Amide compounds as NLRP3 inflammasome inhibitors

Abstract

The invention discloses an amide compound as an NLRP3 inflammasome inhibitor, the amide compound is shown as a general formula (I), and the definition of each substituent group is shown in the specification. The derivative can significantly inhibit NLRP3 inflammasome activation, and has a certain treatment effect on diseases driven by NLRP3 inflammasome activation, such as gout, septicemia, Alzheimer's disease, enteritis and the like.

Description

Technical Field

[0001] This application relates to, but is not limited to, the field of pharmaceutical technology, and specifically to amide compounds that can target NLRP3 (Recombinant NLR Family, Pyrin Domain Containing Protein 3) protein to significantly inhibit the activation of NLRP3 inflammasomes, and can be used for drug development for the treatment of NLRP3-driven diseases. Background Technology

[0002] In mammals, the immune system relies on innate and adaptive immunity to protect the host from any external or internal dangers. The innate immune response, as the first line of defense in recognizing infection and initiating pathogen clearance and tissue repair processes, utilizes pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). The inflammasome, as one of the most important complexes in this process, acts as a signaling platform, processing a large number of pathogenic and cellular products associated with stress and injury. The inflammasome is a high-molecular-weight protein complex that, upon activation, induces the activation of inflammatory pro-caspase-1 and the processing of pro-IL-1β. Furthermore, inflammasome activation can promote a form of cell death called pyroptosis.

[0003] NLRP3 is one of the most well-characterized and important inflammasomes, composed of the sensor molecule NLRP3, the adaptor protein ASC, and pro-caspase-1. The NLRP3 protein includes an N-terminal PYD domain, a NACHT domain, and a C-terminal leucine-rich repeating LRR domain. The PYD domain can bind with other PYD domains to form a PYD-PYD complex and activate downstream responses; the NACHT domain contains ATPase activity and is believed to require ATP binding to activate NLRP3; while the LRR domain can form a complex with the mitotic Ser / Thr kinase NEK7, leading to autoinhibition of NLRP3. Unlike other inflammasomes that typically sense specific stimuli, NLRP3 can be activated by a wide range of stimuli, including the most common PAMPs such as bacterial toxins, microorganisms, and lipopolysaccharide (LPS), and can also respond to various damage-associated DAMPs, including uric acid crystals (MSU), alum, silica, and ATP.

[0004] Due to the crucial role NLRP3 plays in various diseases, it has become a highly attractive drug target. NLRP3 agonists can serve as vaccine adjuvants or anti-cancer immunostimulants. NLRP3 inhibitors, on the other hand, hold even greater therapeutic potential in a variety of autoinflammatory and chronic inflammatory diseases, particularly those requiring better treatment options or lacking sufficient alternatives, as most NLRP3 activations play a detrimental role in disease development and progression. Currently, several therapies targeting NLRP3-dependent cytokines are available for therapeutic use. However, compared to inhibitors directly targeting NLRP3, these therapies often suffer from numerous adverse reactions due to a lack of specificity. While several NLRP3-targeting inhibitors have been reported, such as MCC950, CY09, OLT177, trastuzumab, and Oridonin, no specific NLRP3-targeting inhibitors are currently marketed.

[0005] In summary, inhibitors specifically targeting NLRP3 have shown great potential in a variety of diseases. Although there are already some inhibitors targeting NLRP3 inflammasome activation, none of them are currently on the market due to their low activity, significant side effects, and poor drug-likeness. There is an urgent need to develop new, highly active NLRP3 inflammasome inhibitors. Summary of the Invention

[0006] This application provides an amide compound that can significantly inhibit NLRP3 inflammasome activation.

[0007] In a first aspect, this application provides an amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate as shown in general formula (I):

[0008]

[0009] In equation (I), n is 0 or 1;

[0010] Y is -S(O)2-, -C(O)-, or -CH2-;

[0011] A is a substituted C1-C4 alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted aryl ring-fused C3-C6 cycloalkyl group, optionally a substituted heteroaryl ring-fused C3-C6 cycloalkyl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C4-C8 cycloalkyl group, unsubstituted aryl group, substituted aryl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted heteroaryl group, optionally a substituted C2-C6 heterocyclic alkyl group, or optionally a substituted C3-C6 cycloalkyl group. Fused heteroaryl, and specifying that A is not p-tolyl; and, when A is an optionally substituted C3-C6 cycloalkyl, optionally substituted aryl ring fused C3-C6 cycloalkyl, optionally substituted heteroaryl ring fused C3-C6 cycloalkyl, optionally substituted C2-C6 heterocyclic fused C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkyl fused C3-C6 cycloalkyl, optionally substituted C2-C6 heterocyclic fused aryl, optionally substituted C3-C6 cycloalkyl fused aryl, optionally substituted C2-C6 heterocyclic fused heteroaryl, or optionally substituted C3-C6 cycloalkyl fused heteroaryl, in formula (I) for

[0012] R1 is a C2-C3 alkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl; and it is specified that R1 is not 3-tert-butylphenyl, 3-(N,N-diethylcarbamoyl)phenyl, or 4-(morpholino-4-yl)phenyl.

[0013] R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, phenyl, or substituted phenyl.

[0014] R5 is a C2-C3 alkyl group, or R5 and R4 together with the two carbons of the benzene ring to which they are attached form cyclopentene.

[0015] Secondly, this application provides a pharmaceutical composition comprising the above-mentioned amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate.

[0016] Thirdly, this application provides the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates, or the above-mentioned pharmaceutical compositions for use as drugs, particularly NLRP3 protein inhibitors.

[0017] Fourthly, this application provides a combination drug, wherein the above-mentioned amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate, or the above-mentioned drug composition is used in combination with another drug.

[0018] Fifthly, this application provides a method for preventing or treating a disease and / or disorder mediated by overactivation of the NLRP3 inflammasome / NLRP3 protein in a subject, the method comprising administering to the subject a therapeutically effective amount of the aforementioned amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate, or the aforementioned pharmaceutical composition.

[0019] Sixthly, this application provides methods for preparing the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates.

[0020] In an embodiment of the first aspect, this application provides an amide compound or its stereoisomer as represented by general formula (I), a prodrug, a pharmaceutically acceptable salt, a solvate, or a hydrate:

[0021]

[0022] In equation (I), n is 0 or 1;

[0023] Y is -S(O)2-, -C(O)-, or -CH2-;

[0024] A represents a substituted C1-C4 alkyl group, optionally substituted C3-C6 cycloalkyl group, optionally substituted aryl ring-fused C3-C6 cycloalkyl group, optionally substituted heteroaryl ring-fused C3-C6 cycloalkyl group, optionally substituted C2-C6 heterocyclic alkyl group, optionally substituted C4-C8 cycloalkyl group, unsubstituted aryl group, substituted aryl group, optionally substituted C2-C6 heterocyclic alkyl group, optionally substituted C3-C6 cycloalkyl group, optionally substituted heteroaryl group, optionally substituted C2-C6 heterocyclic alkyl group, or optionally substituted C3-C6 cycloalkyl group; here, the substituted C1-C4 alkyl group refers to C1... -C4 alkyl groups are substituted with hydroxyl groups, unsubstituted phenyl groups, or substituted phenyl groups, wherein the substituted phenyl group refers to benzene substituted with one or more groups selected from the following: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; and / or

[0025] The optionally substituted C3-C6 cycloalkyl group is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; wherein, the C3-C6 cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and / or

[0026] The optionally substituted aromatic ring-fused C3-C6 cycloalkyl, the optionally substituted heteroaromatic ring-fused C3-C6 cycloalkyl, the optionally substituted C2-C6 heterocycloalkyl-fused C3-C6 cycloalkyl, or the optionally substituted C4-C8 cycloalkyl-fused C3-C6 cycloalkyl is an unsubstituted aromatic ring-fused C3-C6 cycloalkyl, an unsubstituted heteroaromatic ring-fused C3-C6 cycloalkyl, an unsubstituted C2-C6 heterocycloalkyl-fused C3-C6 cycloalkyl, or an unsubstituted C4-C8 cycloalkyl-fused C3-C6 cycloalkyl, or is selected from the following One or more of the substituted aromatic rings fused to C3-C6 cycloalkyl, heteroaromatic rings fused to C3-C6 cycloalkyl, C2-C6 heterocyclic alkyl fused to C3-C6 cycloalkyl, or C4-C8 cycloalkyl fused to C3-C6 cycloalkyl: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy The aromatic ring fused C3-C6 cycloalkyl group includes, but is not limited to, benzocyclobutyl, benzocyclopentyl, or benzocyclohexyl; the heterocyclic aromatic ring fused C3-C6 cycloalkyl group includes, but is not limited to, furanocyclobutyl, furanocyclopentyl, furanocyclohexyl, thienocyclobutyl, thienocyclopentyl, thienocyclohexyl, and pyridocyclobutyl. The C2-C6 heterocyclic alkyl fused with C3-C6 cycloalkyl groups includes, but is not limited to, tetrahydropyrrolocyclobutyl, tetrahydropyrrolocyclopentyl, tetrahydropyrrolocyclohexyl, tetrahydrofuranolocyclobutyl, tetrahydrofuranolocyclopentyl, tetrahydrofuranolocyclohexyl, piperidinolocyclobutyl, piperidinolocyclopentyl, piperidinolocyclohexyl, piperazinolocyclopentyl, or piperazinolocyclohexyl; the C4-C8 cycloalkyl fused with C3-C6 cycloalkyl groups includes, but is not limited to, cyclobutylolocyclopentyl, cyclopentylolocyclopentyl, cyclohexylolocyclopentyl, or decahydronaphthyl; and / or

[0027] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or

[0028] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; or, The substituted aryl group is a phenyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C2-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; and / or

[0029] The optionally substituted C2-C6 heterocyclic fused aryl group or the optionally substituted C3-C6 cyclic fused aryl group is an unsubstituted C2-C6 heterocyclic fused aryl group or an unsubstituted C3-C6 cyclic fused aryl group, or is a C2-C6 heterocyclic fused aryl group or a C3-C6 cyclic fused aryl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; wherein, the C2-C6 heterocycloalkane-fused aryl group includes, but is not limited to, dihydropyrrolophenyl, dihydrofuranophenyl, dihydrothienophenyl, piperidinophenyl, or piperazinophenyl; the C3-C6 cycloalkane-fused aryl group includes, but is not limited to, cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl, or cyclohexylphenyl; and / or

[0030] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thiophene, furanyl, pyranyl, pyrroleyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indoleyl, indazinyl, indazoleyl, purinel, quinolinyl, naphridinyl, pteridinyl, carbazolyl, acridinel, benzothiadiazolyl, benzofuranyl, pyrazolopyrimidine, or pyrazoloxazine; the substituted heteroaryl group refers to a group substituted by one or more of the following groups: halogen, Hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl and phenyl; and / or

[0031] The optionally substituted C2-C6 heterocyclic fused heteroaryl group or the optionally substituted C3-C6 cyclic fused heteroaryl group is an unsubstituted C2-C6 heterocyclic fused heteroaryl group or an unsubstituted C3-C6 cyclic fused heteroaryl group, or a C2-C6 heterocyclic fused heteroaryl group or a C3-C6 cyclic fused heteroaryl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine). Substituted C1-C4 alkyl, (diC1-C4 alkylamine)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylacyl, (monoC1-C4 alkylamine)-substituted C1-C4 alkylacyl, (diC1-C4 alkylamine)-substituted C1-C4 alkylacyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; wherein, the heteroaryl fused to the C2-C6 heterocycloalkane includes, but is not limited to, dihydropyrrolopyrrolithioyl, dihydropyrrolothiopheneyl, di... Hydropyrrolofuranyl, dihydropyrrolopyrazolyl, dihydropyrrolotriazolyl, dihydrofuranolopyrryl, dihydrofuranolothiophenyl, dihydrofuranolopyrryl, dihydrofuranolopyrazolyl, dihydrofuranolotriazolyl, dihydrothiophene-pyrryl, dihydrothiophene-thiophenyl, dihydrothiophene-furanyl, dihydrothiophene-pyrazolyl, dihydrothiophene-triazolyl, piperidinopyrryl, piperidinothiophenyl, piperidinofuranyl, piperidinopyrazolyl, piperidinotriazolyl, piperazinopyrryl, piperazinothiophenyl, piperazinofuranyl, piperazinopyrazolyl, piperazinotriazolyl, tetra The heteroaryl groups fused with C3-C6 cycloalkane include, but are not limited to, cyclopentyl-pyrrolithyl, cyclohexane-thiophenyl, cyclopentyl-thiophenyl, cyclohexane-pyrazole, cyclopentyl-pyrrolithyl, cyclohexane-thiophenyl, cyclohexane-pyrazole, or cyclohexane-triazole.

[0032] In an embodiment of the first aspect, this application provides an amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate as represented by general formula (I), wherein, in formula (I), R1 is a C2-C3 alkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl; wherein the C2-C3 alkyl is ethyl, n-propyl, or isopropyl; and / or

[0033] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or

[0034] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocycloalkyl, optionally substituted heteroaryl and phenyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: halogen The following groups are listed: hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkylacyl, (mono-C1-C4 alkylamine). The substituted C1-C4 alkylyl group, (diC1-C4 alkylamino)-substituted C1-C4 alkylyl group, C1-C4 alkoxycarbonyl group, C3-C8 cycloalkyl group, C2-C6 heterocycloalkyl group, optionally substituted heteroaryl group, and phenyl group, and specifying that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl, 3-(N,N-diethylcarbamoyl)phenyl, or 4-(morpholino-4-yl)phenyl; and / or

[0035] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the substituted heteroaryl group is: thiophene, furanyl, pyranyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indoleyl, indazinyl, indazoleyl, purinel, quinolinyl, naphthidyl, pteridinyl, carbazolyl, acridineyl, benzothiadiazolyl, benzofuranyl, pyrazolopyrimidine, or pyrazoloxazine; the substituted heteroaryl group refers to a group substituted by one or more of the following groups: halogen, hydroxyl, nitro, ... Cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocyclic alkyl, and phenyl.

[0036] In an embodiment of the first aspect, this application provides an amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate as represented by general formula (I), wherein, in formula (I), R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkylyl, C1-C4 alkoxycarbonyl, phenyl, or substituted phenyl, wherein the substituted phenyl refers to benzene substituted by one or more groups selected from the following: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkylyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkylyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; and

[0037] R5 is a C2-C3 alkyl group, which can be ethyl, n-propyl, or isopropyl; or, R5 and R4, along with the two carbons of the benzene ring to which they are attached, together form cyclopentene.

[0038] In some embodiments of the first aspect, in equation (I), n is 0 and Y is -S(O)2-, that is, equation (I) is equation (I-1):

[0039]

[0040] In equation (I-1), A and R1 to R5 are defined in the same way as in equation (I).

[0041] In some embodiments of the first aspect, in equation (I), n is 0 and Y is -CH2-, that is, equation (I) is equation (I-2):

[0042]

[0043] In equation (I-2), A and R1 to R5 are defined in the same way as in equation (I).

[0044] In some embodiments of the first aspect, in equation (I), n is 1 and Y is -C(O)-, that is, equation (I) is equation (I-3):

[0045]

[0046] In equation (I-3), A and R1 to R5 are defined in the same way as in equation (I).

[0047] In some embodiments of the first aspect, in equation (I), n is 1 and Y is -S(O)2-, that is, equation (I) is equation (I-4):

[0048]

[0049] In equation (I-4), A and R1 to R5 are defined in the same way as in equation (I).

[0050] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), A is a hydroxyl-substituted C1-C4 alkyl, benzyl, phenyl, or substituted phenyl, naphthyl, or substituted naphthyl, thiophene, or substituted thiophene, furanyl, or substituted furanyl, pyranyl, or substituted pyranyl, pyrrole, or substituted pyrrole, thiazolyl, or substituted thiazolyl, oxazolyl, or substituted oxazolyl, imidazole, or substituted imidazole, pyrazolyl, or substituted pyrazolyl, pyridinyl, or substituted pyridinyl, pyrimidinyl, or substituted pyrimidinyl. Pyrimidinyl, pyrazinyl or substituted pyrazinyl, indolyl or substituted indolyl, inazinyl or substituted inazinyl, indazole or substituted indazole, purine or substituted purine, quinolinyl or substituted quinolinyl, naphthidyl or substituted naphthidyl, pteridyl or substituted pteridyl, carbazoyl or substituted carbazoyl, acridineyl or substituted acridineyl, benzothiadiazolyl or substituted benzothiadiazolyl, benzofuranyl or substituted benzofuranyl, or pyrazoloxazine or substituted pyrazoloxazine, and the substituted phenyl, substituted naphthyl, substituted thiophene, substituted Furanyl, substituted pyranyl, substituted pyrroleyl, substituted thiazolyl, substituted oxazolyl, substituted imidazolyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrazinyl, substituted indoleyl, substituted indazinyl, substituted indazoleyl, substituted purineyl, substituted quinolinyl, substituted naphthidyl, substituted pteridinyl, substituted carbazolyl, substituted acridineyl, substituted benzothiadiazolyl, substituted benzofuranyl, or substituted pyrazoloxazine is substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro. The following groups are specified: cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; and it is specified that A is not p-tolyl.

[0051] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), A is hydroxymethyl, hydroxyethyl, benzyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thiophene, substituted thiophene, furanyl, substituted furanyl, pyrazolyl, substituted pyrazolyl, pyridyl, substituted pyridyl, pyrazoloxazine, or substituted pyrazoloxazine, and the substituted phenyl, substituted naphthyl, substituted thiophene, substituted furanyl, ... The substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and it is specified that A is not p-tolyl.

[0052] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridinyl, pyrazoloxazine, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridinyl, or substituted pyrazoloxazine, and the substituted phenyl, substituted thiophene, substituted furanyl, substituted pyridinyl... The azole group, substituted pyridyl group, or substituted pyrazoloxazine group is substituted by one or more groups selected from the following: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and it is specified that A is not p-tolyl.

[0053] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzo[a]cyclobutyl, benzo[a]cyclopentyl, benzo[a]cyclohexyl, furano[a]cyclobutyl, furano[a]cyclopentyl, furano[a]cyclohexyl, thieno[a]cyclobutyl, thieno[a]cyclopentyl, thieno[a]cyclohexyl, pyridin[a]cyclobutyl, pyridin[a]cyclopentyl, pyridin[a]cyclohexyl, tetrahydropyrrolo[a]cyclobutyl, tetrahydropyrrolo[a]cyclopentyl, tetrahydrofuran[a]cyclobutyl, tetrahydrofuran[a]cyclopentyl, tetrahydrofuran[a]cyclohexyl, piperidin[a]cyclobutyl, piperidin[a]cyclopentyl, piperidin[a]cyclohexyl, piperazine[a]cyclopentyl, piperazine[a]cyclohexyl, cyclobutyl[a]cyclopentyl, cyclopentyl[a]cyclohexyl Pentyl, cyclohexyl-cyclopentyl, decahydronaphthyl, dihydropyrrolophenyl, dihydrofuranophenyl, dihydrothiophenophenyl, piperidophenyl, piperazine-phenyl, cyclopropyl-phenyl, cyclobutyl-phenyl, cyclopentyl-phenyl, cyclohexyl-phenyl, dihydropyrrolopyrryl, dihydropyrrolothiophenyl, dihydropyrrolofuranyl, dihydropyrrolopyrazolyl, dihydropyrrolotriazolyl, dihydrofuranopyrryl, dihydrofuranothiophenyl, dihydrofuranopyrryl, dihydrofuranopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, dihydrothiophenopyrryl, piperidinopyrryl, piperidinothiophenyl, piperidinopyrryl, piperidinopyrryl, piperidinotriazolyl Piperazinopyrrole, piperazinothiophene, piperazinofuranyl, piperazinopyrazolyl, piperazinotriazolyl, tetrahydropyranopyrrole, tetrahydropyranothiophene, tetrahydropyranofuranyl, tetrahydropyranopyrazol, tetrahydropyranotriazolyl, oxazacyclohexane-pyrrole, oxazacyclohexane-thiophene, oxazacyclohexane-furanyl, oxazacyclohexane-pyrazolyl, oxazacyclohexane-triazolyl, cyclopentyl-furanyl, cyclohexyl-furanyl, cyclopentyl-thiophene, cyclohexyl-thiophene, cyclopentyl-pyrazolyl, cyclohexyl-pyrazolyl, cyclopentyl-triazolyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, substituted benzocyclobutyl, substituted benzocyclopentyl, etc. Substituted benzocyclohexyl, substituted furanocyclobutyl, substituted furanocyclopentyl, substituted furanocyclohexyl, substituted thienocyclobutyl, substituted thienocyclopentyl, substituted thienocyclohexyl, substituted pyridinocyclobutyl, substituted pyridinocyclopentyl, substituted pyridinocyclohexyl, substituted tetrahydropyrrolocyclobutyl, substituted tetrahydropyrrolocyclopentyl, substituted tetrahydropyrrolocyclohexyl, substituted tetrahydrofuranocyclobutyl, substituted tetrahydrofuranocyclopentyl, substituted tetrahydrofuranocyclohexyl, substituted piperidinocyclobutyl, substituted piperidinocyclopentyl, substituted piperidinocyclohexyl, substituted piperazinocyclopentyl, substituted piperazinocyclohexyl, substituted cyclobutylcyclopentyl, substituted cyclopentylcyclopentyl, substituted decahydronaphthyl,Substituted dihydropyrrolophenyl, substituted dihydrofuranophenyl, substituted dihydrothiophenophenyl, substituted piperidinophenyl, substituted piperazinophenyl, substituted cyclopropylophenyl, substituted cyclobutylophenyl, substituted cyclopentylophenyl, substituted cyclohexylophenyl, substituted dihydropyrrolopyrryl, substituted dihydropyrrolothiophenyl, substituted dihydropyrrolofuranyl, substituted dihydropyrrolopyrazolyl, substituted dihydropyrrolotriazolyl, substituted dihydrofuranopyrryl, substituted dihydrofuranothiophenyl, substituted dihydrofuranofuranyl, substituted... Dihydrofuranopyrazolyl, substituted dihydrofuranotriazolyl, substituted dihydrothiophene-pyrroleyl, substituted dihydrothiophene-thiophenyl, substituted dihydrothiophene-furanyl, substituted dihydrothiophene-pyrazolyl, substituted dihydrothiophene-triazolyl, substituted piperidinopyrroleyl, substituted piperidinothiophenyl, substituted piperidinofuranyl, substituted piperidinopyrazolyl, substituted piperidinotriazolyl, substituted piperazinopyrroleyl, substituted piperazinothiophenyl, substituted piperazinofuranyl, substituted piperazinopyrazolyl, substituted piperazinotriazolyl, substituted tetrahydropyranopyrrole Substituted tetrahydropyranothiophene, substituted tetrahydropyranofurano, substituted tetrahydropyranopyrazole, substituted tetrahydropyranotriazolyl, substituted oxazacyclohexanepyrrole, substituted oxazacyclohexanethiophene, substituted oxazacyclohexanefurano, substituted oxazacyclohexanepyrazole, substituted oxazacyclohexanetriazolyl, substituted cyclopentylfurano, substituted cyclohexylfurano, substituted cyclopentylthiophene, substituted cyclohexylthiophene, substituted cyclopentylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclopentylthiophene, substituted cyclopentylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclopentylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclopentylthiophene, substituted cyclopentylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclopent ... The substituted cyclopentyltriazolyl or substituted cyclohexyltriazolyl, wherein the substituent is selected from one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, oxy, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), for

[0054] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), A is: benzocyclopentyl, pyridocyclopentyl, cyclohexylcyclopentyl, dihydrofuranophenyl, N-methylpiperidinothiophenyl, N-methylpiperazinone-pyrazolyl, oxazacyclohexane-pyrazolyl or piperidinopyrazolyl; and, in formula (I) for

[0055] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), A is one of the following groups:

[0056]

[0057] Moreover, in equations (I), (I-1), (I-2), (I-3), or (I-4) for

[0058] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), A is 4-(2-hydroxy-prop-2-yl)furan-2-yl, thiophen-2-yl, 3-bromothiophen-2-yl, 4-(methoxycarbonyl)thiophen-2-yl, 4-(2-hydroxy-prop-2-yl)thiophen-2-yl, 2-hydroxyethyl, benzyl, phenyl, 3-aminophenyl, 4-acetylphenyl, 4-(N,N-dimethylaminomethyl)phenyl, naphthyl-2-yl, 1,3-dimethyl-pyrazol-4-yl, pyridin-3-yl, 6-bromo-pyridin-2-yl or 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl.

[0059] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R1 is ethyl or isopropyl, R2, R3 and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl or p-tolyl, and R5 is ethyl or isopropyl.

[0060] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R1 is isopropyl, R2, R3 and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl or ethoxycarbonyl, and R5 is isopropyl.

[0061] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R1 is isopropyl, R2, R3 and R4 are each independently hydrogen or nitro, and R5 is isopropyl.

[0062] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R5 and R4, together with the two carbons of the benzene ring to which they are attached, form a cyclopentene; R1 is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, or a substituted heteroaryl; wherein:

[0063] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or

[0064] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocycloalkyl, optionally substituted heteroaryl and phenyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: halogen The following groups are listed: hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkylacyl, (mono-C1-C4 alkylamine). The substituted C1-C4 alkylyl group, (diC1-C4 alkylamino)-substituted C1-C4 alkylyl group, C1-C4 alkoxycarbonyl group, C3-C8 cycloalkyl group, C2-C6 heterocycloalkyl group, optionally substituted heteroaryl group, and phenyl group, and specifying that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl, 3-(N,N-diethylcarbamoyl)phenyl, or 4-(morpholino-4-yl)phenyl; and / or

[0065] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, pyranyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indoleyl, inazinyl, indazoleyl, purinel, quinolinyl, naphthidyl, pteridinyl, carbazolyl, acridineyl, benzothiadiazolyl, benzofuranyl, pyrazolopyrimidine, or pyrazoloxazine; the substituted heteroaryl group refers to a group substituted by one or more of the following groups: halogen, hydroxyl, nitro, cyano. The following compounds are included: alkyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocyclic alkyl, and phenyl; and

[0066] R2 and R3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl, or p-tolyl.

[0067] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R5 and R4, together with the two carbons of the benzene ring to which they are attached, form a cyclopentene; R1 is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, or a substituted heteroaryl; wherein:

[0068] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or

[0069] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino, methyl, ethyl, and trifluoromethyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, The following are specified: propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl or 3-(N,N-diethylaminoformyl)phenyl; and / or

[0070] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or pyrazoloxazine; the substituted heteroaryl group refers to a group that is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl. Ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl; and

[0071] R2 and R3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl, or p-tolyl.

[0072] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), R5 and R4, together with the two carbons of the benzene ring to which they are attached, form a cyclopentene; R1 is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, or a substituted heteroaryl; and / or

[0073] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; wherein:

[0074] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino, methyl, ethyl, and trifluoromethyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, The following are specified: propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl or 3-(N,N-diethylaminoformyl)phenyl; and / or

[0075] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or pyrazoloxazine; the substituted heteroaryl group refers to a group that is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl. Ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl; and

[0076] R2 and R3 are each independently hydrogen or p-tolyl.

[0077] In some embodiments of the first aspect, in formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4), R5 and R4 together with the two carbons of the benzene ring to which they are attached form cyclopentene;

[0078] R1 is p-tolyl, 3,5-dimethylisoxazol-4-yl, pyrimidin-5-yl, thiophene-2-yl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-ethylphenyl, 3-acetylphenyl, 4-cyclohexyloxyphenyl, 4-methoxycarbonylphenyl, 4-chlorophenyl, 4-(pyridin-3-yl)phenyl, 5-fluoro-3-nitrophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, naphth-2-yl, or quinoline-6-yl; and

[0079] R2 and R3 are each independently hydrogen or p-tolyl.

[0080] In some embodiments of the first aspect, equation (I-1) is equation (I-1-1):

[0081]

[0082] The definitions of R1, R2, R3, R4 and R5 in equation (I-1-1) are the same as those in equation (I) or (I-1) above.

[0083] In some embodiments of the first aspect, in formula (I-1-1), R1 is ethyl or isopropyl, R2, R3 and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl or p-tolyl, and R5 is ethyl or isopropyl; or, R1 is isopropyl, and R2, R3 and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxycarbonyl, phenyl or p-tolyl, and R5 is ethyl or isopropyl; or, R1 is isopropyl, and R2, R3 and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl ... The radical is hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, or ethoxycarbonyl, and R5 is isopropyl; or R1 is isopropyl, R2, R3, and R4 are each independently hydrogen or nitro, and R5 is isopropyl; or R1 is isopropyl, R2 is hydrogen or nitro, R3 and R4 are both hydrogen, and R5 is isopropyl.

[0084] In some embodiments of the first aspect, equation (I-1) is equation (I-1-2):

[0085]

[0086] The definitions of R1, R2, and R3 in equation (I-1-2) are the same as those in equation (I) or (I-1) above.

[0087] In some embodiments of the first aspect, R1 and R2 in formula (I-1-2) are each independently a phenyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocyclic alkyl, optionally substituted heteroaryl and phenyl; R3 is hydrogen.

[0088] In some embodiments of the first aspect, R1 and R2 in formula (I-1-2) are each independently p-tolyl, and R3 is hydrogen.

[0089] In some embodiments of the first aspect, R1 in formula (I-1-2) is an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, or a substituted heteroaryl; wherein:

[0090] The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or

[0091] The substituted aryl group is a naphthyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino, methyl, ethyl, and trifluoromethyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, The following are specified: propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl or 3-(N,N-diethylaminoformyl)phenyl; and / or

[0092] The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or pyrazoloxazine; the substituted heteroaryl group refers to a group that is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, Ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl;

[0093] Both R2 and R3 are hydrogen.

[0094] In some embodiments of the first aspect, R1 in formula (I-1-2) is p-tolyl, 3,5-dimethylisoxazol-4-yl, pyrimidin-5-yl, thiophene-2-yl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-ethylphenyl, 3-acetylphenyl, 4-cyclohexyloxyphenyl, 4-methoxycarbonylphenyl, 4-chlorophenyl, 4-(pyridin-3-yl)phenyl, 5-fluoro-3-nitrophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, naphth-2-yl, or quinoline-6-yl;

[0095] Both R2 and R3 are hydrogen.

[0096] In some embodiments of the first aspect, equation (I-1) is equation (I-1-3):

[0097]

[0098] In formula (I-1-3), A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridinyl, pyrazoloxazines, benzocyclopentyl, pyridocyclopentyl, cyclohexylcyclopentyl, dihydrofuranophenyl, piperidinothiophene, piperazinopyrazolyl, oxazacyclohexane-pyrazolyl, piperidinopyrazolyl, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyrazoloxazines, substituted benzocyclopentyl, substituted pyridinocyclopentyl, substituted cyclohexylcyclopentyl, substituted dihydrofuranophenyl, substituted piperidinothiophene, substituted piperazinopyrazolyl, substituted oxazacyclohexane-pyrazolyl, or substituted piperidinopyrazolyl, and the substituted phenyl, substituted thiophene, substituted... The furanyl, substituted pyrazolyl, substituted pyridinyl, substituted pyrazoloxazinyl, substituted benzocyclopentyl, substituted pyridocyclopentyl, substituted cyclohexylcyclopentyl, substituted dihydrofuranophenyl, substituted piperidothiophenyl, substituted piperazinopyrazolyl, substituted oxazacyclohexanepyrazolyl, or substituted piperidopyrazolyl is substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, oxy, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and it is specified that A is not p-tolyl.

[0099] In some embodiments of the first aspect, A in formula (I-1-3) is 4-(2-hydroxy-prop-2-yl)furan-2-yl, thiophen-2-yl, 3-bromothiophen-2-yl, 4-(methoxycarbonyl)thiophen-2-yl, 4-(2-hydroxy-prop-2-yl)thiophen-2-yl, 2-hydroxyethyl, benzyl, phenyl, 3-aminophenyl, 4-acetylphenyl, 4-(N,N-dimethylaminomethyl)phenyl, naphthyl-2-yl, 1,3-dimethyl-pyrazol-4-yl, pyridin-3-yl, 6-bromo-pyridin-2-yl, or 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl.

[0100] In some embodiments of the first aspect, equation (I-2) is equivalent to equation (I-2-1):

[0101]

[0102] In formula (I-2-1), A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridyl, pyrazoloxazine, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, or substituted pyrazoloxazine, and the substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl.

[0103] In some embodiments of the first aspect, A in formula (I-2-1) is 4-(2-hydroxy-prop-2-yl)thiophen-2-yl.

[0104] In some embodiments of the first aspect, equation (I-3) is equivalent to equation (I-3-1):

[0105]

[0106] In formula (I-3-1), A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridyl, pyrazoloxazine, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, or substituted pyrazoloxazine, and the substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl.

[0107] In some embodiments of the first aspect, A in formula (I-3-1) is 4-(2-hydroxy-prop-2-yl)thiophen-2-yl.

[0108] In some embodiments of the first aspect, equation (I-4) is equation (I-4-1):

[0109]

[0110] In formula (I-4-1), A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridyl, pyrazoloxazine, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, or substituted pyrazoloxazine, and the substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl.

[0111] In some embodiments of the first aspect, A in formula (I-4-1) is 4-(2-hydroxy-prop-2-yl)thiophen-2-yl.

[0112] In some embodiments of the first aspect, the amide compounds provided in this application are selected from one of the following compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates:

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] In embodiments of this application, the amide compounds provided herein are obtained in free form or as pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salt" refers to a salt that retains the bioavailability and properties of the compounds of this application, and generally does not refer to a salt that is biologically or otherwise undesirable. In many cases, due to the presence of amino and / or carboxyl groups or similar groups, the compounds of this application are capable of forming acid salts and / or base salts.

[0119] The compounds of this application can be used to form pharmaceutically acceptable acid addition salts with inorganic and organic acids. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. The organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0120] In some embodiments of this application, the amide compounds are provided in the following forms: acetate, ascorbate, adipic acid salt, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, theophylline, citrate, ethanedisulfonate, fumarate, glucuronide, glucuronide, glutamate, glutamate, glycolate, hippurate, hydroiodide / iodide, hydroxyethylsulfonic acid. Salts, lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebates, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, triphenylacetates, trifluoroacetates, or sine salts.

[0121] The amide compounds provided in this application include compounds having general formula (I), compounds having sub-general formulas thereof and example compounds, pharmaceutically acceptable salts thereof, and all stereoisomers (including diastereomers and enantiomers), tautomers, isotopically labeled compounds (including deuterated derivatives), prodrugs, solvates or hydrates thereof.

[0122] This application includes all possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers can be prepared by chiral synthesis or using chiral reagents, or resolved using conventional techniques.

[0123] Any asymmetric atom (e.g., carbon atom, etc.) of one or more compounds of this application may exist in a racemic or enantiomer-enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomer excess in the (R)- or (S)- configuration.

[0124] In an embodiment of the second aspect, this application provides a pharmaceutical composition comprising the above-described amide compound or its stereoisomer, a prodrug, a pharmaceutically acceptable salt, a solvate or hydrate, and a pharmaceutically acceptable excipient or diluent.

[0125] In embodiments of the second aspect, the pharmaceutical composition of this application can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may include inhalation or intranasal administration. The pharmaceutical composition of this application may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets may be coated with a film or enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following excipients: a) a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol; c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone; d) a disintegrant, such as starch, agar, alginate, or its sodium salt, or an effervescent mixture; and e) an absorbent, colorant, flavoring agent, and sweetener. Those skilled in the art may refer, for example, Remington, The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press 2013. The above pharmaceutical composition can be prepared by conventional pharmaceutical methods. The unit dose of the pharmaceutical composition is 0.1 mg to 1 g.

[0126] In the third aspect of the implementation, this application provides the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates, or pharmaceutical compositions thereof, for use as a medicine.

[0127] In some embodiments of the third aspect, this application provides the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates, or the above-mentioned pharmaceutical compositions for use as NLRP3 protein inhibitors.

[0128] In some embodiments of the third aspect, this application provides the use of the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates, or the above-mentioned pharmaceutical compositions in the preparation of a medicament for an NLRP3 protein inhibitor.

[0129] In some embodiments of the third aspect, this application provides the use of the above-mentioned amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of diseases and / or disorders mediated by NLRP3 overactivation.

[0130] In an embodiment of the fourth aspect, this application provides a combination of drugs, wherein the above-mentioned amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate, or the above-mentioned drug composition is used in combination with another drug.

[0131] In an embodiment of the fifth aspect, this application provides a method for preventing or treating a disease and / or disorder mediated by NLRP3 overactivation in a subject, the method comprising administering to the subject a therapeutically effective amount of the aforementioned amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate, or a pharmaceutical composition thereof.

[0132] In the embodiments of the third, fourth, and fifth aspects, the amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate, or hydrate, or the above-mentioned pharmaceutical composition, treats, alleviates, or prevents the occurrence and development of diseases related to NLRP3 overactivation by inhibiting the activation of the NLRP3 inflammasome; the related diseases include central nervous system inflammation and / or peripheral system inflammation. The above-mentioned inflammatory diseases preferably include one or more of the following: type II diabetes, atherosclerosis, fatty liver, metabolic syndrome, acute or chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, ultraviolet-induced sunburn, contact hypersensitivity reactions, sepsis, tumors, neurodegenerative diseases, multiple sclerosis, and Mue-Wei syndrome. Peritonitis and gout are preferably inflammatory diseases caused by the accumulation of urate crystals. Sepsis is preferably an acute peripheral inflammation caused by intraperitoneal injection of bacterial lipopolysaccharide (LPS).

[0133] In the implementation schemes of the third, fourth, and fifth aspects, diseases and / or disorders mediated by NLRP3 overactivation include hereditary NLRP3-dependent autoinflammatory diseases, diseases driven by metabolic dysfunction, diseases caused by crystal or aggregate formation, and fibrosis following acute tissue injury or chronic inflammation, optionally including: Alzheimer's disease, atherosclerosis, asthma and allergic airway inflammation, gout, inflammatory bowel disease, non-alcoholic steatohepatitis / alcoholic steatohepatitis, myocardial infarction, multiple sclerosis or experimental autoimmune encephalitis, oxalate nephropathy, excessive inflammation after influenza infection, graft-versus-host disease, stroke, silicosis, type 2 diabetes, obesity-related inflammation or insulin resistance, rheumatoid arthritis, and contact hypersensitivity reactions.

[0134] In some embodiments of the sixth aspect, this application provides a method for preparing amide compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates as shown in general formula (I), said preparation method comprising the following steps:

[0135] When equation (I) is equation (I-1):

[0136]

[0137] The reaction of compound (I-1′) with compound (I-1″) yields compound (I-1):

[0138]

[0139] Alternatively, when equation (I) is equation (I-2):

[0140]

[0141] The reaction of compound (I-2′) with compound (I-2″) yields compound (I-2):

[0142]

[0143] Alternatively, when equation (I) is equation (I-3):

[0144]

[0145] The reaction of compound (I-3′) with compound (I-3″) yields compound (I-3):

[0146]

[0147] Alternatively, when equation (I) is equation (I-4):

[0148]

[0149] The reaction of compound (I-4′) with compound (I-4″) yields compound (I-4):

[0150]

[0151] In formulas (I-3′) and (I-4′), the substituent X is a hydroxyl group or a halogen; the definitions of substituent A and R1 to R5 in the above general formulas are the same as above.

[0152] In some embodiments of the sixth aspect, this application provides intermediate compounds for preparing amide compounds or stereoisomers thereof, prodrugs, pharmaceutically acceptable salts, solvates or hydrates of general formula (I), including but not limited to:

[0153]

[0154]

[0155] The beneficial effects of this application are manifested in that it exhibits higher NLRP3 inhibitory activity compared to the following compounds:

[0156]

[0157]

[0158] The compound of this application is a novel compound possessing NLRP3 protein inhibitory activity and inhibitory activity against other NLR subtypes such as NLRC4 or AIM2. It can be used as a selective NLRP3 protein inhibitor, thereby enabling its application in the treatment of various diseases related to the NLRP3 protein, such as type II diabetes, atherosclerosis, fatty liver, metabolic syndrome, acute and chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity reactions, sepsis, tumors, neurodegenerative diseases, multiple sclerosis, and Mue-Weir syndrome. Peritonitis and gout are preferably inflammatory diseases caused by the accumulation of urate crystals. Sepsis is preferably acute peripheral inflammation caused by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Furthermore, the compound of this application offers advantages in pharmaceutical use, such as advantages in one or more aspects of its mechanism of action, binding affinity to the NLRP3 protein, inhibitory activity, safety profile, solubility, or bioavailability.

[0159] Experiments have demonstrated that the amide compounds provided in this application exhibit high inhibitory activity and high selectivity against NRLP3 protein in functional experiments. The inhibitory effect of the screened compounds on NLRP3 activation was preliminarily determined in a cell experiment using LPS / MSU-induced PMA-THP-1 activation. In this experiment, the compounds of this application showed a half-maximal inhibitory concentration (IC50) against NLRP3 activation-induced IL-1β secretion. 50 The concentrations ranged from 10 μM to 800 nM. In addition, the targeting of the compound to NLRP3 was verified by immunoblotting and surface plasmon resonance (SPR) techniques, and the activity of the compound was verified by mouse models of peritonitis, acute arthritis, and sepsis.

[0160] the term

[0161] As used herein, the term "subject" refers to mammals, primates (e.g., humans (male or female)), dogs, rabbits, guinea pigs, pigs, rats, and mice. In some embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0162] As used herein, the term “treatment” for any disease or disorder means relief or improvement of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or improvement of at least one physical parameter or biomarker associated with the disease or disorder, including physical parameters or biomarkers that the subject may not be able to identify.

[0163] As used herein, the term “prevention” for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0164] As used in this article, a subject is considered "needing" treatment if they would benefit from it biologically, medically, or in terms of quality of life.

[0165] As used herein, the term "therapeuticly effective amount" of the compound of this application refers to the amount of the compound of this application that will induce a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.).

[0166] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the embodiments described in the description and the accompanying drawings. Attached Figure Description

[0167] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0168] Figure 1 The results shown are the cytotoxicity test results of compounds SCB022-024, SCB036, SCB038, and SCB040 of this application.

[0169] Figure 2 The results shown are the cytotoxicity test results for compound SCB042 of this application;

[0170] Figure 3 The illustration shows the effect of immunoblotting analysis on the expression of key proteins related to NLRP3 activation.

[0171] Figure 4 The illustration shows the effect of immunoblotting analysis on the effect of the compound SCB042 of this application on NLRP3 activation induced by stimuli from different sources;

[0172] Figure 5The illustration shows the effect of immunoblotting analysis on the activation of other inflammasomes (AIM2 and NLRC4) triggered by poly(dA:dT) and S.thpyi;

[0173] Figure 6 This demonstrates that compound SCB042 of this application does not affect ROS production or mitochondrial damage. ROS and mitochondria were stained using (A) MitoSOX and (B) MitoTracker and analyzed under confocal microscopy.

[0174] Figure 7 The results shown are the SPR binding test results of compound SCB042 of this application with NLRP3;

[0175] Figure 8 The illustration shows that the compound SCB042 of this application can reduce the expression of IL-1β in mice with gouty peritonitis;

[0176] Figure 9 The illustration shows that the compound SCB042 of this application can relieve ankle swelling and pain in mice with gouty arthritis. Figure 9 In the middle (A, B), the changes in VF pain threshold (A) and AUC (B) in arthritic mice after treatment with PBS or SCB042 are shown. Figure 9 In the middle (C, D), the changes in ankle joint diameter (C) and AUC (D) are shown in different groups of arthritic mice.

[0177] Figure 10 This application demonstrates that compound SCB042 significantly improves cognitive function in mice, wherein... Figure 10 (A) shows the mouse's movement trajectory. Figure 10 (B) represents the time required for the mouse to find the island platform. Detailed Implementation

[0178] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.

[0179] The following examples are provided to further illustrate this application and do not constitute any limitation on this application.

[0180] NMR data were measured using a Bruker Avance III 400 NMR spectrometer with TMS (tetramethylsilane) as the internal standard; NMR data were processed using mestReNova (Ver. 6.1.0, mestrelab Research SL) software; high-resolution mass spectrometry (ESI-TOF-MS) data were measured using a Bruker Apex IV FTMS Fourier transform ion cyclotron conversion mass spectrometer.

[0181] Thin-layer chromatography silica gel plates: GF254, Shanghai Shangbang Industrial Co., Ltd.; Column chromatography silica gel: 200-300 mesh, Shanghai Shangbang Industrial Co., Ltd.

[0182] Unless otherwise stated, all solvents, raw materials and reagents are commercially available analytical grade.

[0183] Chemical synthesis methods

[0184] The synthesis of compounds SCB001-008 and SCB015 is as follows (Route 1): Starting with commercially available ethyl 5-aminosulfonylfuran-3-carboxylate (IIIA-1), intermediate IIIA-2 was obtained by two nucleophilic attacks on the ester group using Grignard reagent followed by hydrolysis, yielding 85% yield. Then, different commercially available substituted amines (IIIA-(3-11)) were selected and reacted with triethylamine using triphosgene to generate different isocyanates (IIIA-(12-20)). Finally, the reaction of IIIA-2 with the synthesized isocyanates yielded the target products SCB001-008 and SCB015, as shown in the reaction route below:

[0185]

[0186] Synthetic routes of routes 1-SCB001-008 and SCB015, reaction reagents and conditions: (i) methyl magnesium chloride, dichloromethane, 0℃ to room temperature, 10h; (ii) triphosgene, triethylamine, tetrahydrofuran, 0℃, 1h; (iii) sodium hydride, tetrahydrofuran, room temperature, 12h.

[0187] The synthesis of compounds SCB017-025, SCB027, and SCB029-040 is as follows (Route 2): Starting with commercially available IIIC-1, acetylation in acetic anhydride yields intermediate IIIC-2, followed by 5-bromination with 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride and NBS to give the 5-brominated product IIIC-3. IIIC-3 is deacetylated in hydrochloric acid to give intermediate IIIC-4, which is then Suzuki coupled with different substituted phenylboronic acids IIIC-(5-26) to give different aromatic amine intermediates IIIC-(27-48). The aromatic amines react with triphosgene to give isocyanate intermediates IIIC-(49-70), which then react with the synthesized intermediate IIIA-2 to obtain the target products SCB017-025, SCB027, and SCB029-040. The reaction route is as follows:

[0188]

[0189] Synthetic routes for routes 2-SCB017-025, SCB027, and SCB029-40, reaction reagents and conditions: (i) Acetic anhydride, triethylamine, dichloromethane, 0°C to room temperature, 1 h; (ii) Palladium acetate (Pd(OAc)2), N-bromosuccinimide (NBS), p-toluenesulfonic acid, toluene, room temperature, 6 h; (iii) Hydrochloric acid, ethanol, 80°C, 48 h; (iv) Substituted boric acid or borate ester, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (Pd(dppf)Cl2), potassium carbonate, dioxane / water, 80°C, 12 h; (v) Triphosgene, triethylamine, tetrahydrofuran, 0°C, 1 h; (vi) Sodium hydride, tetrahydrofuran, room temperature, 12 h.

[0190] The synthetic methods for compounds SCB041-047 and SCB049-057 are as follows (Route 3): Starting with synthesized IIIC-46, it reacts with triphosgene to obtain the isocyanate intermediate IIID-1, which is then reacted with synthetic or commercially available sulfonamide IIID-(2-17) to obtain the target products SCB041-047 and SCB049-057. The reaction route is as follows:

[0191]

[0192]

[0193] Synthetic routes of routes 3-SCB041-047 and SCB049-057, reaction reagents and conditions: (i) triphosgene, triethylamine, tetrahydrofuran, 0℃, 1h; (ii) R-SO2NH2, sodium hydride, tetrahydrofuran, room temperature, 12h.

[0194] In Route 3, intermediates IIID-2, IIID-3, IIID-6, IIID-11, and IIID-17 are obtained through synthesis. The synthesis methods for each intermediate (Route 4) are briefly described below:

[0195] Intermediates IIID-2 and IIID-3 were prepared from commercially available methyl thiophene-3-carboxylate (IIID-18) and reacted sequentially with chlorosulfonic acid, pyridine, and phosphorus pentachloride to yield intermediate IIID-19. Then, sulfonyl chloride was converted to sulfonamide intermediate (IIID-2) under ammonium bicarbonate and acetone / water conditions. IIID-2 reacted with methyl magnesium bromide to yield intermediate IIID-3.

[0196] Intermediate IIID-6 was prepared from commercially available 1,3-dimethyl-1H-pyrazole-4-amine (IIID-20) as a diazonium salt intermediate using hydrochloric acid / sodium nitrite conditions. This intermediate was then added to an aqueous solution containing cuprous chloride thionyl chloride to prepare intermediate IIID-21. This intermediate was dissolved in tetrahydrofuran, and ammonia gas was introduced into the solution to obtain intermediate IIID-6.

[0197] Intermediate IIID-11 was prepared by using commercially available 4-methylbenzenesulfonamide (IIID-22) as a starting material and reacting it with dimethylamine under AIBN / NBS conditions to obtain intermediate IIID-23, which was then reacted with dimethylamine to obtain intermediate IIID-11.

[0198] Intermediate IIID-17 was prepared using commercially available 1,2-dihydro-3H-pyrazol-3-one (IIID-24) as a starting material. Potassium carbonate was used as a base, and the mixture underwent a cyclization reaction with 1,3-dibromopropane at 130°C to give intermediate IIID-25. IIID-25 was then added dropwise to chlorosulfonic acid and reacted at 80°C to give chlorosulfonic acid intermediate IIID-26. Finally, it was converted to intermediate IIID-17 using ammonia. The reaction route is as follows:

[0199]

[0200] Route 4 - Synthetic route of intermediates IIID-2, IIID-3, IIID-6, IIID-11 and IIID-17, reaction reagents and conditions: (i) (1) Chlorosulfonic acid, dichloromethane, 0℃ to room temperature, 3h; (2) Pyridine, phosphorus pentachloride, 0℃ to room temperature, 3h; (ii) Ammonium bicarbonate, acetone:water = 1:3, 12h; (iii) Methyl magnesium bromide, tetrahydrofuran, 0℃ to room temperature, 10h; (iv) (1) Hydrochloric acid, sodium nitrite, water, -5℃, 15min; (2) Dichloromethane, sodium nitrite, sodium nitrite, water, -5℃, 15min. Sulfone, water, cuprous chloride, -5°C to room temperature and then to -5°C overnight; (v) ammonia, tetrahydrofuran, room temperature, 12 h; (vi) azobisisobutyronitrile, N-bromosuccinimide, carbon tetrachloride, reflux, 80°C, 6 h; (vii) dimethylamine, potassium carbonate, N,N-dimethylformamide, 0°C to room temperature, 12 h; (viii) potassium carbonate, N,N-dimethylformamide, 130°C, 8 h; (ix) chlorosulfonic acid, 0°C to 80°C, 6 h; (x) ammonia, tetrahydrofuran, room temperature to 60°C, 3 h.

[0201] The synthesis of compounds SCB058-059 and SCB061-062 is as follows (Route 5): Starting with the previously synthesized intermediate IIIC-46, an amide condensation reaction was carried out with 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid under EDCI / DMAP conditions to give intermediate IIIE-3. Then, under acidic conditions, the Boc protecting group was removed to give intermediate IIIE-4. IIIE-4 underwent an amide condensation reaction with IIIE-2 to give SCB061, which was then treated with methylmagnesium chloride to give SCB058. IIIE-4 and IIID-19 underwent a nucleophilic substitution reaction in the presence of pyridine to give SCB062, which was then treated with methylmagnesium chloride to give SCB059. Intermediate IIIE-2 was obtained by oxidation reaction with Jones' reagent using commercially available methyl 5-formylthiophene-3-carboxylate (IIIE-1), which was readily available.

[0202]

[0203] Synthetic routes 5-SCB058-059 and SCB061-062, reaction reagents and conditions: (i) Jones oxidant, acetone, 0°C to room temperature, 1 h; (ii) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 4-dimethylaminopyridine (DMAP), dichloromethane, room temperature, overnight; (iii) tetrahydrofuran / hydrochloric acid, room temperature; (iv) II IE-2,2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide, room temperature, 2 h; (v) methyl magnesium chloride, 0 °C to room temperature, 1 h; (vi) IIID-19, pyridine, 0 °C to 60 °C, 4 h; (vii) methyl magnesium chloride, 0 °C to room temperature, 1 h.

[0204] The synthesis of compounds SCB060 and SCB063 is as follows (route 6): Starting with commercially available methyl 5-methylthiophene-3-carboxylate IIIF-1, a Wohl-Ziegler reaction was carried out under AIBN / NBS conditions to give intermediate IIIF-2. This intermediate then underwent nucleophilic substitution with a methanol solution of ammonia to give intermediate IIIF-3. IIIF-3 underwent an amide condensation reaction with previously prepared IIIC-46 to give SCB063, which was then treated with methylmagnesium chloride to obtain SCB060. The reaction route is as follows:

[0205]

[0206] Synthetic routes of route 6-SCB063 and SCB060, reaction reagents and conditions: (i) azobisisobutyronitrile, N-bromosuccinimide, carbon tetrachloride, reflux, 6h; (ii) ammonia / methanol, 45℃, 12h; (iii) (1) intermediate IIIC-46, triphosgene, triethylamine, tetrahydrofuran, 0℃, 1h; (2) triethylamine, tetrahydrofuran, room temperature, 12h; (iv) methylmagnesium chloride, 0℃ to room temperature, 1h.

[0207] Examples 1-9

[0208] General synthesis methods for SCB001-008 and SCB015

[0209] Preparation of intermediate 4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (IIA-2)

[0210]

[0211] Ethyl 5-aminosulfonylfuran-3-carboxylate (4 g, 1 eq.) was placed in a 250 mL three-necked round-bottom flask and dissolved in 100 mL of tetrahydrofuran under nitrogen purging protection. MeMgCl₂ (10.88 g, 5 eq.) was added dropwise with stirring at 0 °C, and the mixture was stirred at room temperature for 10 hours. After the reaction was complete as monitored by TLC, 50 mL of saturated NH₄Cl was added to quench the reaction. The organic layers were extracted with ethyl acetate and combined, dried over anhydrous Na₂SO₄, and the solvent was removed by rotary evaporation. The mixture was then stirred and separated by column chromatography to give a pale yellow solid in 78% yield. 1 HNMR (400MHz, DMSO-d6) δ7.70-7.65 (m, 3H), 6.95 (d, J = 1.1Hz, 1H), 5.08 (s, 1H), 1.39 (s, 6H).

[0212] Preparation of derivatives of intermediate isocyanate (IIIA-(12-20))

[0213]

[0214] Triphosgene (108 g, 1 eq.) was dissolved in 10 mL of tetrahydrofuran, and an amine derivative (IIIA-(3-11))(3 eq.) dissolved in dichloromethane was added dropwise. Then, triethylamine (0.3 mL, 6 eq.) was added dropwise. After reacting overnight, the reaction was monitored by TLC until completion. The solution was evaporated to dryness, washed with ethyl acetate / petroleum ether (1:1), filtered, and the filtrate was evaporated to dryness to obtain the crude isocyanate intermediate IIIA-(12-20), which was directly used in the next reaction.

[0215] Preparation of final products SCB001-008 and SCB015

[0216]

[0217] Intermediate IIIA-2 (200 mg, 1 eq.) was added to 10 mL of tetrahydrofuran. Sodium hydride (38 mg, 1 eq.) was added under nitrogen protection and an ice-water bath, and the reaction was carried out for 30 min. Isocyanate derivative IIA-(12-20)(1 eq.) was added and the reaction was carried out at room temperature for 12 h. After the reaction was completed by TLC monitoring, methanol was added to quench the reaction, the solvent was removed by rotary evaporation, the sample was mixed, and column chromatography was performed to separate the samples (petroleum ether: ethyl acetate = 5:1 to petroleum ether: ethyl acetate: acetic acid = 200:100:1) to obtain white solids SCB001-008 and SCB015.

[0218] Preparation of the final product N-((3,4-dimethylphenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB001 - Example 1): It was prepared from 4-isocyano-1,2-dimethylbenzene (IIIA-12), as a white solid with a yield of 41%. Mp 110-112℃. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.62(s,1H),7.80(s,1H),7.27(s,1H),7.15(s,1H) ,7.07(s,1H),7.02(d,J=8.1Hz,1H),5.13(s,1H),2.16(s,3H),2.14(s,3H),1.40(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 148.78, 146.93, 144.04, 142.08, 140.69, 139.89, 138.52, 137.23, 135.60, 135.13, 134.38, 130.37, 130.09, 129.24, 128.55, 128.25, 128.17, 124.32, 116.73, 66.62, 32.69, 31.02, 30.94, 24.65, 20.76, 20.57. HRMS (ESI-TOF-) Theoretical value C 16 H 20 N2O5S[MH] - m / z 351.1015, measured value 351.1007.

[0219] Preparation of the final product N-((2,6-dimethylphenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB002 - Example 2): It was prepared from 2-isocyano-1,3-dimethylbenzene (IIIA-13), as a white solid with a yield of 41%. Mp 80-81℃. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.99 (s, 1H), 7.82 (d, J = 1.0Hz, 1H), 7.26 (d, J = 1.0Hz, 1H), 7.10–7.02 (m, 3H), 5.13 (s, 1H), 2.06 (s, 6H), 1.38 (s, 6H). ¹³C NMR (100MHz, DMSO-d⁶) δ 149.51, 147.80, 142.39, 137.63, 136.09, 134.27, 128.24, 127.32, 116.90, 67.04, 31.42, 18.28. HRMS (ESI-TOF-) Theoretical C 16 H 20N2O5S[MH] - m / z 351.1015, measured value 351.1017.

[0220] Preparation of the final product N-((2,3-dihydro-1H-indene-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB003 - Example 3): Obtained from 4-isocyano-2,3-dihydro-1H-indene (IIIA-14), white solid, yield 41%. Mp 1550-151℃. 1 H NMR (400MHz, DMSO-d6) δ11.48-10.42(m,1H),8.14(s,1H),7.80(s,1H),7.50(d,J=7.9Hz,1H),7.27(s,1H),7.05(t,J=7 .5Hz,1H),6.94(d,J=7.8Hz,1H),5.13(s,1H),2.91-2.79(m,2H),2.79-2.65(m,2H),2.16-1.81(m,2H),1.39(s,6H).13C NMR (100MHz, DMSO-d6) δ 149.36, 147.95, 145.24, 142.45, 137.56, 134.33, 134.02, 127.31, 120.21, 117.85, 116.92, 67.00, 33.16, 31.36, 30.12, 24.81. HRMS (ESI-TOF-) Theoretical value C 17 H 20 N2O5S[MH] - m / z 363.1015, measured value 363.1012.

[0221] Preparation of the final product N-((3,5-dichlorophenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB004 - Example 4): Prepared from 1,3-dichloro-5-isocyanobenzene (IIIA-15), white solid, yield 41%. Mp 126-128℃. 1 H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 7.85-7.79 (m, 1H), 7.46 (d, J = 1.8Hz, 2H), 7.30 (s, 1H), 7.24 (t, J = 1.7Hz, 1H), 1.40 (s, 6H). 13C NMR (100MHz, DMSO-d6) δ 149.16, 147.19, 142.19, 140.56, 137.18, 134.14, 122.55, 117.34, 116.80, 66.53, 30.89. HRMS (ESI-TOF-) Theoretical value C 14 H 14 Cl2N2O5S[MH] - m / z 390.9922, measured value 390.9922.

[0222] Preparation of the final product N-((2,6-diisopropylphenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB005 - Example 5): It was prepared from 2-isocyano-1,3-diisopropylbenzene (IIIA-16), as a white solid with a yield of 41%. Mp 74-75℃. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.93(s,1H),7.82(d,J=1.0Hz,1H),7.28-7.24(m,1H),7.24-7. 22(m,1H),7.12(d,J=7.7Hz,2H),5.14(s,1H),2.93(p,J=6.9Hz,2H),1.37(s,6H),1.19-0.92(m,12H). 13 C NMR (100MHz, DMSO-d6) δ 150.63, 147.57, 146.74, 142.40, 137.59, 131.45, 128.38, 123.50, 117.01, 67.06, 31.46, 28.49. HRMS (ESI-TOF-) theoretical value C 20 H 28 N2O5S[MH] - m / z 407.1641, measured value 407.1644.

[0223] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-(2,4,6-trimethylphenylcarbamoyl)furan-2-sulfonamide (SCB006 - Example 6): It was prepared from 2-isocyano-1,3,5-trimethylbenzene (IIIA-17), as a white solid with a yield of 41%. Mp 83-85℃. 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),7.90(s,1H),7.82(s,1H),7.28(s,1H) ,6.86(s,2H),5.16(s,1H),2.21(s,3H),2.03(s,6H),1.41(d,J=3.5Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ 149.63, 147.82, 142.36, 137.63, 136.39, 135.76, 131.62, 128.82, 116.89, 67.05, 31.41, 20.92, 18.21. HRMS (ESI-TOF-) theoretical value C 17 H 22 N2O5S[MH] - m / z 365.1171, measured value 365.1178.

[0224] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((2,4,6-tri-tert-butylphenyl)carbamoyl)furan-2-sulfonamide (SCB007 - Example 7): Prepared from 1,3,5-tri-tert-butyl-2-isocyanobenzene (IIIA-18), white solid, yield 41%. Mp 185-186℃. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),7.77(s,1H),7.55(s,1H),7.29(s,2H),7.18(s,1H),5.11(s,1H),1.35(s,6H),1.24(d,J=9.4Hz,27H). 13 C NMR (100MHz, DMSO-d6) δ 150.63, 149.08, 148.84, 147.14, 142.42, 137.59, 130.25, 122.75, 117.71, 67.09, 36.21, 35.03, 32.01, 31.63, 31.49. HRMS (ESI-TOF-) Theoretical value C 26 H 40 N2O5S[MH] - m / z 491.2580, measured value 491.2573.

[0225] Preparation of the final product N-((2,6-diisopropyl-3-nitrophenyl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB008 - Example 8): Obtained from 2-isocyano-1,3-diisopropyl-4-nitrobenzene (IIIA-19), white solid, yield 41%. Mp 108-109℃. 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),8.18(s,1H),7.82(s,1H),7.60(d,J=8.4Hz,1H),7.38(d,J =8.4Hz,1H),7.24(s,1H),3.24-3.06(m,1H),3.01-2.84(m,1H),1.37(s,6H),1.19-1.02(m,12H). 13 C NMR (100MHz, DMSO-d6) δ 152.08, 150.34, 149.28, 146.90, 142.06, 137.61, 137.19, 133.57, 124.88, 123.07, 116.84, 66.60, 31.00, 28.30, 23.38, 22.57, 20.62, 20.08. HRMS (ESI-TOF-) Theoretical value C 20 H 27 N3O7S[MH] - m / z 452.1491, measured value 452.1489.

[0226] Preparation of the final product N-((5,6-di-p-tolyl-2,3-dihydro-1H-indene-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB015 - Example 9): Obtained from 4-isocyano-5,6-di-p-tolyl-2,3-dihydro-1H-indene (IIIA-20), white solid, yield 41%. Mp 119-121℃. 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.89(s,1H),7.48(s,1H),7.26(s,1H),7 .12(s,1H),7.04(d,J=7.9Hz,2H),6.94(d,J=7.9Hz,2H),6.86(d,J=8.0Hz,2H), 6.77(d,J=7.7Hz,2H),5.16(s,1H),2.93(t,J=7.4Hz,2H),2.61(t,J=7.4Hz,2H ),2.27(d,J=7.5Hz,3H),2.19(s,3H),2.02-1.96(m,2H),1.42(d,J=6.4Hz,6H).13 C NMR (100MHz, DMSO-d6) δ 148.78, 146.93, 144.04, 142.08, 140.69, 139.89, 138.52, 137.23, 135.60, 135.13, 134.38, 130.37, 130.09, 129.24, 128.55, 128.25, 128.17, 124.32, 116.73, 66.62, 32.69, 31.02, 30.94, 24.65, 20.76, 20.57. HRMS (ESI-TOF-) Theoretical value C 31 H 32 N2O5S[MH] - m / z 543.1954, measured value 543.1953.

[0227] Examples 10-31

[0228] General synthetic method for final products SCB017-025, SCB027 and SCB029-040

[0229] Preparation of intermediate N-(2,3-dihydro-1H-inden-4-yl)acetamide (IIIC-2)

[0230]

[0231] 2,3-Dihydro-1H-indene-4-amine (IIIC-1, 300 mg, 1 eq.) was dissolved in 10 mL of dichloromethane and added to a round-bottom flask. Triethylamine (395 mg, 1.3 eq.) was then added dropwise at 0 °C. Acetic anhydride (352 mg, 1.15 eq.) was added dropwise simultaneously. After completion, the temperature was raised to room temperature and the reaction was allowed to proceed for 1 h. After the reaction was complete as monitored by TLC, the mixture was diluted with water, extracted with dichloromethane, and the organic layers were combined, dried, filtered, and concentrated to obtain a white solid in 100% yield. 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.0Hz,1H),7.15(t,J=7.7Hz,1H),7.02(d,J=7.5Hz,1H),6. 95(s,1H),2.95(t,J=7.5Hz,2H),2.81(t,J=7.4Hz,2H),2.19(s,3H),2.11(p,J=7.5Hz,2H).

[0232] Preparation of intermediate N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (IIIC-3)

[0233]

[0234] IIIC-2 (200 mg, 1 eq.), palladium acetate (12 mg, 0.05 eq.), and p-toluenesulfonic acid (108 mg, 1 eq.) were dissolved in 10 mL of toluene and stirred at room temperature for 30 minutes. Then, NBS (224 mg, 1.1 eq.) was added in portions and stirred for 6 hours. After the reaction was complete as monitored by TLC, the solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give a white solid in 59% yield. 1 H NMR (400MHz, CDCl3) δ7.33 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 2.88 (dt, J = 15.6, 7.4 Hz, 4H), 2.21 (s, 3H), 2.07 (q, J = 7.5 Hz, 2H).

[0235] Preparation of intermediate 5-bromo-2,3-dihydro-1H-inden-4-amine hydrochloride (IIIC-4)

[0236]

[0237] Intermediate IIIC-3 (2 g) was dissolved in 10 mL of ethanol solution, then 15 mL of concentrated hydrochloric acid was added dropwise and the temperature was raised to 80 °C. After reacting for 48 h, the mixture was cooled to room temperature, filtered, the filter cake was washed with cold water, and dried to obtain a white solid product with a yield of 59%. 1 HNMR (400MHz, DMSO-d6) δ7.51-7.23(m,2H),7.19(dd,J=8.1,2.6Hz,1H),6.57(t,J=6.4Hz,1H),2.78(dd,J=8.5,6.2Hz,4H),2.00(p,J=7.6Hz,2H).

[0238] Preparation of intermediate aromatic amine derivatives (IIIC-(27-48))

[0239]

[0240] Intermediate IIIC-4 (420 mg, 1 eq.), potassium carbonate (747 mg, 3.2 eq.), boric acid derivatives with different substitutions (IIIC-(5-26), 1.2 eq.), and Pd(dppf)Cl2 (129 mg, 0.053 eq.) were placed in a Shrek reaction tube and a mixed solvent of dioxane:water = 5:1 was added. Under argon protection, the mixture was heated to 80 °C and stirred for 12 h. After the reaction was completed by TLC monitoring, the mixture was filtered and extracted with ethyl acetate. The organic layers were combined, dried, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain intermediate IIIC-(27-48).

[0241] Preparation of intermediate 5-(p-Tolyl)-2,3-dihydro-1H-inden-4-amine (IIIC-27): prepared from p-tolylboronic acid (IIIC-5). White solid, yield 73%. 1 H NMR (400MHz, DMSO-d6) δ7.30-7.21(m,4H),6.77(d,J=7.5Hz,1H),6.55(d,J=7.5Hz,1H),4. 39 (s, 2H), 2.82 (t, J = 7.5Hz, 2H), 2.69 (t, J = 7.3Hz, 2H), 2.34 (s, 3H), 2.02 (p, J = 7.5Hz, 2H).

[0242] Preparation of intermediate 5-(3,5-dimethylisoxazol-4-yl)-2,3-dihydro-1H-inden-4-amine (IIIC-28): prepared from (3,5-dimethylisoxazol-4-yl)boronic acid (IIIC-6). White solid, yield 53%. 1 H NMR (400MHz, CDCl3) δ6.80 (d, J=7.6Hz, 1H), 6.72 (d, J=7.6Hz, 1H), 3.50 (s, 2H) ,2.96(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),2.30(s,3H),2.19-2.12(m,5H).

[0243] Preparation of intermediate 5-(pyrimidin-5-yl)-2,3-dihydro-1H-inden-4-amine (IIIC-29): prepared from (pyrimidin-5-yl)boronic acid (IIIC-7). White solid, yield 35%. 1H NMR (400MHz, CDCl3) δ9.18(s,1H),8.87(s,2H),6.93(d,J=7.6Hz,1H),6.81(d,J=7.6 Hz, 1H), 3.64 (s, 2H), 3.04-2.91 (m, 2H), 2.78 (t, J = 7.4Hz, 2H), 2.18 (p, J = 7.6Hz, 2H).

[0244] Preparation of intermediate 5-(thien-2-yl)-2,3-dihydro-1H-inden-4-amine (IIIC-30): prepared from (thien-2-yl)boronic acid (IIIC-8). A colorless oily substance, yield 40%. 1 H NMR (400MHz, CDCl3) δ7.32 (dd, J=5.1, 1.2Hz, 1H), 7.16 (dd, J=3.5, 1.2Hz, 1H), 7.15-7.09 (m, 2H), 6 .72(d,J=7.6Hz,1H),3.94(s,2H),2.95(t,J=7.5Hz,2H),2.77(t,J=7.3Hz,3H),2.20-2.12(m,2H).

[0245] Preparation of intermediate 5-(3-methoxyphenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-31): prepared from (3-methoxyphenyl)boronic acid (IIIC-9). Colorless liquid, yield 60%. 1 H NMR (400MHz, CDCl3) δ7.42(t,J=7.9Hz,1H),7.13(dt,J=7.5,1.2Hz,1H),7.11-7.05(m,2H),6.96(ddd,J=8.3,2.6,1.0Hz, 1H), 6.83 (d, J = 7.6Hz, 1H), 3.90 (s, 3H), 3.80 (s, 2H), 3.04 (t, J = 7.5Hz, 2H), 2.84 (t, J = 7.4Hz, 2H), 2.25 (q, J = 7.4Hz, 2H).

[0246] Preparation of intermediate 5-(3-nitrophenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-32): prepared from (3-nitrophenyl)boronic acid (IIIC-10). Pale yellow solid, yield 74%. 1H NMR (400MHz, CDCl3) δ8.35(d,J=2.6Hz,1H),8.21-8.15(m,1H),7.85-7.79(m,1H),7.60(t,J=8.0Hz,1H),6.97(d, J=7.6Hz,1H),6.79(d,J=7.6Hz,1H),3.66(s,2H),2.98(t,J=7.6Hz,2H),2.78(t,J=7.4Hz,2H),2.24-2.13(m,2H).

[0247] Preparation of intermediate 5-(3-fluorophenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-33): prepared from (3-fluorophenyl)boronic acid (IIIC-11). Colorless liquid, yield 87%. 1 H NMR (400MHz, CDCl3) δ7.40(td,J=8.0,6.1Hz,1H),7.28-7.23(m,1H),7.18(ddd,J=10.0,2.6,1.6Hz,1H),7.03(tdd,J=8.5,2.7,1.0H z, 1H), 6.97 (d, J = 7.6Hz, 1H), 6.77 (d, J = 7.6Hz, 1H), 3.71 (s, 2H), 2.97 (t, J = 7.5Hz, 2H), 2.78 (t, J = 7.4Hz, 2H), 2.18 (p, J = 7.5Hz, 2H).

[0248] Preparation of intermediate 5-(3-chlorophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-34): prepared from (3-chlorophenyl)boronic acid (IIIC-12). Colorless liquid, yield 92%. 1 H NMR (400MHz, CDCl3) δ7.48-7.45(m,1H),7.40-7.33(m,2H),7.34-7.29(m,1H),6.95(d,J=7.6Hz,1H) ,6.76(d,J=7.5Hz,1H),3.68(s,2H),3.02-2.92(m,2H),2.77(t,J=7.4Hz,2H),2.17(p,J=7.6Hz,2H).

[0249] Preparation of intermediate 5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-35): prepared from (3-(trifluoromethyl)phenyl)boronic acid (IIIC-13). Colorless liquid, yield 88%. 1H NMR (400MHz, CDCl3) δ7.74(td,J=1.7,0.9Hz,1H),7.66(dt,J=7.1,1.8Hz,1H),7.63-7.53(m,2H),6.97(d,J=7 .6Hz, 1H), 6.78 (d, J = 7.5Hz, 1H), 3.65 (s, 2H), 3.04-2.93 (m, 2H), 2.78 (t, J = 7.4Hz, 2H), 2.18 (p, J = 7.6Hz, 2H).

[0250] Preparation of intermediate 5-(3-ethylphenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-36): prepared from (3-ethylphenyl)boric acid (IIIC-14). A viscous, oily substance, yield 83%. 1 H NMR (400MHz, CDCl3) δ7.36(t,J=7.5Hz,1H),7.32-7.26(m,2H),7.18(dt,J=7.6,1.5Hz,1H),6.99(d,J=7.6Hz,1H),6.76(d,J=7.6Hz, 1H),3.76-3.62(m,2H),2.97(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H),2.70(q,J=7.6Hz,2H),2.24-2.11(m,2H),1.27(t,J=7.6Hz,3H).

[0251] Preparation of intermediate 1-(3-(4-amino-2,3-dihydro-1H-inden-5-yl)phenyl)ethane-1-one (IIIC-37): prepared from (3-acetylphenyl)boronic acid (IIIC-15). White solid, yield 91%. 1 H NMR (400MHz, CDCl3) δ8.08-8.02(m,1H),7.93(ddd,J=7.7,1.8,1.2Hz,1H),7.67(ddd,J=7.7,1.8,1.2Hz,1H),7.54(td,J=7.7,0.5Hz,1H), 6.98(dt,J=7.6,0.7Hz,1H),6.78(d,J=7.6Hz,1H),3.66(s,2H),3.07-2.91(m,2H),2.78(t,J=7.3Hz,2H),2.62(s,3H),2.25-2.12(m,2H).

[0252] Preparation of intermediate 5-(4-(cyclohexyloxy)phenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-38): prepared from (4-(cyclohexyloxy)phenyl)boronic acid (IIIC-16). White solid, yield 78%. 1 H NMR (400MHz, CDCl3) δ7.38-7.33(m,2H),7.00-6.94(m,3H),6.74(d,J=7.6Hz,1H),4.28(tt,J=9.1,3.8Hz,1H),3.68(s,2H),2.96(t,J=7.5H z,2H),2.77(t,J=7.4Hz,2H),2.16(p,J=7.5Hz,2H),2.10-1.99(m,2H),1.84(dt,J=14.3,4.5Hz,2H),1.60-1.51(m,3H),1.46-1.29(m,3H).

[0253] Preparation of intermediate methyl 4-(4-amino-2,3-dihydro-1H-inden-5-yl)benzoate (IIIC-39): prepared from (4-(methoxycarbonyl)phenyl)boronic acid (IIIC-17). White solid, yield 87%. 1 H NMR (400MHz, CDCl3) δ8.10(dd,J=8.5,2.0Hz,2H),7.55(dd,J=8.4,1.9Hz,2H),6.98(d,J=7.5Hz,1H),6.77(d,J= 7.6Hz, 1H), 3.94 (d, J = 1.9Hz, 3H), 3.70 (s, 2H), 2.97 (t, J = 7.6Hz, 2H), 2.77 (t, J = 7.4Hz, 2H), 2.24-2.11 (m, 2H).

[0254] Preparation of intermediate 5-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-40): prepared from (4-chlorophenyl)boronic acid (IIIC-18). White solid, yield 48%. 1 H NMR (400MHz, CDCl3) δ7.41 (s, 4H), 6.95 (d, J = 7.6Hz, 1H), 6.77 (d, J = 7.6Hz, 1H), 3.66(s,2H),2.97(t,J=7.5Hz,2H),2.77(t,J=7.4Hz,2H),2.18(p,J=7.5Hz,2H).

[0255] Preparation of intermediate 5-(4-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-41): prepared from (4-(pyridin-3-yl)phenyl)boronic acid (IIIC-19). White solid, yield 82%. 1 H NMR (400MHz, DMSO-d6) δ8.94(dd,J=2.4,0.9Hz,1H),8.58(dd,J=4.7,1.6Hz,1H),8.11(ddd,J=7.9,2.4,1.6Hz,1H),7.84-7.76(m,2H),7.54-7.51(m, 2H),7.51-7.47(m,1H),6.86(d,J=7.5Hz,1H),6.60(d,J=7.6Hz,1H),4.53( s, 2H), 2.84 (t, J = 7.5Hz, 2H), 2.72 (t, J = 7.3Hz, 2H), 2.03 (p, J = 7.4Hz, 2H).

[0256] Preparation of intermediate 5-(4-morpholinophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-42): prepared from (4-morpholinophenyl)boronic acid (IIIC-20). White solid, yield 85%. 1 H NMR (400MHz, DMSO-d6) δ8.37(s,2H),6.75(d,J=7.5Hz,1H),6.55(d,J=7.5Hz,1H),4.60(s,2H),3.73(dd,J=6. 2, 3.9Hz, 4H), 3.68 (dd, J = 5.4, 3.4Hz, 4H), 2.81 (t, J = 7.5Hz, 2H), 2.68 (t, J = 7.3Hz, 2H), 2.00 (p, J = 7.5Hz, 2H).

[0257] Preparation of intermediate 5-(2-fluoro-5-nitrophenyl)-2,3-dihydro-1H-indene-4-amine (IIIC-43): prepared from (2-fluoro-5-nitrophenyl)boronic acid (IIIC-21). Yellow solid, yield 75%. 1 H NMR (400MHz, CDCl3) δ8.34(dd,J=6.3,2.9Hz,1H),8.25(ddd,J=9.0,4.3,2.9Hz,1H),7.32(t,J=8.8Hz,1H),6.95(d,J =7.6Hz, 1H), 6.80 (d, J = 7.6Hz, 1H), 3.59 (s, 2H), 2.98 (t, J = 7.5Hz, 2H), 2.79 (t, J = 7.4Hz, 2H), 2.18 (p, J = 7.5Hz, 2H).

[0258] Preparation of intermediate 5-(3,4-difluorophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-44): prepared from (3,4-difluorophenyl)boric acid (IIIC-22). Colorless liquid, yield 85%. 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,1H),7.26-7.17(m,2H),6.94(d,J=7.6Hz,1H),6.77(d,J= 7.6Hz, 1H), 3.70 (s, 2H), 2.98 (t, J = 7.5Hz, 2H), 2.78 (t, J = 7.3Hz, 2H), 2.19 (p, J = 7.5Hz, 2H).

[0259] Preparation of intermediate 5-(2,4-dichlorophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-45): prepared from (2,4-dichlorophenyl)boric acid (IIIC-23). ​​Colorless liquid, yield 77%. 1 H NMR (400MHz, CDCl3) δ7.53(d,J=2.0Hz,1H),7.34-7.27(m,2H),6.86(d,J=7.6Hz,1H),6.76(d,J=7.6Hz, 1H), 3.45 (s, 2H), 2.98 (dt, J=7.8, 3.8Hz, 2H), 2.78 (td, J=7.2, 4.7Hz, 2H), 2.17 (pd, J=7.6, 1.9Hz, 2H).

[0260] Preparation of intermediate 5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-amine (IIIC-46): prepared from (2,3-dichlorophenyl)boric acid (IIIC-24). White solid, yield 62%. 1 H NMR (400MHz, DMSO-d6) δ7.62(dd,J=8.1,1.6Hz,1H),7.39(t,J=7.8Hz,1H),7.24(dd,J=7.7,1.6Hz,1H),6.68(d,J =7.5Hz, 1H), 6.54 (d, J = 7.5Hz, 1H), 4.36 (s, 2H), 2.89-2.79 (m, 2H), 2.70 (q, J = 7.9Hz, 2H), 2.02 (p, J = 7.2Hz, 2H).

[0261] Preparation of intermediate 5-(naphthyl-2-yl)-2,3-dihydro-1H-inden-4-amine (IIIC-47): prepared from 2-naphthylboronic acid (IIIC-25). White solid, yield 56%. 1H NMR (400MHz, CDCl3) δ7.97-7.85(m,4H),7.62(dt,J=8.3,1.4Hz,1H),7.56-7.48(m,2H),7.10(d,J=7.5Hz,1 H), 6.82 (d, J = 7.6Hz, 1H), 3.76 (s, 2H), 3.01 (t, J = 7.5Hz, 2H), 2.81 (t, J = 7.4Hz, 2H), 2.21 (q, J = 7.5Hz, 2H).

[0262] Preparation of intermediate 5-(quinolin-6-yl)-2,3-dihydro-1H-inden-4-amine (IIIC-48): prepared from quinolin-6-boronic acid (IIIC-26). White solid, yield 86%. 1 H NMR (400MHz, CDCl3) δ8.93(dd,J=4.2,1.7Hz,1H),8.21-8.12(m,2H),7.90(d,J=1.9Hz,1H),7.85(dd,J=8.7,2.0Hz,1H),7.43(dd,J=8.3, 4.3Hz, 1H), 7.08 (d, J = 7.6Hz, 1H), 6.81 (d, J = 7.6Hz, 1H), 3.74 (s, 2H), 2.99 (t, J = 7.5Hz, 2H), 2.80 (t, J = 7.3Hz, 2H), 2.19 (p, J = 7.5Hz, 2H).

[0263] Preparation of final products SCB017-025, SCB027 and SCB029-040

[0264]

[0265] The last two steps of synthesis are the same as those for the final products SCB001-008 and SCB015. Isocyanates are prepared using the intermediate (IIIC-(27-48)) and reacted with IIIA-2 to obtain the target products SCB017-025, SCB027 and SCB029-040.

[0266] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(p-tolyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB017 - Example 10): prepared from intermediate IIIC-27, white solid, yield 41%. Mp 92-94℃. 1H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 7.89 (d, J = 1.0Hz, 1H), 7.81 (s, 1H), 7.27 (d,J=1.0Hz,1H),7.23(s,1H),7.21(s,1H),7.19(d,J=7.6Hz,1H),7.11(d,J=1. 8Hz,1H),7.09(d,J=1.8Hz,1H),7.05(d,J=7.6Hz,1H),5.17(s,1H),2.89(d,J= 7.4Hz, 2H), 2.60 (d, J = 7.5Hz, 2H), 2.36 (s, 3H), 2.03-1.94 (m, 2H), 1.41 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ 149.06, 146.99, 144.19, 142.35, 142.09, 137.22, 136.31, 136.15, 135.96, 129.36, 128.96, 128.55, 128.25, 122.87, 116.75, 66.60, 32.60, 31.00, 30.75, 24.67, 20.70. HRMS (ESI-TOF-) Theoretical value C 24 H 26 N2O5S[MH] - m / z 453.1484, measured value 453.1484.

[0267] Preparation of the final product N-((5-(3,5-dimethylisoxazol-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB018 - Example 11): prepared from intermediate IIIC-28, white solid, yield 53%. Mp 169-170℃. 1 H NMR (400MHz, CD3OD) δ7.70(d,J=1.1Hz,1H),7.23(d,J=7.6Hz,1H),7.20(d,J=1.1Hz,1H),6.99(d,J=7.6Hz, 1H),2.97(t,J=7.4Hz,2H),2.79(t,J=7.3Hz,2H),2.16(s,3H),2.15-2.05(m,2H),2.01(s,3H),1.52(s,6H). 13CNMR (100MHz, CD3OD) δ 167.73, 160.86, 151.03, 149.09, 147.72, 143.64, 143.55, 138.06, 132.45, 130.60, 125.86, 124.41, 117.77, 115.21, 68.60, 34.12, 32.22, 31.05, 30.99, 26.25, 11.21, 10.23. HRMS (ESI-TOF-) Theoretical Value C 22 H 25 N3O6S[MH] - m / z 458.1386, measured value 458.1393.

[0268] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(pyrimidin-5-yl)-2,3-dihydro-1H-indene-4-yl)carbamoyl)furan-2-sulfonamide (SCB019 - Example 12): prepared from intermediate IIIC-29, white solid, yield 42%. Mp 106-108℃. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.14(s,1H),8.69(s,2H),8.26(s,1H),7.77(d,J=1.0Hz,1H),7.29(d,J=7.7Hz,1H),7.21 (d,J=7.6Hz,1H),7.19-7.14(m,1H),5.12(s,1H),2.94(t,J=7.5Hz,2H),2.68(t,J=7.4Hz,2H),2.09-1.97(m,2H),1.39(s,6H). 13 CNMR (100MHz, DMSO-d6) δ 156.81, 155.94, 149.19, 147.06, 146.17, 142.73, 142.03, 136.99, 132.96, 130.34, 130.15, 128.51, 123.47, 116.52, 66.58, 32.75, 30.94, 30.50, 24.62. HRMS (ESI-TOF-) Theoretical value C 21 H 22 N4O5S[MH] - m / z 441.1233, measured value 441.1232.

[0269] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(thiophen-2-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB020 - Example 13): Obtained from intermediate IIIC-30, white solid, yield 65%. Mp 86-87℃. 1 H NMR (400MHz, DMSO-d6) δ8.07 (s, 1H), 7.88 (d, J = 1.1Hz, 1H), 7.58 (dd, J = 5.0, 1.2Hz,1H),7.35(d,J=7.8Hz,1H),7.26(d,J=1.0Hz,1H),7.20(d,J=7.8Hz,1H ),7.17(dd,J=3.6,1.2Hz,1H),7.12(dd,J=5.1,3.6Hz,1H),5.15(s,1H),2.8 9(t,J=7.4Hz,2H),2.61(t,J=7.5Hz,2H),1.97(p,J=7.6Hz,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 149.21, 146.94, 144.66, 143.31, 142.10, 139.81, 137.24, 129.33, 128.96, 127.66, 127.40, 126.47, 125.87, 123.32, 116.87, 66.61, 32.64, 31.01, 30.64, 24.51. HRMS (ESI-TOF-) Theoretical value C 21 H 22 N2O5S2[MH] - m / z 445.0892, measured value 445.0896.

[0270] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(3-methoxyphenyl)-2,3-dihydro-1H-indene-4-yl)carbamoyl)furan-2-sulfonamide (SCB021 - Example 14): Obtained from intermediate IIIC-31, white solid, yield 47%. Mp 86-87℃. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.87(s,1H),7.82(d,J=1.0Hz,1H),7.32(t,J=7. 9Hz,1H),7.24(d,J=1.0Hz,1H),7.20(d,J=7.7Hz,1H),7.09(d,J=7.6Hz,1H),6.92(ddd, J=8.4,2.7,0.9Hz,1H),6.84-6.81(m,1H),6.78(dt,J=7.5,1.2Hz,1H),5.12(s,1H),3. 76(s,3H),2.90(t,J=7.4Hz,2H),2.60(t,J=7.4Hz,2H),2.04-1.93(m,2H),1.40(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 159.09, 149.02, 147.01, 144.44, 142.38, 142.00, 140.28, 137.14, 136.11, 129.37, 129.34, 128.23, 122.82, 120.90, 116.63, 114.01, 112.96, 66.56, 54.93, 32.59, 30.95, 30.71, 24.62. HRMS (ESI-TOF-) Theoretical value C 24 H 26 N2O6S[MH] - m / z 469.1433, measured value 469.1440.

[0271] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(3-nitrophenyl)-2,3-dihydro-1H-indene-4-yl)carbamoyl)furan-2-sulfonamide (SCB022 - Example 15): prepared from intermediate IIIC-32, white solid, yield 33%. Mp 115-116℃. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.20(dd,J=5.9,3.0Hz,1H),8.17-8.11(m,2H),7.77(d,J=1.1Hz,1H),7.68(dt,J=4.3,2.8Hz,2 H),7.28(d,J=7.7Hz,1H),7.20(s,2H),5.12(s,1H),2.95(t,J=7.4Hz,2H),2.68(t,J=7.4Hz,2H),2.02(p,J=7.5Hz,2H),1.39(s,6H). 13C NMR (100MHz, DMSO-d6) δ 149.03, 147.72, 147.10, 145.54, 142.63, 141.94, 140.87, 137.00, 135.19, 134.59, 129.76, 129.69, 128.36, 123.26, 123.18, 121.82, 116.51, 66.54, 32.69, 30.92, 30.55, 24.60. HRMS (ESI-TOF-) Theoretical value C 23 H 23 N3O7S[MH] - m / z 484.1178, measured value 484.1181.

[0272] Preparation of the final product N-((5-(3-fluorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB023 - Example 16): prepared from intermediate IIIC-33, white solid, yield 52%. Mp 95-96℃. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.97(s,1H),7.81(d,J=1.1Hz,1H),7.43(td,J=8.2,6.4Hz,1H),7.25-7.21(m,2H),7.21-7.15(m, 1H),7.11(d,J=7.6Hz,1H),7.10-7.02(m,2H),5.14(s,1H),2.91(t,J=7.4Hz,2H),2.62(t,J=7.4Hz,2H),2.04-1.94(m,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 163.19, 149.08, 147.02, 144.94, 142.58, 142.00, 137.11, 135.27, 130.14, 129.48, 128.32, 124.77, 123.03, 116.62, 115.54, 115.32, 113.90, 113.70, 66.57, 32.63, 30.95, 30.65, 24.61. HRMS (ESI-TOF-) Theoretical value C 23 H 23 FN2O5S[MH] - m / z 457.1233, measured value 457.1242.

[0273] Preparation of the final product N-((5-(3-chlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB024 - Example 17): prepared from intermediate IIIC-34, white solid, yield 48%. Mp 79-81℃. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.98(s,1H),7.82(d,J=1.0Hz,1H),7.45-7.38(m,2H),7.30(d,J=2.1Hz,1H),7.24-7.20(m,2H), 7.19-7.14(m,1H),7.10(d,J=7.6Hz,1H),5.13(s,1H),2.91(t,J=7.4Hz,2H),2.62(t,J=7.5Hz,2H),1.99(q,J=7.3Hz,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 144.74, 142.81, 141.63, 140.21, 136.57, 134.97, 132.84, 129.90, 128.51, 128.16, 127.46, 126.72, 124.99, 122.41, 112.06, 66.58, 32.69, 31.04, 30.81, 24.61. HRMS (ESI-TOF-) Theoretical value C 23 H 23 ClN2O5S[MH] - m / z 473.0938, measured value 473.0943.

[0274] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB025 - Example 18): prepared from intermediate IIIC-35, white solid, yield 54%. Mp 71-72℃. 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.02 (s, 1H), 7.80 (d, J = 1.0Hz, 1H), 7. 69(dd,J=8.9,7.1Hz,1H),7.65-7.58(m,2H),7.52(d,J=7.7Hz,1H),7.25(d, J=7.7Hz,1H),7.22(d,J=1.0Hz,1H),7.15(d,J=7.6Hz,1H),5.13(s,1H),2.9 2(t,J=7.4Hz,2H),2.63(t,J=7.5Hz,2H),1.99(t,J=7.4Hz,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 149.16, 147.11, 145.22, 142.73, 141.98, 140.12, 137.10, 135.18, 132.62, 129.63, 129.32, 129.28, 129.01, 128.41, 125.54, 125.15, 125.11, 123.68, 123.21, 122.83, 116.58, 66.57, 32.65, 30.95, 30.58, 24.59. HRMS (ESI-TOF-) Theoretical value C 24 H 23 F3N2O5S[MH] - m / z 507.1202, measured value 507.1212.

[0275] Preparation of the final product N-((5-(3-ethylphenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB027 - Example 19): prepared from intermediate IIIC-36, white solid, yield 62%. Mp 73-74℃. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.84(d,J=1.1Hz,2H),7.32(t,J=7.6Hz,1H),7.25(d,J=1.1Hz,1H),7.20(dd,J=7.5,2.5Hz,2H),7.13-7.06 (m,2H),7.02(dt,J=7.7,1.5Hz,1H),5.14(s,1H),2.90(t,J=7.4Hz,2H), 2.67-2.57(m,4H),2.04-1.93(m,2H),1.40(s,6H),1.20(t,J=7.6Hz,3H). 13C NMR (100MHz, DMSO-d6) δ 149.13, 147.06, 144.34, 143.83, 142.45, 142.06, 138.87, 137.22, 136.33, 129.38, 128.33, 128.29, 126.61, 126.00, 122.91, 116.76, 66.62, 32.63, 31.01, 30.76, 28.24, 24.69, 15.66. HRMS (ESI-TOF-) Theoretical value C 25 H 28 N2O5S[MH] - m / z 467.1641, measured value 467.1645.

[0276] Preparation of the final product N-((5-(3-acetylphenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB029 - Example 20): prepared from intermediate IIIC-37, white solid, yield 53%. Mp 88-90℃. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.02(s,1H),7.95-7.90(m,1H),7.88(d,J=1 .8Hz,1H),7.80(d,J=1.1Hz,1H),7.71-7.65(m,1H),7.54(t,J=7.7Hz,1H),7.48(dt ,J=7.7,1.5Hz,1H),7.29-7.20(m,2H),7.15(d,J=7.6Hz,1H),5.14(s,1H),2.92(t ,J=7.5Hz,2H),2.63(t,J=7.4Hz,2H),2.59(s,3H),2.06-1.94(m,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 197.85, 149.13, 147.08, 144.91, 142.69, 142.05, 139.48, 137.12, 136.88, 135.84, 133.24, 129.62, 128.80, 128.69, 128.39, 126.54, 123.16, 116.66, 66.61, 32.68, 30.98, 30.66, 26.80, 24.67. HRMS (ESI-TOF-) Theoretical value C 25 H 26 N2O6S[MH] - m / z 481.1433, measured value 481.1438.

[0277] Preparation of the final product N-((5-(4-(cyclohexyloxy)phenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB030 - Example 21): prepared from intermediate IIIC-38, white solid, yield 44%. Mp 94-96℃. 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),7.86(d,J=1.1Hz,1H),7.82(s,1H),7.27(s,1H) ,7.17(d,J=7.7Hz,1H),7.14-7.08(m,2H),7.04(d,J=7.6Hz,1H),6.99-6.90(m,2H),5 .16(s,1H),4.38(dd,J=8.5,4.0Hz,1H),2.89(t,J=7.4Hz,2H),2.59(t,J=7.4Hz,2H), 2.02-1.91(m,4H),1.73(dt,J=8.9,4.1Hz,2H),1.60-1.38(m,10H),1.37-1.22(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 156.53, 149.07, 147.05, 143.90, 142.29, 141.99, 137.26, 135.91, 130.78, 129.83, 129.36, 128.24, 122.82, 116.69, 115.38, 74.21, 66.60, 32.58, 31.39, 30.98, 30.76, 25.14, 24.68, 23.17. HRMS (ESI-TOF-) Theoretical value C 29 H 34 N2O6S[MH] - m / z 537.2059, measured value 537.2065.

[0278] Preparation of the final product methyl 4-(4-(3-((4-(2-hydroxypropyl-2-yl)furan-2-yl)sulfonyl)ureido)-2,3-dihydro-1H-inden-5-yl)benzoate (SCB031 - Example 22): prepared from intermediate IIIC-39, white solid, yield 73%. Mp 101-103℃. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.00(s,1H),7.98-7.93(m,2H),7.80(d,J=1.0Hz,1H),7.41-7.36(m,2H),7.25(d,J=8.2Hz, 2H),7.13(d,J=7.7Hz,1H),5.13(s,1H),3.89(s,3H),2.92(t,J=7.4Hz,2H),2.65(t,J=7.4Hz,2H),2.06-1.98(m,2H),1.40(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 166.10, 149.06, 147.11, 145.23, 144.05, 142.64, 141.89, 137.12, 135.54, 129.52, 129.05, 128.95, 128.26, 128.09, 123.12, 116.60, 66.52, 52.14, 32.65, 30.88, 30.59, 24.58. HRMS (ESI-TOF-) Theoretical value C 25 H 26 N2O7S[MH] - m / z 497.1382, measured value 497.1386.

[0279] Preparation of the final product N-((5-(4-chlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB032 - Example 23): Obtained from intermediate IIIC-40, white solid, yield 74%. Mp 95-97℃. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.94(s,1H),7.87(d,J=1.0Hz,1H),7.46(d,J=2.0Hz,1H),7.45(d,J=2.0Hz,1H),7.27-7.24(m,2H) ,7.24-7.20(m,2H),7.08(d,J=7.6Hz,1H),5.16(s,1H),2.91(t,J=7.4Hz,2H),2.62(t,J=7.4Hz,2H),1.99(q,J=7.3Hz,2H),1.40(s,6H). 13C NMR (100MHz, DMSO-d6) δ 149.11, 147.06, 144.84, 142.56, 142.05, 137.90, 137.17, 135.29, 131.92, 130.44, 129.49, 128.64, 128.26, 123.06, 116.68, 66.57, 32.64, 30.97, 30.66, 24.64. HRMS (ESI-TOF-) Theoretical value C 23 H 23 ClN2O5S[MH] - m / z 473.0938, measured value 473.0943.

[0280] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(4-(pyridin-3-yl)phenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB033 - Example 24): Obtained from intermediate IIIC-41, white solid, yield 33%. Mp 120-122℃. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.97(dd,J=2.4,0.8Hz,1H),8.60(dd,J=4.8,1.6Hz,1H ),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.97(s,1H),7.88(d,J=1.0Hz,1H),7.82-7.76(m,2H),7. 52(ddd,J=8.0,4.7,0.9Hz,1H),7.40-7.35(m,2H),7.30-7.22(m,2H),7.14(d,J=7.6Hz,1H), 5.16(s,1H),2.92(t,J=7.4Hz,2H),2.63(t,J=7.4Hz,2H),2.00(q,J=7.4Hz,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 149.20, 148.47, 147.51, 147.09, 144.71, 142.57, 142.06, 138.88, 137.22, 135.70, 135.08, 134.12, 129.49, 128.35, 126.75, 123.97, 123.04, 116.68, 66.58, 32.65, 30.96, 30.71, 24.66. HRMS (ESI-TOF-) Theoretical value C 28 H 27 N3O5S[MH] -m / z 516.1593, measured value 516.1593.

[0281] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(4-morpholinylphenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB034 - Example 25): Obtained from intermediate IIIC-42, white solid, yield 64%. Mp 105-106℃. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.27(s,2H),8.11(s,1H),7.78(d,J=1.0Hz,1H),7.22(d,J=7.9Hz,2H),7.11(d,J=7.6Hz,1H),5.12(s ,1H),3.75(dd,J=5.8,3.7Hz,4H),3.69(dd,J=5.5,3.6Hz,4H),2.90(t,J=7.4Hz,2H),2.61(t,J=7.4Hz,2H),2.05-1.92(m,2H),1.39(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 160.19, 157.54, 157.08, 147.08, 144.79, 142.77, 141.94, 137.10, 131.04, 129.92, 128.01, 123.29, 121.45, 116.55, 66.62, 66.03, 43.95, 32.68, 30.96, 30.64, 24.67. HRMS (ESI-TOF-) Theoretical value C 27 H 31 N3O6S[MH] - m / z 526.1760, measured value 526.1766.

[0282] Preparation of the final product N-((5-(2-fluoro-5-nitrophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB035 - Example 26): prepared from intermediate IIIC-43, white solid, yield 59%. Mp 82-84℃. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.29(ddd,J=9.1,4.2,2.9Hz,1H),8.12(dd,J=6.2,2.9Hz,1H),8.09(s,1H),7.74(d,J=1.1Hz,1H),7.55(t, J=9.1Hz,1H),7.27(d,J=7.6Hz,1H),7.20-7.13(m,2H),5.11(s,1H),2.9 4(t,J=7.4Hz,2H),2.69(t,J=7.5Hz,2H),2.17-1.93(m,2H),1.38(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 161.57, 148.54, 147.02, 146.32, 143.75, 141.97, 140.24, 136.97, 130.65, 128.75, 128.30, 128.05, 127.87, 127.13, 125.38, 125.28, 122.84, 117.35, 117.09, 116.52, 66.57, 32.77, 30.93, 30.74, 24.65. HRMS (ESI-TOF-) Theoretical value C 23 H 22 FN3O7S[MH] - m / z 502.1162, measured value 502.1088.

[0283] Preparation of the final product N-((5-(3,4-difluorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB036 - Example 27): prepared from intermediate IIIC-44, white solid, yield 39%. Mp 83-85℃. 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.03(s,1H),7.80(d,J=1.1Hz,1H), 7.50-7.41(m,1H),7.30(ddd,J=11.9,7.8,2.2Hz,1H),7.24-7.21(m,2H),7 .10(d,J=7.6Hz,1H),7.05(ddd,J=8.6,4.3,2.0Hz,1H),5.13(s,1H),2.91( t,J=7.4Hz,2H),2.65(d,J=7.4Hz,2H),2.00(d,J=7.7Hz,2H),1.39(s,6H). 13C NMR (100MHz, DMSO-d6) δ149.84,149.09,147.52,147.07,145.05,142.59,141.96,137.09,136.64,134.65,129.60,128. 36,125.49,123.08,117.77,117.60,117.32,117.16,116.62,66.56,32.65,30.92,30.62,24.63.HRMS(ESI-TOF-)calcd for C 23 H 22 F2N2O5S[MH]-m / z 475.1217, measured value 475.1148.

[0284] Preparation of the final product N-((5-(2,4-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB037 - Example 28): prepared from intermediate IIIC-45, white solid, yield 62%. Mp 100-101℃. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.83(d,J=1.0Hz,1H),7.74-7.67(m,2H),7.45(dd,J=8.2,2.2Hz,1H),7.22-7.16(m,3 H),6.98(d,J=7.6Hz,1H),5.34-4.98(m,1H),2.92(dt,J=8.9,4.4Hz,2H),2.78-2.52(m,2H),2.09-1.93(m,2H),1.40(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 148.34, 146.82, 145.59, 142.09, 141.41, 137.07, 136.47, 133.83, 132.99, 132.85, 132.06, 130.23, 128.80, 128.25, 127.21, 122.38, 116.71, 66.57, 32.70, 31.05, 30.97, 24.69. HRMS (ESI-TOF-) Theoretical value C 23 H 22 Cl2N2O5S[MH] - m / z 507.0548, measured value 507.0558.

[0285] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)furan-2-sulfonamide (SCB038 - Example 29): prepared from intermediate IIIC-46, white solid, yield 58%. Mp 71-72℃. 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),7.81(d,J=1.0Hz,1H),7.70(s,1H),7.66(dd,J=8.1,1.5Hz,1H),7.38(t,J=7.9Hz,1H),7.20(d,J=6.6Hz,2H), 7.12(dd,J=7.7,1.6Hz,1H),6.99(d,J=7.6Hz,1H),5.13(s,1H),2.92(t,J =7.9Hz,2H),2.78-2.54(m,2H),1.98(dq,J=13.4,6.9Hz,2H),1.41(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 148.38, 146.77, 145.60, 142.14, 141.49, 139.92, 137.08, 133.01, 131.92, 131.00, 130.15, 130.06, 129.80, 128.13, 128.01, 122.44, 116.78, 66.61, 32.72, 31.07, 31.01, 24.72. HRMS (ESI-TOF-) Theoretical value C 23 H 22 Cl2N2O5S[MH] - m / z 507.0548, measured value 507.0557.

[0286] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(naphthyl-2-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB039 - Example 30): prepared from intermediate IIIC-47, white solid, yield 51%. Mp 90-92℃. 1H NMR (400MHz, CDCl3) δ7.94-7.78(m,4H),7.76(d,J=1.8Hz,1H),7.53-7.44(m,2H),7.40(dd,J=8.5,1.8Hz,1H),7.25- 7.20(m,2H),6.91(d,J=13.2Hz,2H),2.98(t,J=7.4Hz,2H),2.77(q,J=6.1Hz,2H),2.09(h,J=7.1Hz,2H),1.35(s,6H). 13 C NMR (100MHz, CDCl3) δ 149.41, 147.33, 145.71, 142.48, 142.17, 136.74, 135.99, 133.50, 132.50, 129.28, 128.61, 128.40, 128.05, 127.92, 127.76, 127.33, 126.35, 126.19, 123.88, 116.26, 68.17, 33.29, 31.36, 30.67, 25.31. HRMS (ESI-TOF-) Theoretical value C 27 H 26 N2O5S[MH] - m / z 489.1484, measured value 489.1484.

[0287] Preparation of the final product 4-(2-hydroxypropyl-2-yl)-N-((5-(quinolin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)furan-2-sulfonamide (SCB040 - Example 31): prepared from intermediate IIIC-48, white solid, yield 78%. Mp 133-135℃. 1 H NMR (400MHz, DMSO-d6) δ8.94(dd,J=4.3,1.7Hz,1H),8.34(dd,J=8.4,1.7Hz,1H),8.02(d,J=8.8Hz,2H),7.87(d,J=2.0Hz,1H),7.79(d,J=1.0 Hz,1H),7.64-7.55(m,2H),7.30-7.20(m,3H),5.16(s,1H),2.94(t,J=7.4Hz,2H),2.68(t,J=7.4Hz,2H),2.01(t,J=7.3Hz,2H),1.40(s,6H). 13C NMR (100MHz, DMSO-d6) δ 150.51, 149.14, 147.10, 146.67, 144.98, 142.54, 141.98, 137.32, 137.16, 136.27, 135.67, 130.63, 129.78, 128.62, 128.49, 127.90, 127.60, 123.09, 121.78, 116.67, 66.57, 32.70, 30.96, 30.75, 24.68. HRMS (ESI-TOF-) Theoretical value C 26 H 25 N3O5S[MH] - m / z 490.1437, measured value 490.1438.

[0288] Examples 32-47

[0289] General methods for synthesizing final products SCB041-047 and SCB049-057 (Examples 32-47)

[0290] Preparation of intermediate methyl 5-(chlorosulfonyl)thiophene-3-carboxylate (IIID-19)

[0291]

[0292] Methyl thiophene-3-carboxylate (1.00 g, 1 eq.) was dissolved in dichloromethane, and chlorosulfonic acid (983 mg, 1.2 eq.) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 3 h. The mixture was then cooled to 0 °C, and pyridine (668 mg, 1.2 eq.) and phosphorus pentachloride (1.757 g, 1.2 eq.) were added. The mixture was then brought back to room temperature and reacted for 3 h. After the reaction was complete, the mixture was quenched with ice water. The solution was extracted with dichloromethane, dried, filtered, and concentrated to obtain a colorless liquid with a yield of 55%, which was used directly in the next reaction.

[0293] Preparation of intermediate methyl 5-aminosulfonylthiophene-3-carboxylate (IIID-2)

[0294]

[0295] At room temperature, 1.693 g (1 eq.) of the prepared IIID-19 was dissolved in acetone and reacted with an aqueous solution of ammonium bicarbonate (2.244 g, 4 eq.) for 12 h. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The product was dried, filtered, and concentrated to obtain the crude product. The crude product was ground in a mixed solvent of petroleum ether and ethyl acetate in a ratio of 10:1, filtered, and a white solid was obtained. The yield was 50%. 1HNMR (400MHz, DMSO-d6) δ8.55 (t, J = 1.4 Hz, 1H), 7.82 (dd, J = 3.5, 2.0 Hz, 3H), 3.82 (s, 3H).

[0296] Preparation of intermediate 4-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (IIID-3)

[0297]

[0298] The prepared IIID-2 (1.693 g, 1 eq.) was dissolved in tetrahydrofuran, and methylmagnesium bromide (1.693 g, 1 eq.) was added dropwise under ice bath conditions, followed by reaction at room temperature for 12 h. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The solution was dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid in 32% yield. 1 H NMR (400MHz, DMSO-d6) δ7.58 (s, 2H), 7.56 (d, J = 1.7Hz, 1H), 7.52 (d, J = 1.7Hz, 1H), 5.19 (s, 1H), 1.42 (s, 6H).

[0299] Preparation of intermediate 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (IIID-21)

[0300]

[0301] (A) Thionyl chloride (5.267 g, 4.3 eq.) was added dropwise to 13 mL of water under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. The next day, cuprous chloride (102 mg, 0.1 eq.) was added, and the solution was cooled in an ice-salt bath after turning pale yellow. (B) 1-Methyl-1H-pyrazole-3-amine (1.00 g, 1 eq.) was dissolved in concentrated hydrochloric acid under ice bath conditions, and sodium nitrite aqueous solution (2 mL, 817 mg, 1.15 eq.) was added dropwise. After reacting for 15 min, the solution was added dropwise to the solution obtained in step (A), and the reaction was allowed to proceed for 1 h at room temperature. The solution was extracted with ethyl acetate, dried, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a pale yellow liquid with a yield of 14%. This was used directly in the next reaction.

[0302] Preparation of intermediate 1,3-dimethyl-1H-pyrazole-4-sulfonamide (IIID-6)

[0303]

[0304] IIID-21 was dissolved in tetrahydrofuran under ice bath conditions, and ammonia gas was introduced. After reacting at room temperature for 2 hours, concentrated hydrochloric acid was added to adjust the pH to 3-4. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1) to obtain a white solid with a yield of 30%. 1 H NMR (400MHz, DMSO-d6) δ7.57(s,1H),7.19(s,2H),4.91(q,J=5.1Hz,1H),4.68-4.54(m,2H),4.47(dd,J=13.2,6.5Hz,2H),3.01(s,3H).

[0305] Preparation of intermediate 4-(bromomethyl)benzenesulfonamide (IIID-23)

[0306]

[0307] 4-Methylbenzenesulfonamide (1.00 g, 1 eq.), NBS (1.43 g, 1.1 eq.), and AIBN (48 mg, 0.05 eq.) were placed in carbon tetrachloride and refluxed at 80 °C. After 6 h, the mixture was cooled to room temperature, concentrated, extracted with ethyl acetate, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a crude white solid. This crude solid was used directly in the next reaction.

[0308] Preparation of intermediate 4-((dimethylamino)methyl)benzenesulfonamide (IIID-11)

[0309]

[0310] IID-23 (700 mg, 1 eq.) was dissolved in DMF and potassium carbonate (774 mg, 2 eq.) was added. Then, dimethylamine aqueous solution (40% wt, 420 μL, 1.2 eq.) was added dropwise under ice bath conditions. The mixture was heated to room temperature and reacted overnight. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to dichloromethane:methanol = 10:1) to give a white solid in 20% yield. 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=8.2Hz,2H),7.47(d,J=8.0Hz,2H),7.32(s,2H),2.15(s,6H).

[0311] Preparation of intermediate 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (IIID-25)

[0312]

[0313] 1,2-Dihydro-3H-pyrazole-3-one (4.5 g, 1 eq.), potassium carbonate (25.890 g, 3.5 eq.), and 1,3-dibromopropane (11.886 g, 1.1 eq.) were placed in a 250 mL round-bottom flask, dissolved in DMF, and reacted at 130 °C for 8 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give a colorless liquid in 52% yield. 1 H NMR (400MHz, CDCl3) δ7.27 (d, J = 2.0Hz, 1H), 5.44 (d, J = 2.0Hz, 1H), 4.26-4.22 (m, 2H), 4.14 (t, J = 6.3Hz, 2H), 2.21 (dt, J = 10.6, 6.1Hz, 2H).

[0314] Preparation of intermediate 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (IIID-26)

[0315]

[0316] All the prepared IIID-25 was added dropwise to 10 mL of chlorosulfonic acid under ice bath conditions and reacted at 80 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and quenched with ice water. The mixture was then extracted with ethyl acetate, the organic layers were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was ground in petroleum ether and filtered to obtain a pale yellow solid with a yield of 49%. 1 H NMR (400MHz, DMSO-d6) δ8.04 (s, 1H), 4.56-4.47 (m, 2H), 4.14 (t, J = 6.1Hz, 2H), 2.30-2.21 (m, 2H).

[0317] Preparation of intermediate 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (IIID-17)

[0318]

[0319] The prepared IIID-26 was completely dissolved in tetrahydrofuran, and half a volume of ammonia water containing tetrahydrofuran was added. The mixture was reacted at 60°C for 3 hours. After the reaction was complete, the product was concentrated to obtain a crude product, which was then ground with 1M hydrochloric acid, filtered, washed with water, and dried. A pale yellow solid was obtained. The yield was 71%. 1 H NMR (400MHz, DMSO-d6) δ7.47 (s, 1H), 7.07 (s, 2H), 4.44-4.37 (m, 2H), 4.10 (t, J = 6.1Hz, 2H), 2.26-2.12 (m, 2H).

[0320] Preparation of final products SCB041-047 and SCB049-057 (Examples 32-47)

[0321]

[0322] The last two steps of the synthesis method are the same as the synthesis method of the final products SCB001-008 and SCB015 (Examples 1-9). The prepared intermediate (IIIC-46) is used to prepare isocyanate and react with the corresponding synthetic or commercially available sulfonamide intermediate (IIID-(2-17)) to obtain the target products SCB0041-047 and SCB049-057 (Examples 32-47).

[0323] Preparation of the final product methyl 5-(N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)aminosulfonyl)thiophene-3-carboxylate (SCB041 - Example 32): Prepared from the intermediate methyl 5-aminosulfonylthiophene-3-carboxylate (IIID-2), white solid, yield 43%. Mp 116-117℃. 1 H NMR (400MHz, CD3OD) δ8.29(d,J=1.3Hz,1H),7.81(d,J=1.5Hz,1H),7.34(dd,J=6.7,2.8Hz,1H),7.09(t,J=6.6H z,3H),6.88(d,J=7.6Hz,1H),3.83(s,3H),2.90(t,J=7.5Hz,2H),2.80(q,J=7.2Hz,2H),2.00(p,J=7.5Hz,2H). 13 CNMR (100MHz, CD3OD) δ 163.98, 147.55, 146.89, 143.57, 142.22, 137.73, 135.39, 133.75, 133.41, 132.81, 132.67, 131.32, 131.12, 130.40, 129.27, 128.32, 123.09, 52.59, 34.14, 32.39, 26.22. HRMS (ESI-TOF-) Theoretical value C 22 H 18 Cl2N2O5S2[MH] - m / z 522.9956, measured value 522.9966.

[0324] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (SCB042 - Example 33): Obtained from the intermediate 4-(2-hydroxypropyl-2-yl)thiophene-2-sulfonamide (IIID-3), a white solid with a yield of 53%. Mp 105-106℃. 1 H NMR (400MHz, CD3OD) δ7.73(d,J=1.7Hz,1H),7.65(d,J=1.7Hz,1H),7.50(dd,J=8.1,1.5Hz,1H),7.26-7.18(m,2H),7.12(dd,J =7.7,1.6Hz,1H),6.98(d,J=7.6Hz,1H),2.97(t,J=7.5Hz,2H),2.76(dq,J=16.4,7.9Hz,2H),2.16-2.00(m,2H),1.53(s,6H). 13 C NMR (100MHz, CD3OD) δ 153.19, 147.42, 143.48, 141.74, 135.47, 134.10, 133.30, 132.96, 131.15, 131.04, 130.91, 129.46, 128.90, 128.68, 127.78, 124.03, 71.43, 34.13, 32.34, 31.53, 26.28. HRMS (ESI-TOF-) Theoretical value C 23 H 22 Cl2N2O4S2[MH] - m / z 523.0320, measured value 523.0314.

[0325] Preparation of the final product 3-bromo-N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide (SCB043 - Example 34): Prepared from the intermediate 3-bromothiophene-2-sulfonamide (IIID-4), white solid, yield 55%. Mp 145-146℃. 1 H NMR (400MHz, CD3OD) δ7.55(d,J=5.3Hz,1H),7.45(dd,J=7.9,1.5Hz,1H),7.19(t,J=7.8Hz,1H),7.17-7.09(m,2H) ,7.02(d,J=5.3Hz,1H),6.91(d,J=7.6Hz,1H),2.92(t,J=7.4Hz,2H),2.82(t,J=7.0Hz,2H),2.03(p,J=7.3Hz,2H).13 C NMR (100MHz, CD3OD) δ 146.86, 143.55, 142.16, 140.97, 135.38, 133.79, 133.06, 132.81, 132.43, 131.26, 130.76, 130.57, 129.20, 128.47, 123.11, 112.73, 34.12, 32.33, 26.20. HRMS (ESI-TOF-) Theoretical value C 20 H 15 BrCl2N2O3S2[MH] - m / z 542.9006, measured value 542.9016.

[0326] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide (SCB044 - Example 35): Prepared from the intermediate thiophene-2-sulfonamide (IIID-5), white solid, yield 63%. Mp 142-145℃. 1 H NMR (400MHz, CD3OD) δ7.69(d,J=4.9Hz,1H),7.54-7.47(m,1H),7.48-7.43(m,1H),7.15(ddd,J=16.8,8.0,5.8Hz,3H ),7.04(t,J=4.4Hz,1H),6.95(d,J=7.6Hz,1H),2.95(t,J=7.5Hz,2H),2.80(q,J=7.7Hz,2H),2.05(p,J=7.4Hz,2H). 13 C NMR (100MHz, CD3OD) δ 147.16, 143.76, 142.06, 135.70, 133.92, 132.87, 131.91, 131.67, 131.30, 130.70, 129.40, 128.90, 128.52, 127.90, 123.66, 34.15, 32.29, 26.24. HRMS (ESI-TOF-) Theoretical value C 20 H 16 Cl2N2O3S2[MH] - m / z 464.9901, measured value 464.9902.

[0327] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide (SCB045 - Example 36): Obtained from the intermediate 1,3-dimethyl-1H-pyrazole-4-sulfonamide (IIID-6), a white solid, in 67% yield. Mp 123-125℃. 1 H NMR (400MHz, CD3OD) δ7.90(s,1H),7.47(d,J=8.0Hz,1H),7.18(d,J=7.7Hz,2H),7.10(d,J=7.7Hz,1H),6.9 6(d,J=7.6Hz,1H),3.82(s,3H),2.96(t,J=7.6Hz,2H),2.87-2.71(m,2H),2.27(s,3H),2.16-2.01(m,2H). 13 C NMR (100MHz, CD3OD) δ 148.67, 147.27, 143.51, 142.00, 136.32, 135.66, 133.84, 132.80, 131.28, 130.72, 129.44, 128.90, 128.45, 123.81, 115.08, 39.20, 34.13, 32.23, 26.24, 12.41. HRMS (ESI-TOF-) Theoretical value C 21 H 20 Cl2N4O3S[MH] - m / z 477.0555, measured value 477.0562.

[0328] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyrrolidine-1-sulfonamide (SCB046 - Example 37): Prepared from the intermediate pyrrolidine-1-sulfonamide (IIID-7), white solid, yield 51%. Mp 77-79℃. 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.67(dd,J=8.0,1.6Hz,1H),7.59(s,1H),7.41(t,J=7.9Hz,1H),7.21(dd,J=7.7,1.7Hz,2H) ,7.01(d,J=7.6Hz,1H),3.24-3.13(m,4H),2.95(td,J=7.5,2.6Hz,2H),2.88-2.69(m,2H),2.09-1.99(m,2H),1.79-1.68(m,4H). 13C NMR (151MHz, DMSO-d6) δ 149.63, 145.56, 141.38, 140.29, 133.12, 131.84, 131.00, 130.47, 130.27, 129.68, 128.26, 128.09, 128.06, 127.99, 122.22, 48.07, 32.73, 31.11, 25.17, 24.73. HRMS (ESI-TOF-) Theoretical value C 20 H 21 Cl2N3O3S[MH] - m / z 452.0602, measured value 452.0604.

[0329] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide (SCB047 - Example 38): prepared from the intermediate benzenesulfonamide (IIID-8), white solid, yield 44%. Mp 83-85℃. 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=7.6Hz,2H),7.59(q,J=8.9Hz,3H),7.50(t,J=7.6Hz,2H),7.24(t,J=7.7Hz,1H),7.12(d,J=7.6Hz, 1H),7.07(d,J=7.7Hz,1H),6.94(d,J=7.6Hz,1H),2.89(t,J=7.6Hz,2H),2.65(qt,J=15.9,7.4Hz,2H),1.95(dt,J=13.6,6.5Hz,2H). 13 CNMR (100MHz, DMSO-d6) δ 152.90, 145.12, 142.59, 141.70, 140.45, 133.03, 131.76, 130.93, 130.84, 130.30, 129.46, 128.46, 128.03, 127.69, 126.56, 121.55, 32.79, 31.13, 24.68. HRMS (ESI-TOF-) Theoretical value C 22 H 18 Cl2N2O3S[MH] - m / z 459.0337, measured value 459.0337.

[0330] Preparation of the final product 4-acetyl-N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide (SCB049 - Example 39): Prepared from intermediate 4-acetylbenzenesulfonamide (IIID-9), white solid, yield 46%. Mp 145-147℃. 1 H NMR (400MHz, CD3OD) δ8.07-8.00(m,2H),7.88(d,J=8.2Hz,2H),7.37(dd,J=7.7,1.9Hz,1H),7.15-7.05(m,3H), 6.90(d,J=7.6Hz,1H),2.90(t,J=7.5Hz,2H),2.76(dp,J=16.6,8.6Hz,2H),2.65(s,3H),2.08-1.94(m,2H).13C NMR (100MHz, CD3OD) δ 199.41, 147.91, 146.96, 143.45, 142.11, 140.47, 135.38, 133.69, 132.77, 132.26, 131.27, 130.45, 129.55, 129.33, 128.41, 128.32, 128.27, 123.28, 34.10, 32.26, 27.05, 26.16. HRMS (ESI-TOF-) Theoretical value C 24 H 20 Cl2N2O4S[MH] - m / z 501.0521, measured value 501.0440.

[0331] Preparation of the final product 3-amino-N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)benzenesulfonamide (SCB050 - Example 40): Prepared from the intermediate 3-aminobenzenesulfonamide (IIID-10), white solid, yield 55%. Mp 94-96℃. 1 H NMR (400MHz, DMSO-d6) δ7.70-7.60(m,2H),7.31(t,J=7.9Hz,1H),7.23-7.16(m,2H),7.09-7.04(m,2H),6.98( d,J=7.7Hz,1H),6.89-6.79(m,2H),5.75(s,2H),2.90(t,J=7.5Hz,2H),2.76-2.52(m,2H),1.99-1.91(m,2H). 13C NMR (100MHz, DMSO-d6) δ 149.20, 148.93, 145.53, 141.41, 140.26, 139.93, 132.93, 131.90, 130.93, 130.22, 130.07, 129.76, 129.38, 128.07, 127.94, 122.26, 118.00, 113.40, 111.56, 32.72, 31.06, 24.72. HRMS (ESI-TOF-) Theoretical value C 22 H 19 Cl2N3O3S[MH] - m / z 474.0446, measured value 474.0454.

[0332] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-((dimethylamino)methyl)benzenesulfonamide (SCB051 - Example 41): Obtained from the intermediate 4-((dimethylamino)methyl)benzenesulfonamide (IIID-11), a white solid, yield 57%. Mp 150-152℃. 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.0Hz,2H),7.86-7.78(m,2H),7.65(d,J=8.0Hz,2H),7.50(t,J=7.8Hz,1H),7.38-7.29(m, 2H),7.17(d,J=7.6Hz,1H),3.85(s,2H),3.10(t,J=13.8Hz,1H),2.86(qt,J=15.9,7.5Hz,2H),2.50(s,6H),2.30-2.10(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 145.02, 142.48, 141.66, 140.61, 132.98, 132.09, 131.74, 130.95, 130.83, 130.35, 129.38, 128.96, 127.99, 127.67, 126.49, 121.35, 61.98, 44.26, 32.78, 31.17, 24.65. HRMS (ESI-TOF-) Theoretical value C 25 H 25 Cl2N3O3S[MH] - m / z 516.0915, measured value 516.0918.

[0333] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-phenylmethanesulfonamide (SCB052 - Example 42): Obtained from the intermediate benzylsulfonamide (IIID-12), white solid, yield 62%. Mp 80-82℃. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),7.70(d,J=8.0Hz,1H),7.62(s,1H),7.45(t,J=7.6Hz,1H),7.40-7.34(m,3H),7.26(dd,J=11.2,7.8 Hz,2H),7.19(dd,J=6.5,3.1Hz,2H),7.02(d,J=7.6Hz,1H),4.58(s,2H),2.97(t,J=7.6Hz,2H),2.84(q,J=8.6Hz,2H),2.13-2.02(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 149.79, 145.64, 141.51, 140.30, 133.32, 131.83, 131.02, 130.70, 130.35, 130.16, 129.82, 129.47, 128.52, 128.44, 128.19, 128.13, 122.47, 57.51, 32.79, 31.30, 24.78. HRMS (ESI-TOF-) Theoretical value C 23 H 20 Cl2N2O3S[MH] - m / z 473.0493, measured value 473.0493.

[0334] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide (SCB053 - Example 43): Prepared from the intermediate pyridine-3-sulfonamide (IIID-13), white solid, yield 68%. Mp 100-105℃. 1H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.63(d,J=4.2Hz,1H),7.96(d,J=7.9Hz,1H),7.55(d,J=7.0Hz,1H),7.45(dd,J=7.8,4.8Hz,1H),7.38(d,J= 7.9Hz,1H),7.21(t,J=7.8Hz,1H),7.06(t,J=5.9Hz,2H),6.91(d,J=7.6Hz,1H),2.88(t,J=7.3Hz,2H),2.69(q,J=7.5Hz,2H),2.01-1.87(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 153.69, 149.09, 147.70, 145.47, 141.42, 139.86, 135.33, 133.10, 131.83, 130.84, 130.03, 129.69, 128.17, 127.77, 124.00, 122.43, 32.69, 30.93, 24.67. HRMS (ESI-TOF-) Theoretical value C 21 H 17 Cl2N3O3S[MH] - m / z 460.0289, measured value 460.0291.

[0335] Preparation of the final product 6-bromo-N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-2-sulfonamide (SCB054 - Example 44): Prepared from the intermediate 6-bromopyridine-2-sulfonamide (IIID-14), white solid, yield 64%. Mp 185-187℃. 1 H NMR (400MHz, DMSO-d6) δ7.82(t,J=7.7Hz,1H),7.73-7.65(m,2H),7.58(dd,J=8.0,1.6Hz,1H),7.36(d,J=7.3Hz,1H),7.30(t,J=7.8Hz,1H),7 .16(dd,J=7.7,1.6Hz,1H),7.07(d,J=7.6Hz,1H),6.92(d,J=7.6Hz,1H),2.89(t,J=7.5Hz,2H),2.76(t,J=7.5Hz,2H),1.98(p,J=6.9Hz,2H). 13C NMR (100MHz, DMSO-d6) δ 144.67, 142.23, 141.10, 140.33, 140.22, 133.38, 133.19, 131.62, 130.93, 130.60, 129.10, 128.00, 127.48, 120.74, 32.87, 31.32, 24.70. HRMS (ESI-TOF-) Theoretical value C 21 H 16 BrCl2N3O3S[MH] - m / z 537.9395, measured value 537.9400.

[0336] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-hydroxyethane-1-sulfonamide (SCB055 - Example 45): Obtained from the intermediate 2-hydroxyethane-1-sulfonamide (IIID-15), a white solid, yield 52%. Mp 123-125℃. 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),7.74(s,1H),7.66(dd,J=8.0,1.5Hz,1H),7.41(t,J=7.9Hz,1H),7.26-7.19(m,2H),7.02(d,J= 7.6Hz, 1H), 3.69 (q, J = 5.4Hz, 2H), 3.41 (t, J = 6.4Hz, 2H), 2.95 (t, J = 7.5Hz, 2H), 2.82 (dq, J = 14.3, 8.1Hz, 2H), 2.04 (p, J = 6.5Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ 149.70, 145.58, 141.51, 140.11, 133.11, 131.86, 130.97, 130.29, 130.24, 129.75, 128.14, 128.03, 122.33, 55.35, 54.68, 32.75, 31.19, 24.78. HRMS (ESI-TOF-) Theoretical value C 18 H 18 Cl2N2O4S[MH] - m / z 427.0286, measured value 427.0289.

[0337] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)naphthalene-2-sulfonamide (SCB056 - Example 46): Obtained from the intermediate naphthalene-2-sulfonamide (IIID-16), a white solid, yield 37%. Mp 112-114℃. 1 H NMR(400MHz, DMSO-d6)δ10.70(s,1H),8.47(d,J=1.9Hz,1H),8.12(td,J=16.0,8.0Hz,3H),7.80-7.67(m,4H),7.43(dd,J=8.0,1.6Hz,1H),7 .17-7.07(m,2H),6.99(dd,J=7.6,1.6Hz,1H),6.92(d,J=7.6Hz,1H),2.86(dt,J=8.4,4.2Hz,2H),2.75-2.50(m,2H),1.88(m,J=7.8Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ 149.78, 145.37, 141.36, 139.98, 137.27, 134.44, 132.98, 131.72, 131.50, 130.83, 130.46, 130.04, 129.45, 129.32, 128.96, 128.34, 128.06, 127.82, 127.62, 127.51, 122.32, 122.11, 32.66, 30.97, 24.58. HRMS (ESI-TOF-) Theoretical value C 26 H 20 Cl2N2O3S[MH] - m / z 509.0493, measured value 509.0500.

[0338] Preparation of the final product N-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-indene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (SCB057 - Example 47): Obtained from the intermediate 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (IIID-17), a white solid, in 71% yield. Mp 83-85℃. 1H NMR (400MHz, DMSO-d6) δ7.61(d,J=7.8Hz,2H),7.42(s,1H),7.28(t,J=7.8Hz,1H),7.13(dd,J=7.6,4.1Hz,2H),6.95(d,J=7.5Hz,1H),4 .35(hept,J=4.8Hz,2H),4.10(t,J=6.1Hz,2H),2.91(t,J=7.6Hz,2H),2.84-2.59(m,2H),2.17(h,J=6.1Hz,2H),1.99(h,J=6.5Hz,3H). 13 CNMR (100MHz, DMSO-d6) δ 148.52, 145.18, 141.65, 140.44, 138.18, 133.02, 131.71, 131.48, 130.90, 130.37, 129.49, 128.30, 128.09, 127.70, 121.61, 66.59, 43.98, 32.79, 31.16, 24.69, 20.79. HRMS (ESI-TOF-) Theoretical value C 22 H 20 Cl2N4O4S[MH] - m / z 505.0504, measured value 505.0511.

[0339] Examples 48-49 and Examples 51-52

[0340] Preparation of final products SCB058-059 (Examples 48-49) and SCB061-062 (Examples 51-52)

[0341] Preparation of intermediate 4-(methoxycarbonyl)thiophene-2-carboxylic acid (IIIE-2)

[0342]

[0343] Preparation of Jones' reagent: Dissolve 1 g of chromium trioxide crystals in 3 mL of water, heat to 0 °C in an ice bath, and then slowly add 1 mL of concentrated sulfuric acid to obtain approximately 2.5 M Jones' reagent.

[0344] Methyl 5-formylthiophene-3-carboxylate (IIIE-1, 636 mg, 1 eq.) was dissolved in 5 mL of acetone, and Jones' reagent (600 μL, 2.5 M) was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to rise to room temperature for 1 h, quenched with isopropanol, filtered, concentrated, and the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid in 100% yield. 1H NMR (400MHz, DMSO-d6) δ13.51 (s, 1H), 8.64-8.54 (m, 1H), 7.96-7.88 (m, 1H), 3.82 (t, J = 2.4Hz, 3H).

[0345] Preparation of intermediate (1-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclopropyl)tert-butyl carbamate (IIIE-3)

[0346]

[0347] The prepared intermediates IIIC-46 (300 mg, 1 eq.), 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (239 mg, 1.1 eq.), EDCI (309 mg, 1.5 eq.), and DMAP (132 mg, 1 eq.) were dissolved in 15 mL of dichloromethane and reacted with the solution at room temperature for 12 h. After the reaction was complete, the solution was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 2:1) and used directly in the next reaction.

[0348] Preparation of intermediate 1-amino-N-(5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)cyclopropane-1-carboxamide (IIIE-4)

[0349]

[0350] The crude product IIIE-3 from the previous step was dissolved in 4 mL of tetrahydrofuran, and 2 mL of concentrated hydrochloric acid was added. The mixture was reacted at room temperature for 12 h. After the reaction was complete, the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain a white solid in 49% yield. 1 H NMR(400MHz, DMSO-d6)δ8.28(s,1H),7.55(dd,J=7.8,1.8Hz,1H),7.37-7.27(m,2H),7.20(d,J=7.6Hz,1H ), 6.98 (d, J = 7.6Hz, 1H), 6.48 (s, 2H), 3.13 (q, J = 8.6Hz, 2H), 2.93 (t, J = 7.5Hz, 2H), 2.02 (p, J = 6.6Hz, 2H).

[0351] Preparation of the final product methyl 5-((1-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclopropyl)carbamoyl)thiophene-3-carboxylate (SCB061 - Example 51)

[0352]

[0353] Compounds IIIE-4 (100 mg, 1 eq.), IIIE-2 (57 mg, 1.1 eq.), HATU (211 mg, 2 eq.), and DIPEA (107 mg, 3 eq.) were successively dissolved in 5 mL of DMF, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give a white solid in 53% yield. Mp 246-249℃. 1 H NMR (400MHz, DMSO-d6) δ9.12(s,1H),9.03(s,1H),8.49(d,J=1.3Hz,1H),8.17(d,J =1.3Hz,1H),7.54(dd,J=8.0,1.5Hz,1H),7.30(t,J=7.8Hz,1H),7.24-7.16(m,2H) ,7.03(d,J=7.6Hz,1H),3.81(s,3H),2.93(t,J=7.4Hz,2H),2.77(dt,J=11.5,7.8H z,2H),2.09-1.95(m,2H),1.27-1.20(m,1H),1.16-1.08(m,1H),1.00-0.84(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 169.74, 162.18, 161.64, 144.96, 142.57, 140.84, 140.26, 137.46, 134.13, 132.69, 131.70, 131.66, 130.54, 130.25, 129.25, 128.80, 128.41, 127.42, 122.23, 51.92, 34.83, 32.77, 30.89, 24.74, 15.31, 15.19. HRMS (ESI-TOF-) Theoretical value C 26 H 22 Cl2N2O4S[MH] - m / z 527.0677, measured value 527.0605.

[0354] Preparation of the final product N-(1-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclopropyl)-4-(2-hydroxypropyl-2-yl)thiophene-2-carboxamide (SCB058 - Example 48)

[0355]

[0356] SCB061 (49 mg, 1 eq.) was dissolved in 5 mL of tetrahydrofuran, and a methyl magnesium chloride / tetrahydrofuran solution (3 M, 6 eq.) was added dropwise at 0 °C. After the addition was complete, the temperature was raised to room temperature and the reaction was continued for 1 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1 to 1:1) to obtain a white solid in 82% yield. Mp 101-104 °C. 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.52(d,J=1.5Hz,1H),7.34(d,J=1.5Hz,1H),7.30(dd,J =5.4,4.2Hz,1H),7.18(d,J=7.5Hz,1H),7.16-7.12(m,2H),6.97(d,J=7.6Hz,1H),6.87(s,1 H),2.98(t,J=7.5Hz,2H),2.91-2.83(m,2H),2.10(q,J=7.5Hz,2H),1.58(s,6H),1.50(ddd, J=9.8,6.7,3.9Hz,1H),1.42(tt,J=6.7,3.9Hz,1H),0.99(tdd,J=13.2,9.8,5.1Hz,2H).13C NMR (100MHz, CDCl3) δ 169.22, 163.01, 152.00, 146.49, 142.08, 140.66, 137.81, 133.31, 132.87, 131.77, 130.61, 130.25, 129.54, 128.09, 127.69, 127.45, 124.66, 122.90, 71.19, 36.06, 33.41, 31.92, 31.58, 25.34, 16.70, 16.44. HRMS (ESI-TOF-) Theoretical value C 27 H 26 Cl2N2O3S[M+H] + m / z 529.1119, measured value 529.1121.

[0357] Preparation of the final product methyl 5-(N-(1-((5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclopropyl)aminosulfonyl)thiophene-3-carboxylate (SCB062 - Example 52)

[0358]

[0359] Compound IIIE-4 (100 mg, 1 eq.) was dissolved in 10 mL of pyridine and cooled to 0 °C. Then, compound IIID-19 (100 mg, 1.5 eq.) was slowly added, and the mixture was heated to 60 °C and reacted for 4 h. Pyridine was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to give a white solid in 40% yield. Mp 154-155 °C. 1 H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.77(s,1H),8.63(d,J=1.7Hz,1H),7.75(d,J=1.7Hz ,1H),7.60(dd,J=8.0,1.7Hz,1H),7.34(t,J=7.9Hz,1H),7.21(d,J=7.7Hz,1H),7.14(dd,J =7.7,1.7Hz,1H),7.04(d,J=7.6Hz,1H),3.82(d,J=1.7Hz,3H),2.94(t,J=7.6Hz,2H),2.77 -2.55(m,2H),2.00(q,J=7.3Hz,2H),0.95(td,J=13.8,10.2Hz,2H),0.80(d,J=4.1Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ 168.92, 161.51, 145.09, 144.19, 142.19, 140.22, 139.26, 133.75, 132.29, 131.76, 131.29, 131.03, 130.74, 130.30, 129.35, 128.35, 127.58, 122.33, 52.24, 36.50, 32.75, 30.87, 24.65, 13.72, 13.40. HRMS (ESI-TOF-) Theoretical value C 25 H 22 Cl2N2O5S2[MH] - m / z 563.0269, measured value 563.0278.

[0360] Preparation of the final product N-(5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)-1-((4-(2-hydroxypropyl-2-yl)thiophene)-2-sulfonamido)1-cyclopropylformamide (SCB059 - Example 49)

[0361]

[0362] Synthesized using the same method as SCB058. White solid, yield 72%. Synthesized using the same method as SCB058, except that compound SCB061 is replaced with compound SCB0621. White solid, yield 72%. Mp 100-102℃. 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.63(s,2H),7.53(s,1H),7.34(s,1H),7.19(d,J=12.3Hz,2H),7.0 5(s,1H),5.22(s,1H),2.95(s,2H),2.76(s,2H),2.03(s,2H),1.39(s,6H),0.93(s,2H),0.71(s,2H).13C NMR (100MHz, DMSO-d6) δ 169.13, 152.78, 145.16, 141.96, 140.26, 133.53, 131.78, 131.00, 130.73, 130.25, 129.34, 128.28, 127.63, 125.78, 122.24, 69.33, 36.48, 32.74, 31.30, 30.93, 24.73, 13.59, 13.22. HRMS (ESI-TOF-) Theoretical value C 26 H 26 Cl2N2O4S2[MH] - m / z 563.0633, measured value 563.0645.

[0363] Examples 50 and 53

[0364] Synthetic routes for final products SCB060 (Example 50) and SCB063 (Example 53)

[0365] Preparation of intermediate methyl 5-(bromomethyl)thiophene-3-carboxylate (IIIF-2)

[0366]

[0367] 5-Methylthiophene-3-carboxylate (IIIF-1, 1.00 g, 1 eq.) was suspended in 10 mL of carbon tetrachloride at room temperature, followed by the sequential addition of NBS (1.43 g, 1.1 eq.) and AIBN (48 mg, 0.05 eq.), and then the mixture was heated to reflux for 6 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to obtain a colorless liquid in 89% yield. 1H NMR (400MHz, CDCl3) δ8.09-8.02(m,1H),7.52-7.44(m,1H),4.72-4.60(m,2H),3.87-3.81(m,3H).

[0368] Preparation of intermediate methyl 5-(aminomethyl)thiophene-3-carboxylate (IIIF-3)

[0369]

[0370] Intermediate IIIF-2 (672 mg, 1 eq.) was dissolved in 10 mL of methanol, and then an ammonia / methanol solution (7 M, 3.49 mL, 10 eq.) was added. The mixture was then heated to 45 °C and reacted for 12 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate to dichloromethane:methanol = 10:1) to give a white solid in 27% yield. 1 H NMR (400MHz, CD3OD) δ8.18 (d, J = 1.4 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 4.19 (s, 2H), 3.86 (s, 3H).

[0371] Preparation of the final product methyl 5-((3-(5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)ureido)methyl)thiophene-3-carboxylate (SCB063 - Example 53)

[0372]

[0373] Intermediate IIIC-46 (162 mg, 1 eq.) was dissolved in tetrahydrofuran and triethylamine (118 mg, 2 eq.) was added. Triphosgene (66 mg, 0.38 eq.) was added at 0 °C and the reaction was carried out for 1 h. The mixture was filtered and concentrated to obtain crude isocyanate for later use. Intermediate IIIF-3 (100 mg, 1 eq.) was dissolved in tetrahydrofuran and triethylamine (60 mg, 1 eq.) was added. The prepared crude isocyanate was dissolved in tetrahydrofuran at 0 °C and added dropwise to the reaction flask, and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the solvent was removed by concentration, and the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to dichloromethane:methanol = 30:1), yielding a white solid with a yield of 57%. Mp 188-189 °C. 1H NMR(400MHz,DMSO-d6)δ8.18(d,J=1.4Hz,1H),7.60(dd,J=8.1,1.6Hz,1H), 7.48(s,1H),7.33(t,J=7.9Hz,1H),7.22(d,J=1.4Hz,1H),7.20-7.12(m,2H) ,6.98(d,J=7.6Hz,1H),6.59(t,J=6.1Hz,1H),4.36-4.30(m,2H),3.79(s,3H ), 2.94(t,J=7.5Hz,2H), 2.81(td,J=7.3,3.3Hz,2H), 2.02(t,J=7.4Hz,2H). 13 C NMR (100MHz, CDCl3) δ 163.23, 155.72, 146.98, 143.36, 143.05, 140.12, 134.98, 133.43, 132.89, 132.72, 131.79, 130.46, 129.96, 129.72, 129.34, 127.44, 125.82, 123.62, 51.91, 39.13, 33.46, 31.43, 25.22. HRMS (ESI-TOF-) theoretical value C 23 H 20 Cl2N2O3S[M+H] + m / z 475.0650, measured value 475.0641.

[0374] Preparation of the final product 1-(5-(2,3-dichlorophenyl)-2,3-dihydro-1H-inden-4-yl)-3-((4-(2-hydroxypropyl-2-yl)thiophen-2-yl)methyl)urea (SCB060 - Example 50)

[0375]

[0376] Synthesized using the same method as SCB059. White solid, yield 53%. Mp 80-81℃. 1H NMR (400MHz, CDCl3) δ7.40 (dd, J=7.9, 1.7Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 7.14 ( t,J=7.8Hz,1H),7.07(dd,J=7.6,1.7Hz,1H),7.01(d,J=7.7Hz,1H),6.95(d,J=1 .5Hz,1H),6.81(d,J=1.5Hz,1H),5.07(s,1H),4.27(q,J=15.5Hz,2H),2.96(t, J=7.5Hz,2H),2.87(t,J=7.5Hz,2H),2.08(dd,J=14.7,7.3Hz,2H),1.48(s,6H). 13 C NMR (100MHz, CDCl3) δ 155.78, 150.59, 146.69, 142.97, 142.94, 140.34, 134.75, 133.17, 131.80, 130.82, 129.88, 129.73, 129.02, 127.33, 124.12, 123.12, 118.30, 70.94, 39.32, 33.39, 31.41, 31.23, 25.20. HRMS (ESI-TOF-) Theoretical value C 24 H 24 Cl2N2O2S[M+H] + m / z 475.1014, measured value 475.1015.

[0377] Bioactivity

[0378] This invention includes pharmacological and pharmacodynamic experiments to assess pharmacological activity. Pharmacological experiments included inflammatory cell experiments inducing NLRP3 activation and IL-1β release from different stimuli, CCK8 cytotoxicity assays, Western blotting, ROS detection and mitochondrial damage detection, surface plasmon resonance, and ASC polymer and dot assays, all demonstrating the selective inhibitory effect of the amide compounds on NLRP3 protein. Pharmacodynamic experiments included evaluating the in vivo efficacy of the compounds using an MSU-induced peritonitis mouse model, an acute arthritis model, and a water maze test, collectively demonstrating the pharmacological effects of the amide compounds in NLRP3-driven inflammatory diseases.

[0379] (1) Extraction of mouse bone marrow macrophages

[0380] BMDM primary macrophages were extracted from the leg bones of 8-10 week old C57BL / 6 mice. Mice were purchased from the Animal Center of Peking University School of Medicine. Mice were euthanized by cervical dislocation and sterilized in 75% alcohol. In a laminar flow hood, both hind legs of the mice were removed using sterilized surgical instruments, and the skin and flesh were removed with scissors to obtain the leg bones. The intact leg bones were washed in PBS containing 2% penicillin and antibiotics. The leg bones were then cut with sterile scissors. DMEM medium was drawn up with a 5ml syringe, and the bone marrow was expelled using a 1ml syringe tip. This process was repeated until the leg bones turned white. The expelled cells were centrifuged, and erythrocyte lysis buffer was added. This process was repeated for 5 minutes, followed by the addition of 10 times the volume of PBS to terminate lysis, and then centrifuged again to obtain the cells. Finally, the cells were resuspended in DMEM medium containing 10% serum, 30% L929 supernatant, and 1% penicillin and antibiotics, filtered through a cell sieve, counted, and then cultured in non-treated cell culture dishes. BMDM cells were obtained after 7 days of culture.

[0381] (2) Inflammation activation

[0382] For the activation of the NLRP3 inflammasome, THP-1 cells were fed at a concentration of 1×10⁻⁶. 6 Cells were seeded at a density of [number] cells / mL in 96-well plates and stimulated with 50 ng / mL phorbol 12-myristate 13-acetate (PMA) for 24 hours to induce differentiation into macrophages. The next day, after washing three times with medium to remove PMA, PMA-THP-1 cells were cultured overnight in fresh RPMI 1640 medium containing 1% fetal bovine serum. The next day, the medium was discarded, and cells were stimulated for 3 hours with medium containing LPS (50 ng / mL). Then, inhibitors (DMSO was added to the control group, with a final DMSO concentration of 0.1%) were added and incubated for 30 minutes. Finally, NLRP3 activator MSU (200 μg / mL) crystals were added for 4 hours or ATP (5 mM) / Nigericin (10 μM) for 30 minutes to activate NLRP3.

[0383] For BMDM cell stimulation, it was administered at a dose of 5 × 10 5 Cells were seeded at a density of [number] cells / mL in 6-well plates and cultured for 12 hours. The next day, the culture medium was removed and the cells were treated with fresh DMEM containing 200 ng / mL LPS for 3 hours. Then, the compound was added and NLRP3 was activated in the same manner as described above.

[0384] Activation of the AIM2 / NLRC4 inflammasome was achieved by treating cells with LPS (100 ng / mL) for 3 hours, followed by stimulation with poly(dA:dT) sodium salt transfected with liposome 2000 (1 μg / mL) for 4 hours or stimulation with flagellin of S. typhimurium (100 ng / mL) for 2 hours.

[0385] After inflammation is activated, cell supernatant is aspirated and ELISA is performed to test the IC50 of the compound. 50 .

[0386]

[0387]

[0388] (3) CCK8 cell viability analysis

[0389] HEK293T cells were used at a rate of 4 × 10⁻⁶ 4 Cells were seeded at a density of [number] cells / mL in 96-well plates and cultured overnight. Different concentrations of the compound were then added, and the cells were cultured for another 24 hours. Finally, the culture medium was aspirated, CCK8 was added, and the cells were incubated for 4 hours. The absorbance was recorded at 450 nm. The inhibition rate was calculated using the formula: Cell viability = ((OD[value]) / mL) 实验 -OD 空白 ) / (OD 对照 -OD 空白 ))×100%.

[0390] (4) ROS detection and mitochondrial damage detection

[0391] PMA-induced THP-1 cells (1×10⁻⁶) 6 Cells (number of cells / mL) were seeded in glass-bottomed cell culture dishes and activated with LPS / Nigericin. After activation, the cells were washed once with PBS, and then stained with MitoSOX (5 μM) or MitoTracker (20 nM) in the dark for 20 minutes. After staining, the cells were washed three times with PBS, and then fixed with 4% PFA. After fixing for 30 minutes, the cells were washed three times with PBS, and then stained with Hoechst 33342 for 20 minutes. Finally, the cells were washed three times with PBS and photographed using confocal microscopy.

[0392] (5) Western blot analysis (WB)

[0393] For the extraction of cell supernatant proteins: After activating inflammation with BMDM according to the method mentioned in method (2), the supernatant was collected and mixed with methanol and chloroform at a ratio of 10:7:3 and centrifuged. After discarding the supernatant, 500 μL of methanol was added for resuspending and centrifugation was continued. The supernatant was discarded again and the precipitate was allowed to air dry naturally. SDS protein loading buffer was added and heated at 100℃ for 5 min to denature the protein for subsequent assays.

[0394] For intracellular protein extraction: After removing the supernatant from activated BMDM cells, they were washed with PBS. Then, lysis buffer containing RIPA was added, and cells were collected using a cell scraper. The collected cells were placed in EP tubes and lysed on ice for 30 min, followed by centrifugation at 12000 rpm and 4°C for 30 min. Finally, the supernatant was collected, and protein concentration was determined using a BCA protein quantification kit. The remaining protein was denatured by heating for subsequent assays.

[0395] Electrophoresis and transfer: Electrophoresis gels were prepared using a commercial electrophoresis gel kit purchased from Yageo. Samples were then diluted and loaded according to the determined protein concentration. The stacking gel was run at 80V for 30 minutes, and the separating gel at 120V for 90 minutes. After electrophoresis, a suitable PVDF membrane was cut and transferred using a transfer current of 200mA.

[0396] Blocking, antibody incubation, and development: Block the protein using 5% skim milk powder at room temperature. After two hours of blocking, wash three times with TBST for 20 minutes each time. Then add primary antibody and incubate overnight at 4°C. After incubation, wash three times with TBST, incubate with secondary antibody for 1 hour, wash with TBST, and then develop.

[0397] (6) Surface Plasmon Resonance (SPR)

[0398] Surface plasmon resonance (SPR) was used to detect the direct binding of compounds to proteins. The specific experimental procedure was as follows: NLRP3 was diluted to 100 ng / μL with sodium acetate buffer (pH 4.0) to make it positively charged. NLRP3 was then immobilized on a CM5 chip via amino coupling, with a response value of approximately 15000 Ru. For the reference orbital, only the surface of the closed chip was activated, and NLRP3 was not immobilized. PBS-P was used as the buffer solution. Compound solutions containing 5% DMSO and DMSO calibration solutions (4.5%–5.8%) with different concentration gradients were prepared, ensuring that the DMSO content in the buffer solutions was 5%. The compounds of different concentrations were sequentially passed over the surface of the chip. If the compound interacted with NLRP3, binding and dissociation curves were generated. If there was no interaction, no response signal was observed. Finally, regeneration was achieved by rinsing with the buffer solution after each injection.

[0399] (7) Mouse model of peritonitis caused by MSU

[0400] The mice used for in vivo efficacy evaluation of gout medication were all 8-week-old C57BL / 6 mice. For the peritonitis experiment, peritonitis was induced by intraperitoneal injection of MSU (monosodium urate, 3 mg, dissolved in 200 μL PBS). The drug group received intraperitoneal injections of different concentrations of the compound for 3 consecutive days before modeling. The normal group was treated with PBS. Six hours after MSU modeling, the mice were sacrificed and the peritoneal cavity was flushed with 5 mL of PBS. Finally, the level of IL1-β in the peritoneal lavage fluid was measured by ELISA.

[0401] SCB042 can reduce IL-1β expression in mice with MSU-induced gouty peritonitis.

[0402] (8) MSU-induced gouty arthritis mouse model

[0403] For a mouse model of gouty arthritis, 20 μL of MSU suspension (prepared by dissolving 3 mg MSU in PBS) was injected into the footpads of mice to induce gouty arthritis. Mice in the control group were injected with the same volume of PBS. The compound was administered for 3 days prior to MSU injection, while the blank control group received PBS. Improvement in gout was assessed by measuring edema in the mouse footpads. Increase in footpad diameter was used to evaluate the formation of foot edema. Mechanical aberration pain in mice was measured using Von Frey. Pain thresholds were recorded at 1, 3, 6, 12, and 24 hours after MSU injection.

[0404] The experimental results show that the compound SCB042 of this application can reduce paw swelling in mice with MSU-induced gouty arthritis and has good anti-inflammatory and analgesic effects.

[0405] (9) Water Maze Experiment

[0406] Cognitive impairment was induced in mice by intraperitoneal injection of scopolamine (2 mg / kg) for 14 consecutive days. The treatment group received the drug daily, while the control and model groups received the same volume of PBS. Behavioral experiments were conducted on the last five days, with mice artificially trained to locate the central island. During training, a water maze was divided into four quadrants, and mice were randomly dropped into each quadrant once, repeated four times. On the last day, the experiment was conducted, with mice randomly dropped into the water maze at different locations. The improvement in cognitive function of the compound was assessed by recording the mice's paths in the maze and the time required to find the central island.

[0407] Experimental results show that, compared with MCC950, the SCB042 compound of this application can improve cognition in Alzheimer's mice to a certain extent.

[0408] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. An amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate as shown in general formula (I): in, In equation (I), n is 0 or 1; Y is -S(O)2-, -C(O)-, or -CH2-; A is a substituted C1-C4 alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted aryl ring-fused C3-C6 cycloalkyl group, optionally a substituted heteroaryl ring-fused C3-C6 cycloalkyl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C4-C8 cycloalkyl group, unsubstituted aryl group, substituted aryl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted heteroaryl group, optionally a substituted C2-C6 heterocyclic alkyl group, or optionally a substituted C3-C6 cycloalkyl group. Fused heteroaryl; and specifying that A is not p-tolyl; and, when A is an optionally substituted C3-C6 cycloalkyl, optionally substituted aryl ring fused C3-C6 cycloalkyl, optionally substituted heteroaryl ring fused C3-C6 cycloalkyl, optionally substituted C2-C6 heterocyclic fused C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkyl fused C3-C6 cycloalkyl, optionally substituted C2-C6 heterocyclic fused aryl, optionally substituted C3-C6 cycloalkyl fused aryl, optionally substituted C2-C6 heterocyclic fused heteroaryl, or optionally substituted C3-C6 cycloalkyl fused heteroaryl, in formula (I) for R1 is a C2-C3 alkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl; and it is specified that R1 is not 3-tert-butylphenyl, 3-(N,N-diethylcarbamoyl)phenyl, or 4-(morpholino-4-yl)phenyl. R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, phenyl, or substituted phenyl. R5 is a C2-C3 alkyl group, or R5 and R4 together with the two carbons of the benzene ring to which they are attached form cyclopentene.

2. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to claim 1, wherein, Equation (I) is equivalent to Equation (I-1) In equation (I-1), A and R1 to R5 are defined in the same way as in equation (I); or Equation (I) is equivalent to Equation (I-2): In equation (I-2), A and R1 to R5 are defined in the same way as in equation (I); or Equation (I) is equivalent to Equation (I-3): In equation (I-3), A and R1 to R5 are defined in the same way as in equation (I); or Equation (I) is equivalent to Equation (I-4): In equation (I-4), A and R1 to R5 are defined in the same way as in equation (I).

3. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to claim 1 or 2, wherein, In formulas (I), (I-1), (I-2), (I-3), or (I-4), A is a substituted C1-C4 alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted aryl ring-fused C3-C6 cycloalkyl group, optionally a substituted heteroaryl ring-fused C3-C6 cycloalkyl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C4-C8 cycloalkyl group, unsubstituted aryl group, substituted aryl group, optionally a substituted C2-C6 heterocyclic alkyl group, optionally a substituted C3-C6 cycloalkyl group, optionally a substituted heteroaryl group, optionally a substituted C2-C6 heterocyclic alkyl group, or optionally a substituted C3-C6 cycloalkyl group; here The substituted C1-C4 alkyl group refers to a C1-C4 alkyl group that is substituted by a hydroxyl group, an unsubstituted phenyl group, or a substituted phenyl group. The substituted phenyl group refers to benzene that is substituted by one or more groups selected from the following: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; and / or The optionally substituted C3-C6 cycloalkyl group is an unsubstituted C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; wherein, the C3-C6 cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and / or The optionally substituted aromatic ring-fused C3-C6 cycloalkyl, the optionally substituted heteroaromatic ring-fused C3-C6 cycloalkyl, the optionally substituted C2-C6 heterocycloalkyl-fused C3-C6 cycloalkyl, or the optionally substituted C4-C8 cycloalkyl-fused C3-C6 cycloalkyl is an unsubstituted aromatic ring-fused C3-C6 cycloalkyl, an unsubstituted heteroaromatic ring-fused C3-C6 cycloalkyl, an unsubstituted C2-C6 heterocycloalkyl-fused C3-C6 cycloalkyl, or an unsubstituted C4-C8 cycloalkyl-fused C3-C6 cycloalkyl, or is selected from the following One or more of the substituted aromatic rings fused to C3-C6 cycloalkyl, heteroaromatic rings fused to C3-C6 cycloalkyl, C2-C6 heterocyclic alkyl fused to C3-C6 cycloalkyl, or C4-C8 cycloalkyl fused to C3-C6 cycloalkyl: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy The aromatic ring fused C3-C6 cycloalkyl group includes, but is not limited to, benzocyclobutyl, benzocyclopentyl, or benzocyclohexyl; the heterocyclic aromatic ring fused C3-C6 cycloalkyl group includes, but is not limited to, furanocyclobutyl, furanocyclopentyl, furanocyclohexyl, thienocyclobutyl, thienocyclopentyl, thienocyclohexyl, and pyridocyclobutyl. The C2-C6 heterocyclic alkyl fused with C3-C6 cycloalkyl groups includes, but is not limited to, tetrahydropyrrolocyclobutyl, tetrahydropyrrolocyclopentyl, tetrahydropyrrolocyclohexyl, tetrahydrofuranolocyclobutyl, tetrahydrofuranolocyclopentyl, tetrahydrofuranolocyclohexyl, piperidinolocyclobutyl, piperidinolocyclopentyl, piperidinolocyclohexyl, piperazinolocyclopentyl, or piperazinolocyclohexyl; the C4-C8 cycloalkyl fused with C3-C6 cycloalkyl groups includes, but is not limited to, cyclobutylolocyclopentyl, cyclopentylolocyclopentyl, cyclohexylolocyclopentyl, or decahydronaphthyl; and / or The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or The substituted aryl group is a naphthyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; or, The substituted aryl group is a phenyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C2-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; and / or The optionally substituted C2-C6 heterocyclic fused aryl group or the optionally substituted C3-C6 cyclic fused aryl group is an unsubstituted C2-C6 heterocyclic fused aryl group or an unsubstituted C3-C6 cyclic fused aryl group, or is a C2-C6 heterocyclic fused aryl group or a C3-C6 cyclic fused aryl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; wherein, the C2-C6 heterocycloalkane-fused aryl group includes, but is not limited to, dihydropyrrolophenyl, dihydrofuranophenyl, dihydrothienophenyl, piperidinophenyl, or piperazinophenyl; the C3-C6 cycloalkane-fused aryl group includes, but is not limited to, cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl, or cyclohexylphenyl; and / or The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thiophene, furanyl, pyranyl, pyrroleyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indoleyl, indazinyl, indazoleyl, purinel, quinolinyl, naphridinyl, pteridinyl, carbazolyl, acridinel, benzothiadiazolyl, benzofuranyl, pyrazolopyrimidine, or pyrazoloxazine; the substituted heteroaryl group refers to a group substituted by one or more of the following groups: halogen, Hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl and phenyl; and / or The optionally substituted C2-C6 heterocyclic fused heteroaryl group or the optionally substituted C3-C6 cyclic fused heteroaryl group is an unsubstituted C2-C6 heterocyclic fused heteroaryl group or an unsubstituted C3-C6 cyclic fused heteroaryl group, or a C2-C6 heterocyclic fused heteroaryl group or a C3-C6 cyclic fused heteroaryl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine). Substituted C1-C4 alkyl, (diC1-C4 alkylamine)-substituted C1-C4 alkyl, oxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylacyl, (monoC1-C4 alkylamine)-substituted C1-C4 alkylacyl, (diC1-C4 alkylamine)-substituted C1-C4 alkylacyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, optionally substituted heteroaryl and phenyl; wherein, the heteroaryl fused to the C2-C6 heterocycloalkane includes, but is not limited to, dihydropyrrolopyrrolithioyl, dihydropyrrolothiopheneyl, di... Hydropyrrolofuranyl, dihydropyrrolopyrazolyl, dihydropyrrolotriazolyl, dihydrofuranolopyrryl, dihydrofuranolothiophenyl, dihydrofuranolopyrryl, dihydrofuranolopyrazolyl, dihydrofuranolotriazolyl, dihydrothiophene-pyrryl, dihydrothiophene-thiophenyl, dihydrothiophene-furanyl, dihydrothiophene-pyrazolyl, dihydrothiophene-triazolyl, piperidinopyrryl, piperidinothiophenyl, piperidinofuranyl, piperidinopyrazolyl, piperidinotriazolyl, piperazinopyrryl, piperazinothiophenyl, piperazinofuranyl, piperazinopyrazolyl, piperazinotriazolyl, tetra The heteroaryl groups fused with C3-C6 cycloalkane include, but are not limited to, cyclopentyl-pyrrolithyl, cyclohexane-thiophenyl, cyclopentyl-thiophenyl, cyclohexane-pyrazole, cyclopentyl-pyrrolithyl, cyclohexane-thiophenyl, cyclohexane-pyrazole, or cyclohexane-triazole.

4. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to claim 3, wherein, In formulas (I), (I-1), (I-2), (I-3), or (I-4), A is a hydroxyl-substituted C1-C4 alkyl, benzyl, phenyl, or substituted phenyl, naphthyl, or substituted naphthyl, thiophene, or substituted thiophene, furanyl, or substituted furanyl, pyranyl, or substituted pyranyl, pyrrole, or substituted pyrrole, thiazolyl, or substituted thiazolyl, oxazolyl, or substituted oxazolyl, isoxazolyl, or substituted isoxazolyl, imidazolyl, or substituted imidazolyl, pyrazolyl, or substituted pyridyl, pyrimidinyl, or substituted pyrimidinyl, pyrazinyl, or... Substituted pyrazinyl, indolyl or substituted indolyl, inazinyl or substituted inazinyl, indazole or substituted indazole, purine or substituted purine, quinolinyl or substituted quinolinyl, naphthidyl or substituted naphthidyl, pteridyl or substituted pteridyl, carbazolyl or substituted carbazolyl, acridine or substituted acridine, benzothiadiazolyl or substituted benzothiadiazolyl, benzofuranyl or substituted benzofuranyl, pyrazolopyrimidine or substituted pyrazolopyrimidine, or pyrazolooxazine or substituted pyrazolooxazine, and the substituted phenyl, substituted naphthyl, substituted thiophene, substituted Furanyl, substituted pyranyl, substituted pyrroleyl, substituted thiazolyl, substituted oxazolyl, substituted imidazolyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrazinyl, substituted indoleyl, substituted indazinyl, substituted indazoleyl, substituted purineyl, substituted quinolinyl, substituted naphthidyl, substituted pteridinyl, substituted carbazoleyl, substituted acridineyl, substituted benzothiadiazolyl, substituted benzofuranyl, substituted pyrazolopyrimidine, or substituted pyrazoloxazine is substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl. Nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, and phenyl; and specify that A is not p-tolyl; or, A is hydroxymethyl, hydroxyethyl, benzyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thiophene, substituted thiophene, furanyl, substituted furanyl, pyrazolyl, substituted pyrazolyl, pyridyl, substituted pyridyl, pyrazoloxazine, or substituted pyrazoloxazine, and the substituted phenyl, substituted naphthyl, substituted thiophene, substituted furanyl, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted... Pyrazoloxazine is a compound substituted with one or more groups selected from the following: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and it is specified that A is not p-tolyl; or, A is 2-hydroxyethyl, benzyl, phenyl, naphthyl, thiophene, furanyl, pyrazolyl, pyridyl, pyrazoloxazine, substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine, and said substituted phenyl, substituted thiophene, substituted furanyl, substituted pyrazolyl, substituted pyridyl, or substituted pyrazoloxazine is substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and it is specified that A is not p-tolyl; or A represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzo[a]cyclobutyl, benzo[a]cyclopentyl, benzo[a]cyclohexyl, furano[a]cyclobutyl, furano[a]cyclopentyl, furano[a]cyclohexyl, thieno[a]cyclobutyl, thieno[a]cyclopentyl, thieno[a]cyclohexyl, pyridin[a]cyclobutyl, pyridin[a]cyclopentyl, pyridin[a]cyclohexyl, tetrahydropyrrolo[a]cyclobutyl, tetrahydropyrrolo[a]cyclopentyl, tetrahydropyrrolo[a]cyclohexyl Tetrahydrofuranocyclobutyl, tetrahydrofuranocyclopentyl, tetrahydrofuranocyclohexyl, piperidinocyclobutyl, piperidinocyclopentyl, piperidinocyclohexyl, piperazinocyclopentyl, piperazinocyclohexyl, cyclobutylocyclopentyl, cyclopentylocyclopentyl, cyclohexylocyclopentyl, decahydronaphthyl, dihydropyrrolophenyl, dihydrofuranophenyl, dihydrothiophene, piperidinophenyl, piperazinophenyl, cyclopropylophenyl, cyclobutylophenyl, cyclopentylophenyl, cyclohexylophenyl, dihydropyrrolopyrryl, dihydropyrrolothiophene, dihydropyrrolofuranyl, dihydropyrrolopyrazolyl, dihydropyrrolotriazolyl, dihydrofuranopyrryl, dihydrofuranothiophene, dihydrofuranopyrrolyl, dihydrofuranopyrazolyl, dihydrofuranotriazolyl, dihydrothiophene pyrrole, dihydrothiophene-thiophene, dihydrothiophene-furanyl, dihydrothiophene-pyrazolyl, dihydrothiophene-triazolyl, piperidinopyrrole, piperidinothiophene, piperidinofuranyl, piperidinopyrazolyl, piperidinotriazolyl, piperazinopyrrole, piperazinothiophene, piperazinofuranyl, piperazinopyrazolyl, piperazinotriazolyl, tetrahydropyranopyrrole, tetrahydropyranopyrrole Thiopheneyl, tetrahydropyranofuranyl, tetrahydropyranopyrazole, tetrahydropyranotriazolyl, oxazacyclohexane-pyrroleyl, oxazacyclohexane-thiophenyl, oxazacyclohexane-furanyl, oxazacyclohexane-pyrazole, oxazacyclohexane-triazolyl, cyclopentyl-furanyl, cyclohexyl-furanyl, cyclopentyl-thiophenyl, cyclohexyl-thiophenyl, cyclopentyl-pyrazolyl, cyclohexyl-pyrazolyl, cyclopentyl-triazolyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, substituted benzocyclobutyl, substituted benzocyclopentyl, substituted benzocyclohexyl, substituted furanocyclobutyl, substituted furanocyclopentyl, substituted furanocyclohexyl, substituted thiophene-cyclobutyl, substituted Thiophene-cyclopentyl, substituted thieno-cyclohexyl, substituted pyrido-cyclobutyl, substituted pyrido-cyclopentyl, substituted pyrido-cyclohexyl, substituted tetrahydropyrrolo-cyclobutyl, substituted tetrahydropyrrolo-cyclopentyl, substituted tetrahydropyrrolo-cyclohexyl, substituted tetrahydrofurano-cyclobutyl, substituted tetrahydrofurano-cyclopentyl, substituted tetrahydrofurano-cyclohexyl, substituted piperido-cyclobutyl, substituted piperido-cyclopentyl, substituted piperido-cyclohexyl, substituted piperazine-cyclopentyl, substituted piperazine-cyclohexyl, substituted cyclobutyl-cyclopentyl, substituted cyclopentyl-cyclopentyl, substituted decahydronaphthyl, substituted dihydropyrrolo-phenyl, substituted dihydrofurano-phenyl, substituted dihydrothieno-phenyl, substituted piperidine-phenyl, substituted piperazine-phenylSubstituted cyclopropylphenyl, substituted cyclobutylphenyl, substituted cyclopentylphenyl, substituted cyclohexylphenyl, substituted dihydropyrrolopyrryl, substituted dihydropyrrolothiophene, substituted dihydropyrrolofuranyl, substituted dihydropyrrolopyrazolyl, substituted dihydropyrrolotriazolyl, substituted dihydrofuranolopyrryl, substituted dihydrofuranolothiophene, substituted dihydrofuranolopyrazolyl, substituted dihydrofuranolotriazolyl, substituted dihydrothiophene, substituted dihydrothiophene Phenothiophene, substituted dihydrothiophenefuran, substituted dihydrothiophenepyrazol, substituted dihydrothiophenetriazol, substituted piperidinopyrrole, substituted piperidinothiophene, substituted piperidinofuran, substituted piperidinopyrazol, substituted piperidinotriazol, substituted piperazinopyrrole, substituted piperazinothiophene, substituted piperazinofuran, substituted piperazinopyrazol, substituted tetrahydropyranopyrrole, substituted tetrahydropyranothiophene, substituted tetrahydropyranofuran, (repeated) Substituted tetrahydropyranopyrazole, substituted tetrahydropyranotriazolyl, substituted oxazacyclohexanepyrroleyl, substituted oxazacyclohexanethiophenyl, substituted oxazacyclohexanefuranyl, substituted oxazacyclohexanepyrazole, substituted oxazacyclohexanetriazolyl, substituted cyclopentylfuranyl, substituted cyclohexylfuranyl, substituted cyclopentylthiophenyl, substituted cyclohexylthiophenyl, substituted cyclopentylpyrazolyl, substituted cyclohexylpyrazolyl, substituted cyclopentyltriazolyl or substituted cyclohexane The alkyltriazolyl group, wherein the substituents are selected from one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, oxy, hydroxymethyl, hydroxypropyl, hydroxybutyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, and ethoxycarbonyl; and, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), for or A is benzocyclopentyl, pyridocyclopentyl, cyclohexylcyclopentyl, dihydrofuranophenyl, N-methylpiperidinothiophenyl, N-methylpiperazinone-pyrazolyl, oxazacyclohexane-pyrazolyl, or piperidinopyrazolyl; and, in formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4) for or In formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4), A is one of the following groups: Moreover, in equations (I), (I-1), (I-2), (I-3), or (I-4) for or A is 4-(2-hydroxy-prop-2-yl)furan-2-yl, thiophen-2-yl, 3-bromothiophen-2-yl, 4-(methoxycarbonyl)thiophen-2-yl, 4-(2-hydroxy-prop-2-yl)thiophen-2-yl, 2-hydroxyethyl, benzyl, phenyl, 3-aminophenyl, 4-acetylphenyl, 4-(N,N-dimethylaminomethyl)phenyl, naphth-2-yl, 1,3-dimethyl-pyrazol-4-yl, pyridin-3-yl, 6-bromo-pyridin-2-yl, or 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl.

5. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to any one of claims 1 to 4, wherein, In formulas (I), (I-1), (I-2), (I-3), or (I-4), R1 is ethyl or isopropyl, and R2, R3, and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl, or p-tolyl, and R5 is ethyl or isopropyl; or R1 is isopropyl, and R2, R3, and R4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, or ethoxycarbonyl, and R5 is isopropyl; or R1 is isopropyl, R2, R3 and R4 are each independently hydrogen or nitro, and R5 is isopropyl.

6. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to any one of claims 1 to 4, wherein, In formula (I), formula (I-1), formula (I-2), formula (I-3), or formula (I-4): R5 and R4, along with the two carbons of the benzene ring to which they are attached, together form cyclopentene; R1 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; wherein: the unsubstituted aryl group is an unsubstituted phenyl group or an unsubstituted naphthyl group; and / or The substituted aryl group is a naphthyl group substituted with one or more of the following groups: halogen, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocycloalkyl, optionally substituted heteroaryl and phenyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: halogen Element, hydroxyl, nitro, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 alkyl, (mono-C1-C4 alkylamine)-substituted C1-C4 alkyl, (di-C1-C4 alkylamine)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkylacyl, (mono-C1-C4 alkylamine) The substituted aryl group is a C1-C4 alkyl acyl group, a (diC1-C4 alkylamino)-substituted C1-C4 alkyl acyl group, a C1-C4 alkoxycarbonyl group, a C3-C8 cycloalkyl group, a C2-C6 heterocycloalkyl group, an optionally substituted heteroaryl group, or a phenyl group, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl, 3-(N,N-diethylcarbamoyl)phenyl, or 4-(morpholino-4-yl)phenyl; and / or The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the substituted heteroaryl group is: thienyl, furanyl, pyranyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indoleyl, inazinyl, indazoleyl, purinel, quinolinyl, naphthidyl, pteridinyl, carbazolyl, acridineyl, benzothiadiazolyl, benzofuranyl, pyrazolopyrimidine, or pyrazoloxazine; the substituted heteroaryl group refers to a group substituted by one or more of the following groups: halogen, hydroxyl, nitro, cyano. The following compounds are included: alkyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkoxy, C1-C4 haloalkoxy, C1-C4 alkanoyl, (mono-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, (di-C1-C4 alkylamino)-substituted C1-C4 alkanoyl, C1-C4 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 heterocyclic alkyl, and phenyl; and R2 and R3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl, or p-tolyl; or In equation (I), equation (I-1), equation (I-2), equation (I-3), or equation (I-4), R5 and R4, along with the two carbons of the benzene ring to which they are attached, together form cyclopentene; R1 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; wherein: The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or The substituted aryl group is a naphthyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino, methyl, ethyl, and trifluoromethyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, The following are specified: propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl or 3-(N,N-diethylaminoformyl)phenyl; and / or The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or pyrazoloxazine; the substituted heteroaryl group refers to a group that is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl. Ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl; and R2 and R3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, methoxycarbonyl, ethoxycarbonyl, phenyl, or p-tolyl; or In equation (I), equation (I-1), equation (I-2), equation (I-3), or equation (I-4), R5 and R4, along with the two carbons of the benzene ring to which they are attached, together form cyclopentene; R1 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; wherein: The unsubstituted aryl group is an unsubstituted phenyl or an unsubstituted naphthyl group; and / or The substituted aryl group is a naphthyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, hydroxyl, nitro, cyano, amino, methyl, ethyl, and trifluoromethyl; or, the substituted aryl group is a phenyl group substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl, ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, The following are specified: propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl, and it is specified that when the substituted aryl group is a substituted phenyl group, it is not 3-tert-butylphenyl or 3-(N,N-diethylaminoformyl)phenyl; and / or The optionally substituted heteroaryl group is an unsubstituted heteroaryl group or a substituted heteroaryl group; the unsubstituted heteroaryl group or the heteroaryl group in the substituted heteroaryl group is: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or pyrazoloxazine; the substituted heteroaryl group refers to a group that is substituted by one or more of the following groups: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino, methyl. Ethyl, n-propyl, isobutyl, n-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, formyl, acetyl, propionyl, butyryl, N,N-dimethylaminoformyl, N,N-diethylaminoformyl, methoxycarbonyl, ethoxycarbonyl, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, pyridine, and phenyl; and R2 and R3 are each independently hydrogen or p-tolyl; or In equation (I), equation (I-1), equation (I-2), equation (I-3), or equation (I-4), R5 and R4, along with the two carbons of the benzene ring to which they are attached, together form cyclopentene; R1 is p-tolyl, 3,5-dimethylisoxazol-4-yl, pyrimidin-5-yl, thiophene-2-yl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-ethylphenyl, 3-acetylphenyl, 4-cyclohexyloxyphenyl, 4-methoxycarbonylphenyl, 4-chlorophenyl, 4-(pyridin-3-yl)phenyl, 5-fluoro-3-nitrophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, naphth-2-yl, or quinoline-6-yl; and R2 and R3 are each independently hydrogen or p-tolyl.

7. The amide compound or its stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate according to claim 1, selected from one of the following compounds:

8. A pharmaceutical composition comprising an amide compound or a stereoisomer thereof as described in any one of claims 1 to 7, a prodrug, a pharmaceutically acceptable salt, a solvate or a hydrate, and a pharmaceutically acceptable excipient or diluent.

9. Use of any amide compound or stereoisomer thereof, prodrug, pharmaceutically acceptable salt, solvate or hydrate of any one of claims 1 to 7, or the pharmaceutical composition of claim 8, in the preparation of a medicament as an NLRP3 protein inhibitor or for the prevention or treatment of diseases and / or disorders mediated by NLRP3 overactivation.

10. The use of claim 9, wherein, The amide compound or its stereoisomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates, or the pharmaceutical composition thereof, treat, alleviate, or prevent the occurrence or development of diseases related to NLRP3 activation by inhibiting the activation of the NLRP3 inflammasome; the related diseases include central nervous system inflammation and / or peripheral system inflammation; optionally, the inflammation includes one or more of the following: type II diabetes, atherosclerosis, fatty liver, metabolic syndrome, acute or chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, ultraviolet-induced sunburn, contact hypersensitivity, sepsis, tumors, neurodegenerative diseases, multiple sclerosis, and Mue-Wei syndrome; the peritonitis and gout are preferably inflammation caused by the accumulation of urate crystals; the sepsis is preferably acute peripheral inflammation caused by intraperitoneal injection of bacterial lipopolysaccharide (LPS).

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