Condensed pyridazine derivative and application thereof

Abstract

The invention relates to a fused pyridazine derivative and application thereof, in particular to a compound shown in a formula (I) or a medicinal salt thereof, each substituent group is defined in the specification, and the compound or the medicinal salt thereof has NLRP3 inflammasome inhibition activity and can be used for treating or preventing diseases related to NLRP3 activity. # imgabs0 #

Description

Condensed pyridazine derivatives and uses thereof Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to fused pyridazine derivatives and their use in preparing drugs for treating diseases associated with NLRP3 activity. Background Art

[0002] NOD-like receptor protein 3 (NLRP3) is a gene encoding a protein that belongs to the nucleotide-binding and oligomerization domain-like receptor (NLR) family and is also known as "pyrin domain-containing protein 3" (Inoue et al., Immunology, 2013, 139, 11-18). This gene encodes a protein containing a pyrimidine domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with the adaptor protein, apoptosis-associated speck-like protein (ASC), and zymogen-1 to form the NLRP3 inflammasome. Subsequently, activation of the NLRP3 inflammasome leads to the release of the inflammatory cytokines IL-1b and IL-18. Dysregulated NLRP3 inflammasome activation drives the pathogenesis of many diseases.

[0003] Studies have shown that activation of the NLRP3 inflammasome is associated with a variety of diseases, including inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Therefore, new NLRP3 inflammasome pathway inhibitors are needed to provide new treatment options for these diseases.

[0004] Published patent applications for NLRP3 inhibitors include WO2020234715A, WO2022135567A, WO2022216971A, WO2022166890A, WO2021193897A, WO2023028534A, etc.

[0005] Summary of the Invention

[0006] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0007] wherein X1 is selected from -O-, -S-, -CH2-, -CH2-O- or -O-CH2-;

[0008] Ring A is selected from 4- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or phenyl;

[0009] R 1 Selected from hydrogen, C 1-6 Alkyl, 3 to 6 membered cycloalkyl, wherein the C 1-6 Alkyl, 3 to 6 membered cycloalkyl are optionally substituted with one or more halogens;

[0010] for wherein X2, X3, X4 and X5 are each independently selected from -O-, -S-, -CH2-, -NH-,

[0011] R 2 Identical or different, each independently selected from deuterium, halogen or C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0012] R 3 and R 4 are each independently selected from hydrogen, deuterium or halogen;

[0013] R 5 The same or different, each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0014] R 6 The same or different, each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, oxo, deuterium, halogen, hydroxyl, amino, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted with one or more R A Substitution; said R A The same or different, each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, 3- to 7-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, -C(O)R', -C(O)OR', or -C(O)NR'R", said 3- to 7-membered cycloalkyl or 3- to 12-membered heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2, or -CN;

[0015] Or connect to R of X4 and X5 6 Together with the connecting atom, it forms a 3- to 7-membered cycloalkyl group or a 3- to 7-membered heterocycloalkyl group, wherein the 3- to 7-membered cycloalkyl group or the 3- to 7-membered heterocycloalkyl group is optionally substituted with one or more R B Substituted, the R B Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0016] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0017] q is selected from 0, 1, 2 or 3;

[0018] o is selected from 0, 1 or 2;

[0019] m is selected from 0, 1, 2 or 3; and

[0020] n is selected from 0, 1, 2 or 3.

[0021] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is selected from -CH2-O- or -O-CH2-.

[0022] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is -CH2-O-.

[0023] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof,

[0024] Among them, R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, Ring B, m, n and o are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof,

[0026] Among them, R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, Ring B, m, n and o are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0027] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from cyclopentyl or cyclohexyl.

[0028] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a cyclopentyl group.

[0029] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5-membered or 6-membered heterocycloalkyl group, and the 5-membered or 6-membered heterocycloalkyl group contains one or two heteroatoms, and the heteroatoms are selected from O, S or N atoms.

[0030] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heterocycloalkyl group, and the 5-membered heterocycloalkyl group contains one heteroatom, and the heteroatom is an O atom.

[0031] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heterocycloalkyl group containing one heteroatom, which is an S atom.

[0032] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heterocycloalkyl group containing one heteroatom, which is an N atom.

[0033] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5-membered or 6-membered heteroaryl group, and the 5-membered or 6-membered heteroaryl group contains one or two heteroatoms, and the heteroatoms are selected from O, S or N.

[0034] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group containing one or two heteroatoms selected from O, S or N.

[0035] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains one heteroatom, and the heteroatom is an S atom.

[0036] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains at least one heteroatom, and the heteroatom is a N atom.

[0037] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains two heteroatoms, and the heteroatoms are N atoms.

[0038] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group, and the 5-membered heteroaryl group contains two heteroatoms, which are N and O atoms.

[0039] In an optional embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

[0040] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0041] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0042] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-2) or a pharmaceutically acceptable salt thereof,

[0043] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0044] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-3) or a pharmaceutically acceptable salt thereof,

[0045] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0046] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof,

[0047] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III-2) or a pharmaceutically acceptable salt thereof,

[0049] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0050] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III-3) or a pharmaceutically acceptable salt thereof,

[0051] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0052] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III-4) or a pharmaceutically acceptable salt thereof,

[0053] Among them, R 1 、R 2 、R3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0054] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (III-5) or a pharmaceutically acceptable salt thereof,

[0055] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-6) or a pharmaceutically acceptable salt thereof,

[0057] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , Ring B, m, o and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for wherein X2, X3, X4 and X5 are all -CH2-, and q is selected from 0, 1, 2 or 3.

[0059] In an optional embodiment, the R 6 is a hydroxyl group, and n is 1.

[0060] In an optional embodiment, the Selected from

[0061] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for wherein X2, X3, X4 and X5 are each independently selected from -CH2- and -O-, and one of X2, X3, X4 and X5 is -O-, and q is selected from 0, 1, 2 or 3.

[0062] In an optional embodiment, the R 6 Selected from hydroxyl or C 1-6 Alkyl, n is 0 or 1

[0063] In an optional embodiment, the Selected from

[0064] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for wherein X2, X3, X4 and X5 are each independently selected from -CH2- and -NH-, and one or two of X2, X3, X4 and X5 are -NH-, and q is selected from 0, 1 or 2.

[0065] In an optional embodiment, the R 6 Selected from halogen, C 1-6 Alkyl, the R 6 By one or more R A Substituted, the R A are the same or different, each independently selected from halogen or hydroxy, in particular, the halogen is fluorine or chlorine.

[0066] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) or pharmaceutically acceptable salts thereof, wherein: for wherein X2, X3, X4 and X5 are each independently selected from -CH2- and -NH-, and one of X2, X3, X4 and X5 is -NH-, and q is selected from 0, 1 or 2.

[0067] In an optional embodiment, the R 6 Selected from halogen, C 1-6 Alkyl, the R 6 By one or more R A Substituted, the R A are the same or different, each independently selected from halogen or hydroxy, in particular, the halogen is fluorine or chlorine.

[0068] In some embodiments, the compounds of formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6) or pharmaceutically acceptable salts thereof are disclosed, wherein: for X2, X3, X4 and X5 are each independently selected from -CH2- and -NH-, wherein X2 and X5 are both -CH2-, X3 or X4 is -NH-, and q is 2.

[0069] In an optional embodiment, the R 6 Selected from halogen, C 1-6 Alkyl, -S(O)2-C 1-3 Alkyl, the R 6 Optionally one or more R A Substituted, the R A are the same or different, each independently selected from halogen or hydroxy, in particular, the halogen is fluorine or chlorine.

[0070] In an optional embodiment, the R 6 Selected from halogen, C 1-6 Alkyl, -S(O)2-C 1-3 Alkyl, the R 6 By one or more R A Substituted, the R A are the same or different, each independently selected from halogen or hydroxy, in particular, the halogen is fluorine or chlorine.

[0071] In an optional embodiment, the Selected from

[0072] In some embodiments, the compounds of formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6) or pharmaceutically acceptable salts thereof are disclosed, wherein: for Wherein X2, X3 and X5 are -CH2-, X4 is -NH-, q is 2, and R connected to X4 and X5 6 Together with the connecting atoms, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the 5- to 6-membered nitrogen-containing heterocyclic ring is optionally substituted by one or more independently R B Substituted, the R B Selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0073] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for wherein X2, X3, X4 and X5 are each independently selected from -CH2- or And one of X2, X3, X4 and X5 is q is selected from 0, 1, 2 or 3.

[0074] In an optional embodiment, the Selected from

[0075] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for wherein X2, X3, X4 and X5 are each independently selected from -CH2- or And one of X2, X3, X4 and X5 is q is selected from 0, 1, 2 or 3.

[0076] In an optional embodiment, the Selected from

[0077] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 For hydrogen.

[0078] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 C 1-6 alkyl.

[0079] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 is a 3- to 6-membered cycloalkyl group.

[0080] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 is a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is substituted by one or more halogen groups.

[0081] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is substituted by 1, 2 or 3 halogens selected from F or Cl.

[0082] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 is methyl, said methyl being substituted by 1, 2 or 3 halogens selected from F or Cl.

[0083] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 1 It is difluoromethyl.

[0084] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0085] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0086] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0087] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0088] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0089] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0090] In an optional embodiment, the present disclosure provides a compound represented by formula ((I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or a pharmaceutically acceptable salt thereof, wherein, for

[0091] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0092] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0093] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0094] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0095] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0096] In an optional embodiment, the present disclosure provides a compound represented by formula ((I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or a pharmaceutically acceptable salt thereof, wherein, for

[0097] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0098] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0099] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein, for

[0100] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 5 Selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 alkyl.

[0101] In an optional embodiment, the R 5 is selected from halogen, such as fluorine, chlorine.

[0102] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein o is 0 or 1.

[0103] In an optional embodiment, o is 0.

[0104] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 3 is selected from hydrogen or halogen; and / or, R 4 is selected from hydrogen or halogen.

[0105] In an optional embodiment, the R 3 is hydrogen, the R 4 For hydrogen.

[0106] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein R 2 Selected from halogen or C 1-6 alkyl.

[0107] In an optional embodiment, the R 2 is selected from fluoro or methyl.

[0108] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6) or pharmaceutically acceptable salts thereof, wherein m is selected from 0 or 1.

[0109] In an optional embodiment, m is 0.

[0110] In an optional embodiment, the present disclosure provides compounds represented by formula (I), (I-1), (I-2), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (III-4), III-5), (III-6), or pharmaceutically acceptable salts thereof, wherein R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy, amino, -S(O)2-C 1-6 alkyl, 3 to 7-membered cycloalkyl or 3 to 12-membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl are optionally substituted with one or more R A Substitution; said R A The same or different, each independently selected from halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3- to 7-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, -C(O)R', -C(O)OR', or -C(O)NR'R", said 3- to 7-membered cycloalkyl or 3- to 12-membered heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2, or -CN;

[0111] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0112] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, oxo, deuterium, halogen, hydroxyl, amino, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted with one or more R A Substituted, the R A The same or different, each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0113] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy or -S(O)2-C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or -S(O)2-C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identically or differently, each is independently selected from oxo, deuterium, halogen or -OH.

[0114] In an optional embodiment, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, wherein R 6 It is a hydroxyl group.

[0115] In an optional embodiment, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy or -S(O)2-C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy or -S(O)2-C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identically or differently, each is independently selected from oxo, deuterium, halogen or -OH.

[0116] In an optional embodiment, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more RA Substituted, the R A Identically or differently, each is independently selected from oxo, deuterium, halogen or -OH.

[0117] In an optional embodiment, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from halogen or -S(O)2-C 1-6 Alkyl, the -S(O)2-C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identically or differently, each is independently selected from oxo, deuterium, halogen or -OH.

[0118] In an optional embodiment, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl, wherein the 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted by one or more R A Substituted, the R A The same or different, each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0119] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identical or different, each independently selected from halogen, -OH, 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, -C(O)R', -C(O)OR' or -C(O)NR'R", said 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2, -CN;

[0120] Said R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0121] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0122] Among them, R1 selected from hydrogen or difluoromethyl;

[0123] R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0124] q is selected from 0 or 1;

[0125] m is selected from 0 or 1;

[0126] In particular, R 1 For hydrogen.

[0127] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (IV-2) or a pharmaceutically acceptable salt thereof,

[0128] Among them, R 1 selected from hydrogen or difluoromethyl;

[0129] R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0130] R 6 Selected from halogen or C 1-3 alkyl;

[0131] q is selected from 0 or 1;

[0132] n is selected from 0, 1 or 2;

[0133] In particular, R 1 For hydrogen.

[0134] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (IV-3) or a pharmaceutically acceptable salt thereof,

[0135] Among them, R 1 selected from hydrogen or difluoromethyl;

[0136] R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0137] m is selected from 0 or 1;

[0138] R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy, amino, -S(O)2-C 1-6alkyl, 3 to 7-membered cycloalkyl or 3 to 12-membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl are optionally substituted with one or more R A Substitution; said R A The same or different, each independently selected from halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3- to 7-membered cycloalkyl, 3- to 12-membered heterocycloalkyl, -C(O)R', -C(O)OR', or -C(O)NR'R", said 3- to 7-membered cycloalkyl or 3- to 12-membered heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2, or -CN;

[0139] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0140] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identical or different, each independently selected from halogen, -OH, 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, -C(O)R', -C(O)OR' or -C(O)NR'R", said 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2 or -CN;

[0141] Said R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0142] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R AThe same or different, each is independently selected from halogen, -OH or 3 to 7 membered cycloalkyl, said 3 to 7 membered cycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2 or -CN.

[0143] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A Identical or different, each independently selected from halogen, -OH or 3 to 12-membered heterocycloalkyl, the 3 to 12-membered (specifically 5, 6, 7, 8, 9, 1, 11, 12-membered, containing 1 or 2 nitrogen, oxygen, sulfur atoms) heterocycloalkyl is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, -NH2 or -CN.

[0144] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A The same or different, each independently selected from halogen, -OH or -C(O)R', wherein R' is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0145] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A The same or different, each independently selected from halogen, -OH or -C(O)OR', wherein R' is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0146] In an optional embodiment, the R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally replaced by one or more R A Substituted, the R A The same or different, each independently selected from halogen, -OH or -C(O)NR'R", wherein R' and R" are each independently selected from hydrogen, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0147] In an optional embodiment, the present disclosure provides the following compounds in Table a and pharmaceutically acceptable salts thereof:

[0148] Table a.

[0149] In another aspect, the present disclosure provides an isotopic substitution of the aforementioned compound or a pharmaceutically acceptable salt thereof; in some embodiments, the isotopic substitution is a deuterated substance.

[0150] In another aspect, the present disclosure provides a method for preparing a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0151] The compound represented by formula (I-1') is deprotected by removing the phenolic hydroxyl protecting group PG to obtain the compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof.

[0152] Wherein, PG is a hydroxyl protecting group, such as methoxymethyl ether;

[0153] R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, Ring B, m, n and o are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0154] In an optional embodiment, the PG is methyl, the demethylation reaction occurs under the action of BBr3, the reaction solvent is dichloromethane, and the reaction temperature is -50°C to -90°C.

[0155] In another aspect, the present disclosure provides a method for preparing a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0156] Formula (I-2') and the compound represented by formula (I-2') undergo Suzuki reaction under alkaline conditions in the presence of a catalyst and an organic phosphine ligand to obtain the compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof.

[0157] Wherein, R is selected from C 1-6 Alkyl, hydroxyl or C 1-6 alkoxy;

[0158] LG is a leaving group selected from Cl, Br, I or OTf;

[0159] The catalyst is a palladium catalyst;

[0160] R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, Ring B, m, n and o are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0161] In an optional embodiment, the LG is Cl.

[0162] In an optional embodiment, the catalyst and the organic phosphine ligand are tetrakistriphenylphosphine palladium, and the alkaline conditions are provided by a solvent selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, sodium bicarbonate, and the like.

[0163] Another aspect of the present disclosure provides a compound represented by formula (I-1') or a pharmaceutically acceptable salt thereof,

[0164] Among them, R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, Ring B, m, n and o are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0165] PG is a phenolic hydroxyl protecting group, such as methoxymethyl ether.

[0166] In another aspect, the present disclosure provides a pharmaceutical composition comprising the aforementioned compound mentioned in the present disclosure or a pharmaceutically acceptable salt or an isotope thereof, and a pharmaceutically acceptable excipient.

[0167] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0168] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt or an isotope thereof based on the total weight of the composition.

[0169] In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute.

[0170] In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitute.

[0171] In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0172] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition; in some embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient; in some embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient; in some embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient; in some embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0173] In some embodiments, the pharmaceutically acceptable excipient can be, for example, a carrier, a vehicle, a diluent, and / or a delivery polymer.

[0174] In another aspect, the present disclosure provides use of the compound or a pharmaceutically acceptable salt thereof, or an isotope thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating diseases associated with NLRP3 activity.

[0175] On the other hand, the present disclosure further provides a compound of the aforementioned formula or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, or the aforementioned pharmaceutical composition, for use in preventing or treating diseases associated with NLRP3 activity.

[0176] In another aspect, the present disclosure further provides a method for preventing and / or treating a patient suffering from a disease associated with NLRP3 activity, by administering to the patient a compound of the aforementioned formula or a pharmaceutically acceptable salt thereof, or an isotopic substitution thereof, or the aforementioned pharmaceutical composition.

[0177] On the other hand, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, or the pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases.

[0178] On the other hand, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope thereof, or the pharmaceutical composition described herein, for use in preventing and / or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases.

[0179] On the other hand, the present disclosure also provides a method for treating patients with inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and autoinflammatory diseases, by administering the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotopic substitution thereof, or the aforementioned pharmaceutical composition to the patient.

[0180] In another aspect, the present disclosure provides a use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope substituted product thereof, or the pharmaceutical composition in the preparation of an NLRP3 inhibitor.

[0181] In another aspect, the present disclosure provides the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope thereof, or the pharmaceutical composition, for use as an NLRP3 inhibitor.

[0182] In another aspect, the present disclosure further provides a method for inhibiting NLRP3, comprising administering the aforementioned compound or a pharmaceutically acceptable salt thereof, or an isotope thereof, or the aforementioned pharmaceutical composition to the patient.

[0183] In some embodiments, the diseases associated with NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases.

[0184] In some embodiments, the inflammasome-associated disease, immune disease, inflammatory disease, autoimmune disease and autoinflammatory disease can be specifically selected from: autoinflammatory febrile syndrome, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis), inflammatory arthritis-related diseases (such as gout, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, type I or type II diabetes and its complications (such as nephropathy, retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic-related disorders or diseases (such as atherosclerosis, type I and type II diabetes and related complications, acute heart failure and hypertension), wound healing, scar formation, asthma, and cancer-related diseases / conditions (such as leukemia, myelodysplastic syndrome (MDS)).

[0185] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts. The compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.

[0186] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0187] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0188] In the chemical structural formula disclosed herein, One or more of any group may be attached in accordance with the scope of the invention described herein; an asterisk "*" indicates a chiral center.

[0189] In the case of not indicating configuration, compounds of the present disclosure and intermediates can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0190] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0191] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0192] Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have deuterium at an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compounds in the examples may have a natural abundance greater than deuterium of at least 1000 times, a deuterium of at least 2000 times, a deuterium of at least 3000 times, a deuterium of at least 4000 times, a deuterium of at least 5000 times, a deuterium of at least 6000 times, or a higher abundance of deuterium. The present disclosure also includes various deuterated forms of compounds of formula I, II, and III. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula I, II, and III with reference to the relevant literature. Commercially available deuterated starting materials may be used to prepare deuterated forms of the compounds of Formula I, II, and III, or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0193] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0194] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond No configuration is specified, i.e. the bond The configuration can be E-type or Z-type, or include both E and Z configurations.

[0195] The terms "about" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprise" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each case in which a number or numerical range is preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprise" should be assumed to be within an acceptable error range for that specific value.

[0196] Explanation of terms

[0197] In order to make the present disclosure more easily understood, some technical and scientific terms are specifically defined below. Unless otherwise clearly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0198] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0199] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0200] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0201] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, paracyclic, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0202] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include:

[0203] wait.

[0204] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0205] wait.

[0206] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0207] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0208] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0209] The term "hydroxy" refers to an -OH group.

[0210] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0211] The term "cyano" refers to -CN.

[0212] The term "amino" refers to -NH2.

[0213] The term "nitro" refers to -NO2.

[0214] The term "oxo" refers to a =0 substituent.

[0215] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced. DETAILED DESCRIPTION

[0216] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0217] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0218] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of measurement is ppm. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The spatial configuration of the optical isomers (isomers) of the compounds can be further confirmed by measuring single crystal parameters.

[0219] HPLC determinations were performed using a Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1×50MM column, Ultimate XB-C18 3.0×150mm column, or Xtimate C18 2.1×30mm column).

[0220] MS was determined using a Waters SQD2 mass spectrometer in positive / negative ion mode with a mass scan range of 100-1200.

[0221] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, and Chiralcel OJ-3 150×4.6mm ID, 3um columns.

[0222] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0223] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0224] Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0225] Reversed phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45μm, 40g, 80g, 120g, 220g or other specifications).

[0226] The high-pressure column purification system uses Waters AutoP, in conjunction with Waters XBridge BEH C18 OBD Prep Column. 5μm, 19mm×150mm or Atlantis T3 OBD Prep Column, 5μm, 19mm×150mm.

[0227] Chiral preparative columns used were DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm×30 mm, 5 μm).

[0228] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

[0229] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0230] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0231] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0232] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0233] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0234] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0235] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0236] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0237] The preparation method of the disclosed compounds can be better understood with reference to the following synthetic routes, which illustrate methods for preparing the disclosed compounds. The starting materials can be obtained from commercial sources or can be prepared by those of ordinary skill in the art by known literature methods. It will be apparent to those of ordinary skill in the art that the compounds defined above can be synthesized by replacing appropriate reactants and reagents in the synthetic routes shown below. It will also be apparent to those skilled in the art that the selective protection and deprotection steps and the order of the steps themselves can be carried out in different orders, varying according to the nature of the variables to successfully complete the following synthesis. The variables are as defined above, unless otherwise noted below.

[0238] Example 1

[0239] 5-(1-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)-2,3-dihydro-1H-inden-4-ol (1-1)

[0240] 5-(4-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol(1-2)

[0241] 1. Synthesis of compounds 1e and 1f

[0242] Step 1: Compound 1a (1.0 g, 10 mmol) and potassium carbonate (0.14 g, 1 mmol) were mixed in tetrahydropyrrole (0.71 g, 10 mmol). The mixture was stirred at 0°C for sufficient reaction. After the reaction was complete, it was filtered and the filtrate was concentrated in vacuo to obtain crude compound 1b (1.35 g), which was used in the next step without further purification.

[0243] ES-MS m / z=154.1[M+H] + .

[0244] Step 2:

[0245] Compound 1b (305 mg, 2 mmol) and 3,6-dichlorotetrazine (0.2 g, 1.32 mmol) were mixed in dichloromethane (5 mL). The mixture was stirred at 0°C for thorough reaction and diluted with water (5 mL). The mixture was extracted with dichloromethane (5 mL x 3). The layers were separated, and the combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography (eluent: 0-20% ethyl acetate in petroleum ether) to obtain compound 1c (24 mg, 18.3% yield).

[0246] MS m / z(ESI):205.0[M+H] + .

[0247] 1 H NMR (400MHz, CDCl3): δppm 4.70 (s, 2H), 4.05 (t, J = 5.5Hz, 2H), 2.53 (t, J = 6.0Hz, 2H).

[0248] Step 3:

[0249] Compound 1c (30 mg, 0.15 mmol), compound 2d (20 mg, 0.18 mmol), cesium carbonate (205 mg, 0.63 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (23 mg, 0.038 mmol) were mixed in dioxane (5 mL). Palladium acetate (8.3 mg, 0.038 mmol) was added under nitrogen, and the mixture was stirred at 100°C for a thorough reaction. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to yield the crude product, which was purified by flash column chromatography (eluent: 5-20% methanol in dichloromethane) to afford compounds 1e and 1f (10 mg, 24.2% yield).

[0250] MS m / z(ESI):283.2[M+H] + .

[0251] 2. Synthesis of Compound 1i

[0252] Step 1:

[0253] Compound 1g (0.9g, 4.2mmol) was dissolved in DMF (20mL). K2CO3 (1.5g, 10.56mmol) and iodomethane (0.3mL, 5mmol) were slowly added at room temperature. The reaction mixture was stirred overnight until the reaction was complete. Ethyl acetate (10mL) was added for dilution and the mixture was filtered. The filtrate was washed with water (20mL x 3) and brine (20mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography to afford compound 1h (0.9g, 93.82% yield).

[0254] Step 2:

[0255] Under a nitrogen atmosphere, compound 1h (800 mg, 3.523 mmol) was dissolved in dioxane (3 mL). B2Pin2 (1.2 g, 5.3 mmol), KOAc (864.29 mg, 8.8 mmol), and Pd(dppf)Cl2 (261.31 mg, 0.352 mmol) were slowly added at room temperature. The reaction temperature was raised to 100°C. After completion of the reaction, the mixture was filtered, and the filtrate was diluted with ethyl acetate (10 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography to afford compound 1i (380 mg, 39.35% yield).

[0256] 3. Synthesis of Compounds 1-1 and 1-2

[0257] Step 1:

[0258] Under nitrogen atmosphere, compounds 1e and 1f (300 mg, 1.061 mmol) were dissolved in 1,4-dioxane.

[0259] To the mixture of 4-[ ...

[0260] MS m / z(ESI):395.3[M+H] + .

[0261] Step 2:

[0262] Under a nitrogen atmosphere, compounds 1j and 1k (300 mg, 0.760 mmol) were dissolved in dichloromethane (10 mL). BBr3 (0.359 mL, 3.802 mmol) was slowly added at -78°C, and the reaction was slowly warmed to room temperature. After the reaction was completed, water and dichloromethane were slowly added at -5°C to dilute the mixture, followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and filtering. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography to obtain a mixture of compounds 1-1 and 1-2. Subsequently, SFC separation was performed to obtain compound 1-1 (30.7 mg, yield 10.61%) and compound 1-2 (2.5 mg, yield 0.86%).

[0263] Compound 1-1

[0264] MS m / z(ESI):381.3[M+H] + .

[0265] 1 H NMR (400MHz, DMSO): δ9.79(s,1H),6.92(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),5 .77(d,J=7.9Hz,1H),4.40(s,2H),4.31–4.20(m,1H),3.93(t,J=5.7Hz,2H),2.94– 2.81(m,5H),2.65–2.57(m,1H),2.47(t,J=5.6Hz,2H),2.19(s,3H),2.07–1.99(m ,2H),1.99–1.82(m,3H),1.74–1.66(m,1H),1.61–1.50(m,1H),1.47–1.36(m,1H).

[0266] SFC analysis of compound 1-1: Column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm; Mobile phase: A: CO 2 ; B: isopropanol (0.05% DEA); Gradient: 40% B over 2.4 min; Flow rate: 3 mL / min; Temperature: 35° C. Retention time: 0.675 min.

[0267] Compound 1-2

[0268] MS m / z(ESI):381.3[M+H] + .

[0269] 1H NMR (400MHz, DMSO): δ9.62(s,1H),7.01(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),5.60 (d,J=7.8Hz,1H),4.48(s,2H),4.29–4.19(m,1H),3.75(t,J=5.4Hz,2H),3.02–2.92( m,1H),2.91–2.79(m,4H),2.69–2.62(m,1H),2.49(t,2H),2.19(s,3H),2.03(p,J=7. 4Hz,2H),1.96–1.78(m,3H),1.74–1.67(m,1H),1.61–1.49(m,1H),1.40–1.29(m,1H).

[0270] SFC analysis of compound 1-2: Column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: isopropanol (0.05% DEA), gradient: 40% B over 2.4 min; Flow rate: 3 mL / min; Temperature: 35°C. Retention time: 1.250 min.

[0271] Example 2

[0272] 5-(4-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)-2,3-dihydro-1-benzofuran-4-ol (2-1)

[0273] 5-(1-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)-2,3-dihydro-1-benzofuran-4-ol(2-2)

[0274] 1. Synthesis of compound 2c

[0275] Step 1:

[0276] Compound 2c (330 mg, yield 27.37%) was synthesized using compound 2a (1 g, 4.365 mmol) as the starting material according to the method described in Example 1.

[0277] 2. Synthesis of Compounds 2-1 and 2-2

[0278] Compounds 2-1 and 2-2 were synthesized using compounds 1e and 1f (320.28 mg, 1.167 mmol) as starting materials according to the method described in Example 1. Compound 2-1 (3.2 mg, yield 2.55%) and compound 2-2 (4.3 mg, yield 3.43%) were obtained by SFC separation.

[0279] Compound 2-1

[0280] MS m / z(ESI):383.1[M+H] + .

[0281] 1 H NMR (400MHz, DMSO): δ10.15(s,1H),6.99(d,J=8.2Hz,1H),6.34(d,J=8.1Hz,1H),5. 72(d,1H),4.56(t,J=8.7Hz,2H),4.49(s,2H),4.38–4.25(m,1H),3.76(t,J=5.4Hz, 2H),3.14(t,J=8.7Hz,2H),2.99–2.71(m,2H),2.52(t,2H),2.35(s,3H),2.24–1.97 (m,2H),1.93–1.87(m,1H),1.81–1.72(m,1H),1.66–1.57(m,1H),1.51–1.40(m,1H).

[0282] SFC analysis of compound 2-1: Column: ChiralPak IA, 100×4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: MeOH (0.05% DEA), gradient: 8 min, maintain 50% B; Flow rate: 1.808 mL / min; Temperature: 35°C. Retention time: 1.808 min.

[0283] Compound 2-2

[0284] MS m / z(ESI):383.1[M+H] + .

[0285] 1H NMR (400MHz, DMSO): δ10.20(s,1H),6.89(d,J=8.2Hz,1H),6.34(d,J=8.2Hz,1H),5.75 (d,J=7.9Hz,1H),4.56(t,J=8.7Hz,2H),4.41(s,2H),4.29–4.19(m,1H),3.93(t,J=5. 6Hz,2H),3.14(t,J=8.6Hz,2H),2.96–2.88(m,1H),2.64–2.57(m,1H),2.47(t,2H),2. 19(s,3H),1.99–1.82(m,3H),1.73–1.66(m,1H),1.60–1.50(m,1H),1.46–1.36(m,1H).

[0286] SFC analysis of compound 2-2: Column: ChiralPak IA, 100×4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: MeOH (0.05% DEA), Gradient: 50% B over 8 min; Flow rate: 1.808 mL / min; Temperature: 35°C. Retention time: 4.540 min.

[0287] Example 3

[0288] 1-{[(3R)-1-(2-hydroxyethyl)hexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)-2,3-dihydro-1-benzofuran-4-ol (3-1)

[0289] 5-(4-{[(3R)-1-(2-hydroxyethyl)hexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)-2,3-dihydro-1-benzofuran-4-ol(3-2)

[0290] Compound 3-1 and compound 3-2 were synthesized using compound 2a as the starting material according to the method described in Example 2. Compound 3-1 and compound 3-2 were separated by SFC.

[0291] Compound 3-1

[0292] MS m / z(ESI):413.2[M+H] + .

[0293] 11H NMR (400 MHz, DMSO): δ 10.33 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 4.41 (s, 2H), 4.36 (d, J = 18.6 Hz, 1H), 4.29–4.17 (m, 1H), 3.93 (t, J = 5.7 Hz, 2H), 3.50 (t, J = 6.1 Hz, 2H), 3.13 (t, J = 8.7 Hz, 2H), 2.99 (d, J = 7.9 Hz, 1H), 2.72 (d, J = 11.2 Hz, 1H), 2.47 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.06 (t, J = 9.5 Hz, 2H), 1.86 (d, J = 8.3 Hz, 1H), 1.69 (dd, J = 8.6, 4.2 Hz, 1H), 1.60–1.38 (m, 2H).

[0294] Compound 3-2

[0295] MS m / z (ESI): 413.2 [M+H] + .

[0296] 1 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.57 (d, J = 7.9 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 4.47 (s, 2H), 4.38 (s, 1H), 4.29–4.16 (m, 1H), 3.75 (t, J = 5.4 Hz, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.13 (t, J = 8.7 Hz, 2H), 3.02 (d, J = 7.7 Hz, 1H), 2.75 (d, J = 10.9 Hz, 1H), 2.56–2.51 (m, 2H), 2.41 (t, J = 6.3 Hz, 2H), 2.00 (dd, J = 21.5, 11.0 Hz, 2H), 1.91–1.81 (m, 1H), 1.74–1.64 (m, 1H), 1.60–1.47 (m, 1H), 1.38 (qd, J = 11.9, 4.0 Hz, 1H).

[0297] Example 4

[0298] 5-(1-{[(3R)-1-(2-hydroxyethyl)hexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)benzo[b]thiophen-4-ol (4-1)

[0299] 5-(4-{[(3R)-1-(2-hydroxyethyl)hexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)benzo[b]thiophen-4-ol(4-2)

[0300] Compound 4-1 and compound 4-2 were synthesized using 5-bromobenzothiophene-4-ol as the starting material according to the synthesis method of Example 2. Compound 4-1 and compound 4-2 were separated by SFC.

[0301] MS m / z(ESI):427.2[M+H] + .

[0302] Example 5

[0303] 5-(1-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)-2,3-dihydro-1-benzofuran-4-ol (Compound 5-1)

[0304] 5-(4-{[(1R,2R)-2-hydroxycyclohexyl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)-2,3-dihydro-1-benzofuran-4-ol (Compound 5-2)

[0305] Compound 5-1 and compound 5-2 were synthesized using compound 2a as the starting material according to the synthesis method of Example 2. Compound 5-1 and compound 5-2 were separated by SFC.

[0306] Compound 5-1

[0307] MS m / z(ESI):384.3[M+H] + .

[0308] 1H NMR (400MHz, DMSO): δ10.51 (s, 1H), 6.89 (d, J = 8.2Hz, 1H), 6.32 (d, J = 8.2Hz, 1H),5.78(d,J=7.2Hz,1H),4.85(s,1H),4.55(t,J=8.6Hz,2H),4.43(s,2H),3 .99–3.82(m,3H),3.57–3.46(m,1H),3.14(t,J=8.6Hz,2H),2.64–2.51(m,2H) ,2.16–2.04(m,1H),1.97–1.87(m,1H),1.74–1.59(m,2H),1.34–1.17(m,4H).

[0309] Compound 5-2

[0310] MS m / z(ESI):384.3[M+H] + .

[0311] 1 H NMR (400MHz, DMSO): δ10.18(s,1H),7.01(d,J=8.2Hz,1H),6.34(d,J=8.2Hz,1H ),5.56(d,J=7.2Hz,1H),4.74(s,1H),4.60–4.44(m,4H),3.98–3.88(m,1H),3. 76(t,J=5.4Hz,2H),3.51–3.43(m,1H),3.13(t,J=8.6Hz,2H),2.58–2.51(m,2H ),2.14–2.00(m,1H),2.00–1.87(m,1H),1.73–1.59(m,2H),1.34–1.15(m,4H).

[0312] Example 6

[0313] 4-{[4-(4-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl]amino}-1λ6-thiacyclohexane-1,1-dione (Compound 6-1)

[0314] 4-{[1-(4-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl]amino}-1λ6-thiacyclohexane-1,1-dione (Compound 6-2)

[0315] Compound 6-1 and compound 6-2 were synthesized using compound 2a as the starting material according to the synthesis method of Example 2. Compound 6-1 and compound 6-2 were separated by SFC.

[0316] MS m / z(ESI):418.2[M+H] + .

[0317] Example 7

[0318] 4-{[4-(4-Hydroxybenzo[b]thiophen-5-yl)-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl]amino}-1λ6-thiacyclohexane-1,1-dione (Compound 7-1)

[0319] 4-{[1-(4-hydroxybenzo[b]thiophen-5-yl)-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl]amino}-1λ6-thiacyclohexane-1,1-dione (Compound 7-2)

[0320] Compound 7-1 and compound 7-2 were synthesized using 5-bromobenzothiophene-4-ol as the starting material according to the synthesis method of Example 2. Compound 7-1 and compound 7-2 were separated by SFC.

[0321] Compound 7-1

[0322] MS m / z(ESI):432.1[M+H] + .

[0323] 1 H NMR (400MHz, DMSO): δ10.61 (s, 1H), 7.67 (q, J=5.6Hz, 2H), 7.52 (d, J= 8.2Hz,1H),7.16(d,J=8.3Hz,1H),6.15(d,J=7.7Hz,1H),4.61–4.36(m,3H),3.95(t,J=5.5Hz,2H),3.36(t,J= 11.3Hz, 2H), 3.16 (d, J = 12.1Hz, 2H), 2.68–2.43 (m, 2H), 2.30 (d, J = 11.0Hz, 2H), 2.17 (dd, J = 22.7, 10.8Hz, 2H).

[0324] Compound 7-2

[0325] ES-MS m / z=432.1[M+H] + .

[0326] 1 H NMR (400MHz, DMSO): δ10.44(s,1H),7.66(s,2H),7.52(d,J=8.3Hz,1H),7.24(d,J=8.3Hz,1H),5.93(d,J=7.6Hz,1H),4.63–4.48(m,3H),3.7 7(t,J=5.4Hz,2H),3.36(dd,J=19.0,6.2Hz,2H),3.15(d,J=15.6Hz,2H),2.58–2.50(m,2H),2.29(d,J=10.9Hz,2H),2.13(d,J=11.8Hz,2H).

[0327] Example 8

[0328] 5-(1-{[(3R,5R)-5-fluoro-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-4-yl)benzo[b]thiophen-4-ol (8-1)

[0329] 5-(4-{[(3R,5R)-5-fluoro-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazin-1-yl)benzo[b]thiophen-4-ol(8-2)

[0330] 1. Synthesis of Compounds 8e and 8f

[0331] Step 1:

[0332] Compound 1c (400 mg, 1.95 mmol), compound 8 (502 mg, 2.30 mmol), cesium carbonate (1589 mg, 4.88 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (182 mg, 0.29 mmol) were mixed in toluene (10 mL). Palladium acetate (44 mg, 0.20 mmol) was added under nitrogen, and the mixture was stirred at 100°C for thorough reaction. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford compounds 8a and 8b (180 mg, 23.9% yield).

[0333] MS m / z(ESI):387.3[M+H] + .

[0334] Step 2:

[0335] Compounds 8a and 8b (180 mg, 0.47 mmol) from Step 1 were dissolved in dichloromethane (10 mL). A 2M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added at room temperature and stirred until the reaction was complete. The reaction mixture was concentrated in vacuo to afford crude products 8c and 8d (120 mg, 89.9% yield).

[0336] MS m / z(ESI):287.2[M+H] + .

[0337] Step 3:

[0338] Compounds 8c and 8d (120 mg, 0.42 mmol) from step 2 were dissolved in methanol (10 mL). Formaldehyde solution (15%, 126 mg, 0.63 mmol) and sodium triacetoxyborohydride (221 mg, 1.05 mmol) were added at room temperature and stirred until the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compounds 8e and 8f (83 mg, yield 65.9%). MS m / z (ESI): 301.3 [M+H] + .

[0339] 2. Synthesis of Compounds 8-1 and 8-2

[0340] Step 1:

[0341] Using compounds 8e and 8f as starting materials, compounds 8h and 8i were obtained by a similar synthesis method as described in Example 2.

[0342] MS m / z(ESI):459.4[M+H] + .

[0343] Step 2:

[0344] To a solution of compounds 8h and 8i (80 mg, 0.17 mmol) in tetrahydrofuran (10 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) at room temperature and stirred until the reaction was complete. A 7 M solution of ammonia in methanol (1 mL) was added to the reaction solution, which was then concentrated in vacuo. The residue was resolved by SFC to afford compound 8-1 (10.7 mg, 14.8% yield) and compound 8-2 (15.6 mg, 21.57% yield).

[0345] Compound 8-1

[0346] MS m / z(ESI):415.4[M+H] + .

[0347] 1 H NMR (400MHz, DMSO) δ10.30(s,1H),7.67(d,J=5.6Hz,1H),7.64(d,J=5.6Hz,1H),7.50(d,J =8.2Hz,1H),7.16(d,J=8.2Hz,1H),5.89(d,J=8.2Hz,1H),5.05–4.87(m,1H),4.59(dd,J=1 7.2,11.4Hz,1H),4.42(s,2H),3.94(t,J=5.7Hz,2H),3.04–2.94(m,1H),2.94–2.82(m,1H) ,2.56–2.51(m,2H),2.23(s,3H),2.21–2.07(m,2H),2.00–1.94(m,1H),1.87–1.70(m,1H).

[0348] 19 F NMR(377MHz,DMSO)δ-180.71(s).

[0349] SFC analysis of compound 8-1: Column: ChiralCel OJ, 4.6×100 mm ID, 5 μm; Mobile phase: A: CO2; B: MeOH (0.05% DEA), Gradient: 80% B over 8 min; Flow rate: 2.500 mL / min; Temperature: 40°C. Retention time: 4.949 min.

[0350] Compound 8-2

[0351] MS m / z(ESI):415.4[M+H] + .

[0352] 1H NMR(400MHz,MeOD)δ7.59(d,J=5.6Hz,1H),7.51(d,J=1.8Hz,1H),7.50–7.47 (m,1H),7.23(d,J=8.2Hz,1H),5.17–5.01(m,1H),4.85–4.77(m,2H),4.59(s, 2H),3.86(t,J=5.5Hz,2H),3.55–3.46(m,1H),3.39–3.31(m,1H),2.90–2.73( m,1H),2.68–2.63(m,2H),2.62(s,3H),2.53–2.36(m,2H),2.02–1.82(m,1H).

[0353] 19 F NMR(377MHz,MeOD)δ-184.77(s).

[0354] SFC analysis of compound 8-2: Column: ChiralCel OJ, 4.6×100 mm ID, 5 μm; Mobile phase: A: CO2; B: MeOH (0.05% DEA), Gradient: 80% B over 8 min; Flow rate: 2.500 mL / min; Temperature: 40°C. Retention time: 6.281 min.

[0355] Example 9

[0356] 1-(2,3-Dihydro-1-benzofuran-5-yl)-4-{[(3R,5R)-5-fluoro-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]pyridazine (9)

[0357] 1. Synthesis of Compounds 9d-1 and 9d-2

[0358] Step 1:

[0359] To a solution of compound 9a (5.0 g, 22.91 mmol) in dichloroethane (120 mL) was added aqueous formaldehyde (30%, 3.34 mL, 34.36 mmol). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (12.14 g, 57.27 mmol) and acetic acid (0.2 mL) were then added under ice. The reaction mixture was stirred at room temperature overnight. The solvent was removed by concentration under reduced pressure. Water (30 mL) was added to the residual solution, and the pH was adjusted to ~9 with aqueous ammonia. The mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded compound 9b (5.1 g, 95% yield).

[0360] MS m / z(ESI):233.4[M+H] + .

[0361] Step 2:

[0362] Compound 9b (5.1 g, 21.95 mmol) from Step 1 was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (15 mL) was added at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the crude trifluoroacetate salt of 9c (5.9 g, 110% yield), which was used directly in the next reaction.

[0363] MS m / z(ESI):133.4[M+H] + .

[0364] Step 3:

[0365] Combine the crude trifluoroacetate of compound 9c (5.9 g, 21.94 mmol), compound 1c (4.5 g, 21.94 mmol), tris(dibenzylideneacetone)dipalladium (0.8 g, 0.88 mmol), cesium carbonate (25.02 g, 76.79 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.73 g, 4.39 mmol) in dry toluene (120 mL) and stir overnight at 110°C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filter residue was washed with ethyl acetate (20 mL x 3) and the filtrates were combined. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography. The purified product was then separated by SFC to give compounds 9d-1 and 9d-2 (column: ChiralPak AY, 250×20 mm ID, 5 μm, mobile phase: A: CO2; B: MeOH + 0.1% NH3H2O, gradient: B 40%; flow rate: 40 mL / min; temperature: 35°C).

[0366] Compound 9d-1 (290 mg, yield 4.4%).

[0367] 1 H NMR (400MHz, DMSO) δ6.09(d,J=7.9Hz,1H),4.94(d,J=47.2Hz,1H),4.50(s,2H),4.49-4.38(m,1H),3.91(t,J=5.5Hz,2H ),2.99-2.81(m,2H),2.44(t,J=5.4Hz,2H),2.20(s,3H),2.18-2.03(m,2H),1.92(t,J=10.0Hz,1H),1.83-1.61(m,1H).

[0368] 19F NMR (377MHz, DMSO) δ-180.83 (s).

[0369] MS m / z(ESI):301.3[M+H] + .

[0370] Compound 9d-2 (280 mg, yield 4.2%).

[0371] 1 H NMR (400MHz, DMSO) δ5.89(d,J=7.8Hz,1H),4.93(d,J=47.1Hz,1H),4.51-4.43(m,1H),4.41(s,2H),3.87(t,J=5.6Hz,2H ),2.96-2.83(m,2H),2.60(t,J=5.4Hz,2H),2.19(s,3H),2.18-2.04(m,2H),1.87(t,J=10.1Hz,1H),1.76-1.57(m,1H).

[0372] 19 F NMR (377MHz, DMSO) δ-180.76 (s).

[0373] MS m / z(ESI):301.3[M+H] + .

[0374] 2. Synthesis of Compound 9g

[0375] Compound 9g was synthesized using compound 9e as the starting material according to the method described in Example 1.

[0376] 3. Synthesis of Compound 9

[0377] Step 1:

[0378] Under a nitrogen atmosphere, compound 9d-2 (270 mg, 0.90 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). Cesium carbonate (731 mg, 2.24 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (65 mg, 0.09 mmol), and compound 9g (329 mg, 1.08 mmol) were added at room temperature. The reaction temperature was raised to 95°C and stirred. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography to obtain compound 9h (260 mg, 65% yield).

[0379] MS m / z(ESI):445.4[M+H] + .

[0380] Step 2:

[0381] To a solution of compound 9h (260 mg, 0.59 mmol) in tetrahydrofuran (15 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) at room temperature and stirred until the reaction was complete. After concentration, the residue was adjusted to pH ~9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford compound 9 (137 mg, 58% yield).

[0382] MS m / z(ESI):401.4[M+H] + .

[0383] 1 HNMR(400MHz,DMSO)δ10.15(s,1H),7.00(d,J=8.4Hz,1H),6.35(d,J=8.4Hz,1H) ,5.66(d,J=7.6Hz,1H),4.95(d,J=47.4Hz,1H),4.57(t,J=8.8Hz,3H),4.48(s,2H ),3.76(t,J=5.6Hz,2H),3.14(t,J=8.8Hz,2H),2.99-2.86(m,2H),2.52-2.51(m ,2H),2.21(s,3H),2.17-2.08(m,2H),1.91(t,J=10.0Hz,1H),1.79-1.62(m,1H).

[0384] 19 F NMR (377MHz, DMSO) δ-180.68 (s).

[0385] Example 10

[0386] 5-(1-{[(5R)-5-fluoro-1-methylhexahydropyridin-3-yl]amino}-7,8-dihydro-5H-pyrano[4,3-d][1,2]diazepine-4-yl)-2,3-dihydro-1-benzofuran-4-ol (10)

[0387] According to the similar synthetic operation as Example 9, the compound of Example 10 can be synthesized.

[0388] MS m / z(ESI):401.4[M+H] + .

[0389] 1 HNMR (400MHz, DMSO) δ10.24(s,1H),6.89(d,J=8.2Hz,1H),6.34(d,J=8.2Hz,1 H),5.85(d,J=8.0Hz,1H),4.95(d,J=47.4Hz,1H),4.57(t,J=8.7Hz,3H),4.41( s,2H),3.93(t,J=5.6Hz,2H),3.13(d,J=8.7Hz,2H),2.92(dt,J=22.3,11.7Hz, 2H),2.46(d,J=5.4Hz,2H),2.22(s,3H),2.17–2.06(m,2H),2.02–1.89(m,1H), 1.87–1.66(m,1H).

[0390] Biological evaluation

[0391] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0392] Test Example 1. NLRP3 inflammasome inhibitory activity assay in THP1-Null cells

[0393] 1. Experimental instruments and reagents

[0394] 1.1 Experimental Instruments

[0395] Plate reader: PerkinElmer 2104 EnVision Multilabel Plate Reader

[0396] 1.2 Experimental Reagents

[0397] 2. Experimental Plan

[0398] Day 1: THP1-Null cells were seeded in 96-well plates at 10 × 10 4 Cells / 180 μL without Hygromycin B and Normocin TM 20 μL of PMA (final concentration 100 nM) was added to each well and cultured at 37°C in an atmosphere of 5% CO2 for 24 hours.

[0399] Day 2: Dilute compounds in phenol red-free RPMI 1640 medium containing 25 mM HEPES and 0.5% DMSO. Remove medium and pretreat cells with 160 μL of medium containing compound. Incubate at 37°C for 1 hour in a 5% CO₂ atmosphere. Prepare LPS in phenol red-free RPMI 1640 medium containing 25 mM HEPES. Add 20 μL of 9 μg / mL LPS to each well (final concentration 1 μg / mL) and incubate at 37°C for 3.5 hours in a 5% CO₂ atmosphere. Add 20 μL of 50 mM ATP (final concentration 5 mM) to compound-treated wells and high-dose control wells. Add 20 μL of medium to low-dose control wells and incubate at 37°C for 0.5 hours in a 5% CO₂ atmosphere. Transfer 160 μL of supernatant to a new plate and store at -80°C.

[0400] Day 3: The supernatant was used for IL-1β release assay in THP1-Null cells according to the manufacturer's instructions.

[0401] (1) Add 16 μL of IL1β standard Std 0-Std 7 to each standard well or 16 μL of the test sample to each sample well.

[0402] (2) Add 4 μL of premixed IL1β antibody working solution to all wells.

[0403] (3) Seal the plate and incubate overnight at room temperature.

[0404] (4) Read the fluorescence wavelength ratio of 665 / 620 using the Envision instrument.

[0405] 3. Experimental Results

[0406] Table 1. Inhibitory activity of the disclosed compounds on NLRP3

[0407] Activation of the NLRP3 inflammasome leads to the release of the inflammatory cytokine IL-1β. When the activation of the NLRP3 inflammasome is dysregulated, it drives the occurrence of many diseases. The data in the table show that the compounds disclosed herein have NLRP3 inhibitory activity.

[0408] Test Example 2. Toxicity Assay of NLRP3 Inhibitors in HepG2 Cells

[0409] 1. Experimental instruments and reagents

[0410] 1.1 Experimental Instruments

[0411] PerkinElmer 2104 EnVision Multilabel Plate Reader

[0412] Multidrop TMPico 8 Digital Splitter

[0413] 1.2 Experimental Reagents

[0414] Compound A is compound 50 in WO2022135567A.

[0415] 2. Experimental Plan

[0416] Day 1: HepG2 cells were seeded in 384-well plates at 2 × 10 3 Cells were cultured in 50 μL of DMEM medium containing 10% FBS per well at 5% CO 2 and 37° C. overnight.

[0417] Day 2: Via Multidrop TM A Pico 8 digital dispenser was used to add serially diluted compounds to 50 μL of cell culture medium, with final compound concentrations of 150, 50, 16.67, 5.56, 1.85, 0.62, 0.21, 0.069, and 0.023 μM. The DMSO concentration was less than 0.3%. Cells were incubated in a 37°C, 5% CO2 incubator for 2 days.

[0418] Day 4: Add 25 μL of Celltiter Glo detection reagent to each well and shake the plate (protected from light) for 3 minutes. Incubate at room temperature in the dark for 10 minutes before reading the plate using the Envision reader.

[0419] 3. Experimental Results

[0420] Table 2. Cytotoxicity test of the disclosed compounds on HepG2 cells

[0421] Compared with compound A, compound C and compound D, compound 9 has weaker cytotoxicity to HepG2 cells.

[0422] Test Example 3. Inhibition experiment of compounds on hERG potassium ion channel

[0423] 1. Experimental Materials and Instruments

[0424] Compound A is compound 50 in WO2022135567A.

[0425] The CAS number of compound B is 2795101-67-4.

[0426] 2. Cell Lines and Cell Culture

[0427] HEK293 cell line stably expressing hERG ion channel (Cat. No. K1236) was purchased from Invitrogen. The cell line was cultured in a medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1 mM non-essential amino acid solution, 100 U / mL penicillin-streptomycin solution, 25 mM HEPES, 5 μg / mL blasticidin, and 400 μg / mL geneticin. When the cell density grew to 40% to 80% of the bottom area of ​​the culture dish, the cells were digested by trypsin and passaged three times a week. Before the experiment, the cells were plated at 5×10 5 The cells were cultured at a density of 100 μg / mL in 6 cm culture dishes and induced for 48 h by adding 1 μg / mL doxycycline. The cells were then digested and seeded on glass slides for subsequent manual patch clamp experiments.

[0428] 3. Solution Preparation

[0429] 1) Extracellular solution (in mM): 132 NaCl, 4 KCl, 3 CaCl2, 0.5 MgCl2, 11.1 Glucose, and 10 HEPES (pH adjusted to 7.35 with NaOH).

[0430] 2) Intracellular solution (in mM): 140 KCl, 2 MgCl2, 10 EGTA, 5 Mg-ATP, and 10 HEPES (pH adjusted to 7.35 with potassium hydroxide).

[0431] 4. Preparation of test compound solution

[0432] 1) The test compound was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM.

[0433] 2) The stock solution was diluted with DMSO at a ratio of 1:3 to form three other intermediate concentration solutions with concentrations (mM): 3.33, 1.11, and 0.37.

[0434] 3) Prior to the experiment, the intermediate solution of the test compound gradient was further diluted 1:1000 with extracellular fluid to form a series of working solutions with final concentrations (μM): 10, 3.33, 1.11, and 0.37. The 30 μM working solution was prepared by diluting the 10 mM stock solution 333.33-fold. The DMSO content in the working solutions was 0.1-0.3% (v / v).

[0435] 4) Five working solutions with different concentration gradients of 30, 10, 3.33, 1.11 and 0.37 μM were used to determine the potential inhibitory effect of the compound on hERG channels and to fit the dose-effect curve and calculate the IC 50 .

[0436] 5. Experimental Plan

[0437] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank on the microscope stage.

[0438] 2) Using an Olympus IX51, IX71, or IX73 inverted microscope, center the field of view on a suitable cell. Using a ×10 objective lens, locate the tip of the glass electrode and position it in the center of the field of view. Then, use the micromanipulator to lower the electrode while adjusting the coarse focus knob to gradually bring the electrode closer to the cell.

[0439] 3) When approaching the cell, switch to a ×40 objective lens for observation and use the micromanipulator to fine-tune the gear to gradually bring the electrode closer to the cell surface.

[0440] 4) Apply negative pressure to form a seal with a resistance higher than 1G between the electrode tip and the cell membrane.

[0441] 5) In voltage clamp mode, the instantaneous capacitance current C fast Then, short negative pressures were repeatedly applied to rupture the membrane, ultimately establishing whole-cell recording mode.

[0442] 6) Under the condition that the membrane potential is clamped at -60mV, the slow capacitive current C slow , cell membrane capacitance (Cm) and input membrane resistance (Ra) were compensated respectively.

[0443] 7) After the cells stabilize, change the clamping voltage to -90 mV, set the sampling frequency to 20 kHz, and the filtering frequency to 10 kHz. Leakage current detection conditions are: clamping voltage to -80 mV, time duration 500 ms.

[0444] 8) The hERG current measurement method is as follows: a 4.8-second depolarization command voltage is applied to depolarize the membrane potential from -80 mV to +30 mV. Then, a 5.2-second repolarization voltage is applied to reduce the membrane potential to -50 mV to eliminate channel inactivation, thereby observing the hERG tail current. The peak value of the tail current is the magnitude of the hERG current.

[0445] 9) hERG currents used to detect test compounds were recorded for 120 seconds before administration to assess the stability of hERG currents generated by the test cells. Only cells that were stable within the acceptable range of the evaluation criteria were allowed to proceed to subsequent compound testing.

[0446] Test of the inhibitory effect of the test compound on hERG current: First, the hERG current measured in the extracellular fluid containing 0.1% DMSO is used as the detection baseline. After the hERG current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells in sequence from low concentration to high concentration. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cells and record the hERG current synchronously. After the recorded current tends to stabilize, record the last 5 hERG current values, and take the average value as the final current value at a specific concentration. After testing the compound, add 150nM dofetilide (positive drug) to the same cell to completely inhibit its current as a positive control for the cell. At the same time, the positive compound dofetilide is synchronously detected using the same patch clamp system before and after the end of the test drug experiment to ensure the reliability and sensitivity of the entire detection system.

[0447] 6. Data Analysis

[0448] 1) After perfusing the blank solvent or compound gradient solution, the average value of the 5 consecutive current values ​​obtained was calculated and used as the "tail current magnitude" 空白 ” and “tail current size 化合物 ”.

[0449] 2) The current suppression percentage is calculated using the following formula.

[0450] 3) The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC was calculated. 50 value.

[0451] 7. Experimental Results

[0452] Table 3. IC of the compounds disclosed herein for hERG potassium channel 50 The result of the value

[0453] Compared with compound A and compound B, compound 9 provided by the present disclosure has a weaker inhibitory effect on hERG potassium ion channels, and compound 9 may have better cardiac safety.

[0454] Test Example 4. Permeability experiment of NLRP3 inhibitor

[0455] 1. Experimental instruments and reagents

[0456] 1.1 Experimental Instruments

[0457] 1.2 Experimental Reagents

[0458] Compound C is compound 52C in WO2022135567A, and compound D is compound 52 in WO2022135567A.

[0459] 2. Experimental Plan

[0460] 2.1 Evaluation of plate and cell monolayer integrity

[0461] 1) Add 50 μL of cell culture medium to each well of the upper Transwell plate and 25 mL of cell culture medium to the lower Transwell plate, and preheat in a 37°C, 5% CO2 incubator for 1 hour.

[0462] 2) Dilute MDCKII-MDR1 cells to 1.56×10 6 Cells were plated at a concentration of 100 μL / mL, and 50 μL of the cell suspension was then aliquoted into the wells of a 96-well Transwell plate. The cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 4-8 days. After seeding, the cell culture medium was changed every other day, with the first change no later than 24 hours after seeding.

[0463] 3) Remove the culture medium from the Transwell plate and add pre-warmed fresh culture medium.

[0464] 4) The transmembrane electrical resistance (TEER) of the cell monolayer was measured using a resistance meter (Millipore, USA).

[0465] 5) After the measurement is completed, place the cell plate back into the incubator. The resistance value is calculated as follows:

[0466] TEER value (ohm·cm 2 ) = TEER measurement value (ohms) × membrane area (cm 2 )

[0467] The TEER value of each well should be greater than 42 ohms·cm 2 , indicating that the integrity of the MDCKII-MDR1 cell monolayer was good.

[0468] 2.2 Drug penetration test

[0469] 1) Remove the MDCKII-MDR1 Transwell plate from the incubator. Rinse the cell monolayer twice with HBSS (25 mM HEPES, pH 7.4) and incubate in a CO2 incubator at 37°C for 30 minutes.

[0470] 2) Propranolol was diluted to 1 mM using DMSO and then further diluted to a 5 μM working solution using HBSS (25 mM HEPES, pH 7.4); the test compound, prazosin, and quinidine were diluted to 200 μM using DMSO and then further diluted to a 1 μM working solution using HBSS (25 mM HEPES, pH 7.4); the final DMSO content in the system was 0.5%.

[0471] 3) To determine the drug transport rate from the apical to the basolateral side, pipette 150 μL of 1 μM / 5 μM working solution into the top of the Transwell chamber. Immediately, remove 50 μL of sample from the top and quench it in a 96-deep-well plate pre-filled with 200 μL of pre-chilled quencher. This serves as the initial dosing sample (AB). Add 300 μL of HBSS (25 mM HEPES, pH 7.4) to the receiving (basolateral) side.

[0472] 4) To determine the drug transport rate from the basolateral to the apical side, pipette 350 μL of 1 μM / 5 μM working solution into the basolateral side of the Transwell chamber. Simultaneously, remove 50 μL of sample from the basolateral side and quench it in a 96-deep-well plate pre-filled with 200 μL of pre-chilled quencher to serve as the initial drug delivery sample (BA). Add 100 μL of HBSS (25 mM HEPES, pH 7.4) to the apical side of the Transwell chamber.

[0473] 5) Both apical-to-basal and basal-to-apical transport need to be performed simultaneously to initiate bidirectional transport. Then, the cell plate is placed in an incubator at 37°C, 5% CO2, and saturated relative humidity for 2 hours.

[0474] 6) After 2 hours, pipette 50 μL of sample from each of the dosing and receiving ports into a 96-well deep-well plate. Then, add 4 volumes of pre-chilled quencher to each well. Vortex for 15 minutes and centrifuge at 4000 rpm and 4°C for 30 minutes. Remove 100 μL of sample from each well and mix with 100 μL of purified water for LC / MS / MS analysis. All samples should be analyzed in duplicate.

[0475] 7) After the transport experiment, the integrity of the MDCKII-MDR1 cell membrane was tested using the Lucifer Yellow Rejection Assay. After incubation in the Lucifer Yellow solution for 30 minutes, the Lucifer Yellow sample was collected and its fluorescence was measured using a microplate reader at an excitation wavelength of 480 nM and an emission wavelength of 530 nM.

[0476] 2.3 Data Processing

[0477] All calculations were performed using Microsoft Excel. Peak areas were determined using extracted ion chromatograms.

[0478] Apparent permeability coefficient (P app , unit: cm / s×10 -6 ) is used in drug transport experiments and is calculated as follows:

[0479] In the formula: V A is the volume of the solution at the receiving end

[0480] Area is the Transwell-96 well plate membrane area (0.143 cm 2 )

[0481] time is the incubation time (unit: s)

[0482] [drug] acceptor is the peak area ratio of the sample at the receiving end

[0483] [drug]initial,donor is the peak area ratio of the sample at the initial drug administration end

[0484] The efflux rate is calculated using the following formula:

[0485] In the formula: P app(B→A) is the apparent permeability from the base to the top

[0486] P app(A→B) is the apparent permeability from the top to the base

[0487] Efflux Ratio is the efflux ratio

[0488] The percent recovery is determined by the following formula:

[0489] In the formula: V A is the volume of the solution at the receiving end

[0490] V D is the volume of solution at the dosing end

[0491] Area ratio acceptor is the peak area ratio of the sample at the receiving end

[0492] Area ratio donor is the peak area ratio of the sample at the dosing end

[0493] Area ratio initial, donor is the peak area ratio of the sample at the initial dosing end

[0494] The fluorescence value of the cell monolayer was calculated using the following formula:

[0495] In the formula: [LY] acceptor Refers to the fluorescence density of the receiving well (0.3 mL), [LY] donor It refers to the fluorescence density of the drug-added well (0.1 mL), expressed as %LY. LY < 1.0% indicates that the monolayer cell membrane is intact.

[0496] 3. Experimental Results

[0497] Table 4. Permeability results of the compounds of the present disclosure in MDCKII-MDR1 cells

[0498] Compared with Compound C and Compound D, Compound 9 provided by the present disclosure has better permeability and better brain penetration potential.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, X1 is selected from -O-, -S-, -CH2-, -CH2-O- or -O-CH2-; Ring A is selected from 4- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl or phenyl; R 1 Selected from hydrogen, C 1-6 alkyl or 3 to 6-membered cycloalkyl, wherein the C 1-6 The alkyl or 3 to 6 membered cycloalkyl is optionally substituted with one or more halogens; for wherein X2, X3, X4 and X5 are each independently selected from -O-, -S-, -CH2-, -NH-, R 2 are the same or different, each independently selected from deuterium, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 3 and R 4 are each independently selected from hydrogen, deuterium or halogen; R 5 The same or different, each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl; R 6 The same or different, each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, oxo, deuterium, halogen, hydroxyl, amino, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl are optionally substituted with one or more R A Substitution; said R A The same or different, each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, -C(O)R', -C(O)OR' or -C(O)NR'R", wherein the 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2 or -CN; Or connect to R of X4 and X5 6 Together with the connecting atom, it forms a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R B Substitution, the R B Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl; R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl; q is selected from 0, 1, 2 or 3; o is selected from 0, 1 or 2; m is selected from 0, 1, 2 or 3; and n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is selected from -CH2-O- or -O-CH2-; preferably, X1 is -CH2-O-.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is selected from the compound represented by formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, in, R 2 , R 3 , R 4 , R 5 , R 6 , Ring A, Ring B, m, n and o are as defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from cyclopentyl or cyclohexyl; or Ring A is selected from a 5-membered or 6-membered heterocycloalkyl group, wherein the 5-membered or 6-membered heterocycloalkyl group contains one or two heteroatoms selected from O, S or N atoms; or Ring A is selected from a 5-membered or 6-membered heteroaryl group, wherein the 5-membered or 6-membered heteroaryl group contains one or two heteroatoms selected from O, S or N; or Ring A is phenyl; Preferably, Ring A is cyclopentyl; or Ring A is a 5-membered heterocycloalkyl group, the 5-membered heterocycloalkyl group contains one heteroatom, and the heteroatom is an O atom; or Ring A is a 5-membered heteroaryl group. The 5-membered heteroaryl group contains one heteroatom, and the heteroatom is an S atom.

5. A compound according to any one of claims 1, 2 and 4 or a pharmaceutically acceptable salt thereof, which is selected from the compounds represented by formula (II-1), (II-2) and (II-3) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ring B, m, o and n are as defined in claim 1.

6. A compound according to any one of claims 1, 2 and 4 or a pharmaceutically acceptable salt thereof, which is selected from the compounds represented by formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6) or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ring B, m, o and n are as defined in claim 1.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein for wherein X2, X3, X4 and X5 are all -CH2-, q is selected from 0, 1, 2 or 3, R 6 Selected from hydroxyl or C 1-6 Alkyl, and n is 1.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Selected from Best 9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein for wherein X2, X3, X4 and X5 are each independently selected from -CH2- and -O-, and one of X2, X3, X4 and X5 is -O-, q is selected from 0, 1, 2 or 3, preferably, q is selected from 1 or 2, R 6 is a hydroxyl group, and n is 0 or 1.

10. The compound according to any one of claims 1 to 6 and 9, or a pharmaceutically acceptable salt thereof, wherein Selected from Best 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein for wherein X2, X3, X4 and X5 are each independently selected from -CH2- and -NH-, and one or two of X2, X3, X4 and X5 are -NH-, preferably, one of X2, X3, X4 and X5 is -NH-, most preferably, X3 or X4 is -NH-; q is selected from 0, 1 or 2; and / or, R 6 Selected from halogen, C 1-6 Alkyl or -S(O)2-C 1-3 Alkyl, the C 1-6 Alkyl or -S(O)2-C 1-3 The alkyl group is optionally substituted with one or more R A Substitution, the R A are the same or different, each independently selected from halogen or hydroxy, in particular, the halogen is fluorine or chlorine.

12. The compound according to any one of claims 1 to 6 and 11 or a pharmaceutically acceptable salt thereof, wherein Selected from Best 13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein for wherein X2, X3 and X5 are all -CH2-, X4 is -NH-, q is 2, and Connect to R of X4 and X5 6 Together with the connecting atoms, it forms a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the 5- to 6-membered nitrogen-containing heterocyclic ring is optionally substituted with one or more R B Substitution, the R B Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein for wherein X2, X3, X4 and X5 are each independently selected from -CH2- or and one of X2, X3, X4 and X5 is q is selected from 0, 1, 2 or 3; preferably, q is selected from 1 or 2; most preferably, 2.

15. The compound according to any one of claims 1 to 6 and 14, or a pharmaceutically acceptable salt thereof, wherein Selected from 16. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein for wherein X2, X3, X4 and X5 are each independently selected from -CH2- or And one of X2, X3, X4 and X5 is q is selected from 0, 1, 2 or 3, preferably, q is selected from 1 or 2; most preferably, 2.

17. The compound according to any one of claims 1 to 6 and 16, or a pharmaceutically acceptable salt thereof, wherein Selected from Best 18. A compound according to any one of claims 1, 2 and 4 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

19. A compound according to any one of claims 1, 2 and 4 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by 1, 2 or 3 halogens selected from F or Cl. 1 It is difluoromethyl.

20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy; preferably, the R 5 It is a halogen.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein The o is selected from 0 or 1, preferably 0.

22. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen or halogen; and / or, R 4 is selected from hydrogen or halogen; preferably, R 3 is hydrogen, R 4 For hydrogen.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogen or C 1-6 Alkyl, preferably fluorine or methyl.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0 or 1, preferably 0.

25. A compound according to any one of claims 1 to 6 and 19 to 24, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl, halogen, hydroxyl, -S(O)2-C 1-6 Alkyl, the C 1-6 Alkyl or -S(O)2-C 1-6 The alkyl group is optionally substituted with one or more R A Substitution, the R A The same or different, each independently selected from oxo, deuterium, halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy; and n is selected from 0, 1, 2 or 3; or, where R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with one or more R A Substitution, the R A Identically or differently, each is independently selected from oxo, deuterium, halogen or -OH.

26. A compound according to any one of claims 1 to 4, 6 to 8, 18 to 22, 24 and 25, or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (IV-1) or a pharmaceutically acceptable salt thereof, in, R 1 is selected from hydrogen or difluoromethyl, preferably, R 1 is hydrogen; R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; q is selected from 0 or 1; and m is selected from 0 or 1.

27. A compound according to any one of claims 1 to 4, 6, 14, 15, 18 to 22, 24 and 25, or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (IV-2) or a pharmaceutically acceptable salt thereof, in, R 1 is selected from hydrogen or difluoromethyl, preferably, said R 1 is hydrogen; R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 6 Selected from halogen or C 1-3 alkyl; q is selected from 0 or 1; m is selected from 0 or 1; and n is selected from 0, 1 or 2.

28. A compound according to any one of claims 1 to 4, 6, 11, 12, 18 to 22 and 24 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (IV-3) or a pharmaceutically acceptable salt thereof, in, R 1 is selected from hydrogen or difluoromethyl; R 2 Selected from halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; m is selected from 0 or 1; R 6 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, hydroxy, amino, -S(O)2-C 1-6 alkyl, 3 to 7-membered cycloalkyl or 3 to 12-membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -S(O)2-C 1-6 The alkyl group, the 3- to 7-membered cycloalkyl group or the 3- to 12-membered heterocycloalkyl group are optionally substituted with one or more R A Substitution; said R A The same or different, each independently selected from halogen, -OH, -NH2, -CN, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, -C(O)R', -C(O)OR' or -C(O)NR'R", said 3 to 7 membered cycloalkyl or 3 to 12 membered heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NH2 or -CN; and R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with one or more R A Substitution, the R A Identically or differently, each independently selected from halogen, -OH, 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, -C(O)R', -C(O)OR' or -C(O)NR'R", said 3 to 7 membered cycloalkyl, 3 to 12 membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, -NH2 or -CN; and The R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or a pharmaceutically acceptable salt thereof, 31. An isotope substituted compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, preferably, the isotope substituted compound is a deuterated compound.

32. A method for preparing the compound of formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof according to claim 3, comprising the following steps: 1) removing the phenolic hydroxyl protecting group PG from the compound represented by formula (I-1') to obtain the compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, in, PG is a phenolic hydroxyl protecting group, preferably methoxymethyl ether; 2) The compound represented by formula (I-2') and formula (I-2") undergoes Suzuki reaction under alkaline conditions with the action of a catalyst and an organic phosphine ligand to obtain a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof, Wherein, R is selected from C 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy; LG is a leaving group selected from Cl, Br, I or OTf; The catalyst is a palladium catalyst; R 2 , R 3 , R 4 , R 5 , R 6 , Ring A, Ring B, m, n and o are as defined in claim 1.

33. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof or the isotope substitution according to claim 31, and a pharmaceutically acceptable excipient.

34. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or an isotope substitution according to claim 31, or a pharmaceutical composition according to claim 33 in the preparation of a medicament for preventing and / or treating a disease associated with NLRP3 activity.

35. Use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or an isotope substituted product according to claim 31, or a pharmaceutical composition according to claim 33 in the preparation of a medicament for preventing and / or treating an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease, and an autoinflammatory disease; preferably autoinflammatory febrile syndrome, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis), inflammatory arthritis-related diseases (such as gout, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, type I or type II diabetes and its complications (such as nephropathy, retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic-related disorders or diseases (such as atherosclerosis, type I and type II diabetes and related complications, acute heart failure and hypertension), wound healing, scar formation, asthma, cancer-related diseases / conditions (such as leukemia, myelodysplastic syndrome (MDS)).

36. Use of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 31, or the pharmaceutical composition according to claim 33 in the preparation of an NLRP3 inhibitor.

37. A compound represented by formula (I-1') or a pharmaceutically acceptable salt thereof, in, R 2 , R 3 , R 4 , R 5 , R 6 , Ring A, Ring B, m, n and o are as defined in claim 1; PG is a phenolic hydroxyl protecting group, preferably methoxymethyl ether.

Images