Novel GSDMD inhibitor as well as preparation method and application thereof

Abstract

The invention provides a novel GSDMD inhibitor as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The GSDMD inhibitor is a compound as shown in a formula I, a stereoisomer thereof, a solvate thereof, a metabolite thereof, a deuterated substance thereof, a pharmaceutically acceptable salt thereof, a co-crystal thereof or a pharmaceutical composition containing the GSDMD inhibitor. The compound provided by the invention can be used for preparing a GSDMD inhibitor for treating GSDMD-related diseases, such as related diseases caused by pyroptosis, and has a good application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicine, and specifically relates to a novel GSDMD inhibitor and a preparation method and use thereof. Background Art

[0002] Pyroptosis is a process of inflammatory cell death. The main function of pyroptosis 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 kidney disease, inflammatory bowel disease, and sepsis.

[0003] In 2015, Shao Feng's laboratory published an article in Nature magazine to analyze the key molecular mechanism of cell inflammatory necrosis (pyroptosis), revealing for the first time the key molecular mechanism of cell 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) has been widely studied as an effector of cell pyroptosis and a potential target for disease treatment. GSDMD belongs to the Gasdermin family. The currently discovered human Gasdermin family consists of six members: Gasdermins AE and DFNB59. The structure and function of GSDMD and GSDME are relatively detailed. Except for DFNB59, the structures of other family members are composed of an N-terminal domain (Gasdermin-NT) and a C-terminal domain (Gasdermin-CT) connected by a peptide chain. The two domains are similar in structure, with a sequence homology of about 45%. The Gasdermin-NT domain is generally considered to be an effector domain that can form membrane pores. Generally, it is connected to the Gasdermin-CT domain in an autoinhibitory state. When activated by caspases, Gasdermin-NT is cleaved to form transmembrane pores, leading to the release of cellular contents such as cytokines IL-1β and IL-18, disrupting the regulation of ions and water, and ultimately leading to strong 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 so far is Cys191 / 192 (human / mouse).

[0006] Considering the role of pyroptosis and the release of inflammatory cytokines in acute and chronic inflammation, as well as the various diseases it involves, 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; gastrointestinal diseases such as inflammatory bowel disease and sepsis, etc., the current drug market targeting GSDMD still has a large room for exploration, and the development of small molecule inhibitors directly targeting GSDMD is of great clinical significance. Summary of the invention

[0007] The purpose of the present invention is to provide a novel GSDMD inhibitor and a preparation method and use thereof.

[0008] The present invention provides a compound represented by Formula I, a stereoisomer thereof, a solvate thereof, a metabolite thereof, a deuterated substance thereof, a pharmaceutically acceptable salt thereof, a cocrystal thereof, or a pharmaceutical composition comprising the same:

[0009]

[0010] in,

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

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

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

[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, 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, substituted or unsubstituted C2-C8 alkynyl;

[0020] The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0021] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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 dotted line connected to L1 is a bond, L1 is connected with R1 and R2 to form a substituted or unsubstituted 3-10-membered cycloalkyl, a substituted or unsubstituted 3-10-membered heterocycloalkyl, a substituted or unsubstituted 6-8-membered aryl, or a substituted or unsubstituted 5-8-membered heteroaryl, and X is selected from NR6, O, and CR6R7;

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

[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;

[0031] R8 is selected from

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

[0033] The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0034] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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 substituent of the phenyl group is selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, and hydroxyl;

[0036] Preferably,

[0037] Said Selected from substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted The substituent is 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, hydroxyl;

[0038] The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, 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;

[0039] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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, C(O)OR 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;

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

[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, substituted or unsubstituted C2-C8 alkynyl;

[0049] The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0050] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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 compound is 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, C(O)OR 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;

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

[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, substituted or unsubstituted C2-C8 alkynyl;

[0059] The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0060] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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 as shown in Formula IV:

[0062]

[0063] in,

[0064] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 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;

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

[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 substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0069] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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, C(O)OR 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;

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

[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 substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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;

[0079] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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] Further,

[0081] 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 tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted

[0082] and / or, the substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl;

[0083] The cycloalkyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, morpholinyl, 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, 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, substituted or unsubstituted C2-C8 alkynyl;

[0090] The substituents of the alkyl, alkenyl and alkynyl groups are selected from halogen.

[0091] Preferably, the above 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 compound, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same in the preparation of a GSDMD inhibitor;

[0097] And / or, use of the aforementioned compound, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same in the preparation of a drug for treating a disease related to cell pyroptosis;

[0098] Preferably, the disease is Alzheimer's disease, Parkinson's disease, autoimmune encephalomyelitis, diabetic kidney disease, 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, which is a preparation prepared with the aforementioned compound, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition containing the same as an active ingredient, and pharmaceutically acceptable excipients or auxiliary ingredients.

[0100] The compounds and derivatives provided in the present 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] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0102] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

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

[0104] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. Alkyl groups can be straight 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" is fluorine, chlorine, bromine or iodine.

[0106] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, such as but not limited to:

[0107]

[0108] The 3- to 12-membered cycloalkyl group refers to a cycloalkyl group which has 3 to 12 carbon atoms and forms a closed structure.

[0109] "Heterocycloalkyl" means that at least one carbon atom in the cycloalkyl ring is replaced by a heteroatom, and the heteroatom is O, N or S, such as but not limited to:

[0110]

[0111] The 3- to 12-membered heterocycloalkyl group refers to a heterocycloalkyl group which has 3 to 12 atoms and forms a closed structure.

[0112] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused ring, spirocyclic or bridged ring) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. 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, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to:

[0113]

[0114] The 6- to 12-membered aryl group refers to an aryl group having 6 to 12 carbon atoms to form a closed structure.

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

[0116]

[0117] The 5- to 12-membered heteroaryl group refers to a heteroaryl group which has 5 to 12 atoms to form a closed structure.

[0118] Compared with the prior art, the present invention has the following beneficial effects:

[0119] The present invention provides a class of compounds that have an inhibitory effect on GSDMD. Such compounds can be used to prepare GSDMD inhibitors and treat diseases related to GSDMD, such as treating related diseases caused by cell pyroptosis, and have good application prospects.

[0120] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0121] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0122] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

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

[0125]

[0126] The compound represented by general formula (Ia) undergoes nucleophilic substitution under alkaline conditions to obtain the compound represented by general formula (Ib), and then reacts with the compound represented by general formula (IIIc) below under acidic conditions to obtain the compound represented by general formula (Ic) or a pharmaceutically acceptable salt thereof. (2)

[0128]

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

[0131]

[0132] The compound represented by the general formula (IIIa) or its salt is reacted with the corresponding carboxylic acid or acyl chloride to obtain the compound represented by the general formula (IIIb) or its salt, and then de-Boc is carried out under acidic conditions to obtain the compound represented by the 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 100 mL round-bottom flask, add water to dissolve it, and adjust the pH of the reaction solution to 9-10 with 1 M NaOH aqueous solution at room temperature while stirring, and continue stirring for 30 min. The reaction solution is extracted with ethyl acetate (15 mL×3 times), washed with brine, and the organic layers are combined, dried over anhydrous sodium sulfate, concentrated, and purified 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, 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (0.5 g, 1 equiv) was dissolved in n-butanol, and then 4-aminotetrahydropyran (3 equiv) and triethylamine (3 equiv) were added. The reaction mixture was reacted at 110°C overnight. The reaction progress was monitored by TLC. After the reaction was completed, the excess solvent was removed 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: The intermediate 1 obtained in the previous step was dissolved in a 50% fluoroboric acid aqueous solution, and an aqueous solution of NaNO2 (2 equiv) was added dropwise under stirring in an ice bath. After the addition was complete, the reaction solution was allowed to react at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction system was neutralized with a saturated aqueous solution of NaHCO3, and a precipitate was precipitated. The precipitate was filtered, washed with water, and dried to obtain a white solid, namely, the intermediate 2.

[0141] Step c: Dissolve the intermediate 2 (200 mg, 1 equiv) obtained in the previous step and 4-(vinylsulfonyl)aniline (1.2 equiv) in 10 mL of trifluoroethanol solution, then dropwise add trifluoroacetic acid (5 equiv), replace with N2, and heat to reflux in a 90°C oil bath for 48 h. Monitor the reaction progress by TLC. After the reaction is complete, spin off the excess solvent, 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 the compounds of Examples 2 to 4 (Ex. 2 to Ex. 4) in Table 1 refer to Example 1, with the only difference being the raw materials used in step a, such as compound Ex. 2 using cyclohexylmethylamine instead of 4-aminotetrahydropyran.

[0143] Table 1. Structure and characterization data of compounds Ex.2 to Ex.4 in 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: To a DMSO solution of 2,4-dichloropyrimidine (500 mg, 1 equiv), cyclohexylamine (1.1 equiv), triethylamine (1.1 equiv), and TBAF (0.1 equiv) were added, and the reaction was carried out at room temperature for 5 h. After the reaction was completed, the mixture was diluted with water, extracted with EA, and the combined organic layer was washed with brine, dried over anhydrous NaSO4, concentrated under reduced pressure, and purified 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: The intermediate 3 (200 mg, 1 equiv) obtained in the previous step and 4-(vinylsulfonyl)aniline (1.2 equiv) were dissolved in 10 mL of trifluoroethanol solution, and the target compound was prepared 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 the compounds of Examples 6 to 50 (Ex.6 to Ex.50) in Table 2 refer to Example 5, with only the difference in the raw materials used in step a. For example, compound Ex.6 uses 2,4-dichloro-5-methylpyrimidine and cyclohexylmethylamine as raw materials, and compound Ex.12 uses 2,4-dichloro-6-trifluoromethylpyrimidine and n-butylamine as raw materials.

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

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] Embodiment 51

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

[0161]

[0162] Step a: Add cyclohexylmethylamine (1.1 equiv) and triethylamine (3 equiv) to a dichloromethane solution containing 2,4-dichloroquinazoline (1.1 equiv), react at room temperature, and monitor the reaction progress by TLC. After the reaction is completed, dichloromethane is added to dilute the reaction solution, and the solution is washed with brine. The organic phase is then 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] Embodiment 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: 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was dissolved in n-butanol, DIEA (1.1 eq) and cyclohexylmethylamine (1.1 eq) were added, and the mixture was reacted at 70°C for 12 h. After the reaction was completed, the mixture was allowed to stand and cool to room temperature, filtered, washed with n-butanol, and dried. 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] Embodiment 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-pyrazoleboronic acid pinacol ester (1.3 equiv), PdCl2(dppf)·DCM (0.1 equiv), sodium carbonate (2.5 equiv) were added to a solution of 1,4-dioxane / ethanol / water (7 / 4 / 3), nitrogen was replaced three times, and the reaction was carried out at 90°C for three hours. After the reaction was completed, the target intermediate was purified by silica gel column chromatography. 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 above 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 the compounds of Examples 54 to 56 (Ex.54 to Ex.56) in Table 3 refer to Example 53, except that the boric acid pinacol ester used is different. For example, compound Ex.54 uses 1-isopropyl-4-pyrazole boric acid pinacol ester as a raw material, and compound Ex.55 uses 1-ethyl-4-pyrazole boric acid pinacol ester as a raw material.

[0175] Table 3. Structure and characterization data of compounds Ex.54 to Ex.56 of Examples 54 to 56

[0176]

[0177]

[0178] Embodiment 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 above 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] Embodiment 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, N-Boc-p-phenylenediamine (1 equiv), 2-pentynoic acid (1.2 equiv), HATU (1.2 equiv), and DIEA (3 equiv) were dissolved in DMF solvent and reacted at room temperature for 5 h. After the reaction was completed, water was added for dilution, EA was extracted, brine was washed, the organic layer was concentrated, and silica gel column chromatography was used for purification. 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 (1 g) obtained in the previous step in 10 mL DCM, add 10 mL TFA, react at room temperature, and monitor the reaction progress by TLC. After the reaction is completed, remove the excess solvent, neutralize with saturated NaHCO3 solution, extract with DCM, combine the organic layers, and concentrate to obtain the de-Boc 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 the compounds of Examples 59 to 63 (Ex.59 to Ex.63) in Table 4 refer to Example 58, except that the carboxylic acid raw materials used in step a are different. For example, compound Ex.59 uses 2-butynoic acid as the raw material, and compound Ex.60 uses acrylic acid as the raw material.

[0190] Table 4. Structure and characterization data of compounds Ex.59 to Ex.63 of Examples 59 to 63

[0191]

[0192]

[0193] Embodiment 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) and 4-methylsulfonylaniline (1.2 equiv) were reacted 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] Embodiment 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), 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 completed, remove the excess solvent, 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: react the compound obtained in the previous step according to step b of Example 58 to obtain the corresponding de-Boc 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: react the intermediate 2-chloro-N-(cyclohexylmethyl)pyrimidin-4-amine with N-(4-aminophenyl)-2-chloroacetamide 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 the compounds of Examples 66 to 67 (Ex.66 to Ex.67) in Table 5 refer to Example 65, except that the acyl chloride used in step a is different. Compound Ex.66 uses chloroethanesulfonyl chloride as the raw material, and compound Ex.67 uses bromoacetyl chloride as the raw material.

[0204] Table 5. Structure and characterization data of compounds Ex.66 to Ex.67 of Examples 66 to 67

[0205]

[0206] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0207] GSDMD is a key protein in the process of cell pyroptosis, mainly composed of two domains, GSDMD-C and GSDMD-N. Under the action of caspase, GSDMD-NT is released and translocated to the cell membrane, aggregated into pores, thereby destroying ion homeostasis and inducing cell death. During cell pyroptosis, cells experience rupture of the plasma membrane. Accompanying this process, lactate dehydrogenase (LDH) is released into the extracellular fluid. The activity of LDH is stable and easy to detect, so the severity and progression of cell pyroptosis can be evaluated by detecting the amount of LDH released.

[0208] Experimental Example 1. LDH method to detect 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) at 37°C in a 5% CO2 incubator. The medium was changed on the 3rd day, and the cells were used for experiments after the 6th day. To induce inflammasome activation, THP-1 cells were treated with 100 ng / mL PMA for 24 h to differentiate into macrophages. The next day, Opti-MEM medium containing LPS (1 μg / mL) was used for 3 h, followed by pretreatment with 10 μM and 1 μM compounds for 40 min, and then induced 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. Anti-pyroptotic activity of compounds

[0211]

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

[0213] The results in Table 6 show that most of the compounds prepared in the present invention have good anti-pyroptosis activity.

[0214] In summary, the present invention provides a class of compounds that have an inhibitory effect on GSDMD. Such compounds can be used to prepare GSDMD inhibitors and treat diseases related to GSDMD, such as treating diseases related to cell pyroptosis, and have good application prospects.

Claims

1. A compound of formula I, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same: in, The dashed lines connecting L1 and L2 are both absent, L1 is absent, L2 is absent, and R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 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; or, the dotted line connected to L1 is a bond, the dotted line connected to L2 is none, L1 is connected with R1 and R2 to form a substituted or unsubstituted 3-10 membered cycloalkyl, a substituted or unsubstituted 3-10 membered heterocycloalkyl, a substituted or unsubstituted 6-8 membered aryl, a substituted or unsubstituted 5-8 membered heteroaryl, L2 is None, X is selected from NR6, O, CR6R7; or, the dotted line connected to L1 is None, the dotted line connected to L2 is a bond, L1 is selected from None, L2 is connected with X and R1 to form a substituted or unsubstituted 3-10 membered heterocycloalkyl, a substituted or unsubstituted 5-8 membered heteroaryl, and R2 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy; R 1 Selected from substituted or unsubstituted C1-C8 alkyl; R4, R5, R6, and R7 are independently selected from hydrogen and C1-C8 alkyl; 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; R3 is selected from Y is selected from 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, substituted or unsubstituted 5-8 membered heteroaryl; R8 is selected from R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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; The compound shown in formula I is not 2. The compound according to claim 1, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in Formula II: in, The dotted line connected to L1 is a bond, L1 is connected with R1 and R2 to form a substituted or unsubstituted 3-10-membered cycloalkyl, a substituted or unsubstituted 3-10-membered heterocycloalkyl, a substituted or unsubstituted 6-8-membered aryl, or a substituted or unsubstituted 5-8-membered heteroaryl, and X is selected from NR6, O, and CR6R7; R6 and R7 are independently selected from hydrogen and C1-C8 alkyl; 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; Ring A is selected from substituted or unsubstituted phenyl; R8 is selected from R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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; The substituent of the phenyl group is selected from C1-C8 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, and hydroxyl; Preferably, Said Selected from substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted The substituent is 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, hydroxyl; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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.

3. The compound according to claim 1, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in formula III: in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 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; R 1 Selected from substituted or unsubstituted C1-C8 alkyl; R4, R5, R6, and R7 are independently selected from hydrogen and C1-C8 alkyl; 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; R8 is selected from R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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.

4. The compound according to claim 3, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in formula III-1, III-2, III-3 or III-4: in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 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; R 1 Selected from substituted or unsubstituted C1-C8 alkyl; R4, R5, R6, and R7 are independently selected from hydrogen and C1-C8 alkyl; 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; R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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.

5. The compound according to claim 4, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in Formula IV: in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 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; R 1 Selected from substituted or unsubstituted C1-C8 alkyl; R4, R5, R6, and R7 are independently selected from hydrogen and C1-C8 alkyl; 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; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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; Preferably, The compound is shown in Formula V: in, R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, NR4R5, C(O)OR 1 , 3-10 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy; R 1 Selected from substituted or unsubstituted C1-C8 alkyl; R4 and R5 are independently selected from hydrogen and C1-C8 alkyl; 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; The substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, 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; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl 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.

6. The compound according to any one of claims 1 to 5, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: 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 tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted and / or, the substituents of the alkyl, alkenyl, alkynyl and alkoxy groups are selected from halogen, hydroxyl, C1-C8 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl; The cycloalkyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, morpholinyl, 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, hydroxyl; Preferably, the 3-10 membered cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentane, cyclohexyl and adamantyl.

7. The compound according to claim 1, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is shown in Formula VI: in, R8 is selected from R9 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl; The substituents of the alkyl, alkenyl and alkynyl groups are selected from halogen.

8. The compound according to claim 1, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same, characterized in that: The compound is one of the following compounds:

9. Use of the compound according to any one of claims 1 to 8, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same in the preparation of a GSDMD inhibitor; And / or, use of the compound according to any one of claims 1 to 8, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition comprising the same in the preparation of a drug for treating diseases related to cell pyroptosis; Preferably, the disease is Alzheimer's disease, Parkinson's disease, autoimmune encephalomyelitis, diabetic kidney disease, dry eye disease, multiple sclerosis, familial Mediterranean fever, non-alcoholic fatty liver disease, acute kidney injury, inflammatory bowel disease, sepsis or septic shock.

10. A drug, characterized in that: It is a preparation prepared with the compound described in any one of claims 1 to 8, its stereoisomer, its solvate, its metabolite, its deuterated product, its pharmaceutically acceptable salt, its cocrystal or a pharmaceutical composition containing the same as the active ingredient, and pharmaceutically acceptable excipients or auxiliary ingredients.

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