete, the solution was concentrated under reduced pressure to give (Z)-5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboximide acyl chloride 5e (250 mg).

[0326] Step 6

[0327] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0328] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0329] (Z)-5-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)furan-2-carboximide acyl chloride 5e (250 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL), and N-(carbamoyl)acetamide 1j (192.83 mg, 1.91 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was filtered under reduced pressure. The resulting filter cake was mixed with water (10 mL), stirred for 15 minutes, filtered, and the filter cake was collected and dried to give N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-phenylfuran-2-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide 5 (81 mg), yield 28.8%.

[0330] MS m / z (ESI): 589.2 [M+H] +

[0331] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.28(s,1H),8.03(d,J=8.2Hz,2H),7.84(d,J=8.4Hz,3H),7.29-7.22(m,5 H),7.07(d,J=8.5Hz,2H),6.97(dd,J=7.2,2.4Hz,2H),6.53(t,J=4.6Hz,1H),4.58(d,J=3.8Hz,2H),2.09(s,3H).

[0332] Example 6

[0333] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0334] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0335] first step

[0336] dimethyl 2-(4-chlorobenzamido)malonate

[0337] Dimethyl 2-(4-chlorobenzoylamino)malonate

[0338] Diethyl aminomalonate hydrochloride 6b (12.09 g, 57.14 mmol) and triethylamine (17.35 g, 171.42 mmol) were dissolved in dichloromethane (100 mL). 4-Chlorobenzoyl chloride 6a (10 g, 57.14 mmol) was added dropwise under a nitrogen atmosphere at 0 °C. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with water (300 mL), extracted with dichloromethane (200 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was added to methanol (80 mL). The mixture was stirred for 15 minutes, filtered, and the filter cake was collected and dried to give dimethyl 2-(4-chlorobenzoylamino)malonate 6c (13 g), with a yield of 79.6%.

[0339] MS m / z(ESI): 286.1 [M+H] +

[0340] Step 2

[0341] dimethyl 2-(4-chlorobenzamido)-2-(phenyldiazenyl)malonate

[0342] Dimethyl 2-(4-chlorobenzamido)-2-(benzodiazepine)malonate

[0343] Dimethyl 2-(4-chlorobenzoamide)malonate 6c (3 g, 10.50 mmol) and sodium acetate (2.37 g, 28.88 mmol) were dissolved in methanol (50 mL). A methanol solution of diazobenzenetetrafluoroborate 6d (8.06 g, 42.01 mmol) was added dropwise under a nitrogen atmosphere at 0 °C. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-(4-chlorobenzoamide)-2-(benzodiazepine)malonate 6e (4.6 g), yield 97.1%.

[0344] Step 3

[0345] methyl 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazole-3-carboxylate

[0346] 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester

[0347] Dimethyl 2-(4-chlorobenzamido)-2-(benzodiazepine)malonate 6e (3.6 g, 9.24 mmol) was dissolved in methanol (39.83 mL), and sodium methoxide (5.4 M methanol solution, 0.17 mL) was added under a nitrogen atmosphere at room temperature. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give methyl 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-carboxylic acid 6f (3.3 g).

[0348] MS m / z (ESI): 314.1 [M+H] +

[0349] Step 4

[0350] 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazole-3-carboxylic acid

[0351] 5-(4-Chlorophenyl)-1-phenyl-1H-1,2,4-triazole-3-carboxylic acid

[0352] Methyl 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-carboxylic acid ester 6f (2.7 g, 8.61 mmol) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), and lithium hydroxide monohydrate (1.08 g, 25.82 mmol) was added. The mixture was reacted at room temperature for 4 hours. After the reaction was complete, the pH was adjusted to 5 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6 g (3.3 g) of 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-carboxylic acid, which was directly used in the next reaction.

[0353] MS m / z(ESI): 300.0 [M+H] +

[0354] Step 5

[0355] 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazole-3-carboxamide

[0356] 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carboxamide

[0357] 2i of 4-(trifluoromethyl)benzenesulfonamide (700 mg, 3.11 mmol) and 6g of 5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-carboxylic acid (1.12 g, 3.73 mmol) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (893.85 mg, 4.66 mmol) and 4-dimethylaminopyridine (569.65 mg, 4.66 mmol) were added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carboxamide 6h (550 mg), yield 34.9%.

[0358] MS m / z (ESI): 507.1 [M+H] +

[0359] Step 6

[0360] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazole-3-carbimidoyl chloride

[0361] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carboimide chloride

[0362] 5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carboxamide 6h (500 mg, 0.99 mmol) was dissolved in chlorobenzene (20 mL), and phosphorus pentachloride (410.82 mg, 1.97 mmol) was added under a nitrogen atmosphere at room temperature. The mixture was reacted at 100 °C for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carbonimide acyl chloride 6i (518 mg).

[0363] Step 7

[0364] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0365] N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0366] (E)-5-(4-chlorophenyl)-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-1,2,4-triazol-3-carbonimide acyl chloride 6i (518 mg, 0.99 mmol) was dissolved in dichloromethane (20 mL), and N-(carbamoyl)acetamide 1j (398.8 mg, 3.94 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was filtered under reduced pressure. The filtrate was purified by preparative liquid chromatography (Waters 2767 / QDA column: Welch XB-Pheny, 21.2*250mm, 10µm; mobile phase A: 0.1% FA in H2O; B: ACN; flow rate: 20ml / min) to obtain N-((E)-N'-((E)-(5-(4-chlorophenyl)-1-phenyl-1H-1,2,4-triazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 6 (201mg), yield 34.5%.

[0367] MS m / z(ESI): 590.2 [M+H] +

[0368] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.96-8.56(m,2H),8.12-8.02(m,2H),7.92-7.84(m,2H),7.59-7.47(m,5H),7.42-7.34(m,4H),2.07(s,3H).

[0369] Example 7

[0370] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)propanamide

[0371] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)propionamide

[0372] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (200 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-aminopropionamide hydrochloride 7a (92 mg, 0.74 mmol) was added. The reaction solution was stirred at 50 °C under a nitrogen atmosphere for 16 hours. LCMS showed that the reaction was complete. The reaction solution was added with water (80 mL), extracted with ethyl acetate (60 mL x 3), the organic phase was collected, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 PrepOBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to obtain (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)propionamide 7 (87 mg, yield 36.6%).

[0373] MS m / z (ESI): 590.2 [M+H] +

[0374] 1 H NMR (400MHz, DMSO-d6) δ8.36-8.23(m,1H),8.07(d,J=8.1Hz,2H),7.90(d,J=8.4Hz,2H),7.68(s,1H),7.41- 7.30(m,5H),7.28-7.22(m,3H),7.08-6.98(m,2H),6.63-6.50(m,1H),4.64-4.35(m,3H),1.44-1.17(m,3H).

[0375] Example 8

[0376] (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0377] (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-aminosulfonylethyl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0378] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (12 mL), and 2-aminoethanesulfonamide hydrochloride 8a (179 mg, 1.11 mmol) was added. The reaction solution was stirred at 50 °C for 16 hours under nitrogen protection. LCMS showed the reaction was complete. The reaction solution was extracted with water (80 mL) and ethyl acetate (60 mL x 3). The organic phase was collected, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (eluent: system B). It was then purified by reversed-phase column chromatography (Waters 2767 / Qda). The separation column was SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: CAN; flow rate: 20 mL / min). The result was (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-aminosulfonylethyl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide 8 (26 mg, yield: 7.4%).

[0379] MS m / z (ESI): 626.1 [M+H] +

[0380] 1 H NMR (400MHz, DMSO-d6) δ8.47-8.32(m,1H),8.07(d,J=8.0Hz,2H),7.90(d,J=8.2Hz,2H),7.48-7.38(m,2H),7.3 6-7.23(m,5H),7.13-6.98(m,4H),6.60-6.52(m,1H),4.48-4.37(m,2H),3.94-3.80(m,2H),3.31-3.24(m,2H).

[0381] Example 9

[0382] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)acetamide

[0383] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)acetamide

[0384] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (200 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-aminoacetamide 9a (82 mg, 1.11 mmol) was added. The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours. LCMS showed the reaction was complete. The reaction solution was extracted with water (80 mL) and ethyl acetate (60 mL x 3). The organic phase was collected, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and purified by reversed-phase column chromatography (Waters 2767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to obtain (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)acetamide 9 (68 mg, yield: 31.7%).

[0385] MS m / z (ESI): 576.1 [M+H] +

[0386] 1 H NMR (400MHz, DMSO-d6) δ8.44-8.38(m,1H),8.07(d,J=8.0Hz,2H),7.90(d,J=8.2Hz,2H),7.66(s,1H),7.42-7.38(m,2 H),7.36-7.31(m,2H),7.30-7.23(m,4H),7.07-7.00(m,2H),6.59-6.52(m,1H),4.46-4.40(m,2H),4.16-4.10(m,2H).

[0387] Example 10

[0388] (Z)-N-((Z)-1-aminoethylidene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0389] (Z)-N-((Z)-1-aminoethylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0390] Ethamidinium hydrochloride 10a (263.42 mg, 2.79 mmol) was dissolved in N,N-dimethylformamide (10 mL). Under nitrogen protection at -78 °C, N,N-diisopropylethylamine (360 mg, 2.79 mmol) was added dropwise. After stirring the mixture at -78 °C for 30 minutes, a solution of (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.56 mmol) in N,N-dimethylformamide (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 50 °C for 1 hour. LCMS showed the reaction was complete. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase column chromatography (Waters 2767 column: Pursuit XRs 10 C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O; B: ACN; flow rate: 20 mL / min); to obtain (Z)-N-((Z)-1-aminoethylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide 10 (23 mg, yield: 7.3%).

[0391] MS m / z(ESI): 560.0 [M+H] +

[0392] 1 H NMR(400MHz,DMSO-d6)δ8.02-7.96(m,2H),7.90-7.83(m,2H),7.75-7.48(m,2H),7.32-7.27(m,2H),7 .27-7.23(m,3H),7.18-7.10(m,2H),7.03-6.96(m,2H),6.61-6.53(m,1H),4.61(s,2H),1.68(s,3H).

[0393] Example 11

[0394] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-2-methylpropanamide

[0395] (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-methylpropionamide

[0396] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.93 mmol) and 2-amino-2-methylpropionamide 11a (190 mg, 1.86 mmol) were dissolved in N,N-dimethylformamide (8 mL), and the reaction mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water (80 mL), extracted with ethyl acetate (60 mL x 3), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give product (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-methylpropionamide 11 (26 mg, yield: 4.6%).

[0397] MS m / z (ESI): 590.2 [M+H] +

[0398] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.01(d,J=8.2Hz,2H),7.89(d,J=8.3Hz,2H),7.47(d,J=8.6Hz,2H),7.40-7.36(m ,1H),7.35-7.24(m,5H),7.21-7.16(m,1H),7.11-7.04(m,2H),6.62(t,J=4.9Hz,1H),4.70-4.60(m,2H),1.27(s,6H).

[0399] Example 12

[0400] (Z)-N-((E)-amino(ureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0401] (Z)-N-((E)-amino(ureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0402] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (250 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-carbamoylguanidine 12a (95 mg, 0.93 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. LCMS monitoring showed a product peak. The reaction solution was diluted with water (80 mL), extracted with ethyl acetate (60 mL x 3), the organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by silica gel column chromatography (eluent: system A), and then purified by reversed-phase column chromatography (Waters 2767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min), yielding product (Z)-N-((E)-amino(ureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide 12 (50 mg, yield: 18.2%).

[0403] MS m / z (ESI): 590.2 [M+H] +

[0404] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.16-7.74(m,6H),7.31-7.20(m,5H),7. 17-7.10(m,2H),7.03-6.92(m,3H),6.60-6.27(m,2H),4.56(d,J=4.8Hz,2H).

[0405] Example 13

[0406] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0407] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0408] first step

[0409] methyl(Z)-4-(4-chlorophenyl)-2-hydroxy-3-methyl-4-oxobut-2-enoate

[0410] (Z)-4-(4-chlorophenyl)-2-hydroxy-3-methyl-4-oxobut-2-enoic acid methyl ester

[0411] 1-(4-chlorophenyl)prop-1-one 13a (20 g, 118.61 mmol) was dissolved in diethyl ether (200 mL), and bis(trimethylsilylaminolithium) (1 M, 130.47 mL) was added dropwise under a nitrogen atmosphere at -78 °C. After stirring the mixture at -78 °C for 0.5 hours, dimethyl oxalate 3b (18.21 g, 154.19 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was quenched at 0°C with water (200 mL) and dilute hydrochloric acid (70 mL). It was extracted with dichloromethane (300 mL x 3), the organic phases were combined, backwashed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system A) to give product (Z)-4-(4-chlorophenyl)-2-hydroxy-3-methyl-4-oxobut-2-enoic acid methyl ester 13b (10 g, yield: 33.1%).

[0412] MS m / z (ESI): 255.0 [M+H] +

[0413] Step 2

[0414] methyl 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate

[0415] methyl 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate

[0416] (Z)-4-(4-chlorophenyl)-2-hydroxy-3-methyl-4-oxobut-2-enoate methyl ester 13b (9 g, 35.34 mmol) was dissolved in methanol (100 mL), and phenylhydrazine 3d (7.64 g, 70.68 mmol) was added. The reaction mixture was stirred at 75 °C for 16 hours under nitrogen protection. The reaction was monitored by TLC until completion. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, backwashed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate 13c (9 g, yield: 77.9%).

[0417] MS m / z (ESI): 327.1 [M+H] +

[0418] Step 3

[0419] 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

[0420] 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

[0421] Methyl 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid 13c (2 g, 6.12 mmol) was dissolved in tetrahydrofuran (20 mL), ethanol (10 mL), and water (10 mL). Potassium hydroxide (515 mg, 9.18 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The pH of the reaction mixture was adjusted to 2 with 1 M HCl, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid 13d (1.5 g), which was used directly in the next step.

[0422] MS m / z (ESI): 313.1 [M+H] +

[0423] Step 4

[0424] 5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0425] 5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0426] 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid 13d (1.25 g, 4.00 mmol) and 4-(trifluoromethyl)benzenesulfonamide 2i (600 mg, 2.66 mmol) were dissolved in dichloromethane (30 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 766 mg, 4.00 mmol) and 4-dimethylaminopyridine (488 mg, 4.00 mmol) were added. The reaction 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 residue was separated by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 13e (450 mg, yield: 32.6%).

[0427] MS m / z (ESI): 520.0 [M+H] +

[0428] Step 5

[0429] (E)-5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoyl chloride

[0430] (E)-5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride

[0431] 5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 13e (400 mg, 0.77 mmol) was dissolved in chlorobenzene (12 mL), and phosphorus pentachloride (320 mg, 1.54 mmol) was added. The reaction mixture was stirred at 100 °C for 1 hour. LCMS monitoring revealed a product peak. The reaction mixture was concentrated under reduced pressure to obtain (E)-5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 13f (400 mg), which was directly used in the next step.

[0432] MS m / z (ESI): 538.1 [M+H] +

[0433] Step 6

[0434] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0435] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0436] (E)-5-(4-chlorophenyl)-4-methyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 13f (400 mg, 0.74 mmol) was dissolved in dichloromethane (10 mL), and N-carbamoylacetamide 1j (150 mg, 1.49 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by reversed-phase column chromatography (Waters 2767 / Qda column: Sunfire C1819*250mm*10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min), yielding product N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 13 (60mg, yield: 13.3%).

[0437] MS m / z (ESI): 603.4 [M+H] +

[0438] 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.70-8.26 (m, 2H), 8.06 (d, J = 8.2Hz, 2H), 7.86 (d, J = 8.4Hz, 2H), 7.50-7.45(m,2H),7.39-7.30(m,3H),7.20-7.16(m,2H),7.09-7.05(m,2H),2.19(s,3H),2.06(s,3H).

[0439] Example 14

[0440] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0441] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0442] first step

[0443] methyl 4-bromo-5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate

[0444] 4-Bromo-5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester

[0445] methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid ester 3e (1 g, 3.2 mmol) was dissolved in acetic acid (10 mL), and liquid bromine (2.04 g, 12.79 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was quenched with saturated sodium thiosulfate solution (50 mL), extracted with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, concentrated the organic phase under reduced pressure, and concentrated the residue again under reduced pressure with diethyl ether to give methyl 4-bromo-5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid ester 14a (1.2 g, yield: 95.8%).

[0446] MS m / z(ESI): 392.9 [M+H] +

[0447] Step 2

[0448] methyl 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylate

[0449] 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid methyl ester

[0450] Methyl 4-bromo-5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid ester 14a (1 g, 2.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cuprous cyanide (1.26 g, 14.04 mmol) was added. The mixture was stirred at 150 °C for 6 hours under nitrogen protection. LC-MS showed that the reaction was complete. After the reaction solution cooled to room temperature, water (5 mL), ammonia (5 mL), and ethyl acetate (5 mL) were added. The mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid ester 14b (620 mg, yield: 71.9%).

[0451] MS m / z(ESI): 338.0 [M+H] +

[0452] Step 3

[0453] 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid

[0454] 5-(4-Chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid

[0455] Methyl 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid 14b (620 mg, 1.84 mmol) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide monohydrate (308 mg, 7.34 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 5 with 1 M hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid 14c (450 mg), which was directly used in the next step of the reaction.

[0456] MS m / z(ESI): 324.0 [M+H] +

[0457] Step 4

[0458] 5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0459] 5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0460] 4-(trifluoromethyl)benzenesulfonamide 2i (313 mg, 1.39 mmol) and 5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazole-3-carboxylic acid 14c (450 mg, 1.39 mmol) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 400 mg, 2.09 mmol) and 4-dimethylaminopyridine (255 mg, 2.09 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was added to 1M hydrochloric acid aqueous solution (100 mL), extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 14d (380 mg, yield: 51.4%).

[0461] MS m / z(ESI): 531.0 [M+H] +

[0462] Step 5

[0463] (E)-5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoyl chloride

[0464] (E)-5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbonyl chloride

[0465] 5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 14d (180 mg, 0.34 mmol) was dissolved in chlorobenzene (3 mL), and phosphorus pentachloride (141 mg, 0.68 mmol) was added. The mixture was stirred at 100 °C for 0.5 h. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give (E)-5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbonyl chloride 14e (180 mg).

[0466] Step 6

[0467] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0468] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0469] (E)-5-(4-chlorophenyl)-4-cyano-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbonyl chloride 14e (180 mg, 0.33 mmol) was dissolved in dichloromethane (4 mL), and N-(carbamoyl)acetamide 1j (40 mg, 0.39 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated and purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlantis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.05% TFA in H2O, B: ACN; flow rate: 20ml / min) to obtain the product N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-cyano-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 14 (31mg, yield: 15.6%).

[0470] MS m / z (ESI): 614.4 [M+H] +

[0471] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),8.81(s,2H),8.13(d,J=8.2Hz,2H),7.89(d,J=8.4Hz,2H), 7.57(d,J=8.4Hz,2H),7.51-7.40(m,3H),7.35(d,J=8.4Hz,2H),7.27-7.16(m,2H),2.09(s,3H).

[0472] Example 15

[0473] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0474] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)((4-chlorobenzenesulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0475] first step

[0476] methyl((4-chlorophenyl)sulfonyl)carbamate

[0477] Methyl (4-chlorophenyl)sulfonyl)carbamate

[0478] 4-Chlorobenzenesulfonamide 15a (5 g, 26.09 mmol) and triethylamine (7.92 g, 78.27 mmol) were dissolved in dichloromethane (100 mL). Methyl chloroformate (2.96 g, 31.31 mmol) was added dropwise under nitrogen protection at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure to obtain methyl (4-chlorophenyl)sulfonyl)carbamate 15b (6.5 g), which was used directly in the next step.

[0479] Step 2

[0480] 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0481] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (1 g, 3.69 mmol) was dissolved in toluene (30 mL), and methyl (4-chlorophenyl)sulfonyl)carbamate 15b (1.84 g, 7.39 mmol) was added. The mixture was stirred at 120 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with methanol (10 mL) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide 15c (1.6 g, yield: 88.7%).

[0482] MS m / z(ESI): 488.1 [M+H] +

[0483] Step 3

[0484] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidoyl chloride

[0485] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboimide chloride

[0486] 3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide 15c (400 mg, 0.82 mmol) was dissolved in chlorobenzene (20 mL), and phosphorus pentachloride (341 mg, 1.64 mmol) was added. The mixture was reacted at 100 °C for 1 hour under nitrogen protection. LCMS showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was quenched with water (100 mL) at 0 °C, extracted with dichloromethane (80 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 15d (230 mg, yield: 51.8%).

[0487] MS m / z(ESI): 542.0 [M+H] +

[0488] Step 4

[0489] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0490] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)((4-chlorobenzenesulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0491] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 15d (230 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N-acetylguanidine 1j (172 mg, 1.70 mmol) and N,N-diisopropylethylamine (274.59 mg, 2.12 mmol) were added. The mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters column: Pursuit XRs C18 21.2*250 mm*10 μm; mobile phase A: 0.05% TFA in H2O, B: ACN; flow rate: 20 mL / min) to give the product N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)((4-chlorobenzenesulfonyl)imino)methyl)aminomethamidinyl)acetamide 15 (65.76 mg, yield: 27.1%).

[0492] MS m / z (ESI): 569.1 [M+H] +

[0493] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.47-7.62(m,4H),7.57-7.49(m,2H),7.29-7.17(m,5H), 7.12-7.02(m,2H),7.00-6.91(m,2H),6.57-6.45(m,1H),4.72-4.44(m,2H),2.17-2.04(m,3H).

[0494] Example 16

[0495] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0496] N-(E)-N'-(E)-(5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazol-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamine)acetamide

[0497] first step

[0498] ethyl 4-(4-chlorophenyl)-3-oxobutanoate

[0499] Ethyl 4-(4-chlorophenyl)-3-oxobutyrate

[0500] Potassium ethyl malonate 16b (20.97 g, 123.19 mmol) was dissolved in acetonitrile (200 mL), and magnesium chloride (13.98 g, 146.82 mmol) and triethylamine (26.13 g, 258.22 mmol) were added. The mixture was stirred at room temperature for 2 hours and then set aside. 4-Chlorophenylacetic acid 16a (10 g, 58.62 mmol) was dissolved in acetonitrile (200 mL), and carbonyl diimidazole (10.48 g, 64.66 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The prepared solution was then added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, followed by stirring at 80 °C for 2 hours. After cooling the reaction solution to room temperature, 2N hydrochloric acid solution (260 mL) was added. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give colorless liquid ethyl 4-(4-chlorophenyl)-3-oxobutyrate 16c (3.1 g, yield: 22%).

[0501] MS m / z(ESI): 241.1 [M+H] +

[0502] Step 2

[0503] ethyl(Z)-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazono)butanoate

[0504] Ethyl (Z)-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate

[0505] Aniline 16d (1.01 g, 10.80 mmol) was dissolved in 2N hydrochloric acid (10 mL), and sodium nitrite aqueous solution (819.86 mg, 11.88 mmol) was added dropwise at 0 °C. After stirring at 0 °C for 10 minutes, the solution was stirred at room temperature for 2 hours to obtain the stock solution. Ethyl 4-(4-chlorophenyl)-3-oxobutyrate 16c (2.6 g, 10.80 mmol) was dissolved in ethanol (30 mL), and sodium acetate (2.96 g, 35.65 mmol) was added. The mixture was cooled to 0 °C, and the stock solution was slowly added dropwise. After the addition was complete, the solution was stirred at 0 °C for 30 minutes, and then stirred at room temperature for 1 hour. The reaction was detected by LCMS. The reaction solution was filtered and the precipitated solid was collected. After washing twice with water, it was dissolved in chloroform (150 mL). The organic phase was washed with saturated brine (100 mL). The organic phase was separated, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was then slurried with n-hexane. The solid was collected by filtration and dried to obtain ethyl (Z)-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate 16e (3.2 g, yield: 85.9%).

[0506] MS m / z (ESI): 345.1 [M+H] +

[0507] Step 3

[0508] ethyl(Z)-4-bromo-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazono)butanoate

[0509] Ethyl (Z)-4-bromo-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate

[0510] Ethyl (Z)-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate 16e (2.7 g, 7.83 mmol) was dissolved in ethyl acetate (20 mL) and chloroform (20 mL), and copper bromide (3.85 g, 17.23 mmol) was added. The mixture was stirred at 60 °C for 6 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (100 mL), filtered, and the organic phase was washed twice with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl (Z)-4-bromo-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate 16f (3 g, yield: 90.4%).

[0511] MS m / z(ESI): 425.0 [M+H] +

[0512] Step 4

[0513] ethyl 5-(4-chlorophenyl)-4-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate

[0514] 5-(4-chlorophenyl)-4-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0515] Ethyl (Z)-4-bromo-4-(4-chlorophenyl)-3-oxo-2-(2-phenylhydrazine)butyrate 16f (3g, 7.08mmol) was dissolved in ethanol (30mL) and water (10mL), and sodium acetate (2.32g, 28.32mmol) was added. The reaction mixture was stirred at 90°C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (200mL) and water (80mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 5-(4-chlorophenyl)-4-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid 16g (1.8g, yield: 74.2%).

[0516] MS m / z(ESI): 343.1 [M+H] +

[0517] Step 5

[0518] ethyl 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylate

[0519] 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0520] 16 g (1.8 g, 5.25 mmol) of ethyl 5-(4-chlorophenyl)-4-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate was dissolved in 20 mL of N,N-dimethylformamide. Sodium hydride (231 mg, 5.78 mmol, 60% purity) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Iodimethane (894 mg, 6.30 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LCMS until completion. The reaction solution was quenched with ice water (100 mL), and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 16 h (1.6 g, yield: 85.4%) of ethyl 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylate.

[0521] MS m / z (ESI): 357.1 [M+H] +

[0522] Step 6

[0523] 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid

[0524] 5-(4-Chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid

[0525] Ethyl 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid 16h (500 mg, 1.40 mmol) was dissolved in tetrahydrofuran (4 mL), and a solution of lithium hydroxide monohydrate (235 mg, 5.61 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until completion. Water (20 mL) was added to the reaction solution, and the pH was adjusted to about 5 with 1M hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid 16i (420 mg), which was directly used in the next step of the reaction.

[0526] MS m / z(ESI): 329.1 [M+H] +

[0527] Step 7

[0528] 5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0529] 5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0530] 4-(trifluoromethyl)benzenesulfonamide 2i (273 mg, 1.21 mmol) and 5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid 16i (420 mg, 1.28 mmol) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (367 mg, 1.92 mmol) and 4-dimethylaminopyridine (234 mg, 1.92 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was added to 1M hydrochloric acid aqueous solution (100 mL), extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 16j (390 mg, yield: 57.0%).

[0531] MS m / z (ESI): 536.1 [M+H] +

[0532] Step 8

[0533] (E)-5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoyl chloride

[0534] (E)-5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboimide chloride

[0535] 5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 16j (200 mg, 0.37 mmol) was dissolved in chlorobenzene (3 mL), and phosphorus pentachloride (155 mg, 0.75 mmol) was added. The mixture was stirred at 100 °C for 0.5 h. The reaction was monitored by TLC until completion, and the reaction solution was concentrated to obtain (E)-5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbonimide acyl chloride 16k (200 mg), which was directly used in the next step.

[0536] Step 9

[0537] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0538] N-(E)-N'-(E)-(5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazol-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamine)acetamide

[0539] (E)-5-(4-chlorophenyl)-4-methoxy-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbonimide acyl chloride 16k (200 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), and N-acetylguanidine 1j (44 mg, 0.43 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (Waters 2767 separation column: Pursuit XRs C182 1.2*250mm*10μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain N-(E)-N'-(E)-(5-(4-chlorophenyl)-4-methoxy-1-phenyl-1H-pyrazol-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 16 (32.03mg, yield: 14.3%).

[0540] MS m / z (ESI): 619.4 [M+H] +

[0541] 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.85-8.28(m,2H),8.06(d,J=8.0Hz,2H),7.87(d,J=8.4Hz,2H),7.50 -7.43(m,2H),7.42-7.34(m,3H),7.23-7.17(m,2H),7.13(dd,J=8.0,1.6Hz,2H),3.72(s,3H),2.07(s,3H).

[0542] Example 17

[0543] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-methylbutanamide

[0544] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-methylbutyramide

[0545] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (400 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (12 mL), and (S)-2-amino-3-methylbutyramide 17a (86 mg, 0.74 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was diluted with water (80 mL), extracted with ethyl acetate (60 mL x 3), and the organic phase was collected. It was washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B). It was then purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to obtain (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-methylbutyramide 17 (30 mg, yield: 6.6%).

[0546] MS m / z (ESI): 618.1 [M+H] +

[0547] 1 H NMR (400MHz, DMSO-d6) δ8.12-8.02(m,2H),7.95-7.85(m,3H),7.66-7.49(m,1H),7.38-7.31(m,5H),7.28-7. 24(m,3H),7.09-7.01(m,2H),6.58(t,J=4.8Hz,1H),4.64-4.19(m,3H),2.20-2.07(m,1H),0.88-0.80(m,6H).

[0548] Example 18

[0549] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0550] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0551] first step

[0552] methyl 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylate

[0553] Methyl 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylate

[0554] 3.5 g (11.19 mmol) of methyl 5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate 3e was dissolved in acetonitrile (60 mL), and Selectfluor (4.76 g, 13.43 mmol) was added. The mixture was stirred at 90 °C for 48 hours under a nitrogen atmosphere. LC-MS showed a reactant-to-product ratio of 1:1. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylate 18a (3 g, yield: 81%).

[0555] MS m / z(ESI): 331.0 [M+H] +

[0556] Step 2

[0557] 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylic acid

[0558] 5-(4-Chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylic acid

[0559] Methyl 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylic acid 18a (3 g, 9.07 mmol) was dissolved in a solution of methanol (10 mL), tetrahydrofuran (30 mL), and water (10 mL). Potassium hydroxide (763 mg, 13.61 mmol) was added, and the mixture was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated, water (100 mL) was added, the pH was adjusted to 5 with 1 M hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylic acid 18b (2.7 g), which was used directly in the next step of the reaction.

[0560] MS m / z(ESI): 317 [M+H] +

[0561] Step 3

[0562] 5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0563] 5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0564] 4-Trifluoromethylbenzenesulfonamide 2i (1.3 g, 5.77 mmol) and 5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazole-3-carboxylic acid 18b (2.19 g, 6.93 mmol) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.66 g, 8.66 mmol) and 4-dimethylaminopyridine (1.06 g, 8.66 mmol) were added. The mixture was stirred and reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with methanol (10 mL) to give 5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 18c (2.6 g, yield: 85.97%).

[0565] MS m / z(ESI): 524 [M+H] +

[0566] Step 4

[0567] (E)-5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoyl chloride

[0568] (E)-5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride

[0569] 5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 18c (500 mg, 0.95 mmol) was dissolved in chlorobenzene (20 mL), and phosphorus pentachloride (397 mg, 1.91 mmol) was added. The mixture was stirred at 100 °C for 4 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give (E)-5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 18d (510 mg), which was directly used in the next step of the reaction.

[0570] Step 5

[0571] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0572] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0573] (E)-5-(4-chlorophenyl)-4-fluoro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 18d (510 mg, 0.94 mmol) was dissolved in dichloromethane (10 mL), and N-acetylguanidine 1j (190 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-fluoro-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 18 (71.60mg, yield: 12.5%).

[0574] MS m / z (ESI): 607.1 [M+H] +

[0575] 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.82-8.45(m,2H),8.11-8.05(m,2H),7.92- 7.85(m,2H),7.54-7.49(m,2H),7.47-7.39(m,3H),7.26-7.15(m,4H),2.07(s,3H).

[0576] Example 19

[0577] N-((E)-N'-((Z)-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)methyl)carbamimidoyl)acetamide

[0578] N-((E)-N'-((Z)-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)methyl)aminomethylamidinyl)acetamide

[0579] first step

[0580] methyl((3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamate

[0581] Methyl (3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamate

[0582] 3,5-bis(trifluoromethyl)benzenesulfonamide 19a (1 g, 3.41 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.04 g, 10.23 mmol) and methyl chloroformate (386 mg, 4.09 mmol) were added. The mixture was reacted at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give methyl (3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamate 19b (2.23 g), which was used directly in the next step of the reaction.

[0583] Step 2

[0584] N-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0585] N-(3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0586] Methyl (3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamate 19b (2.08 g, 5.91 mmol) was dissolved in toluene (15 mL), and 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (800 mg, 2.95 mmol) was added. The mixture was reacted at 120 °C for 16 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give N-(3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide 19c (1.62 g, yield: 92.9%).

[0587] Step 3

[0588] (E)-N-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-4-chloro-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidoyl chloride

[0589] (E)-N-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-4-chloro-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboimide chloride

[0590] N-(3,5-bis(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide 19c (850 mg, 1.44 mmol) was dissolved in chlorobenzene (10 mL), and phosphorus pentachloride (1.20 g, 5.76 mmol) was added. The mixture was reacted at 100 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-N-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-4-chloro-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboimide acyl chloride 19d (590 mg, yield: 63.7%).

[0591] MS m / z (ESI): 643.9 [M+H] +

[0592] Step 4

[0593] N-((E)-N'-((Z)-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)methyl)carbamimidoyl)acetamide

[0594] N-((E)-N'-((Z)-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)methyl)aminomethylamidinyl)acetamide

[0595] (E)-N-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)-4-chloro-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 19d (590 mg, 0.91 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-acetylguanidine 1j (371 mg, 3.67 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain N-((E)-N'-((Z)-((3,5-bis(trifluoromethyl)phenyl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)methyl)aminomethamidinyl)acetamide 19 (222mg, yield: 36%).

[0596] MS m / z (ESI): 671.1 [M+H] +

[0597] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.37-8.19(m,4H),7.95-7.71(m,1H),7.3 0-7.19(m,5H),7.08-6.93(m,4H),6.59-6.52(m,1H),4.61(s,2H),2.06(s,3H).

[0598] Example 20

[0599] (Z)-N-((E)-amino(1H-1,2,4-triazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0600] (Z)-N-((E)-amino(1H-1,2,4-triazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H-formimide)

[0601] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (12 mL), and 1H-1,2,4-triazole-1-carboximide hydrochloride 20a (164 mg, 1.11 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with water (80 mL) and ethyl acetate (60 mL x 3). The organic phase was collected, washed with saturated brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: system B). The product was then slurried with methanol to give (Z)-N-((E)-amino(1H-1,2,4-triazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-formimide 20 (120 mg, yield: 35.1%).

[0602] MS m / z (ESI): 613.2 [M+H] +

[0603] 1 HNMR (400MHz, DMSO-d6) δ8.61(s,1H),8.42(s,2H),8.35(s,1H),7.98(d,J=8.1Hz,2H),7.84(d,J=8.3Hz,2 H),7.26-7.22(m,3H),7.19-7.14(m,2H),7.01-6.92(m,4H),6.58(t,J=4.6Hz,1H),4.69(d,J=4.6Hz,2H).

[0604] Example 21

[0605] (Z)-N-((E)-amino(1H-pyrazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0606] (Z)-N-((E)-amino(1H-pyrazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0607] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (200 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1H-pyrazole-1-formamidinium hydrochloride 21a (102 mg, 0.7 mmol) and N,N-diisopropylethylamine (179.87 mg, 1.39 mmol) were added. The mixture was reacted at room temperature under nitrogen protection for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give product (Z)-N-((E)-amino(1H-pyrazol-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide 21 (81 mg, yield: 38.3%).

[0608] MS m / z (ESI): 612.2 [M+H] +

[0609] 1H NMR(400MHz,DMSO-d6)δ8.32(s,2H),8.02-7.95(m,2H),7.89-7.80(m,3H),7.72(s,1H),7.2 7-7.20(m,3H),7.16-7.10(m,2H),6.99-6.90(m,4H),6.59-6.50(m,2H),4.72-4.62(m,2H).

[0610] Example 22

[0611] (Z)-N-((Z)-amino(pyridin-2-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0612] (Z)-N-((Z)-amino(pyridin-2-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0613] 2-Aminopyridine hydrochloride 22a (109 mg, 0.7 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (180 mg, 1.39 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (0.2 g, 0.35 mmol) were added. The mixture was stirred at room temperature under nitrogen protection for 16 hours. LCMS showed the reaction was complete. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters 2767 / QDA column: Pursuit XRs10 C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O; B: ACN; flow rate: 20 mL / min). The product (Z)-N-((Z)-amino(pyridin-2-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide 22 (130 mg, yield: 34%) was obtained.

[0614] MS m / z(ESI): 623.1 [M+H] +

[0615] 1 H NMR(400MHz,DMSO-d6)δ8.73-8.64(m,1H),8.34-8.08(m,2H),8.01-7.92(m,2H),7.89-7.77(m,3H),7.59-7.46(m,2H ),7.28-7.19(m,3H),7.16-7.08(m,2H),7.04-6.95(m,2H),6.90-6.83(m,2H),6.53-6.47(m,1H),4.70-4.61(m,2H).

[0616] Example 23

[0617] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0618] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0619] first step

[0620] methyl 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutanoate

[0621] Methyl 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyrate

[0622] 1-(4-chlorophenyl)-2-phenylethyl-1-one 1a (25 g, 108.37 mmol) was dissolved in N,N-dimethylformamide (250 mL). Sodium hydride (3.90 g, 162.56 mmol) was added under nitrogen protection in an ice bath. The mixture was stirred in an ice bath for 0.5 hours, and then methyl 2-bromopropionate 23a (28.96 g, 173.39 mmol) was added dropwise. The mixture was reacted at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride aqueous solution (500 mL) in an ice bath, extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated brine (600 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give methyl 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyrate 23b (41.34 g, yield: 100%).

[0623] MS m / z(ESI): 317.1 [M+H]+

[0624] Step 2

[0625] 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutanoic acid

[0626] 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyric acid

[0627] Methyl 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyrate 23b (41.34 g, 130.50 mmol) was dissolved in ethanol (150 mL), and an aqueous solution of sodium hydroxide (10.44 g, 261.00 mmol) (150 mL) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove ethanol, and then water (600 mL) was added. Methyl tert-butyl ether (200 mL x 3) was added for extraction. The aqueous phase was adjusted to pH 5 with hydrochloric acid aqueous solution (1 M), and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain product 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyrate 23c (50.13 g), which was directly used in the next reaction.

[0628] MS m / z (ESI): 303.1 [M+H] +

[0629] Step 3

[0630] 6-(4-chlorophenyl)-4-methyl-5-phenyl-4,5-dihydropyridazin-3(2H)-one

[0631] 6-(4-Chlorophenyl)-4-methyl-5-phenyl-4,5-dihydropyridazine-3(2H)-one

[0632] 23c of 4-(4-chlorophenyl)-2-methyl-4-oxo-3-phenylbutyric acid (50.13 g, 165.58 mmol) was dissolved in ethanol (350 mL), and hydrazine hydrate (24.87 g, 496.74 mmol) was added. The mixture was stirred at 90 °C for 16 hours under nitrogen protection. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 23d of 6-(4-chlorophenyl)-4-methyl-5-phenyl-4,5-dihydropyridazine-3(2H)-one (5.84 g, yield: 11.8%).

[0633] Step 4

[0634] 3-(4-chlorophenyl)-5-methyl-4-phenyl-1,4,5,6-tetrahydropyridazine

[0635] 3-(4-Chlorophenyl)-5-methyl-4-phenyl-1,4,5,6-tetrahydropyridazine

[0636] 6-(4-chlorophenyl)-4-methyl-5-phenyl-4,5-dihydropyridazine-3(2H)-one 23d (2 g, 6.69 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Lithium aluminum hydride (2.5 M, 8.03 mL) was added dropwise under nitrogen protection in an ice bath. After the addition was complete, the reaction mixture was stirred at 70 °C for 1 hour. LC-MS showed that the reaction was complete. Water (8 mL), 15% sodium hydroxide aqueous solution (8 mL), and water (24 mL) were added dropwise to the reaction mixture in an ice bath. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 3-(4-chlorophenyl)-5-methyl-4-phenyl-1,4,5,6-tetrahydropyridazine 23e (1.82 g, yield: 95.4%).

[0637] MS m / z (ESI): 285.2 [M+H] +

[0638] Step 5

[0639] 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

[0640] 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

[0641] 3-(4-chlorophenyl)-5-methyl-4-phenyl-1,4,5,6-tetrahydropyridazine 23e (1.82 g, 6.39 mmol) was dissolved in toluene (30 mL), and 1 g (3.98 g, 14.06 mmol) of methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate was added. The mixture was stirred at 120 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 23f (2.9 g, yield: 84.6%).

[0642] MS m / z (ESI): 536.1 [M+H] +

[0643] Step 6

[0644] (E)-4-chloro-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbimidoyl chloride

[0645] (E)-4-chloro-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H-carbonimide chloride

[0646] 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 23f (1 g, 1.87 mmol) was dissolved in chlorobenzene (15 mL), and phosphorus pentachloride (1.55 g, 7.46 mmol) was added. The mixture was reacted at 100 °C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-4-chloro-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboimide chloride 23 g (830 mg, yield: 75.5%).

[0647] MS m / z (ESI): 589.9 [M+H] +

[0648] Step 7

[0649] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0650] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0651] 23 g (830 mg, 1.41 mmol) of (E)-4-chloro-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide chloride was dissolved in 10 mL of N,N-dimethylformamide, and 1 j of N-acetylguanidine (570 mg, 5.64 mmol) was added. The mixture was reacted at 50 °C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; mobile phase: 20ml / min) to give the product N-((E)-N'-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethamidinyl)acetamide 23 (311mg, yield: 35.8%).

[0652] MS m / z (ESI): 617.2 [M+H] +

[0653] 1 HNMR(400MHz,DMSO-d6)δ10.62(s,1H),8.40-7.68(m,6H),7.30-7.11(m,5H),7.06-6.90(m,4H),4.50(s,2H),2.09(s,3H),1.87(s,3H).

[0654] Example 24

[0655] N-((E)-N'-((Z)-(((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)methyl)carbamimidoyl)acetamide

[0656] N-((E)-N'-((Z)-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)yl)methyl)aminomethylamidinyl)acetamide

[0657] first step

[0658] tert-butyl 4-(2-chlorobenzyl)piperazine-1-carboxylate

[0659] 4-(2-chlorobenzyl)piperazine-1-carboxylic acid tert-butyl ester

[0660] 2-Chlorobenzyl bromide 24a (10 g, 48.67 mmol) was dissolved in acetonitrile (150 mL), and piperazine-1-carboxylic acid tert-butyl ester 24b (10.88 g, 58.40 mmol) and potassium carbonate (12.78 g, 92.47 mmol) were added. The mixture was reacted at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was diluted with water (500 mL), extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2-chlorobenzyl)piperazine-1-carboxylic acid tert-butyl ester 24c (17 g), which was used directly in the next reaction.

[0661] MS m / z(ESI): 311.2 [M+H] +

[0662] Step 2

[0663] 1-(2-chlorobenzyl)piperazine hydrochloride

[0664] 1-(2-Chlorobenzyl)piperazine hydrochloride

[0665] 4-(2-chlorobenzyl)piperazine-1-carboxylic acid tert-butyl ester 24c (7 g, 22.52 mmol) was dissolved in hydrochloric acid / ethyl acetate (70 mL), and the mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to give 1-(2-chlorobenzyl)piperazine hydrochloride 24d (6 g), which was used directly in the next step of the reaction.

[0666] MS m / z(ESI): 211.2 [M+H] +

[0667] Step 3

[0668] 4-(2-chlorobenzyl)piperazine-1-sulfonamide

[0669] 4-(2-Chlorobenzyl)piperazine-1-sulfonamide

[0670] 1-(2-chlorobenzyl)piperazine hydrochloride 24d (3 g, 12.14 mmol) was dissolved in 1,4-dioxane (30 mL), and sulfonamide 24e (2.33 g, 24.28 mmol) and N,N-diisopropylethylamine (1.57 g, 12.14 mmol) were added. The mixture was stirred at 110 °C for 24 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was slurried with acetonitrile (20 mL) to give 4-(2-chlorobenzyl)piperazine-1-sulfonamide 24f (6 g), which was directly used in the next reaction.

[0671] MS m / z(ESI): 290.1 ​​[M+H] +

[0672] Step 4

[0673] methyl((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)carbamate

[0674] Methyl (4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)carbamate

[0675] 4-(2-chlorobenzyl)piperazine-1-sulfonamide 24f (4.2 g, 14.49 mmol) was dissolved in dichloromethane (50 mL), and methyl chloroformate (1.64 g, 17.39 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give 24 g (5 g) of methyl (4-(2-chlorobenzyl)piperazine-1-yl)sulfonyl)carbamate, which was used directly in the next step of the reaction.

[0676] MS m / z (ESI): 348.1 [M+H] +

[0677] Step 5

[0678] N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0679] N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-carboxamide

[0680] 1f of 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine (1.5 g, 5.54 mmol) was dissolved in toluene (30 mL), and 24 g of methyl (4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)carbamate (3.85 g, 11.08 mmol) was added. The mixture was stirred at 120 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and slurried with methanol (10 mL) to give N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide (24 h, 2.1 g, yield: 64.6%).

[0681] MS m / z (ESI): 586.1 [M+H] +

[0682] Step 6 (E)-4-chloro-N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidoyl chloride

[0683] (E)-4-chloro-N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-carboimide chloride

[0684] N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-carboxamide 24h (500 mg, 0.85 mmol) was dissolved in toluene (30 mL), and phosphorus pentachloride (355 mg, 1.70 mmol) was added. The mixture was reacted at 100 °C for 2 h. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-4-chloro-N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-carboimide acyl chloride 24i (170 mg, yield: 31%).

[0685] MS m / z(ESI): 640.0 [M+H] +

[0686] Step 7

[0687] N-((E)-N'-((Z)-(((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)methyl)carbamimidoyl)acetamide

[0688] N-((E)-N'-((Z)-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)yl)methyl)aminomethylamidinyl)acetamide

[0689] (E)-4-chloro-N-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-carbonimide acyl chloride 24i (170 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-acetylguanidine 1j (53.76 mg, 0.53 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (Waters column: Pursuit XRs C182 1.2*250mm*10μm; mobile phase A: 0.05% FA / H2O, B: ACN; flow rate: 20ml / min) to obtain product N-((E)-N'-((Z)-((4-(2-chlorobenzyl)piperazin-1-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)yl)methyl)aminoformamidinyl)acetamide 24 (4.31mg, yield: 2.4%).

[0690] MS m / z (ESI): 667.2 [M+H] +

[0691] 1 HNMR(400MHz,DMSO-d6)δ10.80(s,1H),8.43(s,1H),7.51-7.47(m,1H),7.46-7.42(m,1H),7.36-7.24(m,8H),7.16-7.0 8(m,2H),7.01-6.96(m,2H),6.53-6.49(m,1H),4.56(s,2H),3.60(s,2H),3.30-3.21(m,4H),3.09(s,4H),2.14(s,3H).

[0692] Example 25

[0693] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0694] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanediamine)acetamide

[0695] first step

[0696] methyl 5-(4-chlorophenyl)-1-phenyl-4-vinyl-1H-pyrazole-3-carboxylate

[0697] Methyl 5-(4-chlorophenyl)-1-phenyl-4-vinyl-1H-pyrazole-3-carboxylate

[0698] Methyl 4-bromo-5-(4-chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate 14a (2.1 g, 5.36 mmol) was dissolved in N,N-dimethylformamide (40 mL), and tributylvinyltin (3.40 g, 10.72 mmol) and tetrakis(triphenylphosphine)palladium (620 mg, 0.54 mmol) were added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. LCMS showed that the reaction was complete. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-1-phenyl-4-vinyl-1H-pyrazole-3-carboxylate 25a (1.2 g, yield: 66.1%).

[0699] MS m / z(ESI): 339.1 [M+H] +

[0700] Step 2

[0701] methyl 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylate

[0702] methyl 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylate

[0703] 1.2 g (3.54 mmol) of methyl 5-(4-chlorophenyl)-1-phenyl-4-vinyl-1H-pyrazole-3-carboxylate 25a was dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), and platinum oxide (80 mg, 0.35 mmol) and H2 (15 psi) were added. The mixture was reacted at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylate 25b (1 g, yield: 82.8%).

[0704] MS m / z(ESI): 341.1 [M+H] +

[0705] Step 3

[0706] 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylic acid

[0707] 5-(4-Chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylic acid

[0708] Methyl 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylic acid 25b (900 mg, 2.64 mmol) was dissolved in tetrahydrofuran (20 mL), ethanol (10 mL), and water (10 mL). Potassium hydroxide (222 mg, 3.96 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The pH of the reaction mixture was adjusted to 2 with 1 M HCl, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylic acid 25c (850 mg, yield: 98.5%), which was used directly in the next step of the reaction.

[0709] MS m / z (ESI): 327.1 [M+H] +

[0710] Step 4

[0711] 5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0712] 5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide

[0713] 5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazole-3-carboxylic acid 25c (850 mg, 2.60 mmol) and 4-(trifluoromethyl)benzenesulfonamide 2i (703 mg, 3.12 mmol) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 748 mg, 3.90 mmol) and 4-dimethylaminopyridine (477 mg, 3.90 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was added to 1M hydrochloric acid aqueous solution (300 mL), extracted with dichloromethane (200 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 25d (580 mg, yield: 41.7%).

[0714] MS m / z (ESI): 534.0 [M+H] +

[0715] Step 5

[0716] (E)-5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carbimidoylchloride

[0717] (E)-5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide chloride

[0718] 5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboxamide 25d (530 mg, 0.99 mmol) was dissolved in chlorobenzene (10 mL), and phosphorus pentachloride (413 mg, 1.99 mmol) was added. The mixture was reacted at 100 °C for 4 hours. TLC showed that the starting material reacted completely. The reaction solution was concentrated under reduced pressure to give (E)-5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 25e (540 mg), which was directly used in the next step of the reaction.

[0719] Step 6

[0720] N-((E)-N'-((E)-(5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0721] N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanediamine)acetamide

[0722] (E)-5-(4-chlorophenyl)-4-ethyl-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole-3-carboximide acyl chloride 25e (540 mg, 0.98 mmol) was dissolved in dichloromethane (10 mL), and N-acetylguanidine 1j (198 mg, 1.96 mmol) was added. The mixture was reacted at 100 °C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (Waters 2767 / Qda). The separation column was SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min. The result was N-((E)-N'-(E)-(5-(4-chlorophenyl)-4-ethyl-1-phenyl-1H-pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 25 (131.45mg, yield: 21.7%).

[0723] MS m / z (ESI): 617.2 [M+H] +

[0724] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.76-8.15(m,2H),8.08-8.00(m,2H),7.92-7.83(m,2H),7.52-7.44(m,2 H),7.39-7.25(m,3H),7.23-7.15(m,2H),7.13-7.02(m,2H),2.64-2.54(m,2H),2.07(s,3H),1.11-0.99(m,3H).

[0725] Example 26

[0726] N-((E)-N'-((E)-(7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0727] N-((E)-N'-(E)-(7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0728] first step

[0729] Methyl 2-(6-chloro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-oxoacetate

[0730] 2-(6-chloro-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoacetic acid methyl ester

[0731] 6-Chloro-3,4-dihydronaphthyl-1(2H)-one 26a (10 g, 55.36 mmol) and dimethyl oxalate 3b (9.81 g, 83.04 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection and an ice bath, bis(trimethylsilylaminolithium) (1 M, 110.72 mL) was added dropwise. The mixture was reacted in an ice bath for 0.5 hours, then at room temperature for 4 hours. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give methyl 2-(6-chloro-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)-2-oxoacetate 26b (14.7 g), which was used directly in the next reaction.

[0732] Step 2

[0733] Methyl 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate

[0734] 7-Chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid methyl ester

[0735] 2-(6-chloro-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)-2-oxoacetic acid methyl ester 26b (14.7 g, 55.12 mmol) was dissolved in acetic acid (150 mL), and phenylhydrazine 3d (11.92 g, 110.25 mmol) was added under nitrogen protection in an ice bath. The mixture was reacted at 100 °C for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane (500 mL x 3), the organic phases were combined, washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid methyl ester 26c (18 g, yield: 96.4%).

[0736] MS m / z(ESI): 339.0 [M+H] +

[0737] Step 3

[0738] 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid

[0739] 7-Chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid

[0740] Methyl 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid ester 26c (5 g, 14.76 mmol) was dissolved in water (30 mL) and ethanol (30 mL), and potassium hydroxide (1.66 g, 29.52 mmol) was added. The mixture was reacted at 90 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was added to water (100 mL). The pH was adjusted to 5 with 1 M hydrochloric acid aqueous solution, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with ethyl acetate (100 mL) to give 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid ester 26d (4.5 g, yield: 93.8%).

[0741] MS m / z (ESI): 325.1 [M+H] +

[0742] Step 4

[0743] 7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide

[0744] 7-Chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide

[0745] 4-(trifluoromethyl)benzenesulfonamide 2i (1 g, 4.44 mmol) and 7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid 26d (1.73 g, 5.33 mmol) were dissolved in dichloromethane (30 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.28 g, 6.66 mmol) and 4-dimethylaminopyridine (813.79 mg, 6.66 mmol) were added. The mixture was reacted at room temperature for 12 hours. LCMS showed that the reaction was complete. The reaction solution was added to 1M hydrochloric acid water (200 mL), extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with methanol (50 mL) to give 7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide 26e (1.8 g, yield: 76.2%).

[0746] MS m / z(ESI): 348.0 [M+H] +

[0747] Step 5

[0748] (E)-7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carbimidoyl chloride

[0749] (E)-7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboximide chloride

[0750] 7-Chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide 26e (500 mg, 0.94 mmol) was dissolved in chlorobenzene (15 mL), and phosphorus pentachloride (391 mg, 1.88 mmol) was added. The mixture was reacted at 130 °C for 1 hour. TLC showed that the starting material reacted completely. The reaction solution was concentrated under reduced pressure to give (E)-7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboximide acyl chloride 26f (517 mg), which was directly used in the next step of the reaction.

[0751] Step 6

[0752] N-((E)-N'-((E)-(7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0753] N-((E)-N'-(E)-(7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0754] (E)-7-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboximide chloride 26f (517 mg, 0.93 mmol) was dissolved in dichloromethane (20 mL), and N-acetylguanidine 1j (380 mg, 3.76 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by reversed-phase column chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain N-((E)-N'-(E)-(7-chloro-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 26 (111.66mg, yield: 19.3%).

[0755] MS m / z (ESI): 615.2 [M+H] +

[0756] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.61-8.19(m,2H),8.13-8.02(m,2H),7.93-7.83(m,2H),7.62-7.52(m,3 H),7.50-7.45(m,1H),7.43-7.36(m,2H),7.16-7.09(m,1H),6.61-6.55(m,1H),3.04-2.91(m,4H),2.06(s,3H).

[0757] Example 27

[0758] N-((E)-N'-((E)-(8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0759] N-((E)-N'-(E)-(8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanediamine)acetamide

[0760] first step

[0761] (E)-5-(3-chlorophenyl)pent-4-enoic acid

[0762] (E)-5-(3-chlorophenyl)pent-4-enoic acid

[0763] (3-Propylcarboxy)triphenylphosphine bromide 27b (61.08 g, 142.28 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL). Potassium tert-butoxide (39.91 g, 355.70 mmol) was added under nitrogen protection in an ice bath. After reacting the mixture in an ice bath for 1 hour, 3-chlorobenzaldehyde 27b (20 g, 142.28 mmol) was added dropwise. The mixture was then reacted at room temperature for 16 hours. TLC showed that the starting material reacted completely. The reaction solution was adjusted to neutral pH by adding 1 M hydrochloric acid solution in an ice bath. The mixture was extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-5-(3-chlorophenyl)pent-4-enoic acid 27c (27.6 g, yield: 92%).

[0764] Step 2

[0765] 5-(3-chlorophenyl)pentanoic acid

[0766] 5-(3-Chlorophenyl)valerate

[0767] (E)-5-(3-chlorophenyl)pentan-4-enoic acid 27c (25.8 g, 122.47 mmol) was dissolved in ethyl acetate (300 mL), and palladium on carbon (2.58 g, 10% purity) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. LC-MS showed that the reaction was complete. The mixture was filtered through diatomaceous earth and washed with ethyl acetate (300 mL × 2). The filtrate was concentrated under reduced pressure to give 5-(3-chlorophenyl)pentanic acid 27d (25.7 g), which was used directly in the next reaction.

[0768] Step 3

[0769] 2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

[0770] 2-Chloro-6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-one

[0771] 27d of 5-(3-chlorophenyl)valerate (24.7 g, 116.14 mmol) was dissolved in polyphosphoric acid (300 mL), and the mixture was reacted at 140 °C for 1 hour. TLC showed that the reaction was complete. The reaction mixture was added to an aqueous sodium hydroxide solution (200 mL, 1 M), extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]anthren-5-one 27e (7.6 g, yield: 33.6%).

[0772] Step 4

[0773] methyl 2-(2-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-2-oxoacetate

[0774] 2-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]arunnel-5-one 27e (3 g, 15.41 mmol) and dimethyl oxalate 3b (2.73 g, 23.12 mmol) were dissolved in anhydrous tetrahydrofuran (60 mL). Bistrimethylsilylaminolithium (1 M, 30.82 mL) was added dropwise under nitrogen protection in an ice bath. The mixture was stirred in an ice bath for 0.5 hours, and then the reaction was carried out at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain methyl 2-(2-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]arunnel-6-yl)-2-oxoacetate 27f (4.3 g), which was directly used in the next step of the reaction.

[0775] Step 5

[0776] methyl 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate

[0777] methyl 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxylate

[0778] 2-(2-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)-2-oxoacetic acid methyl ester 27f (4.3 g, 15.32 mmol) was dissolved in acetic acid (100 mL), and phenylhydrazine 3d (3.31 g, 30.64 mmol) was added. The mixture was reacted at 100 °C for 1 hour. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was adjusted to pH 8 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (500 mL x 3). The organic phases were combined, washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to give 27 g (5.4 g) of methyl 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxylate, which was directly used in the next reaction.

[0779] Step 6

[0780] 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic acid

[0781] 8-Chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxylic acid

[0782] 27 g (5.4 g, 15.31 mmol) of methyl 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic acid was dissolved in methanol (10 mL), tetrahydrofuran (40 mL), and water (10 mL). Potassium hydroxide (1.29 g, 22.96 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The pH of the reaction mixture was adjusted to 2 with 1 M HCl, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 27 h (4.5 g) of 8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic acid. The crude product was used directly in the next step.

[0783] Step 7

[0784] 8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide

[0785] 8-Chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxamide

[0786] 8-Chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxylic acid 27h (4.5 g, 13.28 mmol) and 4-(trifluoromethyl)benzenesulfonamide 2i (3.28 g, 14.58 mmol) were dissolved in dichloromethane (100 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 3.49 g, 18.23 mmol) and 4-dimethylaminopyridine (2.23 g, 18.23 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was added to 1M hydrochloric acid aqueous solution (500 mL), extracted with dichloromethane (200 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboxamide 27i (1.1 g, yield: 16.5%).

[0787] MS m / z (ESI): 546.1 [M+1] +

[0788] Step 8

[0789] (E)-8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carbimidoyl chloride

[0790] (E)-8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazole-3-carboximide chloride

[0791] 8-Chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 27i (500 mg, 0.91 mmol) was dissolved in chlorobenzene (10 mL), and phosphorus pentachloride (381 mg, 1.83 mmol) was added. The mixture was reacted at 100 °C for 4 hours. TLC showed that the starting material disappeared. The reaction solution was concentrated under reduced pressure to give (E)-8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboximide acyl chloride 27j (500 mg), which was directly used in the next step of the reaction.

[0792] Step 9

[0793] N-((E)-N'-((E)-(8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0794] N-((E)-N′-(E)-(8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethanediamine)acetamide

[0795] (E)-8-chloro-1-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboximide chloride 27j (500 mg, 0.88 mmol) was dissolved in dichloromethane (2 mL), and N-acetylguanidine 1j (358 mg, 3.54 mmol) was added. The mixture was stirred and reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase preparation (Waters 2767 / QDA, separation column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min) to give N-((E)-N'-(E)-(8-chloro-1-phenyl-1,4,5,6-tetrahydrobenzo[6,7]cycloheptane[1,2-c]pyrazol-3-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethamidinyl)acetamide 27 (197.6mg, yield: 35.4%).

[0796] MS m / z (ESI): 615.2 [M+H] +

[0797] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.78-8.32(m,2H),8.09-8.00(m,2H),7.90-7.82(m,2H),7.57-7.5 1(m,1H),7.48-7.35(m,3H),7.25-7.12(m,3H),6.66-6.59(m,1H),2.76-2.67(m,4H),2.18-2.03(m,5H).

[0798] Example 28

[0799] (Z)-N-((E)-amino(3-methylureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0800] (Z)-N-((E)-amino(3-methylureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0801] first step

[0802] tert-butyl(NE)-N-[(tert-butoxycarbonylamino)-(methylcarbamoylamino)methylene]carbamate

[0803] (NE)-N-[(tert-Butoxycarbonylamino)-(methylcarbamoyl)methylene]tert-butyl carbamate

[0804] 1,3-Di(tert-butoxycarbonyl)guanidine 28a (5.00 g, 19.28 mmol) and triethylamine (5.85 g, 57.85 mmol) were dissolved in dichloromethane (50 mL), and a dichloromethane (20 mL) solution of methylcarbamoyl chloride 28b (1.98 g, 21.21 mmol) was added dropwise. The mixture was reacted at room temperature under nitrogen protection for 6 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (NE)-N-[(tert-butoxycarbonylamino)-(methylcarbamoyl)methylene] tert-butyl carbamate 28c (5.7 g, yield: 93.4%).

[0805] Step 2

[0806] 1-carbamimidoyl-3-methyl-urea

[0807] 1-Carbamoyl-3-methylurea trifluoroacetate

[0808] (NE)-N-[(tert-Butoxycarbonylamino)-(methylcarbamoyl)methylene] tert-butyl carbamate 28c (2 g, 6.32 mmol) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (20 mL) was added under ice bath conditions. The mixture was reacted at room temperature for 16 hours. TLC showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to give 1-carbamoyl-3-methylurea trifluoroacetate 28d (1 g, yield: 68.7%).

[0809] Step 3

[0810] (Z)-N-((E)-amino(3-methylureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[0811] (Z)-N-((E)-amino(3-methylureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxamide

[0812] 1-Carbamoyl-3-methylurea trifluoroacetate 28d (480 mg, 2.09 mmol) and N,N-diisopropylethylamine (337 mg, 2.61 mmol) were dissolved in N,N-dimethylformamide (5 mL), and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.52 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: CAN; flow rate: 20 mL / min) to give (Z)-N-((E)-amino(3-methylureido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboxyoxime amide (106.75 mg, yield: 33.1%).

[0813] MS m / z (ESI): 618.2 [M+H] +

[0814] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.05-7.79(m,6H),7.27-7.20(m,5H),7.14-7.08(m ,2H),6.98-6.86(m,3H),6.56-6.51(m,1H),4.56(d,J=4.8Hz,2H),2.63(d,J=4.6Hz,3H).

[0815] Example 29

[0816] (S,Z)-2-(3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-1,6-dihydropyridazine-1-carboximidamido)-3-methylbutanamide

[0817] (S,Z)-2-(3-(4-chlorophenyl)-N'-((4-chlorobenzene)sulfonyl)-4-phenyl-1,6-dihydropyridazine-1-carboxamido)-3-methylbutyramide

[0818] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 15d (250 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-2-amino-3-methylbutyramide 17a (107.30 mg, 0.92 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed a product peak. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase preparation (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain (S,Z)-2-(3-(4-chlorophenyl)-N'-((4-chlorobenzene)sulfonyl)-4-phenyl-1,6-dihydropyridazine-1-carboxamido)-3-methylbutyramide 29 (42.23mg, yield: 15.6%).

[0819] MS m / z (ESI): 584.2 [M+H] +

[0820] 1 H NMR(400MHz,DMSO-d6)δ7.86(s,3H),7.69-7.50(m,3H),7.41-7.21(m,8H),7.09-7.0 1(m,2H),6.62-6.54(m,1H),4.81-4.04(m,3H),2.23-2.08(m,1H),0.93-0.75(m,6H).

[0821] Example 30

[0822] (Z)-N-((E)-amino(ureido)methylene)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenylpyridazine-1(6H)-carboximidamide

[0823] (Z)-N-((E)-amino(ureido)methylene)-3-(4-chlorophenyl)-N'-((4-chlorobenzene)sulfonyl)-4-phenylpyridazine-1(6H)-carboxyoxamide

[0824] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 15d (250 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 1-aminomethylguanidine 12a (70 mg, 0.69 mmol) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparation (Waters 2767 / Qda, separation column: Pursuit XRs 10C18, 21.2*250mm, 10um; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20ml / min) to obtain (S,Z)-2-(3-(4-chlorophenyl)-N'-((4-chlorobenzene)sulfonyl)-4-phenyl-1,6-dihydropyridazine-1-carboxamido)-3-methylbutyramide 30 (48mg, yield: 18.5%).

[0825] MS m / z (ESI): 570.2 [M+H] +

[0826] 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.37-7.75(m,4H),7.59-7.49(m,2H),7. 30-7.18(m,5H),7.16-6.82(m,5H),6.64-6.34(m,2H),4.55(d,J=4.8Hz,2H).

[0827] Example 31

[0828] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-hydroxypropanamide

[0829] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-hydroxypropionamide

[0830] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-2-amino-3-hydroxypropionamide hydrochloride 31a (244 mg, 1.74 mmol) and N,N-diisopropylethylamine (449 mg, 3.48 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction solution was extracted with water (200 mL) and ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-hydroxypropionamide (49 mg, yield: 9.4%).

[0831] MS m / z (ESI): 606.1 [M+H] +

[0832] 1 H NMR (400MHz, DMSO-d6) δ8.31-8.18(m,1H),8.14-8.02(m,2H),7.93-7.85(m,2H),7.61(s,1H),7.50-7. 16(m,9H),7.08-7.00(m,2H),6.56(t,J=4.9Hz,1H),5.15(s,1H),4.65-4.33(m,3H),3.86-3.66(m,2H).

[0833] Example 32

[0834] (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-hydroxybutanamide

[0835] (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-hydroxybutyramide

[0836] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (2S,3R)-2-amino-3-hydroxybutyramide hydrochloride 32a (268 mg, 1.74 mmol) and N,N-diisopropylethylamine (449 mg, 3.48 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction solution was extracted with water (200 mL) and ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase chromatography (Waters 2767 / Qda, column: Pursuit XRs 10 C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-hydroxybutyramide 32 (84 mg, yield: 15.6%).

[0837] MS m / z (ESI): 620.3 [M+H] +

[0838] 1 H NMR(400MHz,DMSO-d6)δ8.11-8.01(m,2H),7.92-7.88(m,2H),7.46(s,1H),7.37-7.17(m,9H),7.07- 7.01(m,2H),6.58(t,J=4.9Hz,1H),5.33-5.24(m,1H),4.66-4.28(m,3H),4.19(s,1H),1.04(s,3H).

[0839] Example 33

[0840] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)cyclopropanecarboxamide

[0841] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoformamidinyl)cyclopropaneformamide

[0842] first step

[0843] tert-butyl(NE)-N-[(tert-butoxycarbonylamino(cyclopropanecarbonylamino)methylene]carbamate

[0844] tert-Butyl(NE)-N-[(tert-Butoxycarbonylamino)-(cyclopropanecarbonylamino)methylene]carbamate

[0845] 1.01 g (3.86 mmol) of tert-butyl N-[amino-(tert-butoxycarbonylamino)methyl]carbamate 28a was dissolved in dichloromethane (10 mL), and triethylamine (1.17 g, 11.59 mmol) and cyclopropane carbonyl chloride 33a (525 mg, 5.02 mmol) were added. The mixture was reacted at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl(NE)-N-[(tert-butoxycarbonylamino)-(cyclopropane carbonylamino)methylene]carbamate 33b (0.88 g, yield: 69.5%). MS m / z (ESI): 328.1 [M+H] +

[0846] Step 2

[0847] N-carbamimidoylcyclopropanecarboxamide chloride

[0848] N-ureidylimide cyclopropaneformamide

[0849] tert-butyl(NE)-N-[(tert-butoxycarbonylamino)-(cyclopropanecarbonylamino)methylene]carbamate 33b (680 mg, 2.08 mmol) was dissolved in a solution of trifluoroacetic acid (10 mL) and dichloromethane (20 mL), and the mixture was reacted at room temperature for 16 hours. TLC showed the reaction was complete, and the reaction solution was concentrated under reduced pressure to give N-ureidylcyclopropaneamide chloride 33c (990 mg), which was used directly in the next step.

[0850] MS m / z (ESI): 128.2 [M+H] +

[0851] Step 3

[0852] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)cyclopropanecarboxamide

[0853] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoformamidinyl)cyclopropaneformamide

[0854] N-ureidocyclopropaneamide chloride 33c (265 mg, 2.09 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.52 mmol) and N,N-diisopropylethylamine (337 mg, 2.61 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction mixture was extracted with water (30 mL x 3) and ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethamidinyl)cyclopropaneformamide 33 (93 mg, yield: 28.4%).

[0855] MS m / z (ESI): 629.3 [M+H] +

[0856] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.52-7.89(m,4H),7.87-7.80(m,2H),7.27-7.20(m,5H),7.11-7.0 3(m,2H),7.00-6.93(m,2H),6.56-6.50(m,1H),4.67-4.52(m,2H),2.05-1.92(m,1H),0.98-0.85(m,4H).

[0857] Example 34

[0858] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)-1-methyl-1H-pyrazole-4-carboxamide

[0859] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimino)-1-methyl-1H-pyrazole-4-carboxamide

[0860] first step

[0861] 1-methyl-1H-pyrazole-4-carbonyl chloride

[0862] 1-Methyl-1H-pyrazole-4-carbonyl chloride

[0863] 1-Methyl-1H-pyrazole-4-carboxylic acid 34a (5 g, 39.65 mmol) was dissolved in thionyl chloride (20 mL) under ice bath conditions, and the mixture was reacted at 70 °C for 1 hour under nitrogen protection. The reaction solution was cooled and concentrated under reduced pressure to give 1-methyl-1H-pyrazole-4-carbonyl chloride 34b (5.6 g, yield: 97.7%).

[0864] Step 2

[0865] tert-butyl(NZ)-N-[(tert-butoxycarbonylamino)-[(1-methylpyrazole-4-carbonyl)amino]methylene]carbamate

[0866] (NZ)-N-[(tert-Butoxycarbonylamino)-[(1-Methylpyrazole-4-carbonyl)amino]methylene]tert-butyl carbamate

[0867] N-(N-tert-Butoxycarbonylcarbamoyl)carbamate tert-butyl ester 28a (1 g, 3.86 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.61 mL, 11.57 mmol) was added. Under nitrogen protection and an ice bath, a solution of 1-methyl-1H-pyrazole-4-carbonyl chloride 34b (836 mg, 5.78 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was reacted at room temperature for 6 hours. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (NZ)-N-[(tert-Butoxycarbonylamino)-[(1-methylpyrazole-4-carbonyl)amino]methylene]carbamate tert-butyl ester 34c (850 mg, yield: 59.9%).

[0868] MS m / z (ESI): 368.2 [M+H] +

[0869] Step 3

[0870] N-carbamimidoyl-1-methyl-1H-pyrazole-4-carboxamide

[0871] N-Carbamoyl-1-methyl-1H-pyrazole-4-carboxamide

[0872] (NZ)-N-[(tert-Butoxycarbonylamino)-[(1-methylpyrazole-4-carbonyl)amino]methylene]carbamate tert-butyl ester 34c (850 mg, 2.31 mmol) was dissolved in dichloromethane (32 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature for 16 hours. TLC showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to give trifluoroacetate (600 mg) of N-carbamoyl-1-methyl-1H-pyrazole-4-carboxamide 34d, which was used directly in the next step of the reaction.

[0873] Step 4

[0874] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)-1-methyl-1H-pyrazole-4-carboxamide

[0875] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimino)-1-methyl-1H-pyrazole-4-carboxamide

[0876] The trifluoroacetate of N-carbamoyl-1-methyl-1H-pyrazole-4-carboxamide 34d (587 mg, 2.09 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (337 mg, 2.61 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.52 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimino)-1-methyl-1H-pyrazole-4-carboxamide 34 (88.18 mg, yield: 25.2%).

[0877] MS m / z (ESI): 669.3 [M+H] +

[0878] 1 HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.45(s,1H),8.25-7.93(m,4H),7.85-7.77(m,2H) ,7.37-7.02(m,8H),6.89-6.80(m,2H),6.61-6.51(m,1H),4.63-4.55(m,2H),3.81(s,3H).

[0879] Example 35

[0880] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-2-cyclopropylacetamide

[0881] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetamide

[0882] first step

[0883] methyl(S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-2-cyclopropylacetate

[0884] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetate methyl ester

[0885] (S)-2-amino-2-cyclopropylacetate methyl hydrochloride 35a (161 mg, 1.25 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (404 mg, 3.13 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (600 mg, 1.04 mmol) were added. The mixture was reacted at room temperature for 16 hours, and the reaction was shown to be complete by LCMS. The reaction mixture was added with water (100 mL), extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetic acid methyl ester 35b (670 mg, yield: 100%).

[0886] MS m / z(ESI): 631.0 [M+H] +

[0887] Step 2

[0888] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-2-cyclopropylacetamide

[0889] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetamide

[0890] Ammonium chloride (398 mg, 7.45 mmol) was added to toluene (10 mL), and trimethylaluminum (2 M, 3.72 mL) was added dropwise under nitrogen protection in an ice bath. After the mixture reacted at room temperature for 2 hours, methyl (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetate 35b (470 mg, 0.74 mmol) was added, and the mixture was reacted at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched with water (100 mL) in an ice bath, extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-2-cyclopropylacetamide 35 (135.94 mg, yield: 29.6%).

[0891] MS m / z (ESI): 616.1 [M+H] +

[0892] 1H NMR(400MHz,DMSO-d6)δ8.16-8.02(m,3H),7.94-7.87(m,2H),7.55(s,1H),7.41-7.23(m,8H),7.08-7.0 1(m,2H),6.61-6.55(m,1H),4.55-4.29(m,2H),4.15-3.89(m,1H),1.21-0.98(m,1H),0.54-0.21(m,4H).

[0893] Example 36

[0894] (Z)-1-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)cyclopropane-1-carboxamide

[0895] (Z)-1-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclopropane-1-carboxamide

[0896] (E)-4-chloro-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (6 mL), and 1-aminocyclopropane-1-carboxamide hydrochloride 36a (300 mg, 0.52 mmol) and N,N-diisopropylethylamine (202 mg, 1.57 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed a product peak. The reaction solution was added with water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. It was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclopropane-1-carboxamide 36 (105 mg, yield: 33.5%).

[0897] MS m / z (ESI): 602.1 [M+H] +

[0898] 1 H NMR(400MHz,DMSO-d6)δ8.83-8.33(m,1H),8.07-8.02(m,2H),7.91-7.82(m,2H),7.64-7.42(m,3H),7 .35-7.21(m,6H),7.06-7.00(m,2H),6.60-6.56(m,1H),4.49(s,2H),1.22-0.96(m,2H),0.78(s,2H).

[0899] Example 37

[0900] N-((E)-N'-((E)-(1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0901] N-((E)-N'-((E)-(1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-yl)(((4-(trifluoromethyl)phenyl)thio)amino)methyl)carbamate acetylacetamide

[0902] first step

[0903] methyl(E)-3-((4-chlorophenyl)amino)but-2-enoate

[0904] (E)-3-((4-chlorophenyl)amino)but-2-enoic acid methyl ester

[0905] 4-Chloroaniline 37a (5 g, 39.19 mmol) and indium tribromide (138 mg, 0.39 mmol) were dissolved in methyl acetoacetate 37b (5.01 g, 43.11 mmol) and stirred at room temperature for 3 hours. LCMS showed a product peak. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-3-((4-chlorophenyl)amino)but-2-enoic acid methyl ester 37c (7 g, yield: 79.1%).

[0906] MS m / z (ESI): 226.1 [M+H] +

[0907] Step 2

[0908] methyl 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazole-4-carboxylate

[0909] methyl 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carboxylate

[0910] Methyl (E)-3-((4-chlorophenyl)amino)but-2-enoate 37c (5 g, 22.16 mmol) and benzylamine 37d (4.75 g, 44.31 mmol) were dissolved in N,N-dimethylacetamide (10 mL), and sodium bicarbonate (1.86 g, 22.16 mmol), copper acetate monohydrate (884.69 mg, 4.43 mmol), tert-butyl hydroperoxide (3.99 g, 44.31 mmol), and iodine (5.62 g, 22.16 mmol) were added. The mixture was reacted at room temperature under nitrogen protection for 12 hours. LCMS showed that the reaction was complete. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (200 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carboxylate 37e (3 g, yield: 41.4%).

[0911] MS m / z (ESI): 327.2 [M+H] +

[0912] Step 3

[0913] 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazole-4-carboxylic acid

[0914] 1-(4-Chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-carboxylic acid

[0915] Methyl 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carboxylic acid 37e (5 g, 15.30 mmol) was dissolved in methanol (25 mL) and water (25 mL), and sodium hydroxide (1.22 g, 30.60 mmol) was added. The reaction was carried out at room temperature for 4 hours. LC-MS showed that the reaction was complete. The reaction solution was slowly poured into water (100 mL), and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was extracted with dichloromethane (100 mL * 3), and the organic layer was collected. The residue was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carboxylic acid 37f (2.1 g, yield: 68.5%).

[0916] MS m / z (ESI): 313.1 [M+H] +

[0917] Step 4

[0918] 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazole-4-carbonyl chloride

[0919] 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-carbonyl chloride

[0920] 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carboxylic acid 37f (1.6 g, 5.12 mmol) was dissolved in dichloromethane (15 mL), and oxaloyl chloride (1.30 mL, 15.35 mmol) and N,N-dimethylformamide (0.1 mL) were added under nitrogen protection in an ice bath. The reaction was carried out at room temperature for 1 hour. LC-MS showed that the reaction was complete. The solution was concentrated under reduced pressure to give 37 g (1.6 g) of 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carbonyl chloride, which was used directly in the next step of the reaction.

[0921] Step 5

[0922] 1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazole-4-carboxamide

[0923] 1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboxamide

[0924] 37 g (1.6 g, 4.83 mmol) of 1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazolium-4-carbonyl chloride was dissolved in anhydrous dichloromethane (15 mL). 2 i (1.63 g, 7.25 mmol) of 4-(trifluoromethyl)benzenesulfonamide and N,N-diisopropylethylamine (1.87 g, 14.49 mmol) were added under nitrogen protection in an ice bath, and the reaction was carried out at room temperature for 4 hours. LC-MS showed the reaction was complete. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboxamide 37 h (900 mg, yield: 35.8%). MS m / z (ESI): 520.1 [M+H] +

[0925] Step 6

[0926] (E)-1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazole-4-carbimidoyl chloride

[0927] (E)-1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboximide chloride

[0928] 1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboxamide 37h (500 mg, 0.96 mmol) was dissolved in toluene (50 mL), and phosphorus pentachloride (1.00 g, 4.81 mmol) was added. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboximide acyl chloride 37i (500 mg), which was directly used in the next step of the reaction. MS m / z (ESI): 313.1 [M+H] +

[0929] Step 7

[0930] N-((E)-N'-((E)-(1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0931] N-((E)-N'-((E)-(1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-yl)(((4-(trifluoromethyl)phenyl)thio)amino)methyl)carbamate acetylacetamide

[0932] (E)-1-(4-chlorophenyl)-5-methyl-2-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-imidazol-4-carboximide chloride 37i (500 mg, 0.92 mmol) was dissolved in anhydrous dichloromethane (10 mL), and N-acetylguanidine 1j (469 mg, 4.64 mmol) was added. The reaction was carried out under nitrogen protection at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give N-((E)-N'-((E)-(1-(4-chlorophenyl)-5-methyl-2-phenyl-1H-imidazol-4-yl)(((4-(trifluoromethyl)phenyl)thio)amino)methyl)carbamate acetylacetamide 37 (150 mg, yield: 25.4%).

[0933] MS m / z (ESI): 604.1 [M+H] +

[0934] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.07(d,J=8.1Hz,2H),7.86(d,J=8.2Hz,2H),7.67-7.58(m,2H ),7.39-7.31(m,2H),7.31-7.21(m,3H),7.16(dq,J=6.8,2.7,2.2Hz,2H),2.37(s,3H),2.08(s,3H).

[0935] Example 38

[0936] N-[(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-3H-pyridazin-2-yl]-N-[4-(trifluoromethyl)phenyl]sulfonyl-carbonimidoyl]carbamimidoyl]-1-methyl-cyclopropanecarboxamide

[0937] N-[(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-3H-pyridazin-2-yl]-N-[4-(trifluoromethyl)phenyl]sulfonylcarbonyl]aminoformamido]-1-methylcyclopropaneformamide

[0938] first step

[0939] tert-butylN-[N-(1-methylcyclopropanecarbonyl)carbamimidoyl]carbamate

[0940] N-[N-(1-methylcyclopropanecarbonyl)carbamoyl]tert-butyl carbamate

[0941] 1-Methylcyclopropane-1-carboxylic acid 38a (5 g, 49.94 mmol) was dissolved in dichloromethane (10 mL), and tert-butyl N-[amino-(tert-butoxycarbonylamino)methyl]carbamate 28a (7.95 g, 49.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.36 g, 74.91 mmol) and 4-dimethylaminopyridine (9.15 g, 74.91 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was confirmed to be complete by LCMS. The reaction mixture was added to citric acid solution (300 mL), extracted with dichloromethane (200 mL x 4), and the organic phase was collected. The mixture was washed with sodium bicarbonate (200 mL x 3) and saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give N-[N-(1-methylcyclopropanecarbonyl)carbamoyl]tert-butyl carbamate 38b (4.8 g, yield: 39.8%). MS m / Z (ESI): 242.2 [M+H] +

[0942] Step 2

[0943] N-carbamimidoyl-1-methylcyclopropane-1-carboxamide

[0944] N-aminocarbamoyl-1-methylcyclopropane-1-formamide

[0945] N-[N-(1-methylcyclopropanecarbonyl)carbamoyl]tert-butyl carbamate 38b (1 g, 4.14 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain N-aminocarbamoyl-1-methylcyclopropane-1-carboxamide 38c (1.5 g), which was directly used in the next step of the reaction.

[0946] MS m / Z(ESI): 142.2 [M+H] +

[0947] Step 3

[0948] N-[(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-3H-pyridazin-2-yl]-N-[4-(trifluoromethyl)phenyl]sulfonyl-carbonimidoyl]carbamimidoyl]-1-methyl-cyclopropanecarboxamide

[0949] N-[(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-3H-pyridazin-2-yl]-N-[4-(trifluoromethyl)phenyl]sulfonylcarbonyl]aminoformamido]-1-methylcyclopropaneformamide

[0950] N-aminocarbamoyl-1-methylcyclopropane-1-carboxamide 38c (500 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (112 mg, 0.87 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (50 mg, 0.086 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction solution was added with water (60 mL x 3), extracted with ethyl acetate (60 mL x 3), the organic phases were combined, washed with saturated brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to obtain N-[(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-3H-pyridazin-2-yl]-N-[4-(trifluoromethyl)phenyl]sulfonylcarbonyl]aminoformamido]-1-methylcyclopropaneformamide (57.48 mg, 89.38 mmol).

[0951] MS m / Z (ESI): 643.2 [M+H] +

[0952] 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.62-7.63(m,6H),7.30-7.18(m,5H),7.13-7.06(m,2H),7.0 0-6.93(m,2H),6.57-6.50(m,1H),4.59(s,2H),1.31(s,3H),1.14-1.08(m,2H),0.75-0.69(m,2H).

[0953] Example 39

[0954] (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-4-methylpentanamide

[0955] (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanamide

[0956] first step

[0957] methyl(R)-3-amino-4-methylpentanoate

[0958] (R)-3-amino-4-methylpentanoate methyl ester

[0959] (R)-3-amino-4-methylpentanoic acid 39a (4 g, 30.49 mmol) was dissolved in methanol (50 mL), and thionyl chloride (7.30 mL, 100.63 mmol) was added under ice bath conditions. The mixture was reacted at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give methyl (R)-3-amino-4-methylpentanoic acid 39b (4.4 g), which was used directly in the next step of the reaction.

[0960] Step 2

[0961] methyl(R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-4-methylpentanoate

[0962] (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanoate methyl ester

[0963] Methyl (R)-3-amino-4-methylpentanoate 39b (303 mg, 2.09 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (674 mg, 5.22 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (600 mg, 1.04 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanoate 39c (420 mg, yield: 62.1%).

[0964] MS m / z (ESI): 647.2 [M+H] +

[0965] Step 3

[0966] (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-4-methylpentanamide

[0967] (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanamide

[0968] Under nitrogen protection and an ice bath, trimethylaluminum (2M, 2.47mL) was added to a toluene (10mL) solution of ammonium chloride (264mg, 4.95mmol). After stirring the mixture at room temperature for 2 hours, methyl (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanoate 39c (320mg, 0.49mmol) was added. The mixture was then reacted at 50°C for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched with water (100 mL) in an ice bath, extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (R,Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-4-methylpentanamide 39 (36.92 mg, yield: 11.8%).

[0969] MS m / z (ESI): 632.1 [M+H] +

[0970] 1 H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.10-8.02(m,2H),7.96-7.86(m,2H),7.62 -7.51(m,1H),7.49-7.36(m,2H),7.35-7.21(m,5H),7.18-7.07(m,1H),7.07-6.9 8(m,2H),6.60-6.51(m,1H),4.65-4.52(m,1H),4.41-4.26(m,1H),4.07-3.84(m, 1H),2.56-2.52(m,1H),2.46-2.36(m,1H),1.87-1.75(m,1H),0.85-0.69(m,6H).

[0971] Example 40

[0972] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide

[0973] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide

[0974] first step

[0975] benzyl 4-sulfamoylpiperidine-1-carboxylate

[0976] Benzyl 4-aminosulfonylpiperidine-1-carboxylic acid ester

[0977] 4-(chlorosulfonyl)piperidine-1-carboxylate benzyl ester 40a (4.5 g, 14.16 mmol) was dissolved in tetrahydrofuran (10 mL), and ammonia water (10 mL, 141.60 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was then extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-aminosulfonylpiperidine-1-carboxylate benzyl ester 40b (3 g, yield: 71.0%).

[0978] Step 2

[0979] piperidine-4-sulfonamide

[0980] Piperidine-4-sulfonamide

[0981] Benzyl 4-aminosulfonylpiperidine-1-carboxylate 40b (3 g, 10.06 mmol) was dissolved in ethanol (30 mL), and palladium on carbon (300 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. TLC showed that the reaction was complete. The reaction mixture was filtered through a diatomaceous earth filter and washed with methanol (50 mL × 2). The filtrate was concentrated to obtain piperidine-4-sulfonamide 40c (2 g), which was used directly in the next step of the reaction.

[0982] Step 3

[0983] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide

[0984] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide

[0985] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (350 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (2 mL), and piperidine-4-sulfonamide 40c (399 mg, 2.44 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide (246.78 mg, yield: 60.8%).

[0986] MS m / z (ESI): 666.1 [M+H] +

[0987] 1 H NMR(400MHz,DMSO-d6)δ8.07-8.01(m,2H),7.94-7.88(m,2H),7.37-7.28(m,4H),7.28-7.21(m,3H),7.10-7.03(m,2H),6.8 8(s,2H),6.54-6.48(m,1H),4.32-4.25(m,2H),3.97-3.87(m,2H),3.31-3.14(m,3H),2.15-2.06(m,2H),1.88-1.73(m,2H).

[0988] Example 41

[0989] (Z)-3-amino-3-(((Z)-(3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)imino)propanamide

[0990] (Z)-3-amino-3-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)iminopropionamide

[0991] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (850 mg, 1.48 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (764 mg, 5.91 mmol) and malonylamidine hydrochloride 41a (406 mg, 2.96 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give (Z)-3-amino-3-((Z)-(3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)iminopropionamide 41 (70 mg, yield: 7.8%).

[0992] MS m / z (ESI): 603.4 [M+H] +

[0993] 1 HNMR(400MHz,DMSO-d6)δ8.05-7.96(m,2H),7.90-7.83(m,2H),7.71-7.44(m,3H), 7.28-7.14(m,8H),7.04-6.95(m,2H),6.58-6.51(m,1H),4.61(s,2H),3.02(s,2H).

[0994] Example 42

[0995] (Z)-4-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperazine-1-sulfonamide

[0996] (Z)-4-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperazine-1-sulfonamide

[0997] first step

[0998] tert-butyl 4-sulfamoylpiperazine-1-carboxylate

[0999] 4-Aminosulfonylpiperazine-1-carboxylic acid tert-butyl ester

[1000] Piperazine-1-carboxylate tert-butyl ester 24b (1 g, 5.37 mmol) was dissolved in 1,4-dioxane (30 mL), and sulfonamide 24e (2.58 g, 26.85 mmol) was added. The mixture was reacted at 110 °C for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 4-aminosulfonylpiperazine-1-carboxylate tert-butyl ester 42a (1.4 g, yield: 98.2%).

[1001] Step 2

[1002] piperazine-1-sulfonamide

[1003] Piperazine-1-sulfonamide

[1004] 4-Aminosulfonylpiperazine-1-carboxylic acid tert-butyl ester 42a (500 mg, 1.88 mmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for 16 hours. TLC showed that the starting material disappeared. The reaction solution was concentrated under reduced pressure to give piperazine-1-sulfonamide trifluoroacetate 42b (520 mg), which was used directly in the next step of the reaction.

[1005] Step 3

[1006] (Z)-4-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperazine-1-sulfonamide

[1007] (Z)-4-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperazine-1-sulfonamide

[1008] Piperazine-1-sulfonamide trifluoroacetate 42b (510 mg, 1.83 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (350 mg, 0.61 mmol) and N,N-diisopropylethylamine (393 mg, 3.04 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparation (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-4-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperazine-1-sulfonamide 42 (185 mg, yield: 45.6%).

[1009] MS m / z (ESI): 615.2 [M+H] +

[1010] 1 H NMR(400MHz,DMSO-d6)δ8.09-8.02(m,2H),7.94-7.88(m,2H),7.37-7.30(m,4H),7.28-7.22(m,3H),7.1 2-7.05(m,2H),6.97(s,2H),6.55-6.51(m,1H),4.32-4.24(m,2H),3.70-3.61(m,4H),3.20-3.11(m,4H).

[1011] Example 43

[1012] (Z)-N-((E)-amino(2-oxoazetidin-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[1013] (Z)-N-((E)-amino(2-oxoazacyclobutane-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H-formamidinium)

[1014] first step

[1015] (Z)-3-(2,3-bis((benzyloxy)carbonyl)guanidino)propanoic acid

[1016] (Z)-3-(2,3-bis(benzyloxy)carbonyl)guanidinyl)propionic acid

[1017] (E)-(((benzyloxy)carbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate benzyl ester 43a (5 g, 13.21 mmol) was dissolved in acetonitrile (66 mL) and water (11 mL), and β-alanine 43b (4.71 g, 52.86 mmol) was added. The mixture was reacted at 55 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added again. The pH was adjusted to 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated saline solution (200 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (Z)-3-(2,3-bis(benzyloxy)carbonyl)guanidinyl)propionic acid 43c (5.6 g), which was used directly in the next reaction.

[1018] MS m / z (ESI): 400.3 [M+H] +

[1019] Step 2

[1020] benzyl(E)-(((benzyloxy)carbonyl)amino)(2-oxoazetidin-1-yl)methylene)carbamate

[1021] (E)-(((benzyloxy)carbonyl)imino)(2-oxoazacyclobutane-1-yl)methyl)benzyl carbamate

[1022] (Z)-3-(2,3-bis(benzyloxy)carbonyl)guanidinyl)propionic acid 43c (5.6 g, 14.02 mmol) and N-methylmorpholine (4.25 g, 42.06 mmol) were dissolved in dichloromethane (99.88 mL), and isobutyl chloroformate (2.30 g, 16.83 mmol) was added dropwise under nitrogen protection at -20 °C. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, followed by 1 M hydrochloric acid aqueous solution (100 mL). The mixture was extracted with dichloromethane (80 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (E)-(((benzyloxy)carbonyl)imino)(2-oxozycyclobutane-1-yl)methyl)carbamate 43d (2.6 g, yield: 48.6%).

[1023] MS m / z(ESI): 382.1 [M+H] +

[1024] Step 3

[1025] 2-oxoazetidine-1-carboximidamide

[1026] 2-Oxazonicyclobutane-1-formimide

[1027] (E)-(((benzyloxy)carbonyl)imino)(2-oxazolidinyl-1-yl)methyl)carbamate 43d (2.2 g, 5.77 mmol) was dissolved in dichloromethane (30 mL), and trimethyliodosilane (2.65 g, 13.27 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with methanol (10 mL), concentrated under reduced pressure, and then ethyl acetate (10 mL) was added. The mixture was filtered, the filter cake was collected, and dried to give 2-oxazolidinyl-1-formimide 43e (840 mg), which was used directly in the next reaction.

[1028] MS m / z (ESI): 114.2 [M+H] +

[1029] Step 4

[1030] (Z)-N-((E)-amino(2-oxoazetidin-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboximidamide

[1031] (Z)-N-((E)-amino(2-oxoazacyclobutane-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H-formamidinium)

[1032] 2-oxoazacyclobutane-1-carboximide 43e (393 mg, 3.48 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (1.12 g, 8.70 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (1 g, 1.74 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-N-((E)-amino(2-oxoazacyclobutane-1-yl)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-formamidin 43 (103.39 mg, yield: 9.6%).

[1033] MS m / z (ESI): 615.3 [M+H] +

[1034] 1HNMR(400MHz,DMSO-d6)δ10.58(s,1H),8.15(s,1H),8.06-7.99(m,2H),7.87-7.80(m,2H),7.33-7.21(m,5H),7. 12-7.05(m,2H),7.01-6.93(m,2H),6.55-6.49(m,1H),4.63-4.54(m,2H),3.24-3.16(m,2H),2.45-2.37(m,2H).

[1035] Example 44

[1036] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azetidine-3-carboxamide

[1037] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azacyclobutane-3-carboxamide

[1038] Azacyclobutane-3-carboxamide hydrochloride 44a (62.70 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (269 mg, 2.09 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-iminoformyl chloride 1i (300 mg, 0.52 mmol) were added. The mixture was reacted at room temperature for 16 hours. LC-MS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azacyclobutane-3-carboxamide 44 (103 mg, yield: 32.9%). MS m / z (ESI): 602.4 [M+H] +

[1039] 1 H NMR (400MHz, DMSO-d6) δ8.09-8.02(m,2H),7.93-7.86(m,2H),7.55(s,1H),7.37-7.31(m,2H),7.29-7.22(m,5H ),7.14(s,1H),7.06-6.99(m,2H),6.53-6.47(m,1H),4.75-4.50(m,4H),4.38-4.33(m,2H),3.47-3.35(m,1H).

[1040] Example 45

[1041] (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3,3,3-trifluoropropanamide

[1042] (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3,3,3-trifluoropropionamide

[1043] first step

[1044] methyl(R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3,3,3-trifluoropropanoate

[1045] (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3,3,3-trifluoropropionate methyl ester

[1046] (R)-2-amino-3-3,3-trifluoropropionate methyl hydrochloride 45a (202 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (337 mg, 2.61 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.87 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was added with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was collected, washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3,3,3-trifluoropropionate 45b (370 mg, yield: 64.5%).

[1047] MS m / z (ESI): 659.3 [M+H] +

[1048] Step 2

[1049] 8-(2-chlorophenyl)-9-(4-chlorophenyl)-2-(methylsulfonyl)-6-(4-(trifluoromethyl)phenyl)-9H-purine

[1050] 8-(2-Chlorophenyl)-9-(4-Chlorophenyl)-2-(Methylsulfonyl)-6-(4-(trifluoromethyl)phenyl)-9H-purine

[1051] Ammonium chloride (259 mg, 4.86 mmol) was dissolved in toluene (8 mL). Trimethylaluminum (2 M, 2.43 mL) was added under a nitrogen atmosphere in an ice bath. After stirring the mixture at room temperature for 2 hours, methyl (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3,3,3-trifluoropropionate 45b (320 mg, 0.48 mmol) was added at -78 °C. The reaction mixture was stirred at 50 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (R,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3,3,3-trifluoropropionamide 45 (78.2 mg, yield: 25%).

[1052] MS m / z (ESI): 644.3 [M+H] +

[1053] 1 H NMR(400MHz,DMSO-d6)δ8.42-8.31(m,1H),8.26-8.17(m,1H),8.10-8.01(m,2H),7.99-7.89(m,3H),7.41-7 .32(m,4H),7.30-7.24(m,3H),7.12-7.01(m,2H),6.68-6.58(m,1H),5.37-5.17(m,1H),4.67-4.42(m,2H).

[1054] Example 46

[1055] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-carboxamide

[1056] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-carboxamide

[1057] first step

[1058] piperidine-4-carboxamide hydrochloride

[1059] Piperidine-4-carboxamide hydrochloride

[1060] 4-Carbamoylpiperidine-1-carboxylic acid tert-butyl ester 46a (2 g, 8.76 mmol) was dissolved in dichloromethane (20 mL), and hydrochloric acid / ethyl acetate (4 M, 20 mL) was added. The mixture was reacted at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give piperidine-4-carboxamide hydrochloride 46b (1.4 g), which was used directly in the next step of the reaction.

[1061] Step 2

[1062] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-carboxamide

[1063] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-carboxamide

[1064] Piperidine-4-carboxamide hydrochloride 46b (133 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (2 mL), and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 0.52 mmol) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 4 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction solution under ice bath, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with methanol (20 mL) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)piperidine-4-carboxamide 46 (222 mg, yield: 67.5%).

[1065] MS m / z (ESI): 630.2 [M+H] +

[1066] 1 H NMR(400MHz,DMSO-d6)δ8.06-.00(m,2H),7.94-7.86(m,2H),7.35-7.22(m,8H),7.09-7.02(m,2H),6.89-6.81(m,1H ),6.51-6.46(m,1H),4.33-4.24(m,2H),3.90-3.78(m,2H),3.29-3.15(m,2H),2.46-2.39(m,1H),1.87-1.65(m,4H).

[1067] Example 47

[1068] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazetidine-3-carboxamide

[1069] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxamide

[1070] first step

[1071] 1-(tert-butyl)3-methyl 3-methylazetidine-1,3-dicarboxylate

[1072] 1-(tert-butyl)-3-methyl ester of 3-methylazacyclobutane-1,3-dicarboxylic acid

[1073] 1-(tert-butyl)-3-methylazacyclobutane-1,3-dicarboxylate 47a (10 g, 46.46 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), and bis(trimethylsilylamine) lithium (1 M, 55.75 mL) was added under nitrogen protection at -78 °C. After stirring the mixture at -78 °C for 30 minutes, iodomethane (8.57 g, 60.40 mmol) was added, and the reaction mixture was reacted at room temperature for 16 hours. TLC showed the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution (600 mL) under ice bath conditions. The mixture was extracted with ethyl acetate (500 mL x 3), and the organic phase was collected. The mixture was washed with saturated brine (600 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 47b (4.8 g, yield: 45.0%) of 1-(tert-butyl)-3-methyl 3-methylazacyclobutane-1,3-dicarboxylic acid.

[1074] Step 2

[1075] methyl 3-methylazetidine-3-carboxylate hydrochloride

[1076] 3-Methylazacyclobutane-3-carboxylic acid methyl ester hydrochloride

[1077] 1.8 g (7.85 mmol) of 1-(tert-butyl)-3-methyl 3-methylazacyclobutane-1,3-dicarboxylic acid ester 47b was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid / dioxane (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The solution was directly concentrated under reduced pressure to give methyl 3-methylazacyclobutane-3-carboxylic acid ester hydrochloride 47c (800 mg), which was used directly in the next step of the reaction.

[1078] MS m / z (ESI): 130.3 [M+H] +

[1079] Step 3

[1080] methyl(Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazetidine-3-carboxylate

[1081] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxylic acid methyl ester

[1082] 47c of 3-methylazacyclobutane-3-carboxylic acid methyl ester hydrochloride (216 mg, 1.30 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (337 mg, 2.61 mmol) and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxylic acid methyl ester 47d (470 mg, yield: 85.6%).

[1083] MS m / z (ESI): 631.4 [M+H] +

[1084] Step 4

[1085] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazetidine-3-carboxamide

[1086] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxamide

[1087] Ammonium chloride (356 mg, 6.66 mmol) was added to toluene (10 mL), and trimethylaluminum (2 M, 3.33 mL) was added under nitrogen protection in an ice bath. After stirring the mixture at room temperature for 2 hours, methyl (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxylic acid methyl ester 47d (420 mg, 0.66 mmol) was added at -78 °C. The reaction mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (150 mL x 3), the organic phase was collected, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm*10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-methylazacyclobutane-3-carboxamide 47 (119 mg, yield: 29.1%).

[1088] MS m / z (ESI): 616.4 [M+H] +

[1089] 1 H NMR (400MHz, DMSO-d6) δ8.09-8.02(m,2H),7.94-7.87(m,2H),7.58-7.50(m,1H),7.38-7.32(m,2H),7.31-7.23(m ,5H),7.20-7.16(m,1H),7.05-6.99(m,2H),6.52-6.47(m,1H),4.79-4.66(m,2H),4.38-4.23(m,4H),1.52(s,3H).

[1090] Example 48

[1091] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazetidine-3-carboxamide

[1092] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxamide

[1093] first step

[1094] 1-(tert-butyl)3-methyl 3-cyanoazetidine-1,3-dicarboxylate

[1095] 3-Cyanozycyclobutane-1,3-dicarboxylic acid 1-(tert-butyl)-3-methyl ester

[1096] 48a of 3-cyanozycyclobutane-1-carboxylate 48a (5 g, 27.44 mmol) and methyl chloroformate (3.11 g, 32.93 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, lithium bis(trimethylsilylamine)ol (1 M, 41.16 mL) was added dropwise. The mixture was reacted at -78 °C for 2 hours, and TLC showed that the reaction was complete. The reaction solution was quenched by adding saturated ammonium chloride aqueous solution (100 mL) under ice bath conditions, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-cyanozycyclobutane-1,3-dicarboxylic acid 1-(tert-butyl)-3-methyl ester 48b (3.6 g, yield: 54.6%).

[1097] Step 2

[1098] methyl 3-cyanoazetidine-3-carboxylate hydrochloride

[1099] 3-Cyanozyne-butane-3-carboxylic acid methyl ester hydrochloride

[1100] 1 g (4.16 mmol) of 1-(tert-butyl)-3-methyl 3-cyanoazacyclobutane-1,3-dicarboxylic acid 48b was dissolved in 1,4-dioxane (10 mL). Hydrochloric acid / 1,4-dioxane (4 M, 10 mL) was added under ice bath conditions. The mixture was reacted at room temperature for 16 hours, and TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give 730 mg (3-cyanoazacyclobutane-3-carboxylic acid methyl ester hydrochloride) 48c, which was used directly in the next reaction step.

[1101] Step 3

[1102] methyl(Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazetidine-3-carboxylate

[1103] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxylic acid methyl ester

[1104] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 3-cyanoazacyclobutane-3-carboxylic acid methyl ester hydrochloride 48c (230 mg, 1.30 mmol) and potassium carbonate (360 mg, 2.61 mmol) were added. The mixture was reacted at 50 °C for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxylic acid methyl ester 48d (550 mg, yield: 98.4%).

[1105] MS m / z (ESI): 642.3 [M+H] +

[1106] Step 4 (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazetidine-3-carboxamide

[1107] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxamide

[1108] Ammonium chloride (374 mg, 7.01 mmol) was added to toluene (20 mL), and trimethylaluminum (2 M, 3.50 mL) was added under nitrogen protection in an ice bath. After stirring the mixture at room temperature for 2 hours, methyl (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxylic acid ester 48d (450 mg, 0.70 mmol) was added at -78 °C. The reaction mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched with water (200 mL), extracted with ethyl acetate (150 mL x 3), and the organic phase was collected. It was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm*10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-cyanoazacyclobutane-3-carboxamide 48 (56 mg, yield: 12.7%).

[1109] MS m / z (ESI): 627.3 [M+H] +

[1110] 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.10-8.04(m,2H),7.95-7.87(m,3H),7.37-7.2 3(m,7H),7.07-6.99(m,2H),6.55-6.49(m,1H),5.03-4.83(m,4H),4.46-4.38(m,2H).

[1111] Example 49

[1112] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluoroazetidine-3-carboxamide

[1113] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozahexacyclobutane-3-carboxamide

[1114] first step

[1115] methyl(Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluoroazetidine-3-carboxylate

[1116] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozacrito-3-carboxylic acid methyl ester

[1117] 3-Fluorozylidene-3-carboxylic acid methyl ester hydrochloride 49a (221 mg, 1.30 mmol) and N,N-diisopropylethylamine (562 mg, 4.35 mmol) were dissolved in N,N-dimethylformamide (10 mL), and (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozacylbutane-3-carboxylic acid methyl ester 49b (290 mg, yield: 52.5%). MS m / z (ESI): 635.3 [M+H] +

[1118] Step 2

[1119] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluoroazetidine-3-carboxamide

[1120] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozahexacyclobutane-3-carboxamide

[1121] Ammonium chloride (244 mg, 4.57 mmol) was added to toluene (10 mL), and trimethylaluminum (2 M, 2.28 mL) was added under nitrogen protection in an ice bath. After stirring the mixture at room temperature for 2 hours, (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozahexacyclic butane-3-carboxylic acid methyl ester 49b (290 mg, 0.45 mmol) was added at -78 °C. The reaction mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched in water (200 mL), extracted with ethyl acetate (150 mL x 3), and the organic phase was collected. It was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm*10 μm; mobile phase A: 0.1% FA in H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-3-fluorozahexacyclobutane-3-carboxamide 49 (122 mg, yield: 43.2%).

[1122] MS m / z (ESI): 620.3 [M+H] +

[1123] 1 H NMR(400MHz,DMSO-d6)δ8.11-8.05(m,2H),8.00-7.84(m,4H),7.37-7.21(m,7H),7.09-7 .00(m,2H),6.56-6.49(m,1H),5.07-4.91(m,2H),4.88-4.70(m,2H),4.46-4.37(m,2H).

[1124] Example 50

[1125] (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)cyclobutane-1-carboxamide

[1126] (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxamide

[1127] first step

[1128] methyl(Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)cyclobutane-1-carboxylate

[1129] (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxylic acid methyl ester

[1130] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (200 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (10 mL), and methyl 3-aminocyclobutane-1-carboxylate hydrochloride 50a (67 mg, 0.40 mmol) and N,N-diisopropylethylamine (224 mg, 1.74 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxylic acid ester 50b (150 mg, yield: 68.3%).

[1131] MS m / z (ESI): 631.3 [M+H] +

[1132] Step 2

[1133] (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)cyclobutane-1-carboxamide

[1134] (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxamide

[1135] Trimethylaluminum (2.0M toluene solution) (2M, 1.19mL) was added to a toluene (10mL) solution of ammonium chloride (127mg, 2.38mmol) under nitrogen protection in an ice bath. After stirring the mixture at room temperature for 2 hours, methyl (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxylic acid methyl ester 50b (150mg, 0.23mmol) was added at -78℃. The reaction mixture was stirred at 50℃ for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched in water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. It was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-3-(3-(4-chlorophenyl)-4-phenyl-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)cyclobutane-1-carboxamide 50 (31 mg, yield: 21.5%).

[1136] MS m / z (ESI): 616.4 [M+H] +

[1137] 1H NMR(400MHz,DMSO-d6)δ8.34-7.98(m,3H),7.94-7.87(m,2H),7.51-7.42(m,2H),7.36-7.30(m,2H),7.29-7.20(m,4H),7.04-6 .97(m,2H),6.83-6.75(m,1H),6.55-6.49(m,1H),4.65-4.49(m,1H),4.39-4.30(m,2H),2.88-2.75(m,1H),2.39-2.19(m,4H).

[1138] Example 51

[1139] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxamide

[1140] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxamide

[1141] first step

[1142] methyl(Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxylate

[1143] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxylic acid methyl ester

[1144] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (350 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (10 mL), and pyrrolidine-3-carboxylate hydrochloride 51a (151 mg, 0.91 mmol) and N,N-diisopropylethylamine (393 mg, 3.04 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxylic acid methyl ester 51b (330 mg, yield: 85.8%).

[1145] MS m / z (ESI): 631.3 [M+H] +

[1146] Step 2

[1147] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxamide

[1148] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxamide

[1149] Trimethylaluminum (2.0M toluene solution) (2M, 2.61mL) was added to a toluene (20mL) solution of ammonium chloride (279mg, 5.23mmol) under nitrogen protection in an ice bath. After stirring the mixture at room temperature for 2 hours, (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxylic acid methyl ester 51b (330mg, 0.52mmol) was added at -78℃. The reaction mixture was stirred at 50℃ for 16 hours. LCMS showed the reaction was complete. The reaction solution was quenched in water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. It was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)pyrrolidine-3-carboxamide 51 (64 mg, yield: 19.9%).

[1150] MS m / z (ESI): 616.3 [M+H] +

[1151] 1 H NMR(400MHz,DMSO-d6)δ8.07-7.99(m,2H),7.91-7.84(m,2H),7.52-7.47(m,1H),7.34-7.22(m,7H),7.08-6 .98(m,3H),6.56-6.50(m,1H),4.56-4.38(m,2H),3.73-3.55(m,4H),3.03-2.92(m,1H),2.16-1.90(m,2H).

[1152] Example 52

[1153] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azetidine-3-sulfonamide

[1154] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azacyclobutane-3-sulfonamide

[1155] first step

[1156] benzyl 3-sulfamoylazetidine-1-carboxylate

[1157] Benzyl 3-aminosulfonylazine-1-carboxylic acid ester

[1158] Benzyl 3-(chlorosulfonyl)azacyclobutane-1-carboxylate 52a (500 mg, 1.73 mmol) was added to ammonia water (2.42 g, 17.26 mmol, 25% purity) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. The reaction mixture was adjusted to pH 8-9 with 2 M HCl, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain benzyl 3-aminosulfonylazacyclobutane-1-carboxylate 52b (420 mg), which was used directly in the next reaction. MS m / z (ESI): 271.2 [M+H] +

[1159] Step 2

[1160] azetidine-3-sulfonamide

[1161] Azacyclobutane-3-sulfonamide

[1162] 3-Aminosulfonylazine-1-carboxylic acid benzyl ester 52b (350 mg, 1.29 mmol) was dissolved in methanol (8 mL), and palladium on carbon (157 mg, 10% purity) was added. The reaction mixture was stirred for 4 hours under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction mixture was filtered through a diatomaceous earth filter and concentrated under reduced pressure to obtain azacyclobutane-3-sulfonamide 52c (170 mg), which was used directly in the next step of the reaction.

[1163] Step 3

[1164] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azetidine-3-sulfonamide

[1165] (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azacyclobutane-3-sulfonamide

[1166] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (200 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (5 mL), and aziridine-3-sulfonamide 52c (94 mg, 0.69 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm*10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-1-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)azacyclobutane-3-sulfonamide 52 (144 mg, yield: 64.8%).

[1167] MS m / z (ESI): 638.2 [M+H] +

[1168] 1 H NMR(400MHz,DMSO-d6)δ8.10-8.04(m,2H),7.94-7.87(m,2H),7.38-7.21(m,9H),7.08-6 .98(m,2H),6.56-6.51(m,1H),4.99-4.55(m,4H),4.44-4.35(m,2H),4.24-4.14(m,1H).

[1169] Example 53

[1170] (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxamide

[1171] (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxamide

[1172] first step

[1173] 2-(tert-butyl)6-methyl 2-azaspiro[3.3]heptane-2,6-dicarboxylate

[1174] 2-(tert-butyl)6-methyl-2-azaspiro[3.3]heptane-2,6-dicarboxylate

[1175] 2-(tert-Butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid 53a (3 g, 12.43 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (2.06 g, 14.92 mmol) was added under nitrogen protection in an ice bath. After the mixture reacted in an ice bath for 0.5 hours, iodomethane (2.12 g, 14.92 mmol) was added dropwise, and the reaction solution was reacted at room temperature for 16 hours. TLC showed that the reaction was complete. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-(tert-butyl)-6-methyl-2-azaspiro[3.3]heptane-2,6-dicarboxylate 53b (3 g, yield: 94.5%).

[1176] Step 2

[1177] methyl 2-azaspiro[3.3]heptane-6-carboxylate

[1178] 2-Zazaspiro[3.3]heptane-6-carboxylic acid methyl ester

[1179] 2-(tert-butyl)-6-methyl-2-azaspiro[3.3]heptane-2,6-dicarboxylate 53b (1 g, 3.92 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give trifluoroacetate 53c (600 mg) of methyl 2-azaspiro[3.3]heptane-6-carboxylate, which was used directly in the next step of the reaction.

[1180] Step 3

[1181] methyl(Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxylate

[1182] (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid methyl ester

[1183] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 53c of trifluoroacetate of methyl 2-azaspiro[3.3]heptane-6-carboxylic acid ester (468 mg, 1.74 mmol) and N,N-diisopropylethylamine (562 mg, 4.35 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid ester 53d (550 mg, yield: 96.2%).

[1184] MS m / z (ESI): 657.4 [M+H] +

[1185] Step 4

[1186] (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxamide

[1187] (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxamide

[1188] Under nitrogen protection at 0°C, trimethylaluminum (2.0M toluene solution) (2M, 4.19mL) was added to a toluene (20mL) solution of ammonium chloride (447.73mg, 8.37mmol). After stirring the mixture at room temperature for 2 hours, methyl (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid ester 53d (550mg, 0.83mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. LCMS showed that the reaction was complete. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparation (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (Z)-2-((3-(4-chlorophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-2-azaspiro[3.3]heptane-6-carboxamide 53 (257 mg, yield: 47.8%).

[1189] MS m / z (ESI): 642.3 [M+H] +

[1190] 1 H NMR(400MHz,DMSO-d6)δ8.07-8.01(m,2H),7.93-7.86(m,2H),7.36-7.28(m,4H),7.27-7.18(m,4H),7.05-6.99(m,2H ),6.80-6.72(m,1H),6.51-6.46(m,1H),4.61-4.46(m,4H),4.36-4.29(m,2H),2.90-2.80(m,1H),2.42-2.30(m,4H).

[1191] Example 54

[1192] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-(1H-imidazol-5-yl)propenamide

[1193] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-(1H-imidazol-5-yl)propionamide

[1194] first step

[1195] (S)-2-amino-3-(1H-imidazol-5-yl)propenamide

[1196] (S)-2-amino-3-(1H-imidazol-5-yl)propionamide

[1197] (2S)-2-amino-3-(1H-imidazol-4-yl)propionate methyl hydrochloride 54a (3 g, 14.59 mmol) was dissolved in methanol (10 mL), and ammonia-methanol solution (7 M, 30 mL) was added. The mixture was reacted at room temperature for 72 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure to obtain (S)-2-amino-3-(1H-imidazol-5-yl)propionamide 54b (2 g), which was used directly in the next step of the reaction.

[1198] MS m / z (ESI): 155.4 [M+H] +

[1199] Step 2

[1200] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-(1H-imidazol-5-yl)propenamide

[1201] (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-(1H-imidazol-5-yl)propionamide

[1202] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (300 mg, 521.89 μmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-2-amino-3-(1H-imidazol-5-yl)propionamide 54b (160.9 mg, 1.04 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was confirmed by LCMS. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (Gilson column: Welch XB-Pheny, 21.2*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (S,Z)-2-(3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-(1H-imidazol-5-yl)propionamide 54 (16.3 mg, yield: 4.7%).

[1203] MS m / z (ESI): 656.1 [M+H] +

[1204] 1 H NMR(400MHz,DMSO-d6)δ8.30-8.25(m,1H),8.08-7.96(m,3H),7.92-7.84(m,2H),7.73-7.62(m,1H),7.56-7.34(m,5H),7.29-7 .23(m,3H),7.13-6.92(m,3H),6.92-6.78(m,1H),6.62-6.52(m,1H),4.76-4.33(m,3H),3.12-3.05(m,1H),2.96-2.91(m,1H).

[1205] Example 55

[1206] N-((E)-N'-((Z)-(3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[1207] N-((E)-N'-((Z)-(3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-4-phenylpyridin-1(6H)-yl)((4-(trifluoromethyl)phenyl)sulfonyliminomethyl)carbamoyl)acetamide

[1208] first step

[1209] methyl 4-(4-bromophenyl)-4-oxo-3-phenylbutanoate

[1210] Methyl 4-(4-bromophenyl)-4-oxo-3-phenylbutyrate

[1211] 4-Bromophenylbenzyl ketone 55a (23 g, 83.59 mmol) was dissolved in N,N-dimethylformamide (400 mL). Sodium hydride (5.02 g, 125.39 mmol, 60% purity) was added under nitrogen protection at 0 °C. After stirring the mixture at 0 °C for 0.5 hours, methyl bromoacetate 1b (20.46 g, 133.75 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. LC-MS showed the reaction was complete. The reaction mixture was quenched in ice water (800 mL), extracted with ethyl acetate (800 mL x 3), and the organic phase was collected. The mixture was washed with saturated brine (800 mL x 4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: system A) to give methyl 4-(4-bromophenyl)-4-oxo-3-phenylbutyrate 55b (20 g, yield: 68.9%).

[1212] MS m / z (ESI): 347.1 [M+H] +

[1213] Step 2

[1214] 4-(4-bromophenyl)-4-oxo-3-phenylbutanoic acid

[1215] 4-(4-bromophenyl)-4-oxo-3-phenylbutyric acid

[1216] Methyl 4-(4-bromophenyl)-4-oxo-3-phenylbutyrate 55b (15.5 g, 44.64 mmol) was dissolved in water (100 mL) and ethanol (100 mL). Sodium hydroxide (3.57 g, 89.29 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 16 hours. LCMS showed that the reaction was complete. 6 M hydrochloric acid aqueous solution was added dropwise to the reaction solution at 0 °C to adjust the pH to 5. A white solid precipitated, which was extracted with ethyl acetate (600 mL x 3), washed with saturated brine (800 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(4-bromophenyl)-4-oxo-3-phenylbutyrate 55c (23 g), which was directly used in the next reaction.

[1217] MS m / z(ESI): 333.1 [M+H] +

[1218] Step 3

[1219] 6-(4-bromophenyl)-5-phenyl-4,5-dihydropyridazin-3(2H)-one

[1220] 6-(4-Bromophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one

[1221] 55c of 4-(4-bromophenyl)-4-oxo-3-phenylbutyric acid (20 g, 60.03 mmol) was dissolved in ethanol (200 mL), and hydrazine hydrate (9.02 g, 180.08 mmol) was added. The mixture was reacted at 90 °C for 3 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filter cake was dried under reduced pressure to give 55d of 6-(4-bromophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one (19 g, yield: 96.1%).

[1222] MS m / z(ESI): 371.7 [M+MeCN+H] +

[1223] Step 4

[1224] 3-(4-bromophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine

[1225] 3-(4-bromophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine

[1226] 55d (5g, 15.19mmol) of 6-(4-bromophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one was dissolved in anhydrous tetrahydrofuran (100mL), and lithium aluminum hydride (1.73g, 45.57mmol, 2.5M) was added dropwise under nitrogen protection at 0°C. The mixture was reacted at 0°C for 3 hours. LCMS showed that the reaction was complete. The reaction solution was quenched by adding water (5 ml) dropwise at 0 °C, followed by the addition of 15% sodium hydroxide aqueous solution (5 ml), then water (15 ml), and diluted with water (200 ml) with stirring. The solution was extracted with ethyl acetate (300 ml x 3), washed with saturated sodium chloride (200 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-(4-bromophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 55e (2 g, yield: 41.7%).

[1227] MS m / z (ESI): 315.1 [M+H] +

[1228] Step 5

[1229] 3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamid

[1230] 3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

[1231] 3-(4-bromophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 55e (2 g, 6.35 mmol) was dissolved in toluene (3 mL), and methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate 1 g (8.99 g, 31.73 mmol) was added. The mixture was reacted at 120 °C for 16 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with methanol (100 mL) to give 3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 55f (2.5 g, yield: 69.5%).

[1232] MS m / z (ESI): 566.2 [M+H] +

[1233] Step 6

[1234] (E)-3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carbimidoyl chloride

[1235] (E)-3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H-carbonimide chloride

[1236] 55 f (1.4 g, 2.47 mmol) of 3-(4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 55 f (1.4 g, 2.47 mmol) was dissolved in chlorobenzene (25 mL), and phosphorus pentachloride (2.06 g, 9.89 mmol) was added. The mixture was reacted at 100 °C for 2.5 h under nitrogen protection. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 55 g (1.4 g, yield: 91.4%) of (E)-3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carboimide chloride.

[1237] MS m / z (ESI): 620.2 [M+H] +

[1238] Step 7

[1239] N-((E)-N'-((Z)-(3-(4-bromophenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[1240] N-((E)-N'-((Z)-(3-(4-bromophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[1241] 55 g (1.4 g, 2.26 mmol) of (E)-3-(4-bromophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyridazine-1(6H)-carbonimide chloride was dissolved in N,N-dimethylformamide (20 mL), and N-acetylguanidine 1j (457.14 mg, 4.52 mmol) and N,N-diisopropylethylamine (1.17 g, 9.04 mmol) were added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give N-((E)-N'-((Z)-(3-(4-bromophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomantadinyl)acetamide 55h (1 g, yield: 68.3%).

[1242] MS m / z (ESI): 649.3 [M+H] +

[1243] Step 8

[1244] N-((E)-N'-((Z)-(3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-4-phenylpyridazin-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[1245] N-((E)-N'-((Z)-(3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide

[1246] N-((E)-N'-((Z)-(3-(4-bromophenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylammoniol)acetamide 55h (500 mg, 0.77 mmol) was dissolved in N,N-dimethylformamide (10 mL), and bis(triphenylphosphine) palladium dichloride (27.1 mg, 0.038 mmol), bis(triphenylphosphine) (40.5 mg, 0.15 mmol), cuprous iodide (7.3 mg, 0.038 mmol), triethylamine (78.1 mg, 0.77 mmol) and 4-cyano-1-butyne 55j (122.1 mg, 1.54 mmol) were added. The mixture was reacted at 50 °C for 16 hours under nitrogen protection. LCMS showed the reaction was complete. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase flash (C18, water / acetonitrile) and reverse-phase preparative purification (Waters 2767 / Qda). Separation column: Green ODS 30.0*150mm*5um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give N-((E)-N'-((Z)-(3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-4-phenylpyridazine-1(6H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethamidinyl)acetamide 55 (22.4 mg, yield: 4.4%).

[1247] MS m / z (ESI): 646.3 [M+H] +

[1248] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.63-8.29(m,2H),8.09-8.01(m,2H),7.91-7.81(m,2H),7.72-7.61(m,2H),7.47- 7.41(m,1H),7.32-7.25(m,6H),7.21-7.14(m,1H),5.45-5.38(m,1H),5.01-4.94(m,1H),2.79-2.73(m,4H),2.09(s,3H).

[1249] Example 56

[1250] (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-methylpentanamide

[1251] (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-methylpentanamide

[1252] first step

[1253] (2S,3R)-2-amino-3-methylpentanamide

[1254] (2S,3R)-2-amino-3-methylpentanamide

[1255] L-Isoleucine methyl ester hydrochloride 56a (3 g, 16.51 mmol) was dissolved in ammonia-methanol (7 M, 60 mL), and the mixture was reacted at 70 °C for 16 hours under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to give (2S,3R)-2-amino-3-methylpentanamide 56b (2.7 g), which was directly used in the next step of the reaction.

[1256] MS m / z (ESI): 131.4 [M+H] +

[1257] Step 2 (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboximidamido)-3-methylpentanamide

[1258] (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-methylpentanamide

[1259] (E)-4-chloro-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbonimide acyl chloride 1i (500 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (2S,3R)-2-amino-3-methylpentanamide 56b (339 mg, 2.61 mmol) was added. The mixture was reacted at room temperature for 16 hours. LCMS showed the reaction was complete. The mixture was added to water (80 mL), extracted with ethyl acetate (80 mL x 3), washed with saturated brine (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B). Then, it was purified by reverse-phase preparative chromatography (Waters 2767 / QDA, column: Atlatis T3 Prep OBD, 19*250mm*10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min) to give (2S,3R)-2-((Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-1,6-dihydropyridazine-1-carboxamido)-3-methylpentanamide 56 (15.6 mg, yield: 2.8%).

[1260] MS m / z (ESI): 632.3 [M+H] +

[1261] 1 H NMR (400MHz, DMSO-d6) δ8.10-8.02(m,2H),7.94-7.86(m,3H),7.38-7.31(m,5H),7.29-7.21(m,4H),7.07-7.03(m,2H ),6.63-6.55(m,1H),4.79-4.16(m,3H),2.00-1.74(m,1H),1.52-1.32(m,1H),1.13-0.93(m,1H),0.89-0.75(m,6H).

[1262] Biological evaluation

[1263] Test Example 1: Determination of the cAMP generation function of the compounds of the present invention

[1264] The following method was used to determine the effect of the compounds of this invention on cAMP production in CHO-K1 cells stably transfected with the human CB1R receptor. CHO-K1 cells were purchased from the Cell Bank of the Chinese Academy of Sciences and cultured in F-12K medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. CHO-K1 cells stably transfected with the human CB1R receptor were constructed internally, and cAMP levels were measured using the cAMP TR-FRET Assay Kit (Bioauxilium, catalog number KIT-CAMP-5000).

[1265] The experimental method was performed according to the steps in the kit instructions, and is briefly described as follows: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 1000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 2500 cells per well into 384-well cell culture plates. The test compound was then added, and the plates were incubated at 37°C for 10 minutes. Subsequently, Forskolin (final concentration 1 μM) and CP55940 (1 nM) agonist were added to induce cAMP production, and the plates were incubated for 30 minutes. The cAMP level was then detected using the cAMP TR-FRET Assay Kit. 4 μL of 1X acceptor-labeled anti-cAMP Antibody Working Solution was added and mixed well, followed by 4 μL of 1X Europium-SA / biotin-cAMP Mix. The plates were mixed well and incubated for 1 hour. After incubation, the fluorescence intensity of each well was measured using a microplate reader in TF-FRET mode at an excitation wavelength of 304 nm and emission wavelengths of 620 nM and 665 nM. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was obtained by performing nonlinear regression analysis on the logarithm of compound concentration versus inhibition rate using GraphPad Prism 9 software. 50 Values ​​are shown in Table 1. A: <1 nM; B: 1-10 nM;

[1266] Table 1 IC50 of the compounds of the present invention against CB1R receptor antagonism 50 data

[1267] Conclusion: The IC50 of the compounds of this invention for antagonistic activity against the CB1R receptor is [not specified]. 50 <50 nM, exhibiting good inhibitory effect.

[1268] Test Example 2: Inhibition Experiment of CB2R by the Compound of the Present Invention

[1269] The following method was used to determine the Flp-In effect of the compounds of the present invention on the stable human CB2R receptor. TM The effect of CHO Cell Line cells on cAMP production. (Flp-In) TM -CHO Cell Line cells were purchased from Invitrogen and cultured in F-12 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 g / mL streptomycin. Flp-In cells stably transfected with the human CB2R receptor were... TM -CHO Cell Line was constructed internally, and cAMP levels were measured using the LANCE Ultra cAMP kit (Revvity, catalog number TRF0264).

[1270] according to Prepare 1×Stimulation Buffer according to the Ultra cAMP Kit instructions. Serially dilute the positive control INV-202 and the test compound 10 times using an Apricot instrument, then dilute to 10× working solution using 1×Stimulation Buffer. Culture stable cell lines to 80% confluence, trypsinize and collect cells, count them, and seed 5 μL / well into 384-well plates. Add 1 μL of the diluted 10× working solution, centrifuge, and incubate at 37°C for 10 minutes. Prepare 2.5 μM Forskolin & 1 nM CP55940 solution, add 4 μL to the corresponding wells, centrifuge, and incubate at 37°C for 30 minutes to induce cAMP production. Dilute Eu-cAMP to the working concentration with Detection buffer, and add 4 μL / well to the corresponding wells. TM The anti-cAMP antibody was diluted to the working concentration with detection buffer, and 4 μL / well was added to the corresponding experimental wells; after centrifugation, it was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 337 nm.

[1271] Table 2 IC50 of the compounds of the present invention against CB2 receptor antagonism 50 data

[1272] Conclusion: The compounds of this invention have a weak antagonistic effect on the downstream cAMP signaling pathway of CB2R and exhibit high selectivity.

[1273] Test Example 3: Determination of the recruitment effect of the compound of the present invention on β-arrestin2 downstream of CB1R.

[1274] The following method was used to determine the effect of the compounds of this invention on β-arrestin activation in HEK293T cells stably transfected with the human CB1R receptor. HEK293T cells were purchased from the ATCC cell bank and cultured in DMEM medium containing 10% fetal bovine serum, 100 U penicillin, and 100 g / mL streptomycin. HEK293T cells stably transfected with the human CB1R receptor were constructed internally, and β-arrestin activation levels were determined by... The assay was performed using the Live Cell Substrates kit (Promega, N2013).

[1275] On day 1, HEK293T-CB1-βArrestin2 cells were cultured to 80% confluence, triedpsinized to collect cells, counted, and seeded into 384-well plates (10kJ / well / 25μL) in Opti-MEM + 4% FBS medium, and incubated overnight. On day 2, 1000× positive control INV-202 and the test compound were serially diluted using an Apricot instrument. The diluted 1000× compound was injected into the corresponding wells using an ECHO instrument (25nL / well) and incubated in the dark for 10 minutes. According to the Live Cell Substrates instructions, dilute the substrate to 1× using the provided buffer, add 5 μL / well to each well, and mix well. Transfer 25 nL (1,000×) of the agonist CP55940 (final concentration 100 nM) to the corresponding well using an Echo transducer, centrifuge to mix, and incubate for 10 minutes. After incubation, read the Luminescence signal value using a microplate reader. Plot the signal value against the compound concentration, and perform curve fitting and IC50 analysis using the nonlinear regression method in XLFit software. 50 calculate.

[1276] Table 3. Antagonistic activity of the compounds of this invention against the downstream β-arrestin signaling pathway of CB1R.

[1277] Conclusion: The compounds of this invention have a strong antagonistic effect on the downstream β-arrestin signaling pathway of CB1R.

[1278] Test Example 4: Mouse Pharmacokinetic Test

[1279] Experimental animals: Male ICR (CD-1) mice (6-10 weeks old), purchased from Vital River Laboratory Animal Technology Co., Ltd.

[1280] Drug administration solvent: DMSO: Solutol HS-15: Saline = 5:5:90 (v / v / v)

[1281] Drug administration and blood collection: Six animals per group were administered the drug at a 10 MPk PO dose. Sampling time points were: 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 10.0, and 24.0 hours. Approximately 80 μL of blood was collected from the orbital cavity. The collected whole blood was placed in an EDTA-K2 anticoagulant tube, inverted several times to mix thoroughly, and stored on moist ice. The tube was then centrifuged (1500–1600 g) for 10 minutes within 30 minutes to separate the plasma. The obtained plasma sample was stored at -40 to -20°C for biological sample analysis.

[1282] Biological sample analysis: The drug concentration in plasma was detected using LC-MS / MS analysis.

[1283] Data Analysis: The corresponding pharmacokinetic parameters were calculated using the non-compartmental model in Phoenix WinNonlin 8.3. The test results are shown in Table 4 below.

[1284] Test Example 5: Mouse Brain Penetration Rate (BBB) ​​Test

[1285] Experimental animals: Male ICR (CD-1) mice (6-10 weeks old), purchased from Vital River Laboratory Animal Technology Co., Ltd.

[1286] Drug administration solvent: DMSO: Solutol HS-15: Saline = 5:5:90 (v / v / v)

[1287] Administration and Sampling: Three mice per group were administered the drug at a PO dose of 10 MPk. Sampling time point: Sampling was performed at the Tmax time point of the PK curve. After deep anesthesia with CO2, approximately 0.5 mL of whole blood was collected from the ...

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: Ring A is selected from 5-6-membered heteroaryl, 5-12-membered heterocyclic or 8-12-membered bicyclic fused ring, wherein the 8-12-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl. p is between 0 and 2; the condition is that when p is 2, the two R values ​​are equal. a The same carbon atom bonded to them forms a -C (=O) group. When p is 0, ring A is not selected from the following groups: When p is 1, R a Independently selected from halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano, preferably R a Selected from F, methyl, ethyl, isopropyl, cyclopropyl, or cyano; or R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring, arbitrarily, R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring is further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and amide groups; preferably R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring may be a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring; wherein the 5-membered ring, 6-membered ring, 7-membered ring, or 8-membered ring may optionally be further composed of one or more elements selected from deuterium, hydroxyl, halogen, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of halogenated alkoxy groups and amide groups; R 1 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Haloalkoxy; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 The haloalkoxy group may optionally be further selected from one or more groups selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups; R 2 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Z is selected from S (=O) r Or C (=O) or C (=S) or S (=O)(=N); R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may optionally be further influenced by one or more R groups. A Replaced; R A Whether the groups are the same or different, they are each independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 -S (=O) r R 5 Or C 1-6 Alkyl C 6-10 Aryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; And / or, two Rs A The same carbon atom they are connected to forms -C (=O); R 4 Selected from C 1-6 Alkyl, -OR 5 -SR 5 -S (=O) r R 5 -S (=O) r NR 6 R 7 -N(R) 6 )C(=O)R 7 -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -NH(CH2) m1 CR e R f (CH2) n1 C(=O)NR 6 R 7 -NH-C 3-8 cycloalkyl-C(=O)NR 6 R 7 -NR g (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ; wherein C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic groups optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced; R d Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups optionally further selected from one or more halogens, cyano groups, amino groups, hydroxyl groups, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -(CH2) r C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced; R e and R f Each is independently selected from hydrogen, alkyl, and cycloalkyl; wherein the alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, hydroxyl, halogen, cyano, alkyl, and 5-10 heteroaryl groups; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; R g Independently selected from hydrogen, alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more atoms selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 - NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, 3 or 4; m1 is independently selected from 0, 1, 2, 3 or 4; n1 is independently selected from 0, 1, 2, 3, or 4; and r can be 0, 1, or 2 independently.

2. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: Ring A is selected from 5-6-membered heteroaryl, 5-12-membered heterocyclic or 8-12-membered bicyclic fused ring, wherein the 8-12-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl. p is between 0 and 2; the condition is that when p is 2, the two R values ​​are equal. a The same carbon atom bonded to them forms a -C (=O) group. When p is 0, ring A is not selected from the following groups: When p is 1, R a Independently selected from halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano, preferably R a Selected from F, methyl, ethyl, isopropyl, cyclopropyl, or cyano; or R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring, arbitrarily, R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring is further divided by one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and amide groups; preferably R 1 The connected benzene, R 1 R a The rings A and B combine to form a ring containing 0, 1, or more N, O, or S (=O). r The ring may be a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring; wherein the 5-membered ring, 6-membered ring, 7-membered ring, or 8-membered ring may optionally be further composed of one or more elements selected from deuterium, hydroxyl, halogen, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of halogenated alkoxy groups and amide groups; R 1 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; R 2 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Z is selected from S (=O) r Or C (=O) or C (=S) or S (=O)(=N); R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 3-12-membered heterocyclic groups may optionally be further influenced by one or more R groups. A Replaced; R A Whether the groups are the same or different, they are each independently selected from deuterium, hydroxyl, halogen, nitro, cyano, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 -S (=O) r R 5 Or C 1-6 Alkyl C 6-10 Aryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; And / or, two Rs A The same carbon atom they are connected to forms -C (=O); R 4 Selected from C 1-6 Alkyl, -OR 5 -SR 5 -S (=O) r R 5 -S (=O) r NR 6 R 7 -N(R) 6 )C(=O)R 7 -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -NH(CH2) m1 CR e R f (CH2) n1 C(=O)NR 6 R 7 -NR g (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ; wherein C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic groups optionally further selected from one or more deuterium atoms, hydroxyl groups, halogens, nitro groups, cyano groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced; R d Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR 5 -OC(=O)R 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 ;R e and R f Each is independently selected from hydrogen, alkyl, and cycloalkyl; wherein the alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, hydroxyl, halogen, cyano, and alkyl; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; R g Independently selected from hydrogen, alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; R 5 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more atoms selected from deuterium atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 - NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced; R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, 3 or 4; m1 is independently selected from 0, 1, 2, 3 or 4; n1 is independently selected from 0, 1, 2, 3, or 4; and r can be 0, 1, or 2 independently.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein Z is selected from S(=O)2.

4. The compound according to any one of claims 1-3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R 4 Selected from R d The definition is as described in claim 1.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof of general formula (II): in, R 1 R 2 R 3 R d R a The definitions of p, m and n are as described in claim 1.

6. The compound according to any one of claims 1-5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, R 1 Selected from halogens, preferably chlorine.

7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, R 3 Selected from C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic, wherein the C 6-10 Aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclic group may be selected by one or more groups chosen from halogen, cyano, C 1-6 Alkyl, -OR 5 C 1-6 Halogenated alkyl, -SF5 or -NR 6 R 7 Replaced; R 5 R 6 R 7 Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl.

8. The compound according to any one of claims 1-7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, R 3 Selected from phenyl, wherein the phenyl group is optionally substituted with one or more substituents selected from halogen, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SF5 or amino.

9. The compound according to any one of claims 1-8, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, R d Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -NR g C(=O)NR 6 R 7 -N(R) 6 )C(=O)OR 7 or -N(R) 6 )C(=O)R 7 Preferably, R d Selected from C 1-6 Alkyl, 5-6 membered heteroaryl, -NR g C(=O)NR 6 R 7 -N(R) 6 )C(=O)OR 7 or -N(R) 6 )C(=O)R 7 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl groups optionally further selected from one or more halogens, cyano groups, amino groups, hydroxyl groups, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, -C(=O)NR 6 R 7 -NR g C(=O)NR 6 R 7 -S (=O) r NR 6 R 7 Or -S (=O) r R 5 The substituents are replaced; R 6 Selected from hydrogen atoms or C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl groups optionally further selected from one or more hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Substituted with an aryl or 5-12 heteroaryl group; preferably, R 6 Selected from hydrogen atoms or C 1-6 alkyl; R 7 Selected from hydrogen atom, hydroxyl group, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl groups optionally further selected from one or more hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-12 membered heterocyclic groups, C 6-10 Substituted with an aryl or 5-12 heteroaryl group; preferably, R 7 Selected from hydrogen atom C 1-6 Alkyl, C 3-8 Cycloalkyl or 5-12-membered heteroaryl, wherein the alkyl, cycloalkyl, or heteroaryl group is optionally further selected from one or more hydroxyl, halogen, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups; R g Selected from hydrogen or C 1-6 alkyl.

10. The compound according to claim 9, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, R d for 11. The compound according to any one of claims 1-10, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein ring A is selected from 5-membered heteroaryl, 5-membered heterocyclic, 6-membered heteroaryl, or 6-membered heterocyclic.

12. The compound according to claim 11, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... Selected from the following groups: Preferably, Selected from the following groups:

13. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

14. The compound according to any one of claims 1-12, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

15. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from -NH(CH2) m1 CR e R f (CH2) n1 C(=O)NR 6 R 7 -NR g (CHR e ) m1 (CHR f ) n1 S(=O) r NR 6 R 7 or -NR g (CHR e ) m1 (CHR f )NR 6 R 7 S(=O) r NR 6 R 7 ; R e and R f Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-8 cycloalkyl; wherein the C 1-6 Alkyl, C 3-8 cycloalkyl groups may optionally be further divided by one or more atoms selected from deuterium, hydroxyl, halogen, cyano, C 1-6 Substituents of alkyl groups; or, R e and R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; R g Independently selected from hydrogen and C 1-6 Alkyl; or, R g and R e or R f The atoms bonded to them together form 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; m1 is independently selected from 0, 1, 2, 3 or 4; n1 is independently selected from 0, 1, 2, 3, or 4; and r can be 0, 1, or 2 independently.

16. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from 17. The compound according to any one of claims 1-16, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is:

18. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1-17 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

19. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a CB1 inverse agonist or antagonist.

20. Use of the compound or stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating CB1-mediated diseases; preferably, wherein the CB1-mediated diseases are selected from obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, more preferably obesity, metabolic syndrome or diabetic nephropathy.

21. The use of the compound or stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, more preferably obesity, metabolic syndrome or diabetic nephropathy.

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