Tetrahydropyridazine derivatives, processes for their preparation and uses thereof

Abstract

This invention relates to a tetrahydropyridazine derivative, its preparation method, and the pharmaceutical application of a pharmaceutical composition containing the derivative. Specifically, this invention relates to a tetrahydropyridazine derivative of general formula (I), its preparation method, and its pharmaceutically usable salts, and their use in the treatment or prevention of diseases and conditions related to the cannabinoid CB1 receptor, wherein the definitions of each substituent in general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] This invention relates to a tetrahydropyridazine 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] Endocannabinoid G protein-coupled receptors, coupled with Gi / o proteins, exert a series of functions upon activation, including inhibiting adenylate cyclase activity, opening K+ channels, closing Ca2+ channels, and activating protein kinase activity. These mediate cannabinoid-induced effects, including food intake, memory loss, gastrointestinal motility, rigidity, anxiety, and chronic pain. 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 while simultaneously enhancing leptin sensitivity, promoting mitochondrial formation in adipose tissue to increase energy expenditure and thermogenesis, reducing hepatic lipogenesis, improving β-cell glucose response, and reducing insulin resistance, thus achieving weight loss through multiple approaches.

[0005] Obesity has been recognized as a disease by the WHO. Obesity can also lead to a series of health problems, such as increasing the risk of various chronic diseases such as high blood pressure, diabetes, dyslipidemia, coronary heart disease, myocardial infarction, stroke, and some cancers. Up to 2.8 million people die from obesity every year worldwide, and there is currently a strong demand for weight loss drugs. Obesity can also lead to social and psychological problems, increase the cost of residents' health care services, and increase the burden on the healthcare system.

[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, smegglutide, 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]

[0010] in:

[0011] R 1 R 2 Each was independently selected from C 6-10 aryl or 5-10 heteroaryl, wherein the 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, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic, 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;

[0012] R a Selected from hydrogen atoms, deuterium atoms, fluorine or methyl, preferably, R a It is a hydrogen atom;

[0013] X is selected from S (=O) r C(=O), C(=S) or S(=O)(=N);

[0014] R 3 Selected from the following groups:

[0015] , ,

[0016] Y is selected from C or N, where The atom can be selected from single or double bonds as needed, so that each atom presents a normal valence state;

[0017] R e 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;

[0018] Two Rs g Together with the same or different carbon atoms they are attached to, they form a C 2-6alkenyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 2-6 alkenyl, C 3-8 The cycloalkyl or 3-12-membered heterocyclic group may optionally be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -SF5, =O, -C(=O)R 5 -C(=O)OR 5 -OC(=O)R 5 -NR 6 R 7 -C(=O)NR 6 R 7 -S(=O)2NR 6 R 7 or -N(R) 6 )C(=O)R 7 The substituents are replaced;

[0019] t is 0, 1, or 2;

[0020] p is 0, 1, or 2;

[0021] 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 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic group; wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 The cycloalkyl or 5-12 membered heterocyclic group may optionally be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -SF5, -OR5 -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;

[0022] 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 heterocyclic, 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 ;

[0023] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R8 -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 10 The 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 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;

[0027] r can be 0, 1, or 2 independently.

[0028] 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 X is selected from S(=O)2.

[0029] 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 or R d The definition is as stated in general formula (I).

[0030] 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:

[0031]

[0032] Among them, R b 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;

[0033] m is 0, 1, or 2;

[0034] R 2 R 3 and R d The definition is as stated in general formula (I).

[0035] 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 2 It has the following structure:

[0036]

[0037] Among them, R c 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;

[0038] n is 0, 1, or 2.

[0039] A preferred embodiment of the present invention is a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof is:

[0040]

[0041] Among them, R b Selected from halogens, preferably chlorine;

[0042] m is 1;

[0043] R 3 The definition is as stated in general formula (I).

[0044] A preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IV) or (V) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof:

[0045]

[0046] Where Y is selected from C or N, The atom can be selected from single or double bonds as needed, so that each atom presents a normal valence state;

[0047] R b Selected from halogens, preferably chlorine;

[0048] R e Whether the groups are the same or different, they are each independently selected from halogens, cyano groups, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, -SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0049] Two Rs g Together with the same or different carbon atoms they are attached to, they form a C 2-6 alkenyl, C3-8 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 2-6 alkenyl, C 3-8 The cycloalkyl or 3-12-membered heterocyclic group may optionally be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -SF5, =O, -C(=O)R 5 -C(=O)OR 5 -OC(=O)R 5 -NR 6 R 7 -C(=O)NR 6 R 7 -S(=O)2NR 6 R 7 or -N(R) 6 )C(=O)R 7 The substituents are replaced;

[0050] t is 0, 1, or 2;

[0051] p is 0, 1, or 2;

[0052] m is 1;

[0053] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the following groups: , , , , , , , , , , , .

[0054] In a preferred embodiment of the invention, a compound of general formula (IV) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein... Selected from .

[0055] In a preferred embodiment of the invention, a compound of general formula (V) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein... Selected from the following groups , , , , , , , , , , .

[0056] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0057]

[0058]

[0059]

[0060] Or its stereoisomers, tautomers, or medicinal salts.

[0061] 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.

[0062] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0063] The present invention provides the use of a compound of general formula (I), (II), (III), (IV) or (V) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a CB1 inverse agonist or antagonist.

[0064] The present invention also provides the use of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt 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.

[0065] The present invention also provides the use of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease selected from obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, preferably obesity, metabolic syndrome or diabetic nephropathy.

[0066] Detailed description of the invention

[0067] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0068] 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 10 Alkyl 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.

[0069] "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.

[0070] "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, preferably C2-C6 alkenyl. Alkenyl groups may be optionally substituted or unsubstituted.

[0071] "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. , , , The alkenyl group can be substituted or unsubstituted.

[0072] "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.

[0073] "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.

[0074] "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.

[0075] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. or , .

[0076] Monocyclic alkyl groups can be substituted or unsubstituted.

[0077] "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.

[0078] "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.

[0079] "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, and 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, , The bridged cycloalkyl group can be substituted or unsubstituted.

[0080] 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.

[0081] The heterocyclic group can be substituted or unsubstituted.

[0082] Examples of “monocyclic heterocyclic groups” include, but are not limited to, morpholino, oxetane, azabolo, 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, and hexahydropyrimidine.

[0083] "Spirocycloheterocyclic group" refers to a polycyclic 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, , , , , , , , , , , , .

[0084] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms. 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, , , , , .

[0085] "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 a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of the "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl, , .

[0086] "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 or naphthyl, most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0087] "Heteroaryl" refers to 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, 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, pyridyl, pyridine- 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 or .

[0088] The heteroaryl group can be substituted or unsubstituted. The definition of "substituted" or "substituted" is described below. Examples of "substituted heteroaryl groups" include, but are not limited to, the following structures: , .

[0089] 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, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0090]

[0091]

[0092]

[0093] .

[0094] "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.

[0095] "Alkylthio" refers to a (alkyl-S-) group. The alkyl group is 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.

[0096] "Nitro" refers to the -NO2 group.

[0097] "Hydroxy" refers to the -OH group.

[0098] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0099] "Amino" refers to -NH2.

[0100] "Hydroxyamino group" refers to -NHOH.

[0101] “Cyano” refers to -CN.

[0102] "Benzyl" refers to -CH2-phenyl.

[0103] "Carboxyl group" refers to -C(=O)OH.

[0104] "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.

[0105] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0106] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0107] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0108] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0109] "DMSO" refers to dimethyl sulfoxide.

[0110] “BOC” refers to tert-butoxycarbonyl.

[0111] “Bn” refers to benzyl.

[0112] "THP" refers to 2-tetrahydropyranyl.

[0113] "TFA" refers to trifluoroacetic acid.

[0114] “Ts” refers to p-toluenesulfonyl group.

[0115] “Bn” refers to benzyl.

[0116] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0117] "Formyl group" refers to .

[0118] "Aminomethylammonium" refers to

[0119] 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.

[0120] "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).

[0121] 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, 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, -OR 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 -CH2NHC(=O)OR 5 -CH2NR 6 R 7 -S(=O) r NR 6 R 7 Or -S(=O) r R 5 The substituents are replaced;

[0122] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, 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;

[0123] R 6 and R 7Each 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;

[0124] 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;

[0125] 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;

[0126] r can be 0, 1, or 2 independently.

[0127] 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.

[0128] 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.

[0129] "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.

[0130] "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

[0131] 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.

[0132] Example

[0133] 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.

[0134] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0135] 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.

[0136] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0137] 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.

[0138] CD3OD: Deuterated methanol.

[0139] CDCl3: Deuterated chloroform.

[0140] DMSO-d6: Deuterated dimethyl sulfoxide.

[0141] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0142] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0143] 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.

[0144] Example 1: Synthesis of Compound 1

[0145] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(difluoromethylene)piperidin-1-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0146] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(difluoromethylene)piperidin-1-yl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0147]

[0148]

[0149] first step

[0150] methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutanoate

[0151] Methyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate

[0152] 1-(4-chlorophenyl)-2-phenethyl-1-one 1a (commercially available, 50.0 g, 217.39 mmol) was dissolved in N,N-dimethylformamide (600 mL). o Sodium hydride (13.0 g, 326.09 mmol, 60% purity) was added at temperature C and stirred for 0.5 hours. Then, methyl 2-bromoacetate 1b (commercially available, 32.82 mL, 346.78 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was kept at 0°C. o Quenching was performed at C by adding saturated ammonium chloride aqueous solution (600 mL), followed by extraction with ethyl acetate (500 mL × 3). 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, yield: 78.9%).

[0153] Step 2

[0154] 4-(4-chlorophenyl)-4-oxo-3-phenylbutanoic acid

[0155] 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid

[0156] 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. The reaction mixture was concentrated to remove ethanol, and the pH was adjusted to 5 with 6M hydrochloric acid solution. The mixture was extracted with ethyl acetate (400 mL × 3 times), and the combined organic phases were washed with saturated sodium chloride solution (600 mL × 3 times), 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%.

[0157] MS m / z (ESI): 289.0 [M+H] +

[0158] Step 3

[0159] 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazin-3(2H)-one

[0160] 6-(4-Chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one

[0161] 1 d of 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid (50 g, 173.61 mmol) was dissolved in ethanol (600 mL), and hydrazine hydrate (27.38 g, 519.52 mmol) was added. The mixture was heated at 90 °C. o The reaction was carried out at C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered and the filter cake was dried to give 1e (50 g) of 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one, with a yield of 100%.

[0162] MS m / z (ESI): 289.0 [M+H] +

[0163] Step 4

[0164] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine

[0165] 3-(4-Chlorophenyl)-4-phenyl-1,4,5,6-Tetrahydropyridazine

[0166] 1e of 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one (20 g, 70.24 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere. o Lithium aluminum hydride (2.5 M tetrahydrofuran solution, 84.29 mL) was added dropwise at C. 70 o React at C for 1 hour. o Water (8 mL), 15% sodium hydroxide aqueous solution (8 mL), and water (34 mL) were added dropwise to the reaction solution under pressure. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, 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%.

[0167] MS m / z (ESI): 271.1 [M+H] +

[0168] Step 5

[0169] tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate

[0170] tert-butyl-4-(difluoromethylene)piperidine-1-carboxylate

[0171] 1 g (4.00 g, 20.08 mmol) of N-tert-butoxycarbonyl-4-piperidinone was dissolved in 40 ml of N,N-dimethylformamide. o Difluoromethyl (2-pyridyl) sulfone (commercially available, 3.30 g, 17.06 mmol) and potassium tert-butoxide (3.38 g, 30.11 mmol) were added at C for 1 hour. After the addition was complete, the solution was heated to -40°C. o The mixture was stirred at C for 15 minutes, then saturated ammonium chloride (10 mL) and 3M hydrochloric acid (26 mL) were added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. Ice water (100 mL) was added to the reaction mixture, and the mixture was extracted with methyl tert-butyl ether (3 × 60 mL). The organic phase was washed with saturated sodium chloride solution, 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 tert-butyl-4-(difluoromethylene)piperidine-1-carboxylate 1i (3 g), with a yield of 64.1%.

[0172] Step 6

[0173] 4-(difluoromethylene)piperidine hydrochloride

[0174] 4-(difluoromethylene)piperidine hydrochloride

[0175] tert-butyl-4-(difluoromethylene)piperidine-1-carboxylate 1i (3 g, 12.86 mmol) was dissolved in 4M ethyl acetate hydrochloride solution and stirred at room temperature for 2 hours. The reaction solution was filtered, the filter cake was washed with dichloromethane, and dried under reduced pressure to give 4-(difluoromethylene)piperidine hydrochloride 1j (2 g), yield 91.7%.

[0176] MS m / z (ESI): 134.2 [M+H] +

[0177] Step 7

[0178] 4-(difluoromethylene)piperidine-1-sulfonamide

[0179] 4-(difluoromethylene)piperidine-1-sulfonamide

[0180] Dissolve 1,5 g (11.27 mmol) of 4-(difluoromethylene)piperidine hydrochloride in 20 mL of 1,4-dioxane, add 10 drops of N,N-diisopropylethylamine, adjust the pH of the mixture to alkaline, then add 1,3 g (0.64 mmol) of sulfonamide. Maintain the reaction mixture at 95 °C. o The mixture was stirred at C for 16 hours. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 11 (840 mg) of 4-(difluoromethylene)piperidine-1-sulfonamide, with a yield of 35.1%.

[0181] Step 8

[0182] dimethyl ((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbonimidodithioate

[0183] 4-Dimethyl((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbamate dithioester

[0184] 1 L (840 mg, 3.96 mmol) of 4-(difluoromethylene)piperidine-1-sulfonamide was dissolved in 10 mL of N,N-dimethylformamide. o Sodium hydroxide (475 mg, 11.87 mmol) and carbon disulfide (482 mg, 6.33 mmol) were added at C, and the solution was added at 0°C. oStirring was continued at C for 30 minutes, then iodomethane (1.29 g, 9.10 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated sodium chloride solution, 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 mg (540 mg) of dimethyl ((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbamate dithioester, in a yield of 43.1%.

[0185] MS m / z (ESI): 317.1 [M+H] +

[0186] Step 9

[0187] methyl (E)-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbonochloridoimidothioate

[0188] (E)-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbochloroimide methyl thiocarbamate

[0189] Dimethyl ((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbamate dithioester 1m (440 mg, 1.39 mmol) was dissolved in dichloromethane (6 mL), and sulfonyl chloride 1n (commercially available, 375 mg, 2.78 mmol) was added. The reaction mixture was heated at 40 °C. o Stir at C for 2 hours. Concentrate and purify the residue by silica gel column chromatography (eluent: system A) to give (E)-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbochloroimide methyl thiocarbamate 10 (300 mg), yield 74.2%.

[0190] MS m / z (ESI): 305.0 [M+H] +

[0191] Step 10

[0192] methyl (E)-3-(4-chlorophenyl)-N-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidothioate

[0193] (E)-3-(4-chlorophenyl)-N-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboiminomethylthiocarbamate

[0194] Methyl (E)-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)carbochloropyridinium-1(4H)-carboiminothiocarbamate 1o (185 mg, 0.61 mmol) and 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (150 mg, 0.55 mmol) were dissolved in acetonitrile (10 mL), and triethylamine (168 mg, 1.66 mmol) was added. The mixture was stirred at 90°C for 16 hours under nitrogen atmosphere. The solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: system B) to give methyl (E)-3-(4-chlorophenyl)-N-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboiminothiocarbamate 1p (250 mg), yield 83.7%.

[0195] MS m / z (ESI): 539.2 [M+H] +

[0196] Step 11

[0197] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(difluoromethylene)piperidin-1-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0198] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(difluoromethylene)piperidin-1-yl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0199] N-(carbamoyl)acetamide 1q (70.34 mg, 0.67 mmol) and (E)-3-(4-chlorophenyl)-N-((4-(difluoromethylene)piperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimine methyl thiocarbamate 1p (250 mg, 0.46 mmol) were dissolved in acetonitrile (5 mL), and triethylamine (140 mg, 1.39 mmol) was added. The reaction solution was heated to 90 °C. oStirred at C for 16 hours, concentrated, and the residue was purified by preparative liquid chromatography to obtain N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(difluoromethylene)piperidin-1-yl)sulfonyl)imino)methyl)aminomethanediamine)acetamide 1 (41 mg), yield 15.1%.

[0200] MS m / z (ESI): 592.3 [M+H] +

[0201] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.27 (s, 2H), 7.57 (d, J =8.8 Hz, 2H), 7.35-7.28 (m, 4H), 7.25-7.15 (m, 3H), 4.37 (d, J = 3.6 Hz, 1H), 4.21 (d, J = 13.2 Hz, 1H), 3.09 (t, J = 5.6 Hz, 5H), 2.22 (s, 5H), 2.15 (s,3H), 1.96 (d, J = 11.2 Hz, 1H).

[0202] Example 2 Synthesis of Compound 2

[0203] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0204] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(pentafluoro-λ) 6 -thioalkyl)phenyl)sulfonyl)imino)methyl)carbamate)acetamide

[0205]

[0206] first step

[0207] 4-(pentafluoro-λ 6-sulfaneyl)benzenediazonium tetrafluoroborate

[0208] Tetrafluoroboronic acid 4-(pentafluoro-λ) 6 thioalkyl)benzenediazoium

[0209] 4-(pentafluoro-λ) 6 (-Thioalkyl)aniline 2a (7 g, 31.94 mmol) dissolved in ethanol (90 mL), 0 o Tetrafluoroboric acid (20.79 g, 95.81 mmol, 40% purity) and amyl nitrite 2b (commercially available, 6.36 g, 54.29 mmol) were slowly added under a nitrogen atmosphere. The mixture was then heated at 0°C. o React at C for 2 hours. o Add diethyl ether (400 mL) to C and stir for 25 minutes. Filter to obtain tetrafluoroborate 4-(pentafluoro-6-thioalkyl)benzenediazoium 2c (8 g).

[0210] Step 2

[0211] 4-(pentafluoro-λ 6 -sulfaneyl)benzenesulfonyl chloride

[0212] 4-(pentafluoro-λ) 6 -Thioalkyl)benzenesulfonyl chloride

[0213] 0 o Under a nitrogen atmosphere, thionyl chloride (20.59 g, 173.04 mmol) was added dropwise to water (50 mL), and the mixture was stirred at room temperature for 40 minutes. Then, concentrated hydrochloric acid (1.71 g, 17.30 mmol) and cuprous chloride (68.5 mg, 0.69 mmol) were added, and the mixture was stirred for 10 minutes. Finally, tetrafluoroboric acid 4-(pentafluoro-λ) was added. 6 A solution of thioalkylbenzenediazonium 2c (8 g, 34.61 mmol) in acetonitrile (8 mL) was prepared and placed at 0... o Stirring at C for 1 hour, filtration yielded 4-(pentafluoro-λ) 6 2d (7 g, yield: 66.8%) of thioalkylbenzenesulfonyl chloride.

[0214] Step 3

[0215] 4-(pentafluoro-λ 6 -sulfaneyl)benzenesulfonamide

[0216] 4-(pentafluoro-λ) 6 -Thioalkyl)benzenesulfonamide

[0217] 4-(pentafluoro-λ) 6 2-(thioalkyl)benzenesulfonyl chloride (7 g, 23.13 mmol) was dissolved in ammonia-methanol (20 mL) and stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-(pentafluoro-λ) 6 2e-thioalkyl)benzenesulfonamide (4.5 g, yield: 68.7%).

[0218] MS m / z (ESI): 282.2 [M+H] +

[0219] Step 4

[0220] dimethyl ((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)sulfonyl)carbonimidodithioate

[0221] (4-(pentafluorine-λ) 6 -Thioalkyl)phenyl)sulfonyl)dithiocarbonate dimethyl carbonate

[0222] 4-(pentafluoro-λ) 6 (4-(thioalkyl)benzenesulfonamide 2e) (4.5 g, 15.89 mmol) was dissolved in N,N-dimethylformamide (87 mL). A solution of carbon disulfide (1.94 g, 25.42 mmol) and sodium hydroxide (1.53 g, 38.13 mmol) in 13 mL was added at 0 °C. The mixture was stirred at 0 °C for 1 hour, followed by the addition of iodomethane (5.19 g, 36.54 mmol), and the reaction was carried out at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 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 obtain (4-(pentafluoro-λ) 6 -Thioalkyl)phenyl)sulfonyl)dithiocarbonate dimethyl ester 2f (1.2 g, yield: 19.5%).

[0223] Step 5

[0224] methyl (E)-((4-(pentafluoro-λ 6-sulfaneyl)phenyl)sulfonyl)carbonochloridoimidothioate

[0225] (E)-((4-(pentafluorine-λ) 6 methyl thiocarbamate (-thioalkyl)phenyl)sulfonyl)carbochloroimide

[0226] (4-(pentafluorine-λ) 6 2f of dimethyl dithiocarbonate (1.2 g, 3.10 mmol) was dissolved in dichloromethane (20 mL), and sulfonyl chloride (836 mg, 6.19 mmol) was added under a nitrogen atmosphere at room temperature. The solution was then heated at 40 °C. o The mixture was stirred at C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to obtain (E)-((4-(pentafluoro-λ) 6 2 g (1 g, yield: 85.9%) of methyl thiocarbamate (-thioalkyl)phenyl)sulfonyl)carbochloroimide.

[0227] Step 6

[0228] methyl (E)-3-(4-chlorophenyl)-N-((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidothioate

[0229] (E)-3-(4-chlorophenyl)-N-((4-(pentafluoro-λ) 6 methyl thiocarboxylate (-thioalkyl)phenyl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxylimide

[0230] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (200 mg, 0.74 mmol) was dissolved in acetonitrile (5 mL), and triethylamine (224 mg, 2.22 mmol) and (E)-((4-(pentafluoro-λ) were added under a nitrogen atmosphere at room temperature. 6 2 g (333 mg, 0.89 mmol) of methyl thiocarbamate (-thioalkyl)phenyl)sulfonyl)carbochloroimide was reacted at 90°C. o The mixture was stirred at C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-3-(4-chlorophenyl)-N-((4-(pentafluoro-λ) 64-(4H)-dihydropyridazine-1(4H)-carboximide methyl thiocarbamate 2h (400 mg, yield: 88.7%).

[0231] MS m / z (ESI): 610.0 [M+H] +

[0232] Step 7

[0233] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-(pentafluoro-λ 6 -sulfaneyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0234] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(pentafluoro-λ) 6 -thioalkyl)phenyl)sulfonyl)imino)methyl)carbamate)acetamide

[0235] (E)-3-(4-chlorophenyl)-N-((4-(pentafluoro-λ) 6 Methyl thiocarbamate 2h (202 mg, 0.33 mmol) was dissolved in acetonitrile (1 mL), and triethylamine (101 mg, 1.0 mol) and N-acetylguanidine 1q (commercially available, 40 mg, 0.4 mmol) were added under a nitrogen atmosphere at room temperature. o The reaction was carried out at C for 16 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase preparation to obtain N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(pentafluoro-λ) 6 -Thioalkyl)phenyl)sulfonyl)imino)methyl)aminomethanediamine)acetamide 2 (75 mg, yield: 34%).

[0236] MS m / z (ESI): 663.1 [M+H] +

[0237] 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.35-7.75 (m, 6H), 7.58-7.49 (m, 2H), 7.35-7.26 (m, 4H), 7.26-7.12 (m, 3H), 4.42-4.35 (m, 1H), 4.34-4.21 (m, 1H), 3.26-3.12 (m, 1H), 2.31-2.15 (m, 1H), 2.11 (s, 3H), 2.02-1.93(m, 1H).

[0238] Example 3: Synthesis of Compound 3

[0239] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0240] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide

[0241]

[0242]

[0243] first step

[0244] tert-butyl (1R,5S)-3-(trifluoromethyl)-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0245] tert-Butyl(1R,5S)-3-(trifluoromethyl)-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0246] 20 g (88.78 mmol) of tert-butyl(1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 3a was dissolved in tetrahydrofuran (200 mL). o Trimethyl(trifluoromethyl)silane 3b (15.15 g, 106.53 mmol) and tetrabutylammonium fluoride (232.12 mg, 0.88 mmol) were added at C, and the mixture was stirred at 60 °C for 16 hours. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate aqueous solution, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phases were separated, 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 tert-butyl(1R,5S)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 3c (21 g, yield: 64.4%).

[0247] Step 2

[0248] tert-butyl (1R,5S)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0249] tert-Butyl(1R,5S)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0250] 21 g (57.15 mmol) of tert-butyl(1R,5S)-3-(trifluoromethyl)-3-((trimethylsilyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 3c was dissolved in methanol (210 mL), and potassium carbonate (15.80 g, 114.29 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (300 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, filtered again, and the filtrate was concentrated under reduced pressure to give 15 g (88.9%) of tert-butyl(1R,5S)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 3d.

[0251] MS m / z (ESI): 240.1 [M-56]

[0252] Step 3

[0253] tert-butyl (1S,5R)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

[0254] tert-Butyl(1S,5R)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester

[0255] tert-butyl(1R,5S)-3-hydroxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 3d (15 g, 50.80 mmol) and 4-dimethylaminopyridine (620 mg, 5.08 mmol) were dissolved in 1,4-dioxane (300 mL) under nitrogen protection. o Thionyl chloride (36.26 g, 304.78 mmol) and pyridine (24.11 g, 304.78 mmol) were added dropwise at C, and the reaction solution was 60... o The reaction was carried out at C for 16 hours. The reaction was quenched by adding 200 mL of saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and washed twice with saturated brine. The organic phases were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane 3e (5 g, yield: 35.5%).

[0256] Step 4

[0257] tert-butyl (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0258] (tert-butyl(1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate)

[0259] (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane 3e (4 g, 14.43 mmol) was dissolved in methanol (50 mL), and palladium on carbon (1.54 g, 10% palladium content) was added. The system was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give tert-butyl(1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 3f (3.4 g, yield: 64.1%).

[0260] Step 5

[0261] (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane

[0262] (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane

[0263] 3f (3.4 g, 10.74 mmol) of tert-butyl(1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate was dissolved in 4M 1,4-dioxane hydrochloride (40 mL), stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain 3 g (2.9 g) of (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane, which was directly used in the next step.

[0264] MS m / z (ESI): 180.1 [M+H] +

[0265] Step 6

[0266] 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[0267] 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide

[0268] 3 g (2.8 g, 15.63 mmol) of (1R,5S)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane was dissolved in 1,4-dioxane (30 mL). The pH of the reaction mixture was adjusted to alkaline by adding N,N-diisopropylethylamine. 1 kJ of sulfonamide (1.8 g, 18.75 mmol) was added, and the reaction mixture was stirred overnight at 95 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide 3h (1.7 g, yield: 42.1%).

[0269] Step 7

[0270] dimethyl ((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)carbonimidodithioate

[0271] (3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)dithiocarbonate

[0272] 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-sulfonamide 3h (1.7 g, 6.58 mmol) was dissolved in N,N-dimethylformamide (25 mL), 0 o Add sodium hydroxide (790 mg, 19.75 mmol) aqueous solution (0.8 mL) and carbon disulfide (802 mg, 10.53 mmol) at temperature C, and then... o Stirred at C for 30 minutes, then added iodomethane (2.15 g, 15.14 mmol), and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (60 mL). The organic phase was washed with saturated brine, separated, 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-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)dithiocarbonate 3i (1.8 g, yield: 75.4%).

[0273] MS m / z (ESI): 363.0 [M+H] +

[0274] Step 8

[0275] methyl (E)-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)carbonochloridoimidothioate

[0276] (E)-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)carbochloroimide methyl thiocarbamate

[0277] (3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)dithiocarbonate 3i (1.6 g, 4.41 mmol) was dissolved in dichloromethane (20 mL), and sulfonyl chloride (1.19 g, 8.83 mmol) was added under nitrogen protection at room temperature. The reaction solution was heated at 40 °C. o Stirred at C for 2 hours. Concentrate under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)carbochloroimide methyl thiocarbamate 3j (1.2 g, yield: 77.5%).

[0278] MS m / z (ESI): 351.1 [M+H] +

[0279] Step 9

[0280] methyl (E)-3-(4-chlorophenyl)-4-phenyl-N-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carbimidothioate

[0281] (E)-3-(4-chlorophenyl)-4-phenyl-N-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxylimide methyl thiocarbamate

[0282] Methyl (E)-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)carbochloroimide thiocarbamate 3j (622 mg, 1.77 mmol) and 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (400 mg, 1.48 mmol) were dissolved in acetonitrile (10 mL), and triethylamine (299 mg, 2.95 mmol) was added. The reaction solution was reacted under nitrogen protection at 90°C. o Stirred at C for 16 hours. Concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: system B) to give methyl (E)-3-(4-chlorophenyl)-4-phenyl-N-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxyimide thiocarbamate 3k (410 mg, yield: 47.4%).

[0283] MS m / z (ESI): 585.1 [M+H] +

[0284] Step 10

[0285] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0286] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide

[0287] N-acetylguanidine 1q (106 mg, 1.05 mmol) and (E)-3-(4-chlorophenyl)-4-phenyl-N-((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxylimide methyl thiocarbamate 3k (410 mg, 0.70 mmol) were dissolved in acetonitrile (6 mL), and triethylamine (213 mg, 2.10 mmol) was added. The reaction mixture was kept under nitrogen protection for 90 °C. o Stirred at C for 16 hours. Concentrated under reduced pressure to give N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide 3.

[0288] MS m / z (ESI): 638.5 [M+H] +

[0289] Example 4: Synthesis of compounds 3A and 3B

[0290] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((exo-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0291] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)((exo-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0292] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((endo-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0293] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)((endo-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminomethanemidyl)acetamide

[0294]

[0295] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)imino)methyl)aminomethamidinyl)acetamide 3 was purified by reverse-phase reaction (mobile phase A: 0.05% TFA / H2O, mobile phase B: acetonitrile) to obtain two fractions, with a retention time of 10.8 min for compound 3A (42 mg, yield: 18.9%) and a retention time of 12.3 min for compound 3B (17 mg, yield: 7.92%).

[0296] Compound 3A: MS m / z (ESI): 638.5 [M+H] +

[0297] 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.79-7.61 (m, 2H), 7.57 (d,J = 8.6 Hz, 2H), 7.35-7.28 (m, 4H), 7.25-7.15 (m, 3H), 4.37 (s, 1H), 4.16 (s,2H), 4.09 (d, J = 12.8 Hz, 1H), 3.09 (s, 1H), 2.75 (d, J = 9.2 Hz, 1H), 2.30-2.05 (m, 6H), 1.96 (d, J = 11.8 Hz, 1H), 1.78-1.54 (m, 6H).

[0298] Compound 3B: MS m / z (ESI): 638.5 [M+H] +

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.50-7.75 (m, 2H), 7.57 (d,J = 8.8 Hz, 2H), 7.33-7.26 (m, 4H), 7.24-7.16 (m, 3H), 4.37 (s, 1H), 4.19-4.02 (m, 3H), 3.08 (s, 1H), 2.59 (s, 1H), 2.38-2.32 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 1.97 (d, J = 10.8 Hz, 1H), 1.57-1.41 (m, 4H).

[0300] Example 5: Synthesis of Compound 5

[0301] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0302] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide

[0303]

[0304]

[0305] first step

[0306] 1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0307] 1,1-Difluoro-6-azaspiro[2.5]octane-6-sulfonamide

[0308] 1,1-Difluoro-6-azaspiro[2.5]octane hydrochloride 5a (commercially available, 5 g, 27.23 mmol) was dissolved in 1,4-dioxane (50 mL), and sulfonamide 1k (commercially available, 3.14 g, 32.68 mmol) and N,N-diisopropylethylamine (3.52 g, 27.23 mmol) were added. The mixture was then heated at 95 °C. o The mixture was stirred at C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system A) to give 1,1-difluoro-6-azaspiro[2.5]octane-6-sulfonamide 5b (6 g, yield: 97.4%).

[0309] Step 2

[0310] dimethyl ((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)sulfonyl)carbonimidodithioate

[0311] (1,1-Difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate

[0312] 1,1-Difluoro-6-azaspiro[2.5]octane-6-sulfonamide 5b (2 g, 8.84 mmol) was dissolved in water (2 mL). oCarbon disulfide (1.08 g, 14.14 mmol) and sodium hydroxide (849 mg, 21.22 mmol) were added at temperature C. After stirring for 0.5 hours, iodomethane (2.89 g, 20.33 mmol) was added, and stirring was continued for 1 hour. Water (200 mL) was added to the reaction 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate 5c (1.44 g, yield: 49.3%).

[0313] MS m / z (ESI): 331.0 [M+H] +

[0314] Step 3

[0315] methyl (Z)-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)sulfonyl)carbonochloridoimidothioate

[0316] (Z)-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate

[0317] (1,1-Difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate 5c (1.44 g, 4.36 mmol) was dissolved in dichloromethane (30 mL), and sulfonyl chloride (1.18 g, 8.72 mmol) was added under nitrogen protection at room temperature. The mixture was stirred at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (Z)-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate 5d (715 mg, yield: 51.4%).

[0318] Step 4

[0319] methyl (E)-3-(4-chlorophenyl)-N-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidothioate

[0320] (E)-3-(4-chlorophenyl)-N-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate

[0321] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (550 mg, 2.03 mmol) was dissolved in acetonitrile (20 mL), and (Z)-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate 5d (712 mg, 2.23 mmol) and triethylamine (617 mg, 6.09 mmol) were added. The mixture was stirred at 90°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system A) to give (E)-3-(4-chlorophenyl)-N-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate 5e (500 mg, yield: 44.5%).

[0322] MS m / z (ESI): 553.2 [M+H] +

[0323] Step 5

[0324] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0325] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide

[0326] N-carbamoylacetamide 1q (146 mg, 1.45 mmol) was dissolved in acetonitrile (5 mL), and triethylamine (219 mg, 2.17 mmol) and (E)-3-(4-chlorophenyl)-N-((1,1-difluoro-6-azaspiro[2.5]oct-6-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate 5e (400 mg, 0.72 mmol) were added. The mixture was heated at 90 °C. o Stirred at C for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase reaction to give N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((1,1-difluoro-6-azaspiro[2.5]octyl-6-yl)sulfonyl)imino)methyl)aminoformamidinyl)acetamide 5 (30 mg, yield: 6.8%).

[0327] MS m / z (ESI): 606.2 [M+H] +

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.43-7.69 (m, 2H), 7.69-7.50 (m, 2H), 7.40-7.11 (m, 7H), 4.53-4.12 (m, 2H), 3.23-2.97 (m, 5H), 2.32-2.08 (m, 4H), 2.06-1.89 (m, 1H), 1.80-1.47 (m, 4H), 1.43-1.10 (m, 2H).

[0329] Example 6: Synthesis of Compound 6

[0330] N-((E)-N'-((Z)-(((6-azaspiro[2.5]octan-6-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)methyl)carbamimidoyl)acetamide

[0331] N-((E)-N'-((Z)-(((6-azaspiro[2.5]oct-6-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)yl)methyl)aminoformamidinyl)acetamide

[0332]

[0333]

[0334] first step

[0335] 6-azaspiro[2.5]octane-6-sulfonamide

[0336] 6-aza[2,5]octane-6-sulfonamide

[0337] 6-aza[2.5]octane hydrochloride 6a (5 g, 33.86 mmol) was dissolved in 1,4-dioxane (60 mL), and N,N-diisopropylethylamine (6 mL) and sulfonamide 1k (6.51 g, 67.73 mmol) were added. The mixture was then heated under nitrogen protection for 95°C. o The mixture was stirred at C for 16 hours. The reaction was monitored by TLC until completion, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 6-aza[2.5]octane-6-sulfonamide 6b (6 g, yield: 20.1%).

[0338] Step 2

[0339] dimethyl ((6-azaspiro[2.5]octan-6-yl)sulfonyl)carbonimidodithioate

[0340] (6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate dimethyl ester

[0341] 6-aza[2.5]octane-6-sulfonamide 6b (1.3 g, 6.83 mmol) was dissolved in N,N-dimethylformamide (2 mL), and carbon disulfide (832 mg, 10.93 mmol) and sodium hydroxide (820 mg, 20.50 mmol) were added. The mixture was then heated at 0°C. oAfter stirring at C for 0.5 hours, iodomethane (2.23 g, 15.72 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. Water (100 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 (150 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 (6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate 6c (1.2 g, yield: 59.6%).

[0342] MS m / z (ESI): 295.1 [M+H] +

[0343] Step 3

[0344] methyl (Z)-((6-azaspiro[2.5]octan-6-yl)sulfonyl)carbonochloridoimidothioate

[0345] (Z)-((6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate

[0346] (6-azaspiro[2.5]oct-6-yl)sulfonyl)dithiocarbonate 6c (500 mg, 1.70 mmol) was dissolved in dichloromethane (30 mL), and sulfonyl chloride (458 mg, 3.40 mmol) was added. The mixture was then heated at 40 °C. o Stirring at C for 2 hours. The reaction was monitored by TLC until it was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to obtain (Z)-((6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate 6d (350 mg, yield: 72.9%).

[0347] MS m / z (ESI): 283.0 [M+H] +

[0348] Step 4

[0349] methyl (E)-N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbimidothioate

[0350] (E)-N-((6-azaspiro[2.5]oct-6-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate

[0351] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (350 mg, 1.29 mmol) was dissolved in acetonitrile (20 mL), and (Z)-((6-azaspiro[2.5]oct-6-yl)sulfonyl)carbochloroimide methyl thiocarbamate 6d (438.70 mg, 1.55 mmol) and triethylamine (261.61 mg, 2.59 mmol) were added. The mixture was heated at 90 °C. o Stirred at 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)-N-((6-azaspiro[2.5]oct-6-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate 6e (600 mg, yield: 89.8%).

[0352] MS m / z (ESI): 517.1 [M+H] +

[0353] Step 5

[0354] N-((E)-N'-((Z)-(((6-azaspiro[2.5]octan-6-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)methyl)carbamimidoyl)acetamide

[0355] N-((E)-N'-((Z)-(((6-azaspiro[2.5]oct-6-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)yl)methyl)aminoformamidinyl)acetamide

[0356] N-carbamoylacetamide 1q (87.99 mg, 0.87 mmol) was dissolved in acetonitrile (5 mL), and triethylamine (176 mg, 1.74 mmol) and (E)-N-((6-azaspiro[2.5]oct-6-yl)sulfonyl)-3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carbonimide methyl thiocarbamate 6e (300 mg, 0.58 mmol) were added. The mixture was stirred at 90 °C for 16 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification (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 give N-((E)-N'-((Z)-(((6-azaspiro[2.5]oct-6-yl)sulfonyl)imino)(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)yl)methyl)aminoformamidinyl)acetamide 6 (33 mg, yield: 9.9%).

[0357] MS m / z (ESI): 570.3 [M+H] +

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.94 (s, 2H), 7.58 (d, J =8.8 Hz, 2H), 7.34-7.28 (m, 4H), 7.26-7.18 (m, 3H), 4.38 (d, J = 4.0 Hz, 1H),4.24 (d, J = 12.8 Hz, 1H), 3.2-3.0 (m, 5H), 2.29-2.19 (m, 1H), 2.15 (s, 3H),2.04-1.92 (m, 1H), 1.39 (d, J = 5.2 Hz, 4H), 0.28 (s, 4H).

[0359] Example 7: Synthesis of Compound 7

[0360] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-cyclopropylidenepiperidin-1-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0361] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0362]

[0363]

[0364] first step

[0365] tert-butyl 4-cyclopropylidenepiperidine-1-carboxylate

[0366] 4-Cyclopropylpiperidine-1-carboxylic acid tert-butyl ester

[0367] (3-Bromopropyl)triphenylphosphine bromide 7a (27.96 g, 60.23 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL). Potassium tert-butoxide (13.52 g, 120.45 mmol) was added under nitrogen protection in an ice bath. After stirring the mixture in an ice bath for 1 hour, 1 g (10 g, 50.19 mmol) of N-tert-butoxycarbonyl-4-piperidinone was added. The reaction mixture was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction mixture was extracted with water (500 mL) and ethyl acetate (300 mL x 3). The organic phase was collected, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to silica gel column chromatography (eluent: system A) to give the yellow liquid product tert-butyl 4-cyclopropylpiperidin-1-carboxylate 7b (7.4 g, 66% yield).

[0368] Step 2

[0369] 4-cyclopropylidenepiperidine

[0370] 4-Cyclopropylpiperidine

[0371] 7b (7.4 g, 33.14 mmol) of 4-cyclopropylpiperidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a colorless liquid product, 7c (4 g), which was used directly in the next step of the reaction.

[0372] Step 3

[0373] 4-cyclopropylidenepiperidine-1-sulfonamide

[0374] 4-Cyclopropylpiperidine-1-sulfonamide

[0375] 4-Cyclopropylpiperidine 7c (4 g, 32.47 mmol) was dissolved in dioxane (60 mL), and sulfonamide 1k (12.48 g, 129.88 mmol) and N,N-diisopropylethylamine (4.20 g, 32.47 mmol) were added. The reaction solution was heated to 95 °C. o The mixture was stirred at C for 16 hours. LCMS showed the appearance of a product peak. The reaction solution was concentrated under reduced pressure and then subjected to silica gel column chromatography (eluent: system A) to give a yellow liquid product 4-cyclopropylpiperidine-1-sulfonamide 7d (3.2 g, yield 48.7%).

[0376] MS m / z (ESI): 203.2 [M+H] +

[0377] Step 4

[0378] methyl ((4-cyclopropylidenepiperidin-1-yl)sulfonyl)carbamate

[0379] (4-Cyclopropylpiperidin-1-yl)sulfonyl)methyl carbamate

[0380] 4-Cyclopropylpiperidin-1-sulfonamide 7d (1 g, 4.94 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.50 g, 14.83 mmol) and methyl chloroformate 7e (700 mg, 7.42 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed a product peak. The reaction mixture was concentrated under reduced pressure to give methyl (4-cyclopropylpiperidin-1-yl)sulfonyl)carbamate 7f (1.1 g), which was used directly in the next step of the reaction.

[0381] MS m / z (ESI): 261.1 [M+H]+

[0382] Step 5

[0383] 3-(4-chlorophenyl)-N-((4-cyclopropylidenepiperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0384] 3-(4-Chlorophenyl)-N-((4-Cyclopropylpiperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide

[0385] 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine 1f (700 mg, 2.59 mmol) was dissolved in toluene (20 mL), and methyl (4-cyclopropylpiperidin-1-yl)sulfonyl)carbamate 7f (1.01 g, 3.88 mmol) was added. The reaction solution was heated at 120 °C. o The mixture was stirred at C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: system A) to give 7 g (1.1 g, yield: 85.2%) of 3-(4-chlorophenyl)-N-((4-cyclopropylpiperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide.

[0386] MS m / z (ESI): 499.2 [M+H] +

[0387] Step 6

[0388] (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-cyclopropylidenepiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

[0389] (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridine-1-onium

[0390] 7 g (1.1 g, 2.20 mmol) of 3-(4-chlorophenyl)-N-((4-cyclopropylpiperidin-1-yl)sulfonyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-carboxamide was dissolved in dichloromethane (30 mL), and phosphorus oxychloride (506 mg, 3.31 mmol) and 4-dimethylaminopyridine (807 mg, 6.61 mmol) were added. The reaction solution was heated to 60 °C. o Stirred at C for 16 hours. LCMS showed a product peak. The reaction solution was concentrated under reduced pressure and prepared by reversed-phase flash chromatography (C18, mobile phase: acetonitrile / water) to give (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridine-1-onium 7h (500 mg, yield 37.5%).

[0391] MS m / z (ESI): 603.2 [M]

[0392] Step 7

[0393] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-cyclopropylidenepiperidin-1-yl)sulfonyl)imino)methyl)carbamimidoyl)acetamide

[0394] N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)aminomethylamidanyl)acetamide

[0395] (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-onium 7h (200 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-carbamoylacetamide 1q (50 mg, 0.49 mmol) and triethylamine (100 mg, 0.99 mmol) were added. The reaction solution was heated at 50 °C. oStirred at C for 16 hours. LCMS showed the reaction was complete. The reaction mixture 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, 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 N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-cyclopropylpiperidin-1-yl)sulfonyl)imino)methyl)aminomethamidinyl)acetamide (60 mg, yield: 31%).

[0396] MS m / z (ESI): 582.1 [M+H] +

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.38-6.94 (m, 9H), 4.40-4.32 (m, 1H), 4.23- 4.14 (m, 1H), 3.13-3.08 (m, 4H), 2.38-2.33 (m, 4H), 2.29-2.17 (m, 2H), 2.15 (s, 3H), 1.98-1.90 (m, 1H), 1.00 (s, 4H).

[0398] Biological evaluation

[0399] Test Example 1: Determination of the cAMP generation function of the compounds of the present invention

[0400] The following methods were 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 cAMPTR-FRET Assay Kit (Bioauxilium, catalog number KIT-CAMP-5000).

[0401] 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, followed by 4 μL of 1X Europium-SA / biotin-cAMP Mix. The plates were mixed 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 its fluorescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was then obtained by performing a nonlinear regression analysis using GraphPad Prism 9 software, with the compound concentration as the logarithm of the inhibition rate. 50 value.

[0402] A: <1 nM, B: 1-10 nM,

[0403]

[0404] 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.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: R 1 R 2 Each was independently selected from C 6-10 aryl or 5-10 heteroaryl, wherein the 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 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic, 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 a Selected from hydrogen atoms, deuterium atoms, fluorine or methyl, preferably, R a It is a hydrogen atom; X is selected from S (=O) r C(=O), C(=S) or S(=O)(=N); R 3 Selected from the following groups: 、 ， Y is selected from C or N, where The atom can be selected from single or double bonds as needed, so that each atom presents a normal valence state; R e 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; Two Rs g Together with the same or different carbon atoms they are attached to, they form a C 2-6 alkenyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 2-6 alkenyl, C 3-8 The cycloalkyl or 3-12-membered heterocyclic group may optionally be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -SF5, =O, -C(=O)R 5 -C(=O)OR 5 -OC(=O)R 5 -NR 6 R 7 -C(=O)NR 6 R 7 -S(=O)2NR 6 R 7 or -N(R) 6 )C(=O)R 7 The substituents are replaced; t is 0, 1, or 2; p is 0, 1, or 2; 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 -C(=O)NR 6 R 7 -C(=O)R 5 C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkyl or 5-12 membered heterocyclic group; wherein the 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, 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 heterocyclic, 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 ; R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, 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; r can be 0, 1, or 2 independently.

2. The compound according to claim 1 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein X is selected from S(=O)2.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R 4 Selected from or R d The definition is as described in claim 1.

4. The compound according to claims 1-3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (II): in, R b 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; m is 0, 1, or 2; R 2 R 3 and R d The definition is as described in claim 1.

5. The compound according to any one of claims 1-4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R 2 It has the following structure: in, R c 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; n is 0, 1, or 2.

6. The compound according to any one of claims 1-5, 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 (III): in, R b Selected from halogens, preferably chlorine; m is 1; R 3 The definition is as described in claim 1.

7. The compound according to any one of claims 1-6, 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 (IV) or (V): in, Y is selected from C or N. The atom can be selected from single or double bonds as needed, so that each atom presents a normal valence state; R b Selected from halogens, preferably chlorine; R e Whether the groups are the same or different, they are each independently selected from halogens, cyano groups, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, -SF5, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Two Rs g Together with the same or different carbon atoms they are attached to, they form a C 2-6 alkenyl, C 3-8 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 2-6 alkenyl, C 3-8 The cycloalkyl or 3-12-membered heterocyclic group may optionally be further selected from one or more atoms selected from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -SF5, =O, -C(=O)R 5 -C(=O)OR 5 -OC(=O)R 5 -NR 6 R 7 -C(=O)NR 6 R 7 -S(=O)2NR 6 R 7 or -N(R) 6 )C(=O)R 7 The substituents are replaced; t is 0, 1, or 2; p is 0, 1, or 2; m is 1.

8. 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 the following groups: , , , , , , , , , , , .

9. The compound according to claim 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof. Selected from .

10. The compound according to claim 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof. Selected from the following groups , , , , , , , , , , .

11. The compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is: 。 12. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1-11 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

13. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the pharmaceutical composition according to claim 12, in the preparation of a CB1 inverse agonist or antagonist.

14. Use of the compound or stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the pharmaceutical composition according to claim 12, 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.

15. The use of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for treating a disease selected from obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis or diabetic nephropathy, preferably obesity, metabolic syndrome or diabetic nephropathy.

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