Thienopyrrolotriazinone compounds and their uses

Abstract

The present invention belongs to the field of chemical medicine and provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The present invention provides a class of compounds with a skeleton of thiophenopyrrolotriazinone, which can be used to prepare NLRP3 inflammasome inhibitors and provides a new option for preparing drugs for treating diseases caused by abnormal activation of NLRP3 inflammasome.

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicine, and particularly relates to a class of thiophene pyrrolotriazinone compounds, a preparation method thereof, and uses in medicine. Background Art

[0002] Inflammasomes are a class of protein complexes that can recognize pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) within cells. The assembly of inflammasomes triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1, converting the cytokine precursors pro-IL-1β and pro-IL-18 into mature, biologically active IL-1β and IL-18 respectively, and regulating the expression of inflammation-related genes to produce various biological effects. As sensors of the body's innate immunity, inflammasome activation can resist pathogen infection and stress injury, but its out-of-control activation can also cause amplification of inflammatory effects and organ damage. Currently, the research on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most popular.

[0003] The NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor (ASC, also known as PYCARD), and an effector (caspase 1). Classical NLRP3 inflammasome activation is stimulated by two signals. The first signal activates the TLR4 (Toll like receptor 4) signaling pathway, promotes the nuclear translocation of NF-κB, induces the production of precursors such as IL-1β and IL-18, and induces the post-translational modification of NLRP3. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex, that is, upon activation, it aggregates with apoptosis-associated speck-like protein containing a CARD (ASC) which contains a caspase activation and recruitment domain. ASC then interacts with cysteine protease caspase-1 to form a complex called the inflammasome. Pro-caspase-1 in its precursor form auto-cleaves into the active form. The activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18 in their precursor forms, converting them into the active forms of IL-1β and IL-18 and releasing them extracellularly, recruiting inflammatory cells to aggregate and expanding the inflammatory response. The ASC speck-like protein can also recruit and activate caspase-8, cleaving the precursor forms of IL-Ιβ and IL-18 to convert them into the mature forms and triggering pyroptosis. Non-classical NLRP3 inflammasome activation does not depend on the activation of the TLR4 signaling pathway. It is that caspase-11 directly recognizes intracellular LPS, initiates the activation of the NLRP3 inflammasome, promotes the activation and release of Gasdermin D, thereby mediating cell death.

[0004] The abnormal activation of NLRP3 is associated with many diseases, mainly including cancer, autoimmune diseases, chronic metabolic diseases, and neurological diseases. For example, colon cancer, melanoma, diabetes, gout, cryopyrin-associated periodic syndromes (CAPS), inflammatory bowel disease (IBD), NASH, gout, Alzheimer's disease, and Parkinson's disease. NLRP3 is upstream of cytokines and can block inflammation at the root. Therefore, developing new NLRP3 inflammasome inhibitors has high research value. Summary of the Invention

[0005] The object of the present invention is a class of thiophenopyrrolotriazinone compounds, or their stereoisomers, solvates, metabolites, deuterated compounds, prodrugs, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions containing them, for the treatment of diseases related to abnormal activation of the NLRP3 inflammasome.

[0006] The present invention first provides a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that the structure is as follows:

[0007]

[0008] X is selected from NH, O, S;

[0009] R 1 is selected from H, halogen, 3- to 8-membered cycloalkyl, C1-C8 alkyl, N-C1-C8 alkylamino;

[0010] R 3 is selected from H, C1-C8 alkyl;

[0011] R is selected from N heterocycle

[0012] Y is NH or none;

[0013] R 2 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 ester group, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered bridged cycloalkyl, substituted or unsubstituted 5- to 11-membered spirocycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, n1 is an integer selected from 1 to 3;

[0014] R 2 Among them, the substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered bridged cycloalkyl, and substituted or unsubstituted 5- to 11-membered spirocycloalkyl contain 0 to 3 heteroatoms, and the heteroatoms are N, O, S;

[0015] R 2 Among them, the substituted or unsubstituted 5- to 10-membered heteroaryl contains 1 to 3 heteroatoms, and the heteroatoms are N;

[0016] R 2 Among them, the substituents of the substituted C1-C10 alkyl and substituted C1-C10 ester group are selected from halogen, hydroxyl, nitrile, amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, S, at least one of 6- to 10-membered aryl, R 4 is selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl, and n2 and n3 are independently integers selected from 1 to 3;

[0017] R 2Among them, the substituents of the substituted 3- to 8-membered cycloalkyl group, the substituted 4- to 10-membered bridged cycloalkyl group, and the substituted 5- to 11-membered spirocycloalkyl group are selected from halogen, hydroxyl, nitrile, amino, C1-C8 alkoxycarbonyl, C1-C8 ester group, substituted or unsubstituted C1-C8 alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl group containing at least one heteroatom selected from N, O, and S, C1-C8 alkoxy group, -SO 2 -R 5 Among them, the substituents of the substituted C1-C8 alkyl group in the substituents are selected from halogen, hydroxyl, amino, 3- to 6-membered cycloalkyl group, and R 5 is selected from C1-C4 alkyl group, 3- to 6-membered cycloalkyl group;

[0018] R 2 Among them, the substituents of the substituted 6- to 10-membered aryl group and the substituted 5- to 10-membered heteroaryl group are selected from halogen, hydroxyl, nitrile, C1-C8 alkoxycarbonyl, C1-C8 ester group, 3- to 6-membered cycloalkyl group, substituted or unsubstituted C1-C8 alkyl group, and C1-C8 alkoxy group. Among them, the substituents of the substituted C1-C8 alkyl group in the substituents are selected from halogen, hydroxyl, and amino;

[0019] The N-heterocycle is selected from substituted or unsubstituted 3- to 8-membered N-heterocycloalkane ring, substituted or unsubstituted 4- to 8-membered N-heterobridged cycloalkane ring, and substituted or unsubstituted 5- to 11-membered N-heterospirocycloalkane ring, which contains 0 to 2 O or S heteroatoms in addition to N;

[0020] In the N-heterocycle, the substituents of the substituted 3- to 8-membered N-heterocycloalkane ring, the substituted 4- to 8-membered N-heterobridged cycloalkane ring, and the substituted 5- to 11-membered N-heterospirocycloalkane ring are selected from C1-C6 alkyl group, halogen, hydroxyl, nitrile, and at least one of them.

[0021] Among them, in the compound of formula I above, R 1 is selected from H, halogen, 3- to 6-membered cycloalkyl group, C1-C6 alkyl group, and N-C1-C6 alkylamino.

[0022] Preferably, in the compound of formula I above, R 1 is selected from H, halogen, 3- to 6-membered cycloalkyl group, C1-C4 alkyl group, and N-C1-C4 alkylamino.

[0023] Most preferably, in the compound of formula I above, R 1 is selected from H, Cl, Br, cyclopropyl, ethyl, methyl, and N-ethylamino.

[0024] Among them, in the compound of formula I above, R 2Selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-9 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl,

[0025] Preferably, in the above formula I compound, R 2 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-7 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl,

[0026] More preferably, in the above formula I compound, R 2 Selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 10 membered bridged cycloalkyl, substituted or unsubstituted 5-7 membered spirocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5, 6 or 9 membered heteroaryl,

[0027] Among them, in the above formula I compound, R 2 Among them, the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contain 0-2 heteroatoms, and the heteroatoms are N, O, S; R 2 Among them, the substituted or unsubstituted heteroaryl contains 1-3 heteroatoms, and the heteroatoms are N.

[0028] Preferably, in the above formula I compound, R 2 Among them, the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contain 0-2 heteroatoms, and the heteroatoms are N, O, S; R 2 Among them, the substituted or unsubstituted heteroaryl contains 1-3 heteroatoms, and the heteroatoms are N.

[0029] Among them, in the above formula I compound, R 2 Among them, the substituents of the substituted alkyl and substituted ester group are selected from at least one of halogen, hydroxyl, nitrile, amino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, 6-10 membered aryl; R 4 Selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl; n2 and n3 independently selected from integers of 1-2.

[0030] Among them, in the compound of formula I above, R 2 Among them, the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, and substituted spirocycloalkyl are selected from halogen, hydroxyl, nitrile, amino, C1-C6 alkoxycarbonyl, C1-C6 ester group, substituted or unsubstituted C1-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing at least one heteroatom selected from N, O, S, C1-C6 alkoxy, -SO 2 -R 5 Among them, the substituents of the substituted C1-C6 alkyl in the substituents are selected from halogen, hydroxyl, amino, 3-6 membered cycloalkyl, R 5 is selected from C1-C4 alkyl, 3-6 membered cycloalkyl.

[0031] Among them, in the compound of formula I above, R 2 Among them, the substituents of the substituted aryl and substituted heteroaryl are selected from halogen, hydroxyl, nitrile, C1-C6 alkoxycarbonyl, C1-C6 ester group, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy. Among them, the substituents of the substituted C1-C6 alkyl in the substituents are selected from halogen, hydroxyl, amino.

[0032] Preferably, in the compound of formula I above, R 2 Among them, the substituents of the substituted alkyl and substituted ester group are selected from halogen, hydroxyl, nitrile, amino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing at least one heteroatom selected from N, O, S, at least one of 6-10 membered aryl, R 4 is selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl, n2 and n3 are independently selected from 1.

[0033] Preferably, in the compound of formula I above, R 2 Among them, the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, and substituted spirocycloalkyl are selected from halogen, hydroxyl, nitrile, amino, C1-C4 alkoxycarbonyl, C1-C4 ester group, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing at least one heteroatom selected from N, O, S, C1-C4 alkoxy, -SO 2 -R 5 Among them, the substituents of the substituted C1-C4 alkyl in the substituents are selected from halogen, hydroxyl, amino, 3-6 membered cycloalkyl, R 5 is selected from C1-C4 alkyl, 3-6 membered cycloalkyl.

[0034] Preferably, in the compound of formula I above, R 2Among them, the substituents of the substituted aryl and substituted heteroaryl are selected from at least one of halogen, hydroxy, cyano, C1-C4 alkoxycarbonyl, C1-C4 ester group, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl, and C1-C4 alkoxy. Among them, the substituents of the substituted C1-C4 alkyl in the substituents are selected from halogen, hydroxy, and amino.

[0035] More preferably, in the above compound of formula I, R 2 Among them, the substituents of the substituted alkyl and substituted ester group are selected from hydroxy, amino, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, and S, and at least one of phenyl.

[0036] More preferably, in the above compound of formula I, R 2 Among them, the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, and substituted spirocycloalkyl are selected from halogen, hydroxy, cyano, amino, tert-butoxycarbonyl, C1-C4 ester group, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, and S, C1-C4 alkoxy, -SO 2 -R 5 and at least one of them. Among them, the substituents of the substituted C1-C4 alkyl in the substituents are selected from halogen, hydroxy, and cyclopropyl, and R 5 is selected from methyl and cyclopropyl.

[0037] More preferably, in the above compound of formula I, R 2 Among them, the substituents of the substituted aryl and substituted heteroaryl are selected from at least one of halogen, hydroxy, cyano, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl, and C1-C4 alkoxy. Among them, the substituents of the substituted C1-C4 alkyl in the substituents are selected from halogen.

[0038] Most preferably, in the above compound of formula I, R 2 Among them, the substituents of the substituted alkyl and substituted ester group are selected from hydroxy, amino, cyclopropyl, and at least one of phenyl.

[0039] Most preferably, in the above compound of formula I, R 2 Among them, the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, and substituted spirocycloalkyl are selected from F, hydroxy, cyano, amino, -Boc, methoxycarbonyl, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, cyclobutyl, methoxy, and at least one of them.

[0040] Most preferably, in the compound of formula I above, R 2 Among them, the substituents of the substituted aryl and substituted heteroaryl are selected from at least one of F, Cl, hydroxyl, cyano, methyl, ethyl, propyl, trifluoromethyl, and methoxy.

[0041] Among them, in the compound of formula I above, R is selected from

[0042]

[0043] Among them, in the compound of formula I above, the N-heterocycle is selected from a substituted or unsubstituted 3- to 6-membered N-heterocycloalkane ring, a substituted or unsubstituted 4- to 8-membered N-heterobicycloalkane ring, and a substituted or unsubstituted 5- to 9-membered N-heterospiroalkane ring. In addition to N, it contains 0 to 1 O heteroatom; in the N-heterocycle, the substituents of the substituted 3- to 6-membered N-heterocycloalkane ring, the substituted 4- to 8-membered N-heterobicycloalkane ring, and the substituted 5- to 9-membered N-heterospiroalkane ring are selected from C1-C4 alkyl, halogen, hydroxyl, nitrile, At least one of them.

[0044] Preferably, in the compound of formula I above, the N-heterocycle is selected from a substituted or unsubstituted 4- to 6-membered N-heterocycloalkane ring, an unsubstituted 4- to 8-membered N-heterobicycloalkane ring, and an unsubstituted 5- to 7-membered spiroalkane ring. In addition to N, it contains 0 to 1 O heteroatom; in the N-heterocycle, the substituents of the substituted 4- to 6-membered N-heterocycloalkane ring are selected from methyl, hydroxyl, At least one of them.

[0045] Most preferably, in the compound of formula I above, the N-heterocycle is selected from

[0046] Among them, in the compound of formula I above, R 3 Is selected from H, C1-C6 alkyl.

[0047] Preferably, in the compound of formula I above, R 3 Is selected from H, C1-C4 alkyl.

[0048] Most preferably, in the compound of formula I above, R 3 Is selected from H, methyl.

[0049] The present invention also provides some specific compounds in formula I above, and their structural formulas are as follows:

[0050]

[0051]

[0052]

[0053]

[0054] The present invention also provides a pharmaceutical composition, which is composed of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable auxiliary ingredients.

[0055] The present invention also provides the use of the above-mentioned compound of formula I or its pharmaceutically acceptable salt, and the above-mentioned pharmaceutical composition in the preparation of NLRP3 inhibitors.

[0056] Definition of terms:

[0057] Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. The terms "include," "comprises," "has," "contains," or "involves," and other variations thereof herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. It should be understood by those skilled in the art that the above terms, such as "includes," encompass the meaning of "consisting of."

[0058] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition includes "one or more" pharmaceutically acceptable excipients.

[0059] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of "about a to b", or equivalently, "approximately a to b", or equivalently, "about ab"), should be understood to represent each numerical value and range encompassed within the broader range.

[0060] For example, the expression “C 1-6 " should be understood to include any sub-ranges and each point value therein, such as C 2-5 , C 3-4 、C1-2、C 1-3 , C 1-4 , C 1-5 etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 For example, the expression “C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, for example, C 3-9 , C 6-9 , C 6-8 , C 6-7, C 7-10 , C 7-9 , C7-8, C 8-9 etc. and C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 etc. For another example, the expression "3-10 yuan" should be understood to cover any sub-range and each point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc. and 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. Still for another example, the expression "5-10 yuan" should also be understood in a similar way, for example, it can cover any sub-range and point value included therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.

[0061] In the present invention, unless otherwise specified, halogen refers to fluorine, chlorine, bromine or iodine.

[0062] In the present invention, unless otherwise specified, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 alkyl" in C 1-4 refers to a group arranged in a straight-chain or branched form containing 1, 2, 3 or 4 carbon atoms.

[0063] In the present invention, unless otherwise specified, "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic (such as bicyclic) aromatic group or aromatic ring having a conjugated π electron system. As used herein, the term "C6-10 aryl" refers to an aromatic group containing 6-10 carbon atoms. Examples thereof include, but are not limited to, phenyl and naphthyl, etc. The aryl or aromatic ring in the present invention is optionally substituted by one or more substituents described in the present invention.

[0064] In the present invention, unless otherwise specified, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. The heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5- to 12-membered heteroaryl can contain 5 to 12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, or 10 ring atoms. Examples of heteroaryl include, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; the term also encompasses the situation where the heteroaryl or heteroaromatic ring can optionally be further fused to an aryl or heteroaryl ring to form a fused ring. The heteroaryl or heteroaromatic ring in the present invention is optionally substituted with one or more substituents described in the present invention.

[0065] In the present invention, unless otherwise specified, "substituted" means that one or more hydrogen atoms in a group are each replaced by the same or different substituents.

[0066] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g., 13 C and 14 C); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 17 O and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 34 S).

[0067] In the present invention, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Some compounds of the present invention can exist in more than one crystal form, and the present invention is intended to include all crystal forms and their mixtures. Generally, crystallization results in solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. The compounds of the present invention can form true solvates, but in some cases, they can also retain only indeterminate water or a mixture of water and some indeterminate solvent. The compounds of the present invention can react in a solvent or precipitate or crystallize out from a solvent. The solvates of the compounds of the present invention are also included within the scope of the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any proportion.

[0068] In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0069] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that are able to retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, etc. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that are able to maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in this patent.

[0070] In the present invention, unless otherwise specified, "ester" refers to esters derived from the compounds described herein, which include physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the compounds of the present invention in the form of free acids or alcohols). The compounds of the present invention themselves can also be esters.

[0071] The compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, especially for example water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, can be present in stoichiometric or non-stoichiometric ratios.

[0072] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles that can form nitrogen oxides. Those skilled in the art will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing nitrogen oxides have been widely described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp748 - 750 (A.R. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W.H. Cheeseman and E.S.G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390 - 392 (A.R. Katritzky and A.J. Boulton, Eds., Academic Press).

[0073] In the present invention, "metabolite" refers to a substance formed in the body upon administration of the compounds of the present invention. Metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method of contacting a compound of the present invention with a mammal for a time sufficient to produce its metabolite.

[0074] In the present invention, a "prodrug" refers to certain derivatives of the compounds of the present invention which, when administered to or on the body, can be converted, for example, by hydrolytic cleavage into the compounds of the present invention having the desired activity. Generally, such prodrugs will be functional group derivatives of said compounds which are readily convertible in vivo into the desired therapeutically active compounds. Other information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0075] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thereby exert a biological activity.

[0076] In the present application, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been approved by the relevant government regulatory authorities or is acceptable for use in humans or livestock.

[0077] On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0078] Advantages of the present invention:

[0079] The present invention provides a class of compounds with a skeleton of thiophenopyrrolo[2,3-d]triazinone. Such compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for the treatment of diseases caused by abnormal activation of the NLRP3 inflammasome. Detailed implementation mode

[0080] The solution of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those without specific techniques or conditions noted in the embodiments, the techniques or conditions described in the literature in this field or according to the product specifications are followed. Those reagents or instruments without the manufacturer noted are all conventional products that can be obtained through commercial purchase.

[0081] Table 1 Abbreviations of Some Reagents Used in the Embodiment

[0082] Reagent Abbreviation Petroleum ether PE Ethyl acetate EtOAc Dichloromethane DCM Methanol MeOH Ethanol EtOH N,N-Dimethylformamide DMF Tetrahydrofuran THF

[0083] Preparation of Intermediate 1g

[0084]

[0085] Step a: Methyl 4H-thiazolo[3,2-b]pyrrole-5-carboxylate 1a (1 equiv) and hydrazine hydrate (5 equiv) were added to an ethanol solution, and the mixture was refluxed at 85 °C. The reaction progress was monitored by TLC. After the reaction was completed, a white precipitate was formed, which was filtered, washed with water, and dried to obtain a crude product 1b without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 9.47 (s, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 5.2 Hz, 1H), 4.38 (s, 2H).

[0086] Step b: The crude product 1b (1 equiv) and trimethyl orthoisobutyrate (1.2 equiv) were dissolved in a DMF solution, and the mixture was stirred in an oil bath at 130 °C for 30 min. Then, it was cooled to room temperature, and potassium tert-butoxide (1.2 equiv) was added to the reaction system. The reaction solution was stirred in an oil bath at 90 °C, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water, and acidified to pH 5 with 2 M HCl. The formed precipitate was filtered, thoroughly washed with water and DCM, and the obtained compound was a beige solid 1c without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 10.13 (s, 1H), 7.53 (s, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.28 (d, J = 5.4 Hz, 1H), 3.52 (spt, J = 6.7 Hz, 1H), 1.44 (d, J = 6.7 Hz, 6H).

[0087] Step c: Compound 1c (1 equiv) and ethyl 2-chloroacetate (1.2 equiv) were dissolved in DMF, and Cs2 CO 3 (3 equiv), the reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was diluted with water, acidified with 2 M HCl, and extracted three times with ethyl acetate. The combined organic extracts were washed with 10% NaHCO 3 solution and brine, and the organic layer was dried over anhydrous Na 2 SO 4 and filtered and evaporated to give the crude product 1d without further purification. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 5.6 Hz, 2H), 7.26 (d, J = 4.2 Hz, 1H), 4.80 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.49 (spt, J = 6.7 Hz, 1H), 1.42 (d, J = 6.7 Hz, 6H), 1.29 (t, J = 6.6 Hz, 3H).

[0088] Step d: Compound 1d (1 equiv) and solid NCS (1.2 equiv) were placed in a THF solution, and the reaction system was heated at 55 °C. The reaction progress was monitored by TLC. After completion of the reaction, it was quenched with 10% Na 2 CO 3 solution, and extracted 2 - 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 and filtered and evaporated. Purification by silica gel column chromatography using a petroleum ether and ethyl acetate system (0% - 25%) gave the compound as a white solid 1e. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.39 (s, 1H), 7.19 (s, 1H), 4.79 (s, 2H), 4.24 (d, J = 7.1 Hz, 2H), 3.37 (spt, J = 6.7 Hz, 1H), 1.41 (d, J = 6.7 Hz, 6H), 1.30 (d, J = 7.1 Hz, 3H).

[0089] Step e: Compound 1e (1 equiv) and hydrazine hydrate (5 equiv) were added to an ethanol solution, and the reaction was heated at 85 °C. The reaction progress was monitored by TLC. A white solid formed, which was filtered, washed with water and dried to give the crude product 1f without further purification. 1 1H NMR (400 MHz, DMSO-d 6)δ9.18(s,1H),7.80(s,1H),7.46(s,1H),4.52(s,2H),4.27(s,2H),3.58(spt,J=6.6Hz,1H),1.29(d,J=6.6Hz,6H).

[0090] Step f: Compound 1f (1 equiv) and CDI (1.2 equiv) were dissolved in 1,4 - dioxane solution. The reaction system was heated and stirred in an oil bath at 100 °C, and the reaction progress was monitored by TLC. After the reaction was completed, the excess solvent was removed by rotary evaporation under heating. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated NaCl aqueous solution, and then dried with anhydrous Na 2 SO 4 The organic layer was dried. It was purified by silica gel column chromatography with a dichloromethane - ethyl acetate system (1% - 5%) to obtain intermediate 1g. 1 1H NMR (400 MHz, DMSO - d 6 )δ12.35(s,1H),7.81(s,1H),7.53(s,1H),5.09(s,2H),3.62–3.58(m,1H),1.27(d,J=6.6Hz,6H).

[0091] Example 1. (Ex.1)

[0092] 2 - Chloro - 5 - isopropyl - 7 - ((5 - ((tetrahydro - 2H - pyran - 4 - yl)amino)-1,3,4 - oxadiazol - 2 - yl)methyl)thieno[2',3':4,5]pyrrolo[1,2 - d][1,2,4]triazin - 8(7H) - one

[0093]

[0094] In a 25 mL round - bottom flask, intermediate 1g (100 mg, 1 equiv), 4 - aminotetrahydropyran (2 equiv), and BOP (1.1 equiv) were added to DMF solvent, and then DIEA (2 equiv) was added dropwise. The reaction mixture was reacted at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous Na 2 SO 4 The organic layer was dried. It was purified by silica gel column chromatography with a dichloromethane - methanol system (1% - 5%) to obtain Example 1 (Ex.1). 1 1H NMR (400 MHz, CDCl 3)δ7.38(s,1H),7.16(s,1H),5.32(d,J=8.0Hz,1H),5.29(s,2H),3.94(dd,J=8.6,3.1Hz,2H),3.79–3.72(m,1H),3.46(td,J=11.5,1.8Hz,3H),3.32(spt,J=6.7Hz,1H),2.06–2.00(m,2H),1.59–1.51(m,2H),1.37(d,J=6.7Hz,6H).

[0095] Example 2. (Ex. 2)

[0096] 2-Chloro-5-isopropyl-7-((5-morpholino-1,3,4-oxadiazol-2-yl)methyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one

[0097]

[0098] In a 25 mL round-bottom flask, add intermediate 1 g (100 mg, 1 equiv), morpholine (2 equiv), BOP (1.1 equiv) in DMF solvent, and then dropwise add DIEA (2 equiv). The reaction mixture is reacted at room temperature, and the reaction progress is monitored by TLC. After the reaction is completed, dilute with water, extract three times with ethyl acetate, wash the organic layer with saturated sodium chloride solution, and dry the organic layer over anhydrous Na 2 SO 4 Purify by silica gel column chromatography with a dichloromethane-methanol system (1%-5%) to obtain Example 2 (Ex. 2). 1 1H NMR (400 MHz, CDCl 3 )δ7.41(s,1H),7.18(s,1H),5.33(d,J=6.5Hz,2H),3.79–3.74(m,4H),3.48(dd,J=5.8,3.8Hz,4H),3.35(spt,J=6.7Hz,1H),1.39(d,J=6.7Hz,6H). 13 13C NMR (101 MHz, CDCl 3 )δ164.79,156.52,153.87,142.45,134.11,131.59,127.13,126.46,113.33,104.90,66.02(2C),46.22,43.37(2C),30.31,20.00(2C).

[0099] Example 3. (Ex. 3)

[0100] 2-Chloro-5-isopropyl-7-((5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)methyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one

[0101]

[0102] In a 25 mL round-bottom flask, add 1 g (100 mg, 1 equiv) of the intermediate, N-methylpiperazine (2 equiv), BOP (1.1 equiv) in DMF solvent, and then dropwise add DIEA (2 equiv). The reaction mixture is reacted at room temperature, and the reaction progress is monitored by TLC. After the reaction is completed, dilute with water and extract three times with ethyl acetate. Wash the organic layer with saturated sodium chloride solution, and dry with anhydrous Na 2 SO 4 Dry the organic layer. Purify by silica gel column chromatography with a dichloromethane-methanol system (1%-5%) to obtain Example 3 (Ex. 3). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.40 (s, 1H), 7.17 (s, 1H), 5.30 (s, 2H), 3.54–3.49 (m, 4H), 3.33 (dt, J = 13.4, 6.7 Hz, 1H), 2.50–2.46 (m, 4H), 2.32 (s, 3H), 1.37 (d, J = 6.7 Hz, 6H). 13 13C NMR (101 MHz, CDCl 3 ) δ 164.84, 156.28, 153.85, 142.38, 134.02, 131.55, 127.10, 126.50, 113.31, 104.83, 53.96 (2C), 46.28 (2C), 45.98, 43.33, 30.30, 19.99 (2C).

[0103] The synthesis methods of Examples 4-49 are the same as those of Example 1, only changing the types of amino groups. The types of amino groups, the structural formulas of the obtained compounds, and the NMR data of the obtained compounds are shown in Table 2.

[0104] Table 2 Structures and NMR Data of Examples 4-49

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Example 50. (Ex. 50)

[0115] 2-Chloro-5-isopropyl-7-((5-(tetrahydrofuran-3-yl)-1,3,4-oxadiazol-2-yl)methyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one

[0116]

[0117] In a 25 mL round-bottom flask, intermediate 1f (1 equiv, 200 mg) and 3-tetrahydrofuroic acid (1 equiv) were dissolved in 1,4-dioxane solvent. At room temperature, phosphorus oxychloride (200 μL) was added dropwise with stirring. After the addition was complete, the reaction system was placed in an oil bath at 90 °C and the reaction was monitored by TLC. After the reaction was complete, it was diluted with ethyl acetate, quenched with saturated NaHCO 3 solution, the organic layer was separated, extracted three times with ethyl acetate, the organic layer was concentrated by rotary evaporation, and purified by silica gel column chromatography using a petroleum ether - ethyl acetate system (10% - 25%) to obtain the target compound Ex. 50. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.42 (s, 1H), 7.18 (s, 1H), 5.44 (s, 2H), 4.11 (dd, J = 8.7, 7.8 Hz, 1H), 4.01–3.87 (m, 3H), 3.68–3.61 (m, 1H), 3.35 (dt, J = 13.4, 6.7 Hz, 1H), 2.38–2.32 (m, 2H), 1.37 (d, J = 6.7 Hz, 6H). 13 13C NMR (101 MHz, CDCl 3 ) δ 168.26, 162.62, 153.87, 142.63, 134.22, 131.66, 127.17, 126.36, 113.30, 105.06, 71.02, 68.22, 43.45, 36.07, 30.65, 30.28, 19.98 (2C).

[0118] The synthesis methods of Examples 51 - 82 are the same as those of Example 50, except that the types of carboxylic acids are changed, and the structural formulas and NMR data of the obtained compounds are shown in Table 3 as follows.

[0119] Table 3 Structures and NMR Data of Examples 51 - 82

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] Example 83. (Ex. 83)

[0130] 2 - Bromo - 7 - ((5 - (2 - chloro - 6 - (trifluoromethyl)pyridin - 3 - yl)-1,3,4 - oxadiazol - 2 - yl)methyl)-5 - isopropylthieno[2',3':4,5]pyrrolo[1,2 - d][1,2,4]triazin - 8(7H)-one

[0131]

[0132] Step a: Compound 1d (1 equiv) and solid NBS (1.2 equiv) were placed in a THF solution, and the reaction system was heated at 55 °C. The reaction progress was monitored by TLC. After the reaction was completed, it was quenched with 10% Na 2 CO 3 solution, and extracted with ethyl acetate 2 - 3 times. The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 and filtered and evaporated. Purification by silica gel column chromatography with a petroleum ether and ethyl acetate system (0% - 25%) gave the compound as a white solid 2e. 1 1H NMR (400 MHz, CDCl 3)δ 7.38 (s, 1H), 7.30 (s, 1H), 4.78 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.37 (spt, J = 6.7 Hz, 1H), 1.40 (d, J = 6.7 Hz, 6H), 1.29 (t, J = 7.1 Hz, 3H).

[0133] Step b: Add compound 2e (1 equiv) and hydrazine hydrate (5 equiv) into an ethanol solution, heat and react at 85 °C, and monitor the reaction progress by TLC. A formed white solid is filtered, washed with water and dried to obtain the crude product 2f without further purification. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.19 (s, 1H), 7.86 (s, 1H), 7.45 (s, 1H), 4.52 (s, 2H), 4.26 (d, J = 3.9 Hz, 2H), 3.59 (spt, J = 6.6 Hz, 1H), 1.28 (d, J = 6.6 Hz, 6H).

[0134]

[0135] In a 25 mL round-bottom flask, dissolve intermediate 2f (1 equiv, 200 mg) and 2-chloro-6-trifluoromethylnicotinic acid (1 equiv) in 1,4-dioxane solvent. At room temperature, add phosphorus oxychloride (200 μL) dropwise with stirring. After the addition is complete, place the reaction system in an oil bath at 90 °C to react, and monitor the reaction progress by TLC. After the reaction is complete, dilute with ethyl acetate, quench with saturated NaHCO 3 solution, separate the organic layer, extract with ethyl acetate three times, spin-dry and concentrate the organic layer, and purify by silica gel column chromatography with a petroleum ether - ethyl acetate system (10% - 25%) to obtain the target compound Ex.83. 1 H NMR (400 MHz, CDCl 3 )δ 7.41 (s, 1H), 7.18 (s, 1H), 5.43 (s, 2H), 3.33 (spt, J = 6.6 Hz, 1H), 3.31–3.23 (m, 1H), 2.11–2.03 (m, 2H), 1.92–1.85 (m, 2H), 1.80–1.75 (m, 2H), 1.70–1.64 (m, 2H), 1.36 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDCl 3)δ171.17,162.07,153.86,142.48,134.08,131.59,127.12,126.44,113.30,104.94,77.48,77.16,76.84,43.37,36.05,31.17(2C),30.27,25.54(2C),19.97(2C).

[0136] Example 84. (Ex. 84)

[0137] 2-Bromo-5-isopropyl-7-(1-(5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one

[0138]

[0139] Step a: Compound 1c (1 equiv) and ethyl 2-chloropropionate (1.2 equiv) were dissolved in DMF, and Cs 2 CO 3 (3 equiv) was added. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was diluted with water, acidified with 2 M HCl, and extracted with ethyl acetate three times. The combined organic extracts were washed with 10% NaHCO 3 solution and brine, and the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness. It was purified by silica gel column chromatography to obtain intermediate 3d. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.26 (dd, J = 5.3, 2.2 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 5.3, 1.8 Hz, 1H), 6.58 (qd, J = 7.1, 1.7 Hz, 1H), 4.17 (qd, J = 7.1, 1.9 Hz, 2H), 3.30–3.18 (m, 1H), 1.81 (dd, J = 7.2, 2.0 Hz, 3H), 1.44 (dd, J = 7.0, 2.1 Hz, 6H), 1.16 (td, J = 7.1, 2.1 Hz, 3H).

[0140] Step b: Compound 3d (1 equiv) and solid NCS (1.2 equiv) were placed in a THF solution, and the reaction system was heated at 55 °C. The reaction progress was monitored by TLC. After completion of the reaction, it was treated with 10% Na 2 CO 3Quench with solution and extract 2 - 3 times with ethyl acetate. The combined organic extracts are washed with brine and dried over anhydrous Na 2 SO 4 then filtered and evaporated. Purify by silica gel column chromatography using a petroleum ether - ethyl acetate system (0% - 25%) to obtain the compound as a white solid 3e. 1 H NMR (400 MHz, CDCl 3 ) δ6.98 (s, 1H), 6.87 (s, 1H), 6.56 (q, J = 7.0 Hz, 1H), 4.18 (qd, J = 6.9, 1.0 Hz, 2H), 3.26–3.18 (m, 1H), 1.77 (dd, J = 7.3, 1.0 Hz, 3H), 1.42 (dd, J = 7.0, 1.0 Hz, 6H), 1.19 (td, J = 7.1, 1.1 Hz, 3H).

[0141] Step c: Add compound 3e (1 equiv) and hydrazine hydrate (5 equiv) to an ethanol solution and heat the reaction at 85 °C. Monitor the reaction progress by TLC. A white solid formed is filtered, washed with water and dried to obtain the crude product 3f without further purification. 1 H NMR (400 MHz, DMSO - d 6 ) δ9.34 (s, 1H), 7.29 (s, 1H), 7.13 (s, 1H), 6.06 (q, J = 7.1 Hz, 1H), 4.31 (s, 2H), 3.27 (spt, J = 7.0 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 7.0 Hz, 6H).

[0142] Step d: In a 25 mL round - bottom flask, dissolve intermediate 3f (1 equiv, 200 mg) and 6 - methylnicotinic acid (1 equiv) in 1,4 - dioxane solvent. At room temperature, add phosphorus oxychloride (200 μL) dropwise with stirring. After the addition is complete, place the reaction system in an oil bath at 90 °C and react. Monitor the reaction progress by TLC. After the reaction is complete, dilute with ethyl acetate, quench with saturated NaHCO 3 solution, separate the organic layer, extract three times with ethyl acetate, concentrate the organic layer by rotary evaporation, and purify by silica gel column chromatography using a petroleum ether - ethyl acetate system (10% - 25%) to obtain the target compound Ex.84. 1 H NMR (400 MHz, CDCl 3)δ9.10(s,1H),8.35(d,J=7.8Hz,1H),7.45(s,1H),7.39(d,J=7.8Hz,1H),7.18(s,1H),6.49(q,J=7.0Hz,1H),3.34(dt,J=13.6,6.8Hz,1H),2.72(s,3H),1.97(d,J=6.9Hz,3H),1.38(d,J=6.7Hz,3H),1.27(d,J=6.7Hz,3H).

[0143] Example 85. (Ex. 85)

[0144] 2-Chloro-5-isopropyl-7-((5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)methyl)thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H)-one

[0145]

[0146] In a 25 ml round-bottom flask, raw material 1f (100 mg, 1 equiv) was dissolved in methanol solvent, and then sodium methoxide (0.5 equiv) was added and stirred at room temperature until dissolved. Subsequently, 3-cyanopyridine (1 equiv) was added to the reaction system, and the reaction was refluxed. The reaction process was monitored by TLC. After the reaction was completed, the target compound Ex. 85 was obtained by silica gel column chromatography purification with a dichloromethane-methanol system (1%-5%). 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),9.01(s,1H),8.61(d,J=3.4Hz,1H),8.18(d,J=8.1Hz,1H),7.81(s,1H),7.48(s,1H),7.44(dd,J=8.1,4.6Hz,1H),5.04(s,2H),3.61(spt,J=6.6Hz,2H),1.30(d,J=6.6Hz,6H).

[0147] The beneficial effects of the present invention are demonstrated by the following specific test examples.

[0148] Biological test example: Pharmacological test of the compounds of the present invention

[0149] The present invention also provides a pharmacological activity screening experiment for some of the above compounds, namely an in vitro IL-Ιβ inhibition experiment. THP-1 is a human myeloid leukemia monocyte, originally derived from a patient with acute monocytic leukemia. THP-1 is a commonly used acute monocytic leukemia cell line in major laboratories and is an ideal cell for studying immunity and inflammation.

[0150] Materials: LPS, Nigericin, PMA.

[0151] Compound preparation: 1) Dissolve the compound in 100% DMSO to make a stock solution of 10 mmol / L; 2) Dissolve LPS in Opti-MEM to make a stock solution of 1 mg / mL; 3) Dissolve Nigericin in absolute ethanol to make a stock solution of 10 mM; 4) Dissolve PMA in 100% DMSO to make a stock solution of 100 μg / mL.

[0152] Method: Seed THP-1 cells (3×10 3 ) in a 48-well plate, add PMA (100 ng / mL) and culture for 24 hours. Then change the medium to Opti-MEM, treat with LPS (at a concentration of 1 mg / mL) for 3 hours, then treat with 2 μM of the compound for 40 min, and finally treat with Nigericin (at a concentration of 10 mM) for 40 min. Collect the supernatant. Detect IL-Ιβ in the supernatant using an ELISA kit.

[0153] Read and record the raw data for each well, and perform corresponding conversions on the raw data. The inhibition rate of the compound on interleukin IL-1β is calculated as follows:

[0154] Inhibition rate (%) = 1 - (OD value of the drug well - OD value of the blank well) / (OD value of the negative control well - OD value of the blank well). Use the cell well without drug and inducer as the blank control, and the cell well without drug, with LPS and ATP as the negative control. The results are shown in Table 4.

[0155] Table 4 Inhibitory effects of the compound on THP-1 cells

[0156]

[0157]

Claims

1. The compound of formula I or a pharmaceutically acceptable salt thereof, wherein, the structure is as follows: X is selected from NH, O, S; R 1 selected from H, halogen, C3-C8 cycloalkyl, C1-C8 alkyl, N-C1-C8 alkylamino; R 3 selected from H, C1-C8 alkyl; R is selected from N-heterocycle Y is NH or absent; R 2 selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 ester group, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 4- to 10-membered bridged cycloalkyl, substituted or unsubstituted 5- to 11-membered spirocycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, n1 is an integer selected from 1 to 3; R 2 wherein the substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 4- to 10-membered bridged cycloalkyl group, and substituted or unsubstituted 5- to 11-membered spirocycloalkyl group contain 0 to 3 heteroatoms, and the heteroatoms are N, O, and S; R 2 wherein the substituted or unsubstituted 5- to 10-membered heteroaryl contains 1 to 3 heteroatoms, and the heteroatom is N; R 2 Among them, the substituents of the substituted C1-C10 alkyl group and the substituted C1-C10 ester group are selected from at least one of halogen, hydroxyl, nitrile, amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, and S, at least one of 6- to 10-membered aryl, R 4 is selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl, and n2 and n3 independently are selected from integers of 1 to 3; R 2 Among them, the substituents of the substituted 3- to 8-membered cycloalkyl group, the substituted 4- to 10-membered bridged cycloalkyl group, and the substituted 5- to 11-membered spirocycloalkyl group are selected from halogen, hydroxy, cyano, amino, C1-C8 alkoxycarbonyl, C1-C8 ester group, substituted or unsubstituted C1-C8 alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl group containing at least one heteroatom selected from N, O, S, C1-C8 alkoxy group, -SO 2 -R 5 Among them, the substituents of the substituted C1-C8 alkyl group in the substituents are selected from halogen, hydroxy, amino, 3- to 6-membered cycloalkyl group, and R 5 is selected from C1-C4 alkyl group, 3- to 6-membered cycloalkyl group; R 2 Among them, the substituents of the substituted 6- to 10-membered aryl group and the substituted 5- to 10-membered heteroaryl group are selected from at least one of halogen, hydroxyl, nitrile group, C1-C8 alkoxycarbonyl, C1-C8 ester group, 3- to 6-membered cycloalkyl group, substituted or unsubstituted C1-C8 alkyl group, and C1-C8 alkoxy group. Among them, the substituents of the substituted C1-C8 alkyl group in the substituents are selected from halogen, hydroxyl, and amino groups; The N-heterocycle is selected from a substituted or unsubstituted 3- to 8-membered N-heterocycloalkane ring, a substituted or unsubstituted 4- to 8-membered N-heterobicycloalkane ring, a substituted or unsubstituted 5- to 11-membered N-heterospiroalkane ring, which contains 0 to 2 O or S heteroatoms in addition to N; In the N-heterocycle, the substituents of the substituted 3- to 8-membered N-heterocycloalkane ring, substituted 4- to 8-membered N-heterobicycloalkane ring, and substituted 5- to 11-membered N-heterospiroalkane ring are selected from at least one of C1-C6 alkyl, halogen, hydroxyl, nitrile, and the like.

2. The compound according to claim 1, wherein, R 1 Selected from H, halogen, 3- to 6-membered cycloalkyl, C1-C6 alkyl, N-C1-C6 alkylamino.

3. The compound according to claim 2, wherein, R 1 Selected from H, halogen, C3-C6 cycloalkyl, C1-C4 alkyl, N-C1-C4 alkylamino.

4. The compound according to claim 3, wherein, R 1 Selected from H, Cl, Br, cyclopropyl, ethyl, methyl, N-ethylamino.

5. The compound according to claim 1, wherein, R 2 selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-9 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6. The compound according to claim 5, wherein, R 2 selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-7 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 7. The compound according to claim 6, wherein, R 2 selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 ester group, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 10 membered bridged cycloalkyl, substituted or unsubstituted 5-7 membered spirocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5, 6 or 9 membered heteroaryl, 8. The compound according to claim 1, wherein, R 2 wherein the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, or substituted or unsubstituted spirocycloalkyl contains 0 to 2 heteroatoms, and the heteroatoms are N, O, or S; R 2 wherein the substituted or unsubstituted heteroaryl contains 1 to 3 heteroatoms, and the heteroatoms are N.

9. The compound according to claim 1, wherein, R 2 Among them, the substituents of the substituted alkyl group and the substituted ester group are selected from at least one of halogen, hydroxyl, nitrile, amino, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, and S, 6- to 10-membered aryl, R 4 is selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl; n2 and n3 are independently selected from integers of 1 to 2; R 2 Among them, the substituents of the substituted cycloalkyl group, the substituted bridged cycloalkyl group, and the substituted spirocycloalkyl group are selected from at least one of halogen, hydroxyl, nitrile, amino, C1-C6 alkoxycarbonyl, C1-C6 ester group, substituted or unsubstituted C1-C6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, and S, C1-C6 alkoxy, -SO 2 -R 5 Among them, the substituents of the substituted C1-C6 alkyl group in the substituents are selected from halogen, hydroxyl, amino, 3- to 6-membered cycloalkyl, R 5 is selected from C1-C4 alkyl, 3- to 6-membered cycloalkyl; R 2 Among them, the substituents of the substituted aryl group and the substituted heteroaryl group are selected from at least one of halogen, hydroxyl, nitrile, C1-C6 alkoxycarbonyl, C1-C6 ester group, 3- to 6-membered cycloalkyl, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy. Among them, the substituents of the substituted C1-C6 alkyl group in the substituents are selected from halogen, hydroxyl, amino.

10. The compound according to claim 9, wherein, R 2 Among them, the substituents of the substituted alkyl group and the substituted ester group are selected from at least one of halogen, hydroxyl, nitrile, amino, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, and S, 6- to 10-membered aryl, R 4 is selected from unsubstituted or hydroxyl-substituted C1-C4 alkyl, n2 and n3 are independently selected from 1; R 2 Among them, the substituents of the substituted cycloalkyl group, the substituted bridged cycloalkyl group, and the substituted spirocycloalkyl group are selected from at least one of halogen, hydroxyl, nitrile, amino, C1-C4 alkoxycarbonyl, C1-C4 ester group, substituted or unsubstituted C1-C4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from at least one of N, O, and S, C1-C4 alkoxy, -SO 2 -R 5 Among them, the substituents of the substituted C1-C4 alkyl group in the substituents are selected from halogen, hydroxyl, amino, 3- to 6-membered cycloalkyl, R 5 is selected from C1-C4 alkyl, 3- to 6-membered cycloalkyl; R 2 Among them, the substituents of the substituted aryl group and the substituted heteroaryl group are selected from at least one of halogen, hydroxyl, nitrile, C1-C4 alkoxycarbonyl, C1-C4 ester group, 3- to 6-membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy, and among them, the substituents of the substituted C1-C4 alkyl group in the substituents are selected from halogen, hydroxyl, amino.

11. The compound according to claim 10, wherein, R 2 Among them, the substituents of the substituted alkyl group and the substituted ester group are selected from the group consisting of hydroxyl group, amino group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl group containing 1 heteroatom selected from N, O, and S, phenyl, and at least one of them; R 2 Among them, the substituents of the substituted cycloalkyl group, the substituted bridged cycloalkyl group, and the substituted spirocycloalkyl group are selected from the group consisting of halogen, hydroxyl group, nitrile group, amino group, tert-butoxycarbonyl group, C1-C4 ester group, substituted or unsubstituted C1-C4 alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl group containing 1 heteroatom selected from N, O, and S, C1-C4 alkoxy group, -SO 2 -R 5 and at least one of them, wherein the substituent of the substituted C1-C4 alkyl group in the substituents is selected from the group consisting of halogen, hydroxyl group, and cyclopropyl, and R 5 is selected from methyl group and cyclopropyl group; R 2 Among them, the substituents of the substituted aryl group and the substituted heteroaryl group are selected from the group consisting of halogen, hydroxyl group, nitrile group, 3- to 6-membered cycloalkyl group, substituted or unsubstituted C1-C4 alkyl group, and C1-C4 alkoxy group, and at least one of them, wherein the substituent of the substituted C1-C4 alkyl group in the substituents is selected from the group consisting of halogen.

12. The compound according to claim 11, wherein, R 2 Among them, the substituents of the substituted alkyl group and the substituted ester group are selected from at least one of hydroxyl group, amino group, cyclopropyl group, phenyl group; R 2 Among them, the substituents of the substituted cycloalkyl group, the substituted bridged cycloalkyl group, and the substituted spirocycloalkyl group are selected from F, hydroxyl group, cyano group, amino group, -Boc, methoxycarbonyl group, methyl group, trifluoromethyl group, hydroxymethyl group, cyclopropyl group, cyclobutyl group, methoxy group, among at least one of; R 2 Among them, the substituents of the substituted aryl group and the substituted heteroaryl group are selected from at least one of F, Cl, hydroxyl group, cyano group, methyl group, ethyl group, propyl group, trifluoromethyl group, and methoxy group.

13. The compound according to claim 1, wherein, 14. The compound according to claim 1, wherein, The N-heterocycle is selected from a substituted or unsubstituted 3- to 6-membered N-heterocycloalkane ring, a substituted or unsubstituted 4- to 8-membered N-heterobicycloalkane ring, and a substituted or unsubstituted 5- to 9-membered N-heterospiroalkane ring, which, in addition to N, contains 0 to 1 O heteroatom; in the N-heterocycle, the substituents of the substituted 3- to 6-membered N-heterocycloalkane ring, the substituted 4- to 8-membered N-heterobicycloalkane ring, and the substituted 5- to 9-membered N-heterospiroalkane ring are selected from C1-C4 alkyl, halogen, hydroxyl, nitrile, at least one of which.

15. The compound according to claim 14, wherein, The N-heterocycle is selected from a substituted or unsubstituted 4- to 6-membered N-heterocycloalkane ring, an unsubstituted 4- to 8-membered N-heterobicycloalkane ring, and an unsubstituted 5- to 7-membered spiroalkane ring, which contains 0 to 1 O heteroatom in addition to N; in the N-heterocycle, the substituents of the substituted 4- to 6-membered N-heterocycloalkane ring are selected from methyl, hydroxyl, at least one of 16. The compound according to claim 15, wherein, The N-heterocycle is selected from 17. The compound according to claim 1, wherein, R 3 selected from H, C1-C6 alkyl groups.

18. The compound according to claim 17, wherein, R 3 selected from H, C1-C4 alkyl groups.

19. The compound according to claim 18, wherein, R 3 Selected from H, methyl.

20. The compound according to any one of claims 1 to 19, wherein, the structural formula is as follows:

21. A pharmaceutical composition, which consists of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable auxiliary ingredient.

22. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 21 in the preparation of an NLRP3 inhibitor.

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