New type of gsdmd inhibitors, methods of making and uses thereof

Abstract

The application provides a new type of GSDMD inhibitor and a preparation method and application thereof, and belongs to the field of chemical medicines. The GSDMD inhibitor is a compound shown in formula I, a stereoisomer, a solvate, a metabolite, a deuterated compound, a pharmaceutically acceptable salt, a co-crystal or a pharmaceutical composition containing the same. The compound provided by the application can be used for preparing a GSDMD inhibitor, treating diseases related to GSDMD, such as treating diseases caused by cell pyroptosis, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to a novel type of GSDMD inhibitor, its preparation method, and its uses. Background Technology

[0002] Pyroptosis is the process of inflammatory cell death. Its primary function is to induce a strong inflammatory response and protect the host from microbial infection. However, excessive pyroptosis can lead to several inflammatory diseases, including Alzheimer's disease, Parkinson's disease, autoimmune encephalomyelitis, diabetic nephropathy, inflammatory bowel disease, and sepsis.

[0003] In 2015, Shao Feng’s laboratory published an article in Nature to elucidate the key molecular mechanism of pyroptosis, revealing for the first time the key molecular mechanism of pyroptosis and inflammatory necrosis (Nature 526, 660–665 (2015)), providing a new drug target for a variety of autoinflammatory diseases and endotoxin-induced sepsis.

[0004] Gasdermin D (GSDMD), as an effector of pyroptosis and a potential therapeutic target, has been extensively studied. GSDMD belongs to the Gasdermin family, which currently consists of six members: Gasdermins AE and DFNB59. The structure and function of GSDMD and GSDMD are relatively well-studied. Except for DFNB59, the structures of other family members consist of an N-terminal domain (Gasdermin-NT) and a C-terminal domain linked by a peptide chain (Gasdermin-CT). These two domains are structurally similar, with approximately 45% sequence homology. The Gasdermin-NT domain is generally considered to be an effector domain capable of forming membrane pores, and is normally in a self-inhibited state linked to the Gasdermin-CT domain. When activated by caspases, Gasdermin-NT is cleaved, forming transmembrane pores, leading to the release of cellular contents such as cytokines IL-1β and IL-18, disrupting ion and water regulation, and ultimately resulting in severe inflammation and cell death.

[0005] Several promising GSDMD inhibitors have been reported for inflammatory diseases, such as NSA, DMF, C-202-2729, NU6300, and disulfiram. Although mutation studies have revealed several potential targets, the most effective site of action to date remains Cys191 / 192 (human / mouse).

[0006] Considering the role of pyroptosis and the release of inflammatory cytokines in acute and chronic inflammation, and the various diseases involved, including cardiovascular diseases such as atherosclerosis and myocardial infarction; neurological diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease; liver diseases such as non-alcoholic fatty liver disease; lung diseases such as silicosis, asthma, and chronic obstructive pulmonary disease; and gastrointestinal diseases such as inflammatory bowel disease and sepsis, the current market for drugs targeting GSDMD still has significant room for exploration. Developing small-molecule inhibitors that directly target GSDMD has important clinical significance. Summary of the Invention

[0007] The purpose of this invention is to provide a novel type of GSDMD inhibitor, its preparation method, and its uses.

[0008] This invention provides compounds of Formula I, their stereoisomers, their solvates, their metabolites, their deuterated derivatives, their pharmaceutically acceptable salts, their cocrystals, or pharmaceutical compositions comprising them:

[0009]

[0010] in,

[0011] The dashed lines connecting L1 and L2 are both empty; L1 is empty, L2 is empty; R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, and C(O)OR, respectively. 1 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, X selected from none, NR6, O, CR6R7; or, the dashed line connected to L1 is a bond, the dashed line connected to L2 is none, L1 is connected to R1, R2 to form a substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, L2 If X is absent, X is selected from NR6, O, CR6R7; or, if the dashed line connected to L1 is absent, and the dashed line connected to L2 is a bond, L1 is selected from absent, and L2 is connected to X and R1 to form a substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted 5-8 membered heteroaryl, and R2 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, 3-10 membered cyclic alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy;

[0012] R 1 Selected from substituted or unsubstituted C1-C8 alkyl groups;

[0013] R4, R5, R6, and R7 are each independently selected from hydrogen and C1-C8 alkyl groups;

[0014] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0015] R3 is selected from

[0016] Y is selected from

[0017] Ring A is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, or substituted or unsubstituted 5-8 membered heteroaryl;

[0018] R8 is selected from

[0019] R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, or substituted or unsubstituted C2-C8 alkynyl.

[0020] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0021] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0022] The compound shown in Formula I is not

[0023] Furthermore, the compound is as shown in Formula II:

[0024]

[0025]

[0026] in,

[0027] The dashed line connecting L1 is a bond. L1 is connected to R1 and R2 to form substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, and X is selected from NR6, O, CR6R7.

[0028] R6 and R7 are independently selected from hydrogen and C1-C8 alkyl groups, respectively;

[0029] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0030] Ring A is selected from substituted or unsubstituted phenyl groups;

[0031] R8 is selected from

[0032] R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, or substituted or unsubstituted C2-C8 alkynyl.

[0033] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0034] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0035] The substituents of the phenyl group are selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, and hydroxyl groups.

[0036] Preferably,

[0037] The Selected from substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0038] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0039] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0040] Furthermore, the compound is as shown in Formula III:

[0041]

[0042] in,

[0043] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, and C(O)OR, respectively. 1 , 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, X is selected from none, NR6, O, CR6R7;

[0044] R 1 Selected from substituted or unsubstituted C1-C8 alkyl groups;

[0045] R4, R5, R6, and R7 are each independently selected from hydrogen and C1-C8 alkyl groups;

[0046] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0047] R8 is selected from

[0048] R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, or substituted or unsubstituted C2-C8 alkynyl.

[0049] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0050] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0051] Furthermore, the compounds are as shown in formula III-1, III-2, III-3, or III-4:

[0052]

[0053] in,

[0054] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, and C(O)OR, respectively. 1 , 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, X is selected from none, NR6, O, CR6R7;

[0055] R 1 Selected from substituted or unsubstituted C1-C8 alkyl groups;

[0056] R4, R5, R6, and R7 are each independently selected from hydrogen and C1-C8 alkyl groups;

[0057] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0058] R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, or substituted or unsubstituted C2-C8 alkynyl.

[0059] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0060] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0061] Furthermore, the compound is shown in Formula IV:

[0062]

[0063] in,

[0064] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, and C(O)OR, respectively. 1 , 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, X is selected from none, NR6, O, CR6R7;

[0065] R 1 Selected from substituted or unsubstituted C1-C8 alkyl groups;

[0066] R4, R5, R6, and R7 are each independently selected from hydrogen and C1-C8 alkyl groups;

[0067] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0068] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0069] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0070] Preferably,

[0071] The compound is shown in formula V:

[0072]

[0073] in,

[0074] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, and C(O)OR, respectively. 1 , 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy;

[0075] R 1Selected from substituted or unsubstituted C1-C8 alkyl groups;

[0076] R4 and R5 are independently selected from hydrogen and C1-C8 alkyl groups, respectively;

[0077] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl.

[0078] The alkyl, alkenyl, alkynyl, and alkoxy substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups, substituted or unsubstituted 6-8 membered aryl groups, and substituted or unsubstituted 5-8 membered heteroaryl groups.

[0079] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, 6-8 membered aryl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0080] Furthermore,

[0081] R is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 ynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azacyclic butyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced

[0082] And / or, the substituents of the alkyl, alkenyl, alkynyl, and alkoxy groups are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3-10 membered cycloalkyl groups, substituted or unsubstituted tetrahydropyranyl groups, substituted or unsubstituted piperidinyl groups, substituted or unsubstituted piperazine groups, substituted or unsubstituted pyrrolidinyl groups, substituted or unsubstituted azacyclobutyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted furanyl groups, substituted or unsubstituted thiophenyl groups, substituted or unsubstituted pyrrolidinyl groups, substituted or unsubstituted imidazolyl groups, substituted or unsubstituted pyrazolyl groups, substituted or unsubstituted pyridinyl groups, substituted or unsubstituted pyrimidinyl groups, substituted or unsubstituted pyridazinyl groups, and substituted or unsubstituted pyrazinyl groups.

[0083] The cycloalkyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, azacyclobutyl, phenyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, morpholinyl, etc. The substituents are selected from C1-C8 alkyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, 3-10 membered cycloalkyl, phenyl, halogen, cyano, nitro, carboxyl, and hydroxyl.

[0084] Preferably, the 3-10 membered cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentane, cyclohexyl, and adamantyl.

[0085] Furthermore, the compound is as shown in Formula VI:

[0086]

[0087] in,

[0088] R8 is selected from

[0089] R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, or substituted or unsubstituted C2-C8 alkynyl.

[0090] The alkyl, alkenyl, and alkynyl substituents are selected from halogens.

[0091] Preferably, R8 is selected from...

[0092] Furthermore, the compound is one of the following compounds:

[0093]

[0094]

[0095]

[0096] The present invention also provides the use of the aforementioned compounds, their stereoisomers, their solvates, their metabolites, their deuterated derivatives, their pharmaceutically acceptable salts, their cocrystals, or pharmaceutical compositions comprising them in the preparation of GSDMD inhibitors.

[0097] And / or, the use of the aforementioned compounds, their stereoisomers, their solvates, their metabolites, their deuterated derivatives, their pharmaceutically acceptable salts, their cocrystals, or pharmaceutical compositions comprising them in the preparation of medicaments for treating diseases related to pyroptosis.

[0098] Preferably, the disease is Alzheimer's disease, Parkinson's disease, autoimmune encephalomyelitis, diabetic nephropathy, dry eye disease, multiple sclerosis, familial Mediterranean fever, non-alcoholic fatty liver disease, acute kidney injury, inflammatory bowel disease, sepsis, or septic shock.

[0099] The present invention also provides a drug preparation comprising, as an active ingredient, the aforementioned compound, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its eutectic or a pharmaceutical composition containing the aforementioned compound, plus pharmaceutically acceptable excipients or auxiliary ingredients.

[0100] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0101] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0102] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0103] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1 to C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms; "C1 to C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms.

[0104] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0105] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0106] "Cycloalkyl" refers to saturated or unsaturated all-carbon monocyclic or polycyclic (including fused, spiro, or bridged rings) that do not have a conjugated π-electron system, such as including but not limited to:

[0107]

[0108] 3- to 12-membered cycloalkyl refers to cycloalkyl groups that form a closed structure with 3 to 12 carbon atoms.

[0109] "Heterocyclic alkyl" refers to a cycloalkyl group in which at least one carbon atom on the ring is replaced by a heteroatom, which is O, N, or S, including but not limited to:

[0110]

[0111] 3- to 12-membered heterocyclic alkyl refers to heterocyclic alkyl groups that form a closed structure consisting of 3 to 12 atoms.

[0112] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spirocyclic or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthracene, fluorenyl, and indene. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to:

[0113]

[0114] 6-12 aryl refers to an aryl group that has a closed structure consisting of 6-12 carbon atoms.

[0115] "Heteroaryl" refers to an aryl group in which at least one carbon atom on the ring of a conjugated π-electron system is replaced by a heteroatom, which is O, N, or S, including but not limited to:

[0116]

[0117] 5-12 membered heteroaryl refers to heteroaryl groups that form a closed structure consisting of 5-12 atoms.

[0118] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0119] This invention provides a class of compounds that inhibit GSDMD. These compounds can be used to prepare GSDMD inhibitors for the treatment of GSDMD-related diseases, such as diseases caused by pyroptosis, and have good application prospects.

[0120] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0121] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0122] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0123] Preparation methods of some compounds of this invention: (1)

[0125]

[0126] The compound of general formula (Ia) undergoes nucleophilic substitution under basic conditions to give the compound of general formula (Ib), which is then reacted under acidic conditions with the compound of general formula (IIIc) below to give the compound of general formula (Ic) or its pharmaceutically usable salt. (2)

[0128]

[0129] The compound of general formula (IIa) undergoes nucleophilic substitution under basic conditions to give the compound of general formula (IIb), which is then reacted with the compound of general formula (IIIc) below under acidic conditions to give the compound of general formula (IIc) or a pharmaceutically acceptable salt thereof. The compound of general formula (IIb) can also be alkylated to give the compound of general formula (IId), which is then reacted with the compound of general formula (IIIc) below under acidic conditions to give the compound of general formula (IIe) or a pharmaceutically acceptable salt thereof. (3)

[0131]

[0132] The compound of general formula (Ⅲa) or its salt reacts with the corresponding carboxylic acid or acyl chloride to give the compound of general formula (Ⅲb) or its salt, and then deBoc under acidic conditions to give the compound of general formula (Ⅲc) or its salt.

[0133] Synthesis of 4-(vinylsulfonyl)aniline

[0134]

[0135] Take 5g of the raw material and place it in a 100mL round-bottom flask. Dissolve it in water and, while stirring at room temperature, adjust the pH of the reaction solution to 9-10 with 1M NaOH aqueous solution. Continue stirring for 30 min. Extract the reaction solution with ethyl acetate (15 mL × 3 times), wash with brine, combine the organic layers, dry to anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain the target compound. 1 H NMR (400 MHz, CDCl3) δ7.64 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 6.62 (dd, J = 16.5, 9.8 Hz, 1H), 6.32 (d, J = 16.5 Hz, 1H), 5.90 (d, J = 9.8 Hz,1H),4.21(s,2H).

[0136] Example 1

[0137] N 6 -(tetrahydro-2H-pyran-4-yl)-N 2 Synthesis of -(4-(vinylsulfonyl)phenyl)-9H-purine-2,6-diamine

[0138]

[0139] Step a: In a 100 mL round-bottom flask, 0.5 g of 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (1 equiv) was dissolved in n-butanol, followed by the addition of 4-aminotetrahydropyran (3 equiv) and triethylamine (3 equiv). The reaction mixture was reacted overnight at 110 °C. The reaction progress was monitored by TLC. After the reaction was complete, excess solvent was removed by vortexing, and the residue was purified by silica gel column chromatography to obtain intermediate 1. 1 H NMR (400MHz, DMSO-d6) δ7.65(s,1H),6.94(s,1H),5.64(s,2H),3.91–3.84(m,2H),3.39–3.32(m,3H),1.83–1.74(m,2H),1.66–1.57(m,2H).

[0140] Step b: Dissolve intermediate 1 obtained in the previous step in a 50% aqueous solution of fluoroboric acid. While stirring in an ice bath, add an aqueous solution of NaNO2 (2 equal v) dropwise. After the addition is complete, bring the reaction mixture to room temperature. Monitor the reaction progress using TLC. After the reaction is complete, neutralize the reaction system with a saturated aqueous solution of NaHCO3. A precipitate forms; filter, wash with water, and dry to obtain a white solid, which is intermediate 2.

[0141] Step c: Dissolve intermediate 2 (200 mg, 1 equiv) and 4-(vinylsulfonyl)aniline (1.2 equiv) obtained in the previous step in 10 mL of trifluoroethanol solution, then add trifluoroacetic acid (5 equiv) dropwise, replace with N2, and heat under reflux in an oil bath at 90 °C for 48 h. Monitor the reaction progress by TLC. After the reaction is complete, remove excess solvent by vortexing, and purify by silica gel column chromatography to obtain the target compound. 1 H NMR (400MHz, CD3OD) δ8.03(d,J=8.9Hz,2H),7.87(s,1H),7.74(d,J=8.9Hz,2H),6 .87(dd,J=16.5,9.9Hz,1H),6.33(d,J=16.5Hz,1H),6.05(d,J=9.9Hz,1H),4.39( s,1H),4.04(dd,J=8.3,3.3Hz,2H),3.62(td,J=11.5,2.0Hz,2H),2.11(d,J=10.9 Hz),4.07–4.00(m,2H),3.65–3.58(m,2H),2.14–2.08(m,2H),1.75–1.64(m,2H).

[0142] The synthesis methods of compounds (Ex.2 to Ex.4) in Examples 2 to 4 in Table 1 are the same as those in Example 1, except that the raw materials used in step a are different. For example, cyclohexylmethylamine is used instead of 4-aminotetrahydropyran in compound Ex.2.

[0143] Table 1. Structural and characterization data of compounds Ex.2 to Ex.4 from Examples 2 to 4

[0144]

[0145] Example 5

[0146] N 4 -(cyclohexylmethyl)-N 2 Synthesis of -(4-(vinylsulfonyl)phenyl)pyrimidine-2,4-diamine

[0147]

[0148] Step a: Add cyclohexylmethylamine (1.1 equiv), triethylamine (1.1 equiv), and TBAF (0.1 equiv) to a DMSO solution of 2,4-dichloropyrimidine (500 mg, 1 equiv). React at room temperature for 5 h. After the reaction is complete, dilute with water, extract with EA, wash the combined organic layers with brine, dry with anhydrous NaSO4, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain intermediate 3. 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 6.22 (d, J = 5.9Hz, 1H), 5.41 (s, 1H), 3.12 (s, 2 H),1.82–1.66(m,5H),1.61–1.49(m,1H),1.31–1.11(m,3H),1.03–0.93(m,2H).

[0149] Step b: Dissolve intermediate 3 (200 mg, 1 equiv) and 4-(vinylsulfonyl)aniline (1.2 equiv) obtained in the previous step in 10 mL of trifluoroethanol solution, and prepare the target compound according to step c of Example 1. 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),7.91(s,1H),7.81(d,J=8.8Hz,2H),7.73(d,J=8.9Hz,2H),6.62(dd,J=16.5,9.8Hz,1H),6 .34(d,J=16.5Hz,1H),5.97–5.88(m,2H),5.27(s,1H),3.16(s,2H),1.78–1.56(m,6H),1.22–1.14(m,3H),0.90–0.91(m,2H).

[0150] The synthesis methods of compounds 6-50 (Ex.6-Ex.50) in Table 2 are the same as those in Example 5, with the only difference being the starting materials used in step a. For example, compound Ex.6 uses 2,4-dichloro-5-methylpyrimidine and cyclohexylmethylamine as starting materials, and compound Ex.12 uses 2,4-dichloro-6-trifluoromethylpyrimidine and n-butylamine as starting materials.

[0151] Table 2. Structural and characterization data of compounds Ex.6 to Ex.50 from Examples 6 to 50

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] Example 51

[0160] N 4 -(cyclohexylmethyl)-N 2 Synthesis of 2,4-(vinylsulfonyl)phenyl)quinazoline-2,4-diamine

[0161]

[0162] Step a: In a dichloromethane solution containing 1.1 equiv of 2,4-dichloroquinazoline, cyclohexylmethylamine (1.1 equiv) and triethylamine (3 equiv) were added. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed with brine, and then the organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target intermediate. 1 H NMR (400MHz, CDCl3) δ7.82–7.66 (m, 3H), 7.45 (t, J = 7.5Hz, 1H), 6.07 (s, 1H), 3.60–3.49(m,2H),1.87–1.65(m,6H),1.34–1.18(m,3H),1.12–1.01(m,2H).

[0163] Step b: The synthesis method is similar to step c of Ex.1. 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.94(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),7.66–7.56(m,3H),7.25–7.18(m,1H),6.65(dd,J=16.5,9.8Hz, 1H),6.36(d,J=16.5Hz,1H),6.05(s,1H),5.93(d,J=9.8Hz,1H),3.47(t ,J=6.2Hz,2H),1.85–1.65(m,6H),1.29–1.15(m,3H),1.08–0.98(m,2H).

[0164] Example 52

[0165] N 4-(cyclohexylmethyl)-N 2 Synthesis of -(4-(vinylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0166]

[0167] Step a: Dissolve 2,4-dichloro-7H-pyrrole[2,3-d]pyrimidine in n-butanol, add DIEA (1.1 eq) and cyclohexylmethylamine (1.1 eq), react at 70°C for 12 h. After the reaction is complete, let stand and cool to room temperature, filter, wash with n-butanol, and dry to obtain the product. 1 H NMR(400MHz, DMSO-d6)δ11.60(s,1H),7.79(t,J=5.8Hz,1H),7.07–7.01(m,1H),6.57( s,1H),3.26(t,J=6.4Hz,2H),1.76–1.54(m,6H),1.24–1.12(m,3H),0.99–0.89(m,2H).

[0168] Step b: The synthesis method is similar to step c of Ex.1. 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),7.91(s,1H),7.81(d,J=8.8Hz,2H),7.73(d,J=8.9Hz,2H),6.62(dd,J=16.5,9.8Hz,1H),6 .34(d,J=16.5Hz,1H),5.97–5.88(m,2H),5.27(s,1H),3.16(s,2H),1.78–1.56(m,6H),1.22–1.14(m,3H),0.90–0.91(m,2H).

[0169] Example 53

[0170] Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-N-(4-(vinylsulfonyl)phenyl)pyrimidin-2-amin e

[0171]

[0172] In a 50 mL three-necked flask, 2,4-dichloropyrimidine (1 equiv), 1-methyl-4-pyrazolone pinacol ester (1.3 equiv), PdCl2 (dppf)·DCM (0.1 equiv), and sodium carbonate (2.5 equiv) were added to a solution of 1,4-dioxane / ethanol / water (7 / 4 / 3). The mixture was purged with nitrogen three times and reacted at 90 °C for three hours. After the reaction was complete, the intermediate was purified by silica gel column chromatography to obtain the target intermediate. 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=5.3Hz,1H),8.55(s,1H),8.17(d,J=0.7Hz,1H),7.75(d,J=5.3Hz,1H),3.91(s,3H).

[0173] The intermediate obtained in the previous step is used to obtain the corresponding final product according to step c of Example 1. 1 HNMR (400MHz, DMSO-d6) δ10.14(s,1H),8.48(d,J=5.2Hz,2H),8.16(s,1H),8.11(d,J=8.9Hz,2H),7.80(d,J=8.9Hz, 2H), 7.21 (d, J = 5.2Hz, 1H), 7.05 (dd, J = 16.4, 9.8Hz, 1H), 6.25 (d, J = 16.4Hz, 1H), 6.11 (d, J = 9.8Hz, 1H), 3.94 (s, 3H).

[0174] The synthesis methods of compounds 54-56 (Ex.54-Ex.56) in Table 3 are the same as those in Example 53, except for the pinacol borate esters used. For example, compound Ex.54 uses 1-isopropyl-4-pyrazole borate pinacol ester as the starting material, and compound Ex.55 uses 1-ethyl-4-pyrazole borate pinacol ester as the starting material.

[0175] Table 3. Structural and characterization data of compounds Ex.54–Ex.56 from Examples 54–56

[0176]

[0177]

[0178] Example 57

[0179] N 4 -(cyclopropylmethyl)-N 2 Synthesis of -(4-(vinylsulfonyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

[0180]

[0181] Using 2,4-dichloro-5,7-dihydrofuranopyrimidine as the starting material, the corresponding intermediate was obtained according to step a of Example 5. 1 H NMR(400MHz,DMSO-d6)δ7.88(t,J=5.6Hz,1H),4.85(s,2H),4.74(t,J=2.8Hz,2H) ,3.19(t,J=6.2Hz,2H),1.08–0.97(m,1H),0.49–0.42(m,2H),0.27–0.20(m,2H).

[0182] The intermediate obtained in the previous step is used to obtain the corresponding final product according to step c of Example 1. 1 HNMR (400MHz, CDCl3) δ7.99–7.67(m,4H),7.64(s,1H),6.64(dd,J=16.5,9.8Hz,1H),6.37(d,J=16.5Hz,1H),5.95(d,J=9.8Hz,1H),4.9 9(t,J=2.6Hz,2H),4.84(t,J=2.6Hz,2H),4.69(s,1H),3.32(t,J=6.2Hz,2H),1.22–1.02(m,1H),0.73–0.48(m,2H),0.32–0.24(m,2H).

[0183] Example 58

[0184] Synthesis of N-(4-((4-((cyclohexylmethyl)amino)pyrimidin-2-yl)amino)phenyl)pent-2-yn amide

[0185]

[0186] Step a: In a 50 mL round-bottom flask, dissolve N-Boc-p-phenylenediamine (1 equivalent), 2-pentyneic acid (1.2 equivalent), HATU (1.2 equivalent), and DIEA (3 equivalent) in DMF solvent and react at room temperature for 5 h. After the reaction is complete, dilute with water, extract with EA, wash with brine, concentrate the organic layer, and purify by silica gel column chromatography to obtain the final product. 1H NMR (400MHz, CDCl3) δ10.44(s,1H),9.26(s,1H),7.44(d,J=9.0Hz,2H),7.35 (d,J=8.9Hz,2H),2.39(q,J=7.5Hz,2H),1.45(s,9H),1.15(t,J=7.5Hz,3H).

[0187] Step b: Dissolve the compound (1g) obtained in the previous step in 10mL DCM, then add 10mL TFA, react at room temperature, and monitor the reaction progress by TLC. After the reaction is complete, remove excess solvent by vortexing, neutralize with saturated NaHCO3 solution, extract with DCM, combine the organic layers, and concentrate to obtain the Boc-free intermediate. 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.22(d,J=8.8Hz,2H),6.48(d,J=8.8Hz,2H),4.92(s,2H),2.37(q,J=7.5Hz,2H),1.14(t,J=7.5Hz,3H).

[0188] Step c: The intermediate 2-chloro-N-(cyclohexylmethyl)pyrimidin-4-amine (200 mg, 1 equiv) and N-(4-aminophenyl)acrylamide (1.2 equiv) were reacted according to step c of Example 1 to obtain the corresponding final product. 1 H NMR (400MHz, CD3OD) δ7.60 (s, 1H), 7.54 (d, J = 9.1Hz, 2H), 7.48 (d, J = 9.0Hz, 2H), 5.95 (d, J = 6.4Hz, 1H),3.18(s,2H),2.37(q,J=7.5Hz,2H),1.77–1.61(m,6H),1.25–1.17(m,6H),0.98–0.89(m,2H).

[0189] The synthesis methods of compounds 59-63 (Ex.59-Ex.63) in Table 4 are the same as those in Example 58, except that the carboxylic acid starting material used in step a is different. For example, compound Ex.59 uses 2-butynedic acid as the starting material, and compound Ex.60 uses acrylic acid as the starting material.

[0190] Table 4. Structural and characterization data of compounds Ex.59–Ex.63 from Examples 59–63

[0191]

[0192]

[0193] Example 64

[0194] N 4 -(cyclohexylmethyl)-N 2 Synthesis of -(4-(methylsulfonyl)phenyl)pyrimidine-2,4-diamin e

[0195]

[0196] The intermediate 2-chloro-N-(cyclohexylmethyl)pyrimidin-4-amine (1 equiv) was reacted with 4-methanesulfonylaniline (1,2 equiv) according to step c of Example 1 to obtain the corresponding final product. 1 H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.82 (s, 4H), 7.72 (s, 1H), 5.94 (d, J = 6.0Hz, 1H), 5.04 (s, 1 H),3.20(s,2H),1.84–1.66(m,5H),1.65–1.55(m,1H),1.30–1.12(m,3H),1.05–0.93(m,2H).

[0197] Example 65

[0198] Synthesis of 2-chloro-N-(4-((4-((cyclohexylmethyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide

[0199]

[0200] Step a: Dissolve N-Boc-p-phenylenediamine (1 equiv) in dichloromethane solution, add triethylamine (1.5 equiv), and then add chloroacetyl chloride (1.2 equiv) dropwise while stirring. React at room temperature, and monitor the reaction progress by TLC. After the reaction is complete, remove excess solvent by vortexing, and purify by silica gel column chromatography to obtain the corresponding intermediate. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.28(s,1H),7.45(d,J=9.0Hz,2H),7.39(d,J=9.0Hz,2H),4.21(s,2H),1.46(s,9H).

[0201] Step b: The compound obtained in the previous step is reacted according to step b of Example 58 to obtain the corresponding deBoc intermediate. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),7.61(d,J=8.2Hz,2H),7.18(d,J=8.2Hz,2H),4.24(s,2H).

[0202] Step c: The intermediate 2-chloro-N-(cyclohexylmethyl)pyrimidin-4-amine and N-(4-aminophenyl)-2-chloroacetamide were reacted according to step c of Example 1 to obtain the corresponding final product. 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.88(s,1H),7.60(d,J=8.8Hz,2H),7.46(d,J=8.9Hz,2H),7.35(s,1H),5.84(d,J=6.0H z,1H),4.99(s,1H),4.18(s,2H),3.17(s,2H),1.81–1.67(m,5H),1.62–1.54(m,1H),1.23–1.12(m,3H),1.03–0.93(m,2H).

[0203] The synthesis methods of compounds 66-67 (Ex. 66-Ex. 67) in Table 5 are the same as those in Example 65, except that the acyl chloride used in step a is different. Compound Ex. 66 uses chloroethanesulfonyl chloride as a starting material, and compound Ex. 67 uses bromoacetyl chloride as a starting material.

[0204] Table 5. Structural and characterization data of compounds Ex. 66–Ex. 67 from Examples 66–67

[0205]

[0206] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0207] GSDMD is a key protein in pyroptosis, primarily composed of two domains: GSDMD-C and GSDMD-N. Under the action of caspase, GSDMD-NT is released and translocates to the cell membrane, accumulating to form pores, thereby disrupting ion homeostasis and inducing cell death. During pyroptosis, the cell membrane ruptures. Accompanying this process, lactate dehydrogenase (LDH) is released into the extracellular fluid. LDH activity is stable and easily detectable; therefore, detecting the amount of LDH released can assess the severity and progression of pyroptosis.

[0208] Experimental Example 1. LDH method for detecting the anti-pyroptosis activity of compounds

[0209] THP-1 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (Gibco, Carlsbad, CA, USA) and 1% penicillin / streptomycin (100×, Beyotime Biotechnology, Shanghai, China) in a 37°C, 5% CO2 incubator. The medium was changed on day 3, and experiments were performed on day 6. To induce inflammasome activation, THP-1 cells were treated with 100 ng / mL PMA for 24 h to differentiate into macrophages. The following day, the medium was changed to Opti-MEM medium containing LPS (1 μg / mL) for 3 h, followed by pretreatment with 10 μM and 1 μM compounds for 40 min, and then induction with nigericin (10 μM) for 35 min. LDH release was measured using the CytoTox96 non-radioactive cytotoxicity assay kit (Promega) according to the manufacturer's instructions. NU6300 was used as a positive control.

[0210] Table 6. Antipyretic activity of the compounds

[0211]

[0212] Note: "-" indicates untested; "()" indicates IC 50 / μM.

[0213] Table 6 shows that most of the compounds prepared in this invention have good anti-pyroptosis activity.

[0214] In summary, this invention provides a class of compounds that inhibit GSDMD. These compounds can be used to prepare GSDMD inhibitors for the treatment of GSDMD-related diseases, such as diseases caused by pyroptosis, and have promising application prospects.

Claims

1. A compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in Formula II: Formula II in, The Selected from substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents are selected from C1-C8 alkyl, C2-C6 alkynyl, and C2-C6 alkenyl groups. X is selected from NR6 and O; R6 is selected from hydrogen and C1-C8 alkyl groups; R is selected from substituted or unsubstituted C1-C8 alkyl, 3-10 membered cycloalkyl, tetrahydropyranyl; the substituent of the alkyl group is selected from 3-10 membered cycloalkyl; Ring A is selected from phenyl; R8 is selected from ; R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, and substituted or unsubstituted C2-C8 alkynyl groups; the substituents of the alkyl, alkenyl, and alkynyl groups are selected from halogens; The compound is not .

2. A compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the thereof, characterized in that: The compound is shown in Formula III: III in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, NR4R5, and C(O)OR, respectively. 1 The substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy group, wherein the substituent of the alkyl group is selected from halogens; X is selected from none, NR6, and O; R 1 Selected from C1~C8 alkyl groups; R4, R5, and R6 are each independently selected from hydrogen and C1-C8 alkyl groups; R is selected from substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, 3-10 membered cycloalkyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted pyrazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl group are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, 3-10 membered cycloalkyl groups, tetrahydropyranyl groups, substituted or unsubstituted piperidinyl groups, phenyl groups, and pyridinyl groups; the piperidinyl, piperazineyl, pyrazolyl, morpholinyl, and other substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, C1-C8 alkoxy groups, C1-C8 cycloalkyl ... , , , , The substituents are selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, phenyl, and halogen; R8 is selected from , , , ; R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, and substituted or unsubstituted C2-C8 alkynyl groups; the substituents of the alkyl, alkenyl, and alkynyl groups are selected from halogens; The compound is not .

3. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound according to claim 2, characterized in that: The compounds are shown as those of formula III-1, III-2, III-3, or III-4: III-1 III-2 III-3 III-4 in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, NR4R5, and C(O)OR, respectively. 1 The substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy group, wherein the substituent of the alkyl group is selected from halogens; X is selected from none, NR6, and O; R 1 Selected from C1~C8 alkyl groups; R4, R5, and R6 are each independently selected from hydrogen and C1-C8 alkyl groups; R is selected from substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, 3-10 membered cycloalkyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted pyrazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl group are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, 3-10 membered cycloalkyl groups, tetrahydropyranyl groups, substituted or unsubstituted piperidinyl groups, phenyl groups, and pyridinyl groups; the piperidinyl, piperazineyl, pyrazolyl, morpholinyl, and other substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, C1-C8 alkoxy groups, C1-C8 cycloalkyl ... , , , , The substituents are selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, phenyl, and halogen; R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, and substituted or unsubstituted C2-C8 alkynyl groups; the substituents of the alkyl, alkenyl, and alkynyl groups are selected from halogens.

4. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound according to claim 3, characterized in that: The compound is shown in Formula IV: Formula IV in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, NR4R5, and C(O)OR, respectively. 1 The substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy group, wherein the substituent of the alkyl group is selected from halogens; X is selected from none, NR6, and O; R 1 Selected from C1~C8 alkyl groups; R4, R5, and R6 are each independently selected from hydrogen and C1-C8 alkyl groups; R is selected from substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, 3-10 membered cycloalkyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted pyrazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl group are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, 3-10 membered cycloalkyl groups, tetrahydropyranyl groups, substituted or unsubstituted piperidinyl groups, phenyl groups, and pyridinyl groups; the piperidinyl, piperazineyl, pyrazolyl, morpholinyl, and other substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, C1-C8 alkoxy groups, C1-C8 cycloalkyl ... , , , , The substituents are selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, phenyl, and halogen.

5. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound according to claim 4, characterized in that: The compound is shown in formula V: Formula V in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, NR4R5, and C(O)OR, respectively. 1 The substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy group, wherein the substituent of the alkyl group is selected from halogens; R 1 Selected from C1~C8 alkyl groups; R4 and R5 are independently selected from hydrogen and C1-C8 alkyl groups, respectively; R is selected from substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, 3-10 membered cycloalkyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, substituted or unsubstituted pyrazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl group are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, 3-10 membered cycloalkyl groups, tetrahydropyranyl groups, substituted or unsubstituted piperidinyl groups, phenyl groups, and pyridinyl groups; the piperidinyl, piperazineyl, pyrazolyl, morpholinyl, and other substituents are selected from halogens, hydroxyl groups, C1-C8 alkoxy groups, C1-C8 alkoxy groups, C1-C8 cycloalkyl ... , , , , The substituents are selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, 3-10 membered cycloalkyl, phenyl, and halogen.

6. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound according to any one of claims 1 to 5, characterized in that: The 3-10 membered cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentane, cyclohexyl, and adamantyl.

7. A compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the thereof, characterized in that: The compound is shown in Formula VI: Style VI in, R8 is selected from , , , ; R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, and substituted or unsubstituted C2-C8 alkynyl groups; the substituents of the alkyl, alkenyl, and alkynyl groups are selected from halogens.

8. A compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, characterized in that: The compound is one of the following compounds: 。 9. Use of the compound, stereoisomer, deuterated form, pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising any one of claims 1 to 8 in the preparation of a medicament for a GSDMD inhibitor; And / or, the use of the compound of any one of claims 1 to 8, its stereoisomer, its deuterated form, its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it in the preparation of an antipyroptosis medicament.

10. A drug, characterized in that: It is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1 to 8, its stereoisomers, its deuterated derivatives, its pharmaceutically acceptable salts, or pharmaceutical compositions containing the same as the active ingredient.

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