A class of pyridazine-containing compounds and medical uses thereof

Abstract

A class of pyridazine-containing compounds and medical uses thereof. Specifically, a compound represented by formula I or a pharmaceutically acceptable salt thereof, the compound or the pharmaceutically acceptable salt thereof has NLRP3 inflammasome inhibitory activity and can be used for treating or preventing NLRP3-related diseases.

Description

Technical Field

[0001] This disclosure relates to the pharmaceutical field, specifically to a class of pyridazine-containing compounds and their pharmaceutical uses. Background Technology

[0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene belonging to the nucleotide-binding and oligomerization domain-like receptor (NLR) family, also known as "pyrine domain-containing protein 3" (Inoue et al., Immunology, 2013, 139, 11-18). This gene encodes a protein containing a pyridine domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with adaptor proteins, apoptosis-associated speckle-like protein (ASC), and prozymogen-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome subsequently leads to the release of the inflammatory cytokines IL-1β and IL-18, while dysregulation of NLRP3 inflammasome activation drives the development of many diseases.

[0003] Studies have shown that activation of the NLRP3 inflammasome is associated with multiple disease classes, including inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Therefore, there is a need to develop novel NLRP3 inflammasome pathway inhibitors to provide new treatment options for these diseases. Summary of the Invention

[0004] In a first aspect, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0005]

[0006] Wherein, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0007] R2, R3, R4, R5, R6, and R7:

[0008] (a) R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0009] R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0010] Alternatively, R6 and R7, together with the atoms they are attached to, can form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring, a phenyl group, or a 5-6 membered heteroaryl group, optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R4 and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0011] (b) R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogens, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0012] (c) R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0013] Alternatively, (d) R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring, a phenyl group, or a 5-6 membered heteroaryl group, optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0014] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0015] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6 Alkyl and -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0016] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0017] When R6 and R7 together with the atoms they are attached to form an unsubstituted 5-6 membered ring hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.

[0018] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0019] R2, R3, R4, R5, R6, and R7:

[0020] (a) R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0021] (b) R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogens, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0022] (c) R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, phenyl, heterocyclic, or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0023] Alternatively, (d) R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring, a phenyl group, or a 5-6 membered heteroaryl group, optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0024] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0025] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6Alkyl and -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0026] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0027] When R6 and R7 together with the atoms they are attached to form an unsubstituted 5-6 membered ring hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.

[0028] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0029] R2, R3, R4, R5, R6, and R7:

[0030] (a) R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0031] (b) R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon or phenyl group, optionally substituted with one or more substituents selected from: deuterium, halogens, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0032] (c) R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon or phenyl group optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0033] Alternatively, (d) R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocycle, or a phenyl group optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0034] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0035] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6 Alkyl and -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0036] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0037] When R6 and R7 together with the atoms they are attached to form an unsubstituted 5-6 membered ring hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.

[0038] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0039] R2, R3, R4, R5, R6, and R7:

[0040] (a) R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0041] (b) R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon or phenyl group, optionally substituted with one or more substituents selected from: deuterium, halogens, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0042] (c) R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0043] Alternatively, (d) R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocycle, or a phenyl group optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0044] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0045] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6 Alkyl and -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0046] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0047] When R6 and R7 together with the atoms they are attached to form an unsubstituted 5-6 membered ring hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.

[0048] In some embodiments, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, and optionally substituted with one or more of the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0049] R2, R3, R4, R5, R6, and R7:

[0050] (a) R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0051] (b) R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0052] (c) R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0053] Alternatively, (d) R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon or heterocycle optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0054] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0055] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6 Alkyl and -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0056] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and C3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0057] When R6 and R7 together with the atoms they are attached to form an unsubstituted 5-6 membered ring hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.

[0058] In some embodiments, R1 is selected from halogens, -OH, -NH2, -CN, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl group, -NHC(=O)-C 1-6 Alkyl groups and -(C=O)NH-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0059] In some embodiments, R1 is selected from -OH, -NH2, and optionally substituted with one or more of the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl groups and -NHC(=O)-C 1-6 Alkyl group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0060] In some embodiments, R1 is selected from -OH, -NH2, and optionally substituted with one or more -OH groups: C 1-6 Alkyl, -OC 1-6 Alkyl groups and -NHC(=O)-C 1-6 alkyl.

[0061] In one implementation, R1 is -OH.

[0062] In some implementations, R1 is -OC 1-6 Alkyl group, preferably -OCH3 or -OCH2CH3, more preferably -OCH3.

[0063] In some embodiments, R1 is a C that is optionally substituted with one or more -OH groups. 1-6 Alkyl group, preferably -CH2OH or -CH2CH2OH, more preferably -CH2OH.

[0064] In one implementation, R1 is -NH2.

[0065] In some embodiments, R1 is -NHC(=O)-C optionally substituted with one or more -OH groups. 1-6 Alkyl group, preferably -NH2C(=O)CH3.

[0066] In some embodiments, R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0067] R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0068] In some embodiments, the compound of formula I is:

[0069]

[0070] R 9a Independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; m is an integer selected from 0-8.

[0071] In some embodiments, the compound of formula I is selected from:

[0072]

[0073] In some embodiments, the compound of formula I is selected from compounds of formulas II'-a, II'-b, II'-c, II'-d, II'-f, II'-g, II'-k, II'-l, and II'-m; preferably from compounds of formulas II'-a, II'-c, II'-d, II'-k, II'-l, and II'-m; more preferably from compounds of formulas II'-a, II'-d, II'-k, and II'-m; and most preferably from compounds of formula II'-a or II'-k.

[0074] In other embodiments, R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0075] R6 and R7, together with the atoms they are attached to, form a phenyl, 5-6 membered heteroaryl group optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0076] R4 and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0077] In some embodiments, R2 and R3, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon; preferably, the 5-6 membered cyclic hydrocarbon is cyclopentyl or cyclohexyl; the cyclopentyl or cyclohexyl group is optionally selected from hydrogen, deuterium, halogen, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Substituents of alkyl groups;

[0078] R6 and R7, together with the atoms they are attached to, form a phenyl or a 5-6-membered heteroaryl group; preferably, the 5-6-membered heteroaryl group is pyridine; the phenyl or 5-6-membered heteroaryl group is optionally selected from hydrogen, deuterium, halogen, -OH, C. 1-6 Alkyl, Halogenated C 1-6 Substituents of alkyl groups;

[0079] R4 and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C3-6 cycloalkyl and C 3-6 The cycloalkylmethylene group, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2, and -CN; preferably R4 and R5 are independently selected from hydrogen, deuterium, halogen, -OH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl; more preferably R4 and R5 are independently selected from hydrogen or deuterium.

[0080] In other embodiments, R2 and R3, together with the atoms they are attached to, form a 5-6 membered heterocycle optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0081] R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0082] In some implementations, the 5-6 quinary heterocycle is a 5-6 quinary S-containing heterocycle.

[0083] In some embodiments, the compound of formula I is selected from:

[0084]

[0085]

[0086] R 9b Selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0087] R 9c Selected from hydrogen, deuterium, and C 1-6Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; p is an integer selected from 0-6.

[0088] In some embodiments, the compound of formula I is selected from:

[0089]

[0090]

[0091] In some embodiments, the compound of formula I is selected from compounds of formulas III'-a, III'-b, III'-c, III'-d, III'-f, III'-g, III'-h and III'-i; preferably from compounds of formulas III'-a, III'-b, III'-c, III'-f, III'-g and III'-h; more preferably from compounds of formulas III'-a, III'-c, III'-f and III'-h; and most preferably from compounds of formula III'-a or III'-f.

[0092] In other embodiments, R2 and R3, together with the atoms they are attached to, form a 5-6 membered heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0093] R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0094] In some implementations, the 5-6 nucleotide heteroaromatic ring is a 5-nucleotide S-containing heteroaromatic ring.

[0095] In some embodiments, the compound of formula I is selected from:

[0096]

[0097]

[0098] R 9d Selected from hydrogen, deuterium, halogens, -OH, -NH2, -CN, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0099] R 9e Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; q is an integer selected from 0 to 3.

[0100] In some embodiments, the compound of formula I is selected from:

[0101]

[0102]

[0103] In some embodiments, the compound of formula I is selected from compounds of formulas IV'-a, IV'-b, IV'-c, IV'-d, IV'-e, IV'-f, IV'-g, IV'-h, IV'-i, IV'-j, IV'-k, and IV'-l; preferably from compounds of formulas IV'-a, IV'-b, IV'-c, IV'-d, IV'-g, IV'-h, IV'-i, and IV'-j; more preferably from compounds of formulas IV'-a, IV'-d, IV'-g, and IV'-j; and most preferably from compounds of formulas IV'-a or IV'-g.

[0104] In some embodiments, in formulas II-a, II-b, II'-a to II'-q, III-a to III-p, III'a to III'-r, IV-a to IV-n, and IV'-a to IV'-p, R4, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen.

[0105] In some embodiments, R4 and R7 are independently selected from hydrogen, deuterium, and halogens, and R5 and R6 are independently selected from hydrogen, deuterium, halogens, and C optionally substituted with one or more deuterium or halogens. 1-6 alkyl.

[0106] In some embodiments, R4, R5, and R7 are hydrogens, and R6 is a methyl group; or, R4, R6, and R7 are hydrogens, and R5 is a methyl group.

[0107] In other embodiments, R3 and R4, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, C. 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0108] R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0109] In some embodiments, the compound of formula I is selected from:

[0110]

[0111]

[0112] In some embodiments, the compound of formula I is selected from compounds of formula Va, Vb, Vc, Vd, Vf, Vg, Vk, Vl, and Vm; preferably from compounds of formula Va, Vc, Vd, Vk, Vl, and Vm; more preferably from compounds of formula Va, Vd, Vk, and Vm; and most preferably from compounds of formula Va or Vk.

[0113] In some embodiments, in compounds of formula Va to Vq, R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogens, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen.

[0114] In some embodiments, R2 and R7 are independently selected from hydrogen, deuterium, and halogens, and R5 and R6 are independently selected from hydrogen, deuterium, halogens, and C optionally substituted with one or more deuterium or halogens. 1-6 alkyl.

[0115] In some embodiments, R2, R5, and R7 are hydrogens, and R6 is a methyl group; or, R2, R6, and R7 are hydrogens, and R5 is a methyl group.

[0116] In other embodiments, R4 and R5, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, oxometalates, and C. 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0117] R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0118] In some embodiments, the compound of formula I is selected from:

[0119]

[0120]

[0121] In some embodiments, the compound of formula I is selected from compounds of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-h, VI-i, VI-j, VI-k and VI-l; preferably from compounds of formulas VI-a, VI-b, VI-c, VI-h, VI-i and VI-j; more preferably from compounds of formula VI-a or VI-h.

[0122] In some embodiments, in compounds of formulas VI-a to VI-l, R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen.

[0123] In some embodiments, R2 and R7 are independently selected from hydrogen, deuterium, and halogens, and R3 and R6 are independently selected from hydrogen, deuterium, halogens, and C optionally substituted with one or more deuterium or halogens. 1-6 alkyl.

[0124] In some embodiments, R2 and R7 are hydrogen, R3 is trifluoromethyl, and R6 is methyl; or, R2 and R7 are hydrogen, R3 is chlorine, and R6 is methyl.

[0125] In some embodiments, R4 and R5, together with the atoms they are attached to, form a phenyl group optionally substituted with one or more substituents selected from: deuterium, halogen, oxo, C. 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0126] R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0127] Preferably, R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and C. 1-6 Alkyl, -OC 1-6 alkyl;

[0128] More preferably, R2, R3, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and C. 1-6 Alkyl, -OC 1-6 alkyl;

[0129] The optimal selections for R2, R3, R6 and R7 are independently selected from hydrogen or deuterium.

[0130] In some embodiments, the compound of formula I is selected from:

[0131]

[0132] R 18b Independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN; preferably R. 18b It is hydrogen.

[0133] In some embodiments, R3 and R4, together with the atoms they are attached to, form a phenyl group optionally substituted with one or more substituents selected from: deuterium, halogens, C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0134] R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0135] Preferably, R2, R5, R6, and R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and C. 1-6 Alkyl, -OC 1-6 alkyl;

[0136] More preferably, R2, R5, or R7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and C. 1-6 Alkyl, -OC 1-6 Alkyl group; R6 is selected from C 1-6 alkyl;

[0137] The most preferred R2, R5 and R7 are independently selected from hydrogen or deuterium, and R6 is methyl.

[0138] In some embodiments, the compound of formula I is selected from:

[0139]

[0140] R 18a Independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0141] Preferred R 18aIndependently selected from hydrogen, deuterium, halogen, -OH, -NH2, or C 1-6 Alkyl, -OC 1-6 Alkyl; more preferably R 18a It is hydrogen.

[0142] In other embodiments, R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogens, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN;

[0143] R2, R4, and R5 are preferably selected independently from hydrogen, deuterium, and C. 1-6 Alkyl groups and halogens, R3 is selected from trifluoromethyl, cyclopropyl, -S-trifluoromethyl;

[0144] More preferably, R2, R4 and R5 are independently selected from hydrogen or deuterium, and R3 is selected from trifluoromethyl.

[0145] In some embodiments, the compound of formula I is selected from:

[0146]

[0147] In some embodiments, the compound of formula I is selected from compounds of formulas VII-a, VII-b, VII-c, VII-g, VII-h and VII-i; preferably from compounds of formulas VII-a, VII-b, VII-g and VII-h; more preferably from compounds of formula VII-a or VII-g; and most preferably from compounds of formula VII-g.

[0148] In other embodiments, R6 and R7, together with the atoms they are attached to, form a 5-6 membered heterocycle optionally substituted with one or more substituents selected from: deuterium, halogens, oxometalates, and C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0149] R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0150] In some embodiments, the compound of formula I is selected from:

[0151]

[0152] R 9f Independently selected from deuterium, halogen, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0153] R 9g Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; r is an integer selected from 0-6.

[0154] In some embodiments, the compound of formula I is selected from:

[0155]

[0156]

[0157] In some embodiments, the compound of formula I is selected from compounds of formulas VIII'-a, VIII'-c, VIII'-d, VIII'-f, VIII'-g, VIII'-j, VIII'-k, VIII'-l, and VIII'-m; preferably from compounds of formulas VIII'-a, VIII'-c, VIII'-d, VIII'-f, VIII'-g, VIII'-j, and VIII'-l; more preferably from compounds of formulas VIII'-a, VIII'-c, VIII'-d, and VIII'-j; and most preferably from compounds of formula VIII'-a or VIII'-d.

[0158] In some embodiments, R6 and R7, together with the atoms they are attached to, form a benzene ring optionally substituted with one or more substituents selected from: deuterium, halogens, oxometalates, and C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0159] R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0160] In some embodiments, the compound of formula I is selected from:

[0161]

[0162] R 9k Independently selected from deuterium, halogen, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0163] Preferred R 9k Independently selected from deuterium, halogen, oxo, C 1-6 Alkyl, -OC 1-6Alkyl groups. In some embodiments, in compounds of formulas VII-a to VII-k, VII'-a, VIII-a to VIII-g, and VIII'-a to VIII'-m, R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, and optionally the following groups substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen; more preferably R 9k Independently selected from deuterium, halogen, oxo, and halogenated C 1-6 Alkyl, halogenated -OC 1-6 Alkyl; most preferred R 9k Independently selected from deuterium, halogens, and C 1-6 Alkyl, -OC 1-6 alkyl.

[0164] In some embodiments, R2 and R4 are independently selected from hydrogen, deuterium, and halogens, and R3 and R5 are independently selected from hydrogen, deuterium, halogens, and C optionally substituted with one or more deuterium or halogens. 1-6 alkyl.

[0165] In some embodiments, R2 and R4 are hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen, halogen or methyl; preferably R2, R4 and R5 are hydrogen, and R3 is trifluoromethyl.

[0166] In some embodiments, R6 and R7, together with the atoms they are attached to, form a 5-6 membered heteroaryl group optionally substituted with one or more substituents selected from: deuterium, halogen, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; preferably, the 5-6 membered heteroaryl group is pyridine;

[0167] R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0168] In some embodiments, R6 and R7, together with the atoms they are attached to, form a 5-6 membered heteroaryl group comprising 1-2 heteroatoms, optionally substituted with one or more substituents selected from: deuterium, halogens, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; the heteroatom is selected from oxygen, nitrogen, and sulfur atoms, preferably from nitrogen atoms.

[0169] In some embodiments, the compound of formula I is selected from:

[0170]

[0171] X is selected from oxygen atoms or sulfur atoms; R 18c Selected from deuterium, halogens, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more halogens; preferably R 18c Independently selected from deuterium, halogens, and C 1-6 Alkyl, -OC 1-6 alkyl;

[0172] a is selected from an integer between 0 and 3; preferably a is selected from an integer between 0 and 1; more preferably a is 0;

[0173] Z, R2, R3, R4, R5, and R8 are defined as in Equation I.

[0174] In some embodiments, compounds of formulas Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or pharmaceutically acceptable salts thereof, wherein R 18c Independently selected from deuterium, halogens, and C 1-6 Alkyl, -OC 1-6 alkyl.

[0175] In some embodiments, compounds of formulas Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or pharmaceutically acceptable salts thereof, wherein R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, and optionally substituted with one or more of the following groups: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6Cycloalkylmethylene, wherein the substituent is deuterium or halogen.

[0176] In some embodiments, compounds of formulas Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or pharmaceutically acceptable salts thereof, wherein R2 and R4 are independently selected from hydrogen, deuterium, and halogens, and R3 and R5 are independently selected from hydrogen, deuterium, halogens, and C optionally substituted with one or more deuterium or halogens. 1-6 alkyl.

[0177] In some embodiments, compounds of formulas Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or pharmaceutically acceptable salts thereof, wherein R2 and R4 are hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen or methyl; preferably R2, R4, and R5 are hydrogen, and R3 is trifluoromethyl.

[0178] This disclosure also provides compounds of formula I' or pharmaceutically acceptable salts thereof.

[0179]

[0180] Among them, R 11 Selected from -OH, -NH2, -CN, -OC 1-6 Alkyl, -C 1-6 Alkyl-OH or -NHC(=O)-C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted by one or more substituents selected from the following: deuterium, halogen, -OH, -NH2 and -CN;

[0181] R 13 Selected from the following groups, which may be substituted with one or more substituents: C 2-6 Alkyl, -SC 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the substituent is selected from deuterium, halogens and -OH.

[0182] R 15 R 16 and R 17 Independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted by one or more substituents selected from the following: deuterium, halogen, -OH, -NH2 and -CN;

[0183] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0184] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C1-6 Alkyl or -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0185] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or C 3-6 The cycloalkylmethylene group may be further substituted with one or more deuterium or halogens.

[0186] In some implementation schemes, R 13 Selected from ethyl, n-propyl, isopropyl, and n-butyl, preferably ethyl;

[0187] In one implementation, R 13 It is -S-CF3.

[0188] In some implementation schemes, R 13 Selected from:

[0189]

[0190] Preferred More Optimal

[0191] In one implementation, R 11 It is -OH.

[0192] In one implementation, R 11 It is -NH2.

[0193] In some implementation schemes, R 11 -OC can be optionally replaced by deuterium or halogen. 1-6 Alkyl; preferably methoxy or ethoxy; more preferably methoxy.

[0194] In one implementation, R 11 It is -CH2OH.

[0195] In some implementation schemes, R 11 -NHC(=O)-C can be optionally substituted with deuterium or halogen. 1-6 Alkyl group; preferably -NHC(=O)-CH3.

[0196] In some implementation schemes, R 15 R 16 and R 17 It is independently selected from hydrogen, deuterium, fluorine and methyl.

[0197] This disclosure also provides compounds of formula I” or pharmaceutically acceptable salts thereof.

[0198]

[0199] Among them, R 21 Selected from -NH2, -OC 1-6 Alkyl, -C 1-6 Alkyl-OH or -NHC(=O)-C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted by one or more substituents selected from the following: deuterium, halogen, -OH, -NH2 and -CN;

[0200] R 23 Selected from chlorine or C, optionally substituted with one or more deuterium or halogens. 1-6 alkyl;

[0201] R 25 R 26 and R 27 Independently selected from hydrogen, deuterium, halogens, -OH, -NH2, and C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted by one or more substituents selected from the following: deuterium, halogen, -OH, -NH2 and -CN;

[0202] Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3;

[0203] R8 is selected from aryl, heteroaryl, heterocyclic, and C groups, which are optionally substituted with one or more substituents. 3-8 cycloalkyl, C 1-6 Alkyl or -OC 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogen, oxo, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl or C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0204] R 8a and R 8b The following groups are independently selected from hydrogen, deuterium, or optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkylmethylene, wherein the above substituents may optionally be further substituted with one or more deuterium or halogens;

[0205] And, when R 23 When it is methyl, R 21 It is not methoxylated.

[0206] In one implementation, R 21 It is -NH2.

[0207] In some implementation schemes, R 21-OC can be optionally replaced by deuterium or halogen. 1-6 Alkyl; preferably methoxy or ethoxy; more preferably methoxy.

[0208] In one implementation, R 21 It is -CH2OH.

[0209] In some implementation schemes, R 21 -NHC(=O)-C can be optionally substituted with deuterium or halogen. 1-6 Alkyl group; preferably -NHC(=O)-CH3.

[0210] In some implementation schemes, R 23 C is optionally substituted with one or more fluorine molecules. 1-6 Alkyl group, preferably trifluoromethyl.

[0211] In one implementation, R 23 It is chlorine.

[0212] In some implementation schemes, R 25 R 26 and R 27 It is independently selected from hydrogen, deuterium, fluorine and methyl.

[0213] In some embodiments, Z is O in the compounds disclosed herein.

[0214] In some embodiments, in the compounds disclosed herein, Z is -NH-(CH2)n-, and n is an integer selected from 0 to 2; n is preferably 0 or 1; n is more preferably 0.

[0215] In some embodiments, in the compounds disclosed herein, R8 is selected from 5-10 membered heterocyclic groups optionally substituted with one or more substituents, said substituents being selected from deuterium, halogen, oxo, -OR 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0216] R 8a and R 8b Independently selected from hydrogen, deuterium, and the following groups optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or C 3-6 The cycloalkylmethylene group may be further substituted with one or more deuterium or halogens.

[0217] In some implementations, R8 is selected from:

[0218]

[0219] R 10a Selected from hydrogen, deuterium, halogen, oxo, -OH, -NH2, -COOH, -CN, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0220] R 10b Selected from hydrogen, deuterium, and C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; s is an integer selected from 0-15.

[0221] In some implementations, R8 is selected from:

[0222]

[0223] Preferred More preferably Optimal

[0224] In some implementations, R8 is Preferred

[0225] In other embodiments, in the compounds of this disclosure, R8 is selected from aryl or heteroaryl groups optionally substituted with one or more substituents, said substituents being selected from deuterium, halogen, oxo, -OR 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0226] R 8a and R 8b Independently selected from hydrogen, deuterium, and the following groups optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or C 3-6 The cycloalkylmethylene group may be further substituted with one or more deuterium or halogens.

[0227] In some implementations, R8 is selected from:

[0228]

[0229] R 10c Selected from hydrogen, deuterium, halogens, -OH, -NH2, -COOH, -CN, -C(=O)2NH2, -S(=O)2NH2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0230] R 10d Selected from hydrogen, deuterium, and C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; t is an integer selected from 0-7.

[0231] In some implementations, R8 is selected from:

[0232]

[0233] Preferred More preferably

[0234] In other embodiments, in the compounds of the present disclosure described above, R8 is selected from C14 compounds optionally substituted with one or more substituents. 3-8 cycloalkyl groups, wherein the substituents are selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, the C 1-4 The alkyl group may optionally be further substituted with one or more deuterium, halogen, or -OH groups.

[0235] In some implementations, R8 is selected from:

[0236]

[0237] R 10e R 10f R 10e’ R 10f’ Independently selected from hydrogen, deuterium, halogens, -OH and C 1-4 Alkyl, the C 1-4 The alkyl group may optionally be further substituted with one or more deuterium, halogen, or -OH groups.

[0238] In some implementations, R8 is selected from:

[0239]

[0240] R 10e R 10e’ Independently selected from hydrogen, deuterium, halogens, -OH and C 1-4 Alkyl, the C 1-4 The alkyl group may optionally be further substituted with one or more deuterium, halogen, or -OH groups.

[0241] In some implementations, R8 is selected from:

[0242] Preferred More preferably

[0243] In other embodiments, in the compounds of the present disclosure described above, R8 is selected from C14 compounds optionally substituted with one or more substituents. 2-6 Alkyl groups, wherein the substituents are selected from deuterium, halogens, and -OR. 8a -SR 8a -C(=O)R 8a -OC(=O)R 8a -C(=O)OR 8a -C(=O)NR 8a R 8b -NR 8a R 8b -NR 8a C(=O)R 8b -NR 8a S(=O)2R 8b -S(=O)2R 8a -S(=O)2NR 8a R 8b -CN, -NO2, C 1-4 Alkyl and C 3-6 cycloalkyl, the C 1-4 Alkyl or C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium, halogen or -OH groups;

[0244] R 8a and R 8b Independently selected from hydrogen, deuterium, and the following groups optionally substituted with one or more substituents: C 1-4 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -NH2, -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or C 3-6 The cycloalkylmethylene group may be further substituted with one or more deuterium or halogens.

[0245] In some implementations, R8 is selected from:

[0246]

[0247] R 10g Selected from hydrogen, deuterium, halogens, -NH2, -OH, -CN, -NH-C 1-4 Alkyl and -N(C) 1-4 Alkyl)2, the C 1-4 The alkyl group may be optionally substituted with one or more deuterium, halogen or -OH groups.

[0248] Secondly, this disclosure provides compounds selected from the following or pharmaceutically acceptable salts thereof:

[0249]

[0250]

[0251] Thirdly, this disclosure provides compounds selected from the following or pharmaceutically acceptable salts thereof:

[0252]

[0253]

[0254] Fourthly, this disclosure also provides an isotopically substituted derivative of the aforementioned compound, preferably wherein the isotopic substitution is deuterium substitution.

[0255] Fifthly, this disclosure also provides a pharmaceutical composition comprising the compounds described in the first to third aspects or their pharmaceutically acceptable salts or isotopic substitutes described in the fourth aspect, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0256] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0257] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.

[0258] This disclosure also provides the use of the compounds described in the first, second, or third aspects, or their pharmaceutically acceptable salts, as medicines.

[0259] In a sixth aspect, this disclosure also provides the use of the compounds described in the first, second, or third aspects or their pharmaceutically acceptable salts, or the isotope substitutes described in the fourth aspect, or the pharmaceutical compositions described in the fifth aspect, in the preparation of medicaments for treating diseases related to NLRP3 activity.

[0260] This disclosure also provides a method for preventing and / or treating a patient with a disease associated with NLRP3 activity, by administering to the patient a therapeutically effective amount of the compound described in the first, second, or third aspect or a pharmaceutically acceptable salt thereof, or an isotope substitute described in the fourth aspect, or a pharmaceutical composition described in the fifth aspect.

[0261] This disclosure also provides a compound or pharmaceutically acceptable salt thereof as described in the first, second, or third aspect for the prevention or treatment of diseases associated with NLRP3 activity, or an isotope substitute as described in the fourth aspect, or a pharmaceutical composition as described in the fifth aspect.

[0262] This disclosure also provides a method for preventing and / or treating a patient with a disease associated with NLRP3 activity by administering to the patient a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0263] Diseases associated with NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0264] This disclosure also provides the use of the compounds described in the first, second, or third aspect or their pharmaceutically acceptable salts, or the isotope substitutes described in the fourth aspect or the pharmaceutical compositions described in the fifth aspect in the preparation of medicaments for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0265] This disclosure also provides the use of the compounds described in the first, second, or third aspect or their pharmaceutically acceptable salts, or the isotope substitutes described in the fourth aspect or the pharmaceutical compositions described in the fifth aspect in the preparation of medicaments for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

[0266] This disclosure also provides a compound or pharmaceutically acceptable salt thereof described in the first, second, or third aspect for treating inflammatory body-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases, or an isotope substitute described in the fourth aspect or a pharmaceutical composition described in the fifth aspect.

[0267] This disclosure also provides a method for treating and / or preventing patients with inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases by administering a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, to the patient. The inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases may specifically be selected from: autoinflammatory febrile syndromes (such as cryopyridine-associated periodic syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation), type I or type II diabetes and its complications (such as nephropathy, visual impairment). Retinopathy), neuroinflammatory diseases (such as brain infections, acute injuries, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases), cardiovascular and metabolic disorders or diseases (such as reduced risk of cardiovascular disease (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure, and hypertension), wound healing, scar formation, inflammatory skin diseases (such as acne, hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / conditions (such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, and colon cancer).

[0268] In some embodiments, the compounds described in this disclosure, compared to compound R1, compound R2, or compound R3, have different AUC or C values ​​in blood after oral administration. max It is expected to increase by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or even higher.

[0269] This disclosure also provides the following compounds,

[0270]

[0271] Y is selected from fluorine, chlorine, bromine, and iodine; preferably, Y is selected from fluorine, chlorine, and bromine; more preferably, Y is selected from chlorine;

[0272] R6, R7, Z, and R8 are defined as in Equation I;

[0273] In some implementations, the compound is used as an intermediate.

[0274] In some embodiments, R6 and R7, together with the atoms they are attached to, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring, a phenyl group, or a 5-6 membered heteroaryl group optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens;

[0275] R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

[0276] The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure can react with acidic or basic substances to form the corresponding salts.

[0277] On the other hand, the compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0278] Furthermore, the compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0279]

[0280] All compounds in this invention can be designated as type A or type B. All tautomers are within the scope of this invention. The nomenclature of compounds does not exclude any tautomers.

[0281] The compounds disclosed herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0282] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, 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 desired enantiomer in pure form. 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 salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0283] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0284] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium 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 natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0285] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0286] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. Although all the above structural formulas are drawn in some isomer forms for simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0287] Terminology Explanation:

[0288] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0289] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0290] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. 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 their various branched isomers. Unless otherwise specified, alkyl groups may be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 The aryl or 5- to 6-membered heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0291] "Cycloalkyl" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0292] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. Unless otherwise specified, the cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0293] "Heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being 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 monocyclic heterocyclic alkyl groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups. Non-limiting examples of "heterocyclic alkyl" include:

[0294]

[0295] etc.

[0296] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from: halogen, deuterium, hydroxyl, oxo, nitro, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 The aryl or 5- to 6-membered heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0297] The heterocyclic group ring can be fused to an aromatic ring, a heteroaromatic ring, or a cyclic hydrocarbon, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0298] wait.

[0299] "Aryl" or "aromatic ring" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.

[0300] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 The aryl or 5- to 6-membered heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0301] The aryl ring may be fused to a heteroaromatic ring, heterocycle, or cyclic hydrocarbon, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0302]

[0303] "Heteroaryl" or "heteroary ring" refers to a heteroaryl 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, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. etc.

[0304] Examples of heteroaryl groups containing a nitrogen atom include, but are not limited to, pyrrole, piperazine, pyrimidinyl, imidazole, pyridazinyl, pyrazine, tetrazolyl, triazolyl, pyridinyl, pyrazolyl, oxazolyl, or thiazolyl.

[0305] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy group, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 The aryl or 5- to 6-membered heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0306] The heteroaryl ring may be fused to an aromatic ring, heterocycle, or cyclic hydrocarbon, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0307]

[0308] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0309] "Being replaced by one or more A, B..." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents, or a combination of one or a plurality of different substituents. Detailed Implementation

[0310] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0311] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0312] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. 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 configurations of the optical isomers (isomers) of the compounds were further confirmed by measuring single-crystal parameters.

[0313] HPLC determinations were performed using a Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC high performance liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column, or Ultimate C18 2.1*30mm column).

[0314] MS measurements were performed using a Waters SQD2 mass spectrometer in positive / negative ion mode, with a mass scan range of 100–1200.

[0315] Chiral HPLC analysis was performed using the following columns: Chiralpak IC-3 100×4.6mm ID, 3µm; Chiralpak AD-3 150×4.6mm ID, 3µm; Chiralpak AD-3 50×4.6mm ID, 3µm; Chiralpak AS-3 150×4.6mm ID, 3µm; Chiralpak AS-3 100×4.6mm ID, 3µm; ChiralCel OD-3 150×4.6mm I.D., 3µm; Chiralcel OD-3 100×4.6mm ID, 3µm; ChiralCel OJ-H 150×4.6mm ID, 5µm; and Chiralcel OJ-3 150×4.6mm ID, 3µm.

[0316] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0317] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0318] Normal column chromatography generally uses Yantai Huanghai silica gel of 100-200 mesh, 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0319] Reversed-phase column chromatography typically uses Changzhou Sante pre-packed ultrapure C18 silica gel columns (20-45μm). 40g, 80g, 120g, 220g or other sizes).

[0320] The high-pressure column purification system uses Waters AutoP, in conjunction with the Waters XBridge BEH C18 OBDPrep Column. 5μm, 19mm x 150mm or Atlantis T3OBD Prep Column, 5μm, 19mm x 150mm.

[0321] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0322] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0323] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0324] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0325] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0326] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0327] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0328] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0329] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0330] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0331] Example 1

[0332] (R)-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol

[0333]

[0334] Step 1: Synthesis of (R)-4-chloro-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine (compound 1c)

[0335]

[0336] Compound 1a (100 mg, 0.492 mmol), compound 1b (56.23 mg, 0.492 mmol), and diisopropylethylamine (0.24 mL, 1.48 mmol) were mixed in NMP and reacted thoroughly in a microwave oven at 180 °C. After cooling to room temperature, the reaction was quenched with 1 M sodium hydroxide. The mixture was extracted with dichloromethane, separated, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to give compound 1c (30 mg, yield 19.5%).

[0337] LCMS:t R =0.575min in 5-95AB_1min_220&254_Agilent.M ES-MS m / z 281.1[M+H] + .

[0338] Step 2: Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol (Compound 1)

[0339]

[0340] Compound 1c (15 mg, 0.053 mmol), compound 1d (17.60 mg, 0.085 mmol), and 1 M sodium bicarbonate solution (0.13 mL) were mixed in dioxane (1 mL). Tetraphenylphosphine palladium (12.35 mg, 0.011 mmol) was added under nitrogen atmosphere. The mixture was then microwaved at 160 °C under nitrogen atmosphere until fully reacted. After cooling to room temperature, the mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by reversed-phase preparative HPLC [column: Boston Prime C18 150*30 mm*5 μm, 20-60% (A: water 0.05% ammonia v / v, B: acetonitrile), flow rate: 30 mL / min] and then lyophilized to obtain compound 1 (5.1 mg, yield 23.7%).

[0341] LCMS:tR=3.140min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m / z 407.2[M+H]+.

[0342] 1H NMR: (400MHz, DMSO-d6)δ=7.41-7.15(m,3H),3.89(br d,J=15.3Hz,1H),3.97-3.80(m,1H),3.51-3.37(m,7H),2.56-2.51(m,3H),2.47-2.25(m,3H),2.15-1.51(m,3H),1.30-1.11(m,2H)

[0343] Example 2 (R)-2-(4-((1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-cyclopentane[d]pyridazin-1-yl)-5-(trifluoromethyl)

[0344] phenol

[0345]

[0346] Compound 2 was prepared using 2a as the starting material, following the method described in Example 1.

[0347] LCMS:t R =3.75 min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m / z 393.2[M+H]+.

[0348] 1 H NMR: (400 MHz, DMSO-d6) δppm 13.52(br s,1H),7.75(br d,J=8.4 Hz,1H),7.22(br s,2H),6.35(br d,J=7.6 Hz,1H),4.29-4.19(m,1H),3.11(br t,J=7.2 Hz,2H),2.94(br d,J=8.8 Hz,1H),2.78(br t,J=7.2 Hz,2H),2.69-2.60(m,1H),2.18(s,3H),2.12-2.01(m,2H),1.96-1.81(m,3H),1.75-1.66(m,1H),1.62-1.49(m,1H),1.44-1.30(m,1H).

[0349] Example 3

[0350] (R)-2-(4-((1-methylpiperidin-3-yl)amino)o-phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0351]

[0352] Compound 3 was prepared using 3a as the starting material, following the method described in Example 1.

[0353] LCMS:t R =1.027 min in 10-80AB_4min_220&254_Shimadzu.lcm(ChromolithFlash RP-C18 25-3mm),MS(ESI)m / z=403.2[M+H]+.

[0354] 1 H NMR: (400MHz, CDCl3) δppm 8.88 (br s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.96 (t, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.0 Hz,1H),7.39(s,1H),7.24(d,J=8.4 Hz,1H),5.12(br,1H),3.87-3.67(m,1H),3.66-3.53(m,1H),3.14-3.03(m,1H),2.94-2.8 0(m,4H),2.77(br,1H),2.57-2.43(m,1H),2.36(br,1H),1.89(br,1H),1.81-1.70(m,1H).

[0355] Example 4

[0356] (R)-5-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol

[0357]

[0358] Step 1: Synthesis of (Compound 4c)

[0359]

[0360] Compound 4a (250 mg, 1.173 mmol), compound 4b (1.520 mL, 5.867 mmol), and potassium acetate (345.45 mg, 3.520 mmol) were mixed in dioxane (6 mL). Pd(dppf)Cl2·CH2Cl2 (96.76 mg, 0.117 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 90 °C under nitrogen atmosphere until fully reacted. After cooling to room temperature, water (15 mL) was added for dilution. The mixture was extracted with ethyl acetate (20 mL x 2), separated, and the combined organic phases were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 0-20% ethyl acetate in n-hexane) to give compound 4c (170 mg, yield 55.7%).

[0361] 1 H NMR (400MHz, CDCl3) δppm 7.92 (s, 1H), 7.44 (d, J = 7.6Hz, 1H), 6.82 (d, J = 7.2Hz, 1H), 2.93-2.88 (m, 4H), 2.11-2.06 (m, 2H), 1.36 (s, 12H).

[0362] Step 2: Synthesis of (compound 4f)

[0363]

[0364] Compound 4d (200 mg, 1.227 mmol), compound 4e (168.12 mg, 1.472 mmol), and diisopropylethylamine were mixed in NMP (2 mL) and reacted thoroughly in a microwave at 120 °C. After cooling to room temperature, the mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), separated, and the combined organic phases were washed with brine (5 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 0-10% methanol in dichloromethane) to give compound 4f (80 mg, yield 27.1%).

[0365] Step 3: Synthesis of (Compound 4)

[0366]

[0367] Compound 4 was prepared using compounds 4c and 4f as starting materials, following the method described in step 2 of Example 1.

[0368] LCMS:t R=2.8min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m / z 339.2(M+H) + .

[0369] 1 H NMR(400MHz,DMSO-d6)δppm 9.71(s,1H),7.02(d,J=8.0Hz,1H),6.78(d,J=7.6Hz,1H),6.72(s,1H),6.61(d,J=8.0Hz,1H),4.04(s,1H),2.90-2 .84(m,4H),2.18(s,3H),2.08(s,3H),2.04-2.02(m,3H),1.89-1.77(m,2H),1.45-1.64(m,2H),1.23-1.33(m,2H).

[0370] Example 5

[0371] (R)-3-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)naphthyl-2-ol

[0372]

[0373] Compound 5 was prepared from compound 5a using the method described in Example 4.

[0374] 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 8.22(s,1H),7.82(d,J=8.0Hz,1H),7.72(d,J=8Hz,2H),7.42(t,J=7.4Hz,1H), 7.29(t,J=7.4Hz,1H),7.24(s,1H),6.71(s,1H),6.65(d,J=8.0Hz,1H),4.06(s, 1H),2.94(br,1H),2.60-2.55(m,1H),2.47-2.41(m,1H),2.33(s,1H),2.09(s,1 H),1.87-1.84(m,1H),1.72-1.75(m,1H),1.60-1.56(m,1H),1.37-1.42(m,1H).

[0375] Example 6

[0376] (R)-6-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-5-ol

[0377]

[0378] Compound 6 was prepared using compound 6a as the starting material, following the method described in Example 4.

[0379] LCMS:t R =2.9min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m / z 339.2(M+H) + .

[0380] 1 H NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),6.97(s,1H),6.76(s,1H),6.65(s,1H),6.50(d,J=8.0Hz,1H),4.08-3.95(m,1H),2.8 0(br,5H),2.17(s,3H),2.07-1.97(m,6H),1.85(br,3H),1.70(br,1H),1.53(br,1H),1.27(br,1H)

[0381] Example 7

[0382] 4-(4-methyl-6-((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-5-ol

[0383]

[0384] Step 1: Synthesis of (Compound 7b)

[0385]

[0386] Compound 7a (100 mg, 0.415 mmol) and zinc powder (271 mg, 4.15 mmol) were mixed in acetic acid (2 mL) and stirred at 100 °C until fully reacted. After cooling to room temperature, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3). The liquid-liquid mixture was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 10-20% ethyl acetate in petroleum ether) to give compound 7b (40 mg, yield 34.0%).

[0387] 1¹H NMR: (400MHz, CDCl₃) δppm 7.09 (d, J = 8.0Hz, 1H), 6.70 (d, J = 8.4Hz, 1H), 3.88 (s, 3H), 2.96 (q, J = 7.2Hz, 4H), 2.15–2.06 (m, 2H). Step 2: Synthesis of (compound 7d)

[0388]

[0389] Compound 7d was prepared using compound 7b as the starting material, following the method described in Example 4.

[0390] LCMS:t R =2.973min in 0-30AB_7min_220&254_Shimadzu.lcm ES-MS m / z=353.2[M+H] + .

[0391] 1 H NMR: 1 H NMR (400MHz, CDCl3) δppm 7.23-7.18(m,1H),6.87-6.74(m,2H),3.75(s,1H),3.71-3.71(m,1H),3.71(s,2H),2.93-2.86(m,4H ),2.60-2.46(m,4H),2.42-2.32(m,3H),2.07-2.01(m,3H),1.99(s,3H),1.90-1.72(m,2H),1.26(br t,J=7.2Hz,1H).

[0392] Step 3: Synthesis of (Compound 7)

[0393]

[0394] A solution of compound 7d (30 mg, 0.085 mmol) in dichloromethane (2 mL) was cooled to -78 °C, and boron tribromide (213 mg, 0.85 mmol) was added dropwise. The mixture was then brought to room temperature and stirred until fully reacted. The reaction was quenched with methanol (2 mL), and the solvent was removed under vacuum to obtain the crude product. Compound 7 (5.8 mg, yield 20.1%) was purified by reversed-phase preparative HPLC (Column Boston Prime C18 150*30mm*5µm; Condition water (0.05% ammonia hydroxide v / v)-ACN; Begin B 40; End B 70; Flow Rate (ml / min)).

[0395] LCMS:t R =4.403min in 0-60CD_7min_220&254_Shimadzu.lcm,MS(ESI)m / z=339.3[M+H] + .

[0396] 1 H NMR: (400MHz, CD3OD) δppm 7.08(d,J=8.0Hz,1H),6.76(s,1H),6.68(d,J=8.0Hz,1H),4.12(dt,J=4.6,9.2Hz,1H),3.17-3 .02(m,1H),2.92-2.83(m,2H),2.79(brdd,J=8.0,16.4Hz,2H),2.33(d,J=2.1Hz,4H),2.20(br d,J=6.4Hz,2H),2.04(d,J=0.8Hz,6H),1.90-1.78(m,1H),1.78-1.64(m,1H),1.45-1.41(m,1H).

[0397] Example 8

[0398] (R)-6-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazine-3-amine

[0399]

[0400] Step 1: Synthesis of (Compound 8b)

[0401]

[0402] Compound 8a (3.0 g, 11.86 mmol) was dissolved in dichloromethane (30 mL), and DAST (3.82 g, 23.7 mmol) was added. The mixture was stirred at room temperature until fully reacted. The reaction was quenched with water (50 mL), diluted with dichloromethane (50 mL), separated, and the organic phase was washed with saturated sodium bicarbonate solution (30 mL). The separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give compound 8b (3.10 g, yield 95.1%).

[0403] 1 H NMR (400MHz, CDCl3)Shift=7.92(s,1H),7.77(d,J=8.3Hz,1H),7.59(d,J=8.3Hz,1H),6.92(t,J=54.4Hz,1H)

[0404] Step 2: Synthesis of (Compound 8)

[0405]

[0406] Compound 8 was prepared from compound 8b using the method described in Example 4.

[0407] LCMS:t R =2.25min in 5-95AB_7min_220&254_Agilent.M ES-MS m / z 362.2[M+H] + .

[0408] 1 H NMR (400MHz, CDCl3)Shift=8.61(s,1H),8.05(s,1H),7.79(d,J=7.9Hz,1H),7.43(d,J=8.1Hz,1H),7.68(t,J=55.4Hz,1H),6.72(s,1H),4.46(br s,2H),3.03-2.73(m,2H),2.48(s,4H),2.24-1.87(m,5H),1.82-1.66(m,2H)

[0409] Example 9

[0410] (R)-3-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)naphthyl-2-ol

[0411]

[0412] Compound 9 was prepared using compound 9a as the starting material, following the method described in Example 4.

[0413] LCMS:t R =2.76min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m / z349.2[M+H] + .

[0414] Example 10

[0415] (R)-1-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)naphthyl-2-ol

[0416]

[0417] Synthesis of Step 1 (Compound 10b)

[0418]

[0419] Compound 10b was prepared using compound 10a as the starting material, following the method described in step 2 of Example 4.

[0420] 1 H NMR: (400MHz, CDCl3) δppm 7.35(d,J=9.2Hz,1H),6.93(d,J=9.2Hz,1H),4.00-3.94(m,1H),2.79-2.75(m,1H),2.49-2.47(m,1H),2.16(s,3H) ,2.06-2.03(m,1H),1.93-1.90(m,1H),1.77-1.75(m,1H),1.69-1.67(m,1H),1.54-1.49(m,1H),1.28-1.21(m,1H).

[0421] Synthesis of step 2 (compound 10)

[0422]

[0423] Compound 10 was prepared using compound 10c as the starting material, following the method described in Example 7.

[0424] LCMS: ES-LCMS m / z 335.2 [M+H] + .

[0425] 1 H NMR: (400MHz, CDCl3) δppm 7.90 (d, J = 8.4Hz, 1H), 7.85-7.74 (m, 3H), 7.43 (t, J = 7.2Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (d, J = 9.2Hz, 1H), 6.89 (br d,J=9.2Hz,1H),4.34(br s,1H),2.83-2.51(m,3H),2.36(br s,3H),1.89(br s,5H),1.26(br s,1H).

[0426] Example 11

[0427] rac-(R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-((trifluoromethyl)thio)phenol

[0428]

[0429] Synthesis of step 1 (compound 11b)

[0430]

[0431] Compound 11a (2 g, 10.0 mmol) was mixed in 50% sulfuric acid (40 mL). The mixture was cooled to -5 °C, and sodium nitrite (759 mg, 11 mmol) solution (20 mL) was added dropwise while maintaining the temperature. Then, cuprous thiocyanate (20 mmol) and potassium thiocyanate (20 mmol) were added, and the final mixture was stirred at 0 °C until fully reacted. The mixture was filtered, and the filter cake was collected and dissolved in ethyl acetate (50 mL). The cake was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered again. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 2-10% ethyl acetate in petroleum ether) to give compound 11b (0.5 g, yield 20.7%).

[0432] 1 H NMR: (400MHz, CDCl3) δppm 7.59 (d, J = 8.0Hz, 1H), 7.04-6.98 (m, 2H), 3.95 (s, 3H).

[0433] Synthesis of step 2 (compound 11c)

[0434]

[0435] Potassium trifluoroacetate (374 mg, 2.46 mmol), ferrous chloride (78 mg, 0.61 mmol), and compound 11b (500 mg, 2.05 mmol) were mixed in DMF (5 mL) and stirred thoroughly at 140 °C under a nitrogen atmosphere. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), separated, and the combined organic phases were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 0-3% ethyl acetate in petroleum ether) to give compound 11c (40 mg, yield 34.0%).

[0436] 1 H NMR: (400MHz, DMSO-d6) δppm 7.76 (d, J = 8.4Hz, 1H), 7.39 (d, J = 1.6Hz, 1H), 7.24 (dd, J = 1.6, 8.0Hz, 1H), 3.91 (s, 3H).

[0437] Synthesis of step 3 (compound 11)

[0438]

[0439] Compound 11 was prepared using compound 11c as the starting material, following the method described in Example 7.

[0440] LCMS:t R =1.161min in 10-80AB_7min_220&254_Shimadzu.lcm; MS(ESI)m / z=399.2[M+H] + .

[0441] 1 H NMR: (400MHz, CDCl3) δppm 8.58 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.42-7.37 (m, J = 1.5Hz, 1H), 7.17 (d, J = 8.4Hz, 1H), 6.85 (s, 1H), 4.56 (br s,1H),3.09(br s,2H),2.79(br s,2H),2.55(br s,3H),2.46(s,4H),1.82-1.63(m,J=14.9Hz,2H),1.26(s,1H).

[0442] Example 12

[0443] (R)-3-hydroxy-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzoic acid

[0444]

[0445] Compound 12 was prepared using compound 12a as the starting material, following the method described in Example 7.

[0446] LCMS: ES-LCMS m / z 343.1 [M+H] + .

[0447] 1 H NMR: (400MHz, DMSO-d6) δppm 13.97 (br s, 1H), 8.08 (s, 1H), 7.87 (d, J=8.4Hz, 1H), 7.44-7.36 (m, 2H), 6.21 (br d, J=7.6Hz, 1H), 4.24 (br d,J=8.4Hz,1H),2.92(br d,J=7.6Hz,2H),2.61(br s,2H),2.23(s,3H),2.19(s,3H),1.97-1.90(m,2H),1.86(br s,1H),1.73-1.67(m,1H),1.62-1.53(m,1H),1.48-1.39(m,1H).

[0448] Example 13

[0449] (R)-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)pyridin-3-ol

[0450]

[0451] Compound 13 was prepared using compound 13a as the starting material, following the method described in Example 7.

[0452] 1 H NMR: (400MHz, CDCl3) δ = 8.48 (s, 1H), 8.16 (d, J = 5.2Hz, 1H), 7.35 (d, J = 5.2Hz, 1H), 6.67 (s, 1H), 5.57 (br s, 1H), 4.20 (br s, 1H), 2.55 (br s,2H),2.49(s,3H),2.30(s,3H),2.24-2.18(m,1H),1.91-1.52(m,6H).

[0453] Example 14

[0454] 5-(6-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol

[0455]

[0456] Synthesis of Step 1 (Compound 14b)

[0457] Compound 14b was prepared using compound 14a as the starting material, following the method described in step 2 of Example 4.

[0458] LCMS:t R =0.4min in 5-95AB_1min_220&254_Agilent.M ES-MS m / z 228.1[M+H] + .

[0459] 1 H NMR: (400MHz, CDCl3) δppm 7.03(s,1H),4.42(br s,1H),4.28(br s,1H),3.87(br s,1H),2.73(br s,2H),2.44(s,3H),2.20-2.16(m,2H),1.46(s,3H).

[0460] Synthesis of step 2 (compound 14)

[0461] Compound 14 was prepared using compound 14b as the starting material, following the method described in step 2 of Example 1.

[0462] LCMS:t R =2.761min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m / z 326.2[M+H] + .

[0463] 1 H NMR:(400MHz,DMSO-d6)δppm 9.70(br s,1H),7.01(d,J=7.6Hz,1H),6.95(d,J=6.8Hz,1H),6.77(d,J=7.6Hz,1H),6.64(s,1H),4.99(s,1H),3.97-3.8 5(m,1H),2.89-2.82(m,4H),2.45-2.37(m,2H),2.09(s,3H),2.07-1.99(m,2H),1.98-1.90(m,2H),1.28(s,3H).

[0464] Example 15

[0465] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)o-phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0466]

[0467] Compound 15 was prepared using 3a as the starting material, following the method described in Example 14.

[0468] LCMS:t R =2.415min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m / z 390.1[M+H] + .

[0469] 1H NMR: (400MHz, DMSO-d6) δppm 10.34 (br s, 1H), 8.42 (d, J = 8.4Hz, 1H), 7.89-7.82 (m, 1H), 7.77 (t, J = 7.2Hz, 1H), 7.62 (br d,J=5.6Hz,1H),7.50(d,J=7.8Hz,1H),7.43(d,J=8.0Hz,1H),7.32-7.24(m,2H),5.00(s,1H),4.31-4.14(m,1H),2.46(br d,J=2.8Hz,2H),2.22-2.13(m,2H),1.33(s,3H).

[0470] Example 16

[0471] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0472]

[0473] Synthesis of Step 1 (Compound 16b)

[0474]

[0475] Compound 16a (1 g, 11.6 mmol) and potassium carbonate (0.16 g, 1.16 mmol) were mixed in tetrahydropyrrole (0.95 mL, 11.6 mmol). The mixture was stirred at 0 °C until fully reacted, filtered, and the filtrate was concentrated under vacuum to give compound 16b (1.5 g, yield 92.8%).

[0476] LCMS: ES-LCMS m / z 140.1 [M+H] + .

[0477] Synthesis of step 2 (compound 16c)

[0478]

[0479] Compound 16b (300 mg, 2.16 mmol) and 3,6-dichlorotetraazine (325 g, 2.16 mmol) were mixed in dichloromethane (5 mL). The mixture was stirred at 0 °C until fully reacted, diluted with water (5 mL), and extracted with dichloromethane (5 mL x 3). The mixture was separated, and the combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 0-20% ethyl acetate in petroleum ether) to give compound 16c (70 mg, yield 15.3%).

[0480] LCMS:t R =0.568min in 5-95AB_1min_220&254_Agilent.M ES-MS m / z 191.0(M+H)+

[0481] 1 H NMR: (400MHz, CDCl3) δppm 5.24 (s, 4H)

[0482] Synthesis of step 3 (compound 16)

[0483]

[0484] Compound 16 was prepared using 16c as the starting material, following the method described in Example 1.

[0485] 1 H NMR (400MHz, DMSO-d6) δ=8.14(s,1H),7.47(br d,J=8.0Hz,1H),7.26-7.22(m,2H),6.88(br d,J=7.0Hz,1H),5.26(br s,2H),4.97(br s,2H),4.30(br s,1H),2.33(br s,3H),2.15-1.88(m,4H),1.77(br s,1H),1.61(br d,J=12.0Hz,1H),1.38(br d,J=12.3Hz,1H),1.23(br s,2H).

[0486] Example 17

[0487] 4-(4-methyl-6-((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-5-ol

[0488]

[0489] Compound 17 was prepared using 7c as the starting material, following the method described in Example 7.

[0490] LCMS: ES-LCMS m / z 339.2 [M+H] + .

[0491] Example 18

[0492] (R)-5-Cyclopropyl-2-(4-Methyl-6-((1-Methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0493]

[0494] Synthesis of Step 1 (Compound 18b)

[0495]

[0496] Compound 18a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol), and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL). Pd(dppf)Cl₂·CH₂Cl₂ (65.9 mg, 0.080 mmol) was added under nitrogen atmosphere, and the mixture was stirred at 120 °C under nitrogen atmosphere until fully reacted. After cooling to room temperature, ethyl acetate (20 mL) was added for dilution. The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain crude compound 18b, which was used directly in the next step.

[0497] Synthesis of step 2 (compound 18)

[0498]

[0499] Compound 18 was prepared using 18b as the starting material, following the method described in Example 7.

[0500] LCMS: ES-LCMS m / z 339.3 [M+H] + .

[0501] 1H NMR (400MHz, CDCl3) δ = 7.20 (d, J = 8.0Hz, 1H), 6.73 (d, J = 8.0Hz, 1H), 6.69 (s, 1H), 6.63 (br s, 1H), 4.32 (br s,1H),2.95-2.45(m,4H),2.41(s,3H),2.36-2.19(m,1H),2.05(s,3H),1. 98-1.92(m,1H),1.88-1.54(m,4H),1.05-0.95(m,2H),0.81-0.71(m,2H).

[0502] Example 19

[0503] rac-(R)-2-(4-(1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-o-phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0504]

[0505] Synthesis of step 1 (compound 19c)

[0506]

[0507] Compound 19c was prepared using 19a as the starting material, following the method described in Example 1.

[0508] LCMS: ES-LCMS m / z 493.3 [M+H] + .

[0509] Synthesis of step 2 (compound 19d)

[0510]

[0511] Compound 19c (180 mg, 0.365 mmol) was dissolved in a solution of dioxane hydrochloride (2 mL), and the mixture was stirred at room temperature until fully reacted. The solution was concentrated under vacuum to give the hydrochloride salt of compound 19d (220 mg, yield 92.0%).

[0512] LCMS: ES-LCMS m / z 393.3 [M+H] + .

[0513] Synthesis of step 3 (compound 19)

[0514]

[0515] Compound 19d (20 mg, 0.05 mmol) and diisopropylethylamine (0.017 mL, 0.10 mmol) were dissolved in acetonitrile (2 mL), and bromoethanol (6.37 mg, 0.05 mmol) was added. The mixture was stirred at 70 °C until fully reacted, and concentrated under vacuum to obtain a crude product. Compound 19 (2.9 mg, yield 12.9%) was purified by reverse-phase preparative HPLC.

[0516] LCMS: ES-LCMS m / z 437.2 [M+H] + .

[0517] 1 H NMR (400MHz, CD3OD) δ=7.37(d,J=7.8Hz,1H),7.24(d,J=8.0Hz,1H),7.18(s,1H),4.71-4.60(m,2H),3.80-3.55(m,4H),3.06(br d,J=7.3Hz,2H),2.55-2.44(m,4H),2.21-2.07(m,2H),2.03-1.84(m,4H),1.83-1.70(m,3H).

[0518] Example 20

[0519] rac-3-fluoro-2-(4-((R)-1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-cyclopentane[d]pyridazine-1-yl)phenol

[0520]

[0521] Compound 20 was prepared using 2b as the starting material, following the method described in Example 2.

[0522] LCMS:t R =0.719min in 5-95AB_1min_220&254_Agilent.M ES-MS m / z 343.1[M+H] + .

[0523] 1H NMR (400MHz, CD3OD)Shift=7.26(dt,J=6.8,8.3Hz,1H),6.78-6.66(m,2H),4.48-4.38(m,1H),3.09(br s,1H),2.88(t,J=7.5Hz,2H),2.80(t,J=7.7Hz,2H),2.70(brs,1H),2.36(s,3H),2.31(br d,J=13.1Hz,2H),2.15(quin,J=7.7Hz,2H),2.00(br s,1H),1.92-1.81(m,1H),1.79-1.68(m,1H),1.57(br s,1H)

[0524] Example 21

[0525] 5-(6-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-4,5-dimethylpyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol

[0526]

[0527] Compound 21 was prepared using 21a as the starting material, following the method described in Example 14.

[0528] LCMS:t R =0.774min in 5-95AB_1min_220&254_Agilent.M ES-MS m / z 340.2[M+H] + .

[0529] 1 H NMR (400MHz, CDCl3)Shift=7.05(d,J=7.8Hz,1H),6.81(d,J=7.8Hz,1H),4.62(br s,1H),4.41-4.24(m,1H),2.97(td,J=7.4,19.0Hz,4H),2.75(ddd,J=2.8,7.4,9.9Hz,2H),2.35(s,3H),2.18-2.06(m,8H),1.47(s,3H)

[0530] Example 22

[0531] 2-(5-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol (compound 22)

[0532]

[0533] 2-(8-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridyl[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol (compound 23)

[0534]

[0535] Compounds 22 and 23 were prepared using 22a as the starting material, following the method described in Example 15.

[0536] Compound 22

[0537] 1 H NMR: (400MHz, CD3OD) δppm 9.08(m,1H),8.00(d,J=8.0Hz,1H),7.80(dd,J=8.0,4.4Hz,1H),7.58(d,J=8.0Hz,1H),7.31(d,J =8.0Hz,1H),7.26(s,1H),4.39-4.31(m,1H),2.72-2.67(m,2H),2.27-2.21(m,2H),1.45(s,3H).

[0538] Compound 23

[0539] 1 H NMR: (400MHz, CD3OD) δppm 9.15 (br s,1H),8.80(dd,J=8.4,2.4Hz,1H),8.49(d,J=8.0Hz,1H),7.89(d,J=8.4Hz,1H),7.22( d,J=6.8Hz,1H),4.34-4.26(m,1H),2.71-2.66(m,2H),2.27-2.22(m,2H),1.46(s,3H).

[0540] Example 23

[0541] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0542] (Compound 24)

[0543]

[0544] 2-(1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0545]

[0546] Compounds 24 and 25 were prepared from compound 24a using the method described in Example 15.

[0547] Compound 24

[0548] 1 H NMR: (400MHz, CD3OD) δppm 9.70 (br s,1H),8.84(d,J=6.0Hz,1H),7.58(d,J=7.6Hz,1H),7.47(d,J=5.6Hz,1H),7.32(d,J=8.0H z,1H),7.26(s,1H),4.39-4.31(m,1H),2.72-2.67(m,2H),2.29-2.24(m,2H),1.46(s,3H).

[0549] Compound 25

[0550] 1 H NMR: (400MHz, CD3OD) δppm 8.91(m,2H),8.21(d,J=5.6Hz,1H),7.62(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),7 .28(s,1H),4.35-4.27(m,1H),2.71-2.66(m,2H),2.28-2.23(m,2H),1.45(s,3H).

[0551] Example 24

[0552] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0553]

[0554] Compound 26 was prepared from compound 16c using the method described in Example 16.

[0555] 1 H NMR (400MHz, CD3OD)Shift=7.42(d,J=8.4Hz,1H),7.21-7.20(m,2H),5.39(t,J=3.2 Hz,2H),5.05(t,J=3.2Hz,2H),4.19(m,1H),2.61(m,2H),2.14(m,2H),1.43(s,3H).

[0556] Example 25

[0557] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5,6,7,8-tetrahydronaphthyl-1-ol

[0558]

[0559] Step 1: Synthesis of (Compound 27b)

[0560]

[0561] Compound 27a (1.0 g, 6.17 mmol) was dissolved in DMF (6 mL), and NBS (0.99 g, 5.55 mmol) was added. The mixture was stirred at room temperature until fully reacted. The reaction mixture was diluted with dichloromethane (10 mL) and saturated sodium chloride solution (10 mL), and separated. The organic phase was washed with water, and the separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain the crude product, which was purified by reversed-phase rapid column chromatography (eluent: 0-60% acetonitrile in water) to give compound 27b (680 mg, yield 45.7%).

[0562] Step 2: Synthesis of (Compound 27c)

[0563]

[0564] Compound 27b (300 mg, 1.24 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (TCA) and triethylsilane (TSA), and the mixture was stirred at 90 °C until fully reacted. The solvent was directly evaporated from the mixture, and the mixture was diluted with 10 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The mixture was separated, and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (eluent: 10% dichloromethane in petroleum ether) to give compound 27c (200 mg, yield 70.8%).

[0565] Step 3: Synthesis of (Compound 27)

[0566]

[0567] Compound 27 was prepared from compound 27c using the method described in Example 4.

[0568] 1H NMR (400MHz, CD3OD)Shift=7.00(d,J=8.0Hz,1H),6.81(s,1H),6.69(d,J=8.0Hz,1H),4.18(m,1H),2.96(m,1H),2.77(t, J=5.6Hz,2H),2.69(t,J=5.8Hz,2H),2.56(m,5H),2.20(m,4H),2.03(m,1H),1.98(m,1H),1.85-1.79(m,5H),1.61(m,2H).

[0569] Example 26

[0570] 5-Cyclopropyl-2-(6-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazine-3-yl)phenol

[0571]

[0572] Compound 28 was prepared from compound 18c using the method described in Example 18.

[0573] LCMS:t R =2.657min in 5-95AB_7min_220&254_Agilent.M ES-MS m / z 326.1[M+H] + .

[0574] 1 H NMR (400MHz, CD3OD)Shift=7.10(d,J=7.6Hz,1H),6.74(s,1H),6.69(d,J=7.6Hz,1H),6.63(s,1H),4.05-3.98(m,1H),2 .62-2.57(m,2H),2.16(s,3H),2.08-2.03(m,2H),1.91-1.87(m,1H),1.41(s,3H),1.01-0.98(m,2H),0.72-0.69(m,2H).

[0575] Example 27

[0576]

[0577] 5-Cyclopropyl-2-(6-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-4,5-dimethylpyridazine-3-yl)phenol

[0578]

[0579] Compound 29 was prepared from compound 18c using the method described in Example 18.

[0580] LCMS:t R =0.57min in 5-95AB_1.5min_220&254_Agilent.M ES-MS m / z 340.2[M+H] + .

[0581] 1 H NMR (400MHz, CD3OD)Shift=7.07(d,J=7.6Hz,1H),6.68(d,J=7.6Hz,1H),6.63(s,1H),4.19-4.09(m,1H),2.64 -2.59(m,2H),2.18(s,3H),2.15-2.08(m,5H),1.90(m,1H),1.42(s,3H),1.01-0.98(m,2H),0.72-0.70(m,2H).

[0582] Example 28

[0583] 5-Cyclopropyl-2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)o-phthalazin-1-yl)phenol

[0584]

[0585]

[0586] Compound 30 was prepared from compound 18c using the method described in Example 18.

[0587] LCMS:t R =3.11min in 5-95AB_7min_220&254_Agilent.M ES-MS m / z 362.2[M+H] + .

[0588] 1H NMR (400MHz, CD3OD)Shift=8.27(d,J=8.0Hz,1H),7.86(t,J=7.6Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),6.75(d, J=8.0Hz,1H),6.71(s,1H),4.35-4.27(m,1H),2.71-2.66(m,2H),2.26-2. 22(m,2H),1.94(m,1H),1.46(s,3H),1.04-1.00(m,2H),0.77-0.74(m,2H).

[0589] Example 29

[0590] 5-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)o-phthalazin-1-yl)-2,3-dihydro-1H-inden-4-ol

[0591]

[0592] Compound 31 was prepared from compound 15a using the method described in Example 14.

[0593] LCMS:t R =0.81min in 5-95AB_1.5min_220&254_Agilent.M ES-MS m / z 362.2[M+H] + .

[0594] 1 H NMR (400MHz, DMSO-d) 6 )Shift=9.47(br,1H),8.42(d,J=7.6Hz,1H),7.86(t,J=7.2Hz,1H),7.79(t,J=7.2Hz,1H),7.65(d,J=7.6Hz,1H),7.55(d,J=6.4Hz,1H),7.10(d,J =7.6Hz,1H),6.86(d,J=7.6Hz,1H),5.00(s,1H),2.94(t,J=7.4Hz,2H),2 .88(t,J=7.4Hz,1H),2.21-2.18(m,2H),2.10-2.06(m,2H),3.16(br,4H).

[0595] Example 30

[0596] rac-(R)-2-(4-(1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0597]

[0598] Compound 32 was prepared from compound 16c using the method described in Example 19.

[0599] 1 H NMR (400MHz, CD3OD) δ = 8.50 (s, 1H), 7.43 (d, J = 8.5Hz, 1H), 7.27-7.16 (m, 2H), 5.36 (t, J = 3.0Hz, 2H), 5.05 (br s,2H),4.55-4.44(m,1H),3.80(t,J=5.5Hz,2H),3.50(brd,J=10.8Hz,1H),3.13(br s,1H),3.01-2.83(m,2H),2.76-2.64(m,1H),2.59(br s,1H),2.09(br d,J=8.8Hz,1H),2.03-1.93(m,1H),1.92-1.79(m,1H),1.74-1.55(m,1H).

[0600] Example 31

[0601] 3-Fluoro-2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 33)

[0602]

[0603] 3-Fluoro-2-(1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridine[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (compound 34)

[0604]

[0605]

[0606] Compounds 33 and 34 were prepared using compounds 24b and 24c as starting materials, according to the method described in Example 15.

[0607] Compound 33

[0608] 1H-NMR: (400MHz, METHANOL-d4)Shift=9.71(s,1H),8.84(d,J=5.7Hz,1H),7.38(d,J=5.5Hz,1H),7.05(s,1H),7.01(br d,J=8.8Hz,1H),4.36(quin,J=7.8Hz,1H),2.78-2.61(m,2H),2.34-2.20(m,2H),1.45(s,3H).

[0609] Compound 34

[0610] 1 H-NMR: (400MHz, METHANOL-d4)Shift=8.93(d,J=5.8Hz,1H),8.83(s,1H),8.24(d,J=6.1Hz,1H),7.12(br s,2H),4.34(br d,J=8.3Hz,1H),2.75-2.64(m,3H),2.28(brd,J=8.6Hz,3H),1.45(s,3H).

[0611] Example 32

[0612] 3-Fluoro-2-(4-((R)-1-methylpiperidin-3-yl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)

[0613] phenol

[0614]

[0615] Compound 35 was prepared using compound 16d as the starting material, following the method described in Example 15.

[0616] 1 H-NMR: (400MHz, CD3OD)δ=7.08-6.96(m,2H),5.10-5.04(m,2H),4.65-4.56(m,2H),3.68-3.60(m,1H),3.01-2.86(m,1H),2.56- 2.45(m,3H),2.43-2.30(m,1H),2.15-2.01(m,1H),1.97-1.90(m,1H),1.86-1.74(m,1H),1.65-1.53(m,1H),1.40-1.24(m,2H).

[0617] Example 33

[0618] rac-(R)-5-cyclopropyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)phenol

[0619]

[0620] Compound 36 was prepared from compounds 4d and 19a using the method described in compound 19.

[0621] 1 H NMR: (400MHz, CD3OD) δ = 8.50 (s, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.3Hz, 1H), 6.65 ( d,J=8.0Hz,1H),6.62(s,1H),4.52-4.40(m,1H),3.83(t,J=5.4Hz,2H),3.57(br d,J=10.0Hz,1H),3.28-3.19(m,1H),3.12-2.95(m,2H),2.83(br t,J=10.4Hz,1H),2.75(br t,J=10.8Hz,1H),2.28(s,3H),2.09(br d,J=12.0Hz,1H),2.05-1.97(m,1H),1.95-1.83(m,2H),1.79-1.67(m,1H),1.03-0.94(m,2H),0.74-0.67(m,2H).

[0622] Example 34

[0623] 7-Fluoro-5-(6-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol

[0624]

[0625] Compound 37 was prepared using compound 14b as the starting material, following the method described in Example 4.

[0626] 1 H NMR: (400MHz, CD3OD) δ = 6.79 (d, J = 9.2Hz, 1H), 6.77 (s, 1H), 4.01 (penta, J = 7.8Hz, 1H), 2.99 (t, J = 7.6 Hz,2H),2.94(t,J=7.6Hz,2H),2.61-2.58(m,2H),2.21-2.18(m,5H),2.06-2.03(m,2H),1.42(s,3H).

[0627] Example 35

[0628] 5-(8-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridyl[2,3-d]pyridazine-5-yl)-2,3-dihydro-1H-indene

[0629] -4-ol

[0630]

[0631] Compound 38 was prepared using 22c as the starting material, following the method described in Example 15.

[0632] 1 H NMR: (400MHz, DMSO-d6) δ = 9.39 (br, 1H), 9.10 (dd, J = 8.4, 1.2Hz, 1H), 8.02 (d, J=8.4Hz,1H),7.86(d,J=8.4Hz,1H),7.52(d,J=7.2Hz,1H),7.14(d,J=7.6Hz, 1H),6.88(d,J=7.6Hz,1H),5.00(s,1H),4.36-4.26(m,1H),2.93(t,J=7.2Hz, 2H),2.88(t,J=7.2Hz,2H),2.32-2.22(m,2H),2.18-2.08(m,2H),1.33(s,3H).

[0633] Example 36

[0634] 5-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazine-1-yl)-2,3-dihydro-1H-indene-4-

[0635] Alcohol (compound 39)

[0636]

[0637] 5-(1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazin-4-yl)-2,3-dihydro-1H-indene-4-

[0638] Alcohol (compound 40)

[0639]

[0640]

[0641] Compounds 39 and 40 were prepared using 24b and 24c as starting materials, following the method described in Example 15. Compound 39.

[0642] 1 H NMR: (400MHz, CD3OD) δppm 9.05 (br s,1H),8.90(d,J=5.6Hz,1H),8.21(d,J=5.6Hz,1H),7.24(d,J=7.6Hz,1H),6.97(d,J=7.6Hz,1H),4.01(penta, J=7.8Hz,1H),3.01(t,J=7.6Hz,2H),2.70(t,J=7.6Hz,2H),2.70-2.61(m,2H),2.26-2.17(m,4H),1.42(s,3H).

[0643] Compound 40

[0644] 1 H NMR: (400MHz, CD3OD) δppm 9.69(s,1H),8.85(d,J=5.6Hz,1H),7.64(d,J=5.6Hz,1H),7.21(d,J=7.6Hz,1H),6.92(d,J=7.6Hz,1H),4.35(pen ta,J=7.8Hz,1H),3.01(t,J=7.6Hz,2H),2.96(t,J=7.6Hz,2H),2.71-2.61(m,2H),2.28-2.16(m,4H),1.47(s,3H).

[0645] Example 37

[0646] 5-Cyclopropyl-2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridyl[3,4-d]pyridazin-1-yl)phenol

[0647]

[0648] Compound 41 was prepared from compound 18c using the method described in compound 18.

[0649] 1H NMR (400MHz, CD3OD) δppm 9.70 (s, 1H), 8.86 (d, J = 5.7Hz, 1H), 7.57 (d, J = 5.6Hz, 1H), 7.28 (d, J = 7.8Hz, 1H), 6.79 (br d,J=7.8Hz,1H),6.73(s,1H),5.43-5.43(m,1H),4.34(quin,J=7.8Hz,1H),2.76-2.6 5(m,2H),2.35-2.23(m,2H),2.02-1.90(m,1H),1.08-0.99(m,2H),0.81-0.70(m,2H).

[0650] Example 38

[0651] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 42)

[0652]

[0653] 2-(1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (compound 43)

[0654]

[0655] Compounds 42 and 43 were prepared using 42a as the starting material, following the method described in Example 15.

[0656] Compound 42

[0657] 1 H NMR: (400MHz, CD3OD) δppm 7.40(d,J=7.6Hz,1H),7.24(d,J=7.6Hz,1H),4.48(s,2H),4.21(penta,J=7.6Hz ,1H),4.02(t,J=7.6Hz,2H),2.68-2.56(m,4H),2.16-2.02(m,2H),1.43(s,3H).

[0658] Compound 43

[0659] 1H NMR: (400MHz, CD3OD) δppm 7.42(d,J=7.6Hz,1H),7.23(d,J=7.6Hz,1H),4.61(s,2H),4.19(penta,J=7.6Hz ,1H),3.89(t,J=7.6Hz,2H),2.70-2.58(m,4H),2.14-2.00(m,2H),1.41(s,3H).

[0660] Example 39

[0661] 3-Fluoro-2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)o-phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0662]

[0663] Compound 44 was prepared using compound 15a as the starting material, following the method described in Example 15.

[0664] 1 H-NMR: (400MHz, DMSO-d6) δ = 10.78 (br, 1H), 8.48 (d, J = 8.0Hz, 1H), 7.90 (t, J = 7.8Hz, 1H), 7.81 (t, J = 7.7Hz, 1H), 7.36 (d,J=8.0Hz,1H),7.27(d,J=7.6Hz,1H),7.17(s,1H),5.05(s,1H),4.28-4.22(m,1H),2.28-2.20(m,2H),1.34(s,3H).

[0665] Example 40

[0666] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyridin[3,4-d]pyridazine-1-yl)-3-methyl-5-(trifluoromethyl)phenol

[0667]

[0668] Compound 45 was prepared using compound 24b as the starting material, following the method described in Example 15.

[0669] 1H-NMR: (400MHz, DMSO-d6) δ = 9.81 (s, 1H), 8.81 (d, J = 5.2Hz, 1H), 8.08 (d, J = 6.4Hz, 1H), 7.20 (s, 1H), 7.13-7.03 (m, 2H), 5.05 (br s,1H),4.49-4.15(m,1H),2.52-2.52(m,2H),2.26(br t,J=9.2Hz,1H),2.16(br t,J=10.0Hz,1H),1.99(s,3H),1.35(s,3H).

[0670] Example 41

[0671] 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)o-phthalazin-1-yl)-3-methyl-5-(trifluoromethyl)

[0672] phenol

[0673]

[0674] Compound 46 was prepared using compound 15a as the starting material, following the method described in Example 15.

[0675] 1 H-NMR: (400MHz, CD3OD) δ = 8.39 (d, J = 8.4Hz, 1H), 7.97-7.87 (m, 1H), 7.86-7.78 (m, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.17(s,1H),7.08(s,1H),4.39-4.22(m,1H),2.76-2.63(m,2H),2.36-2.20(m,2H),2.06(s,3H),1.45(s,3H).

[0676] Example 42

[0677] 3-Methyl-2-(4-((R)-1-methylpiperidin-3-yl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0678]

[0679] Compound 47 was prepared using compound 16d as the starting material, following the method described in Example 15.

[0680] 1H-NMR: (400MHz, DMSO-d6)δ=8.16(s,1H),7.12(s,1H),7.05(s,1H),6.50(br d,J=6.9Hz,1H),4.95(br s,2H),4.81(br s,1H),4.69(br s,1H),4.29(br s,1H),3.13-3.01(m,1H),2.78-2.63(m,1H),2.26(s,3H),2.08(s,3H),1.94(br d,J=12.8Hz,2H),1.75(br d,J=13.9Hz,1H),1.59(br d,J=12.1Hz,1H),1.34(br d,J=11.4Hz,1H).

[0681] Example 43

[0682] 3-Fluoro-2-(4-((R)-1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-cyclopentane[d]pyridazine-1-yl)

[0683] -5-(trifluoromethyl)phenol

[0684]

[0685] Compound 48 was prepared using compound 2b as the starting material, following the method described in Example 15. LCMS: ES-LCMS m / z 411.3 [M+H] + .

[0686] Example 44

[0687] 3-Fluoro-2-(4-((R)-1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,7-dihydrofurfural[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0688]

[0689] Compound 49 was prepared from compound 32a using the method described in Example 19.

[0690] LCMS: ES-LCMS m / z 443.3 [M+H] + .

[0691] Example 45

[0692] (R)-2-(4-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Compound 50)

[0693]

[0694] (R)-2-(1-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)

[0695] 5-(trifluoromethyl)phenol (compound 51)

[0696]

[0697] Compounds 50 and 51 were prepared from compound 42c using the method described in compound 16.

[0698] Compound 50: LCMS: ES-LCMS m / z 409.3 [M+H] + .

[0699] Compound 51: LCMS: ES-LCMS m / z 409.3 [M+H] + .

[0700] Example 46

[0701] (R)-2-(4-(1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 52)

[0702]

[0703] (R)-2-(1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-

[0704] 5-(trifluoromethyl)phenol (compound 53)

[0705]

[0706] Compounds 52 and 53 were prepared from compound 16c using the method described in compound 32.

[0707] Compound 52: LCMS: ES-LCMS m / z 439.3 [M+H] + .

[0708] Compound 53: LCMS: ES-LCMS m / z 439.3 [M+H] + .

[0709] Biological evaluation

[0710] The following test examples further describe and explain the present disclosure, but these test examples are not intended to limit the scope of the present disclosure.

[0711] Experiment 1: Determination of NLRP3 inflammasome inhibitory activity in human monocytes

[0712] 1. Experimental instruments and reagents

[0713] 1.1 Experimental Apparatus

[0714] Plate washer:BioTek 405Select 405TSUS Microplate Washer 96and 384Wellw / Ultrasonic(6025)(BioTek,cat#405TSUS)

[0715] Plate reader:PerkinElmer 2104EnVision Multilabel Plate Readers

[0716] 1.2 Experimental Reagents

[0717] Human IL-1b ELISA Kit BD Penicillin / Streptomycin Gibco RPMI1640 medium Gibco HEPES Gibco FBS Gibco Lipopolysaccharide Sigma Hygromycin B Client Normocin Client ATP Sigma 96-well plate, Elisa Greiner 96-hole plate Corning

[0718] Compound R1

[0719]

[0720] Compound R2

[0721]

[0722] Compound R3

[0723]

[0724] Compounds R1, R2, and R33 were synthesized using a method consistent with that described in the reported literature (WO2020234715).

[0725] 2. Experimental Design

[0726] Day 1: PBMCs were isolated from human blood by density gradient centrifugation. PBMCs were washed twice with PBS containing 2% FBS (centrifuged at 300g for 8 minutes). Monocytes were then isolated from PBMCs using a Human Panmonocyte Isolation Kit and an LS column. Cells were stained with CD14-FITC at 4°C for 30 minutes, and FACS was run on a BD FACSVerse to analyze panmonocyte purity. Cells were counted and the cell density was adjusted to 2.5 x 10⁻⁶ cells / mL. 5 Cells / mL. Seed cells into 96-well plates at a density of 2.5 x 10⁶ cells / mL. 4Mononuclear cells / 100 mL suspension / well. Incubate overnight at 37°C with 5% CO2.

[0727] Day 2: Pre-titrate the test compounds to ensure all titration points, including the DMSO control wells, contain 0.1% DMSO. Remove the culture medium and pre-treat the monocytes (by adding 150 mL of the compound (diluted in serum-free 1640 medium) or DMSO to their respective wells and incubating at 37°C for 0.5 h in 5% CO2). Then treat the cells (by adding 25 mL of 1640 (serum-free) solution containing 700 ng / mL LPS (final concentration 100 ng / mL) and incubating at 37°C in 5% CO2 for 3.5 h). At the end of the 3.5 h incubation, stimulate the cells (by adding 25 mL of 40 mM ATP (final concentration will be 5 mM) and treating for 45 min). Transfer 80 mL of the supernatant to a new plate and store at -80°C.

[0728] Day 3: Dilute the supernatant 20-fold according to the manufacturer's instructions for use in human mononuclear cell IL-1b ELISA.

[0729] Days 3-4: ELISA experiment

[0730] 1) Day 3: Add 100 mL / well of capture antibody (diluted with coating buffer) to the plate. Seal the plate and incubate overnight at 4°C.

[0731] 2) Day 4: Aspirate the liquid from the wells and wash 3 times with 300 μL / ≥ wash buffer each time. After the last wash, invert the plate and blot dry on absorbent paper to remove any residual buffer.

[0732] 3) Add the test diluent to the plate, ≥200 μL / well. Incubate at room temperature for 1 hour.

[0733] 4) Blot dry / wash, as in step 2.

[0734] 5) Prepare standard and sample diluents using the test diluent.

[0735] 6) Add 100 mL of each standard, sample, and control to the corresponding well. Seal the plate and incubate at room temperature for 2 hours.

[0736] 7) Blot dry / wash as in step 2, but wash 5 times.

[0737] 8) Dilute the detection antibody with the test diluent and add it to the well, 100 mL / well.

[0738] 9) Seal the plate and incubate at room temperature for 1 hour.

[0739] 10) Blot dry / wash as in step 2, but wash 5 times.

[0740] 11) Dilute the enzyme reagent with the test diluent and add it to the wells, 100 mL / well. Seal the plate and incubate at room temperature for 30 minutes.

[0741] 12) Blot dry / wash, use a soaking step of 30 seconds to 1 minute, wash a total of 7 times.

[0742] 13) Add 100 mL of substrate solution to each well. Incubate the plate (without plate sealant) in the dark at room temperature for 30 minutes.

[0743] 14) Add 50 mL of stop solution to each well.

[0744] 15) Within 30 minutes of stopping the reaction, read the absorbance at 450 nm using the Envision instrument. If wavelength correction is available, subtract the absorbance at 570 nm from the absorbance at 450 nm.

[0745] 3. Experimental Results

[0746]

[0747] *The average of n test results after stabilizing experimental conditions.

[0748] Experimental Example 2: Rat Pharmacokinetic Experimental Protocol

[0749] 1. Three healthy adult male SPF-grade SD rats, aged 6-8 weeks, weighing 200-300 grams.

[0750] 2. Required equipment: HPLC-MS, analytical balance, animal weight scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0751] 3. Weigh an appropriate amount of the test sample and dissolve it in 10% DMA / 33% PEG400 / 57% Water (V / V / V). Vortex and sonicate to prepare the required dosage form for intravenous administration. Alternatively, weigh an appropriate amount of the test sample and dissolve it in 0.5% HPMC and 0.1% Tween in water. Vortex and sonicate to prepare the required dosage form for oral administration.

[0752] 4. Animals were housed in rat cages and fasted for at least 10 hours before the experiment, but water was allowed. They were weighed before administration, and the dosage was calculated based on their body weight. On the day of administration, the animal was given once by intravenous injection or oral gavage.

[0753] 5. Blood collection time points: Intravenous group: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. Oral group: 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration.

[0754] 6. Blood was collected via the jugular vein, approximately 0.20 mL per time point, anticoagulated with K2-EDTA, and placed on ice after collection. Plasma was separated by centrifugation within 1 hour of collection (centrifugation conditions: 6800 g / min, 6 minutes, 2-8℃). The collected plasma samples were stored at -80℃ before analysis, and any remaining plasma samples after analysis were also stored at -80℃.

[0755] 7. In bioanalysis, when plotting plasma drug concentration-time curves, BLQ is recorded as 0. When calculating pharmacokinetic parameters, the concentration before administration is calculated as 0; BLQ before Cmax (including "No peak") is calculated as 0; BLQ after Cmax (including "No peak") is not included in the calculation. Using plasma drug concentration data at different time points, WinNonlin is used to calculate pharmacokinetic parameters such as AUC(0-t), T1 / 2, Cmax, Tmax, and MRT.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, I in, R1 is selected from -OH; R6 and R7, together with the atoms they are attached to, form a phenyl, 5-6 membered heteroaryl group optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN; Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3; R8 is selected from 5-6 membered heterocyclic groups optionally substituted with one or more substituents, C 3-6 cycloalkyl, C 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogens, and -OR. 8a -NR 8a R 8b -CN,C 1-4 Alkyl and C 3-6 cycloalkyl; R 8a and R 8b Independently selected from hydrogen, deuterium, and C 1-4 Alkyl, C 3-6 cycloalkyl; The condition is that the compound of formula I does not include the following compounds or their isomers, or their pharmaceutically acceptable salts: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A compound of formula I or a pharmaceutically acceptable salt thereof, I in, R1 is selected from -OH; R6 and R7, together with the atoms they are attached to, form a phenyl group optionally substituted with one or more substituents selected from: deuterium, halogens, -OH, -NH2, -CN, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN; Z is either O or -NH-(CH2)n-, where n is an integer selected from 0 to 3; R8 is selected from 5-6 membered heterocyclic groups optionally substituted with one or more substituents, C 3-6 cycloalkyl, C 1-6 Alkyl groups, wherein the substituents are selected from deuterium, halogens, and -OR. 8a -NR 8a R 8b -CN,C 1-4 Alkyl and C 3-6 cycloalkyl; R 8a and R 8b Independently selected from hydrogen, deuterium, and C 1-4 Alkyl, C 3-6 Cycloalkyl.

3. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein, R6 and R7, together with the atoms they are attached to, form a benzene ring optionally substituted with one or more substituents selected from: deuterium, halogens, oxometalates, and C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein, Compounds of Formula I are selected from: ； R 9k Independently selected from deuterium, halogen, oxo, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens; or R 9k Independently selected from deuterium, halogen, oxo, and halogenated C 1-6 Alkyl, halogenated -OC 1-6 alkyl; or R 9k Independently selected from deuterium, halogens, and C 1-6 Alkyl, -OC 1-6 alkyl.

5. The compound according to any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, wherein, R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen; Alternatively, R2 and R4 are independently selected from hydrogen, deuterium, and halogens, and R3 and R5 are independently selected from hydrogen, deuterium, halogens, and C substituted with one or more deuterium or halogens. 1-6 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, R2 and R4 are hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen, halogen or methyl; or R2, R4 and R5 are hydrogen, and R3 is trifluoromethyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R6 and R7, together with the atoms they are attached to, form a 5-6 membered heteroaryl group optionally substituted with one or more substituents selected from: deuterium, halogen, oxo, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more substituents selected from deuterium or halogen; R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkylmethylene, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 and -CN.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein, R6 and R7, together with the atoms they are attached to, form a pyridine that may be optionally substituted with one or more substituents selected from: deuterium, halogens, C. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more deuterium or halogens.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein, Compounds of Formula I are selected from: 、 、 ； The R 18c Selected from deuterium, halogens, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 The cycloalkyl group may optionally be further substituted with one or more halogens; or R 18c It is hydrogen; a is an integer selected from 0 to 3; Z, R2, R3, R4, R5, and R8 are as defined in claim 1.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7-9, wherein, R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogens, and the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, wherein the substituent is deuterium or halogen; Alternatively, R2 and R4 are independently selected from hydrogen, deuterium, and halogens, and R3 and R5 are independently selected from hydrogen, deuterium, halogens, and C substituted with one or more deuterium or halogens. 1-6 alkyl.

11. The compound according to any one of claims 7-9 or a pharmaceutically acceptable salt thereof, wherein, R2 and R4 are hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen or methyl; or R2, R4 and R5 are hydrogen, and R3 is trifluoromethyl.

12. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein, Z is -NH-(CH2)n-, where n is an integer selected from 0 to 2.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, Z stands for -NH-(CH2)n-, where n is selected from 0 or 1.

14. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein, R8 is selected from 5-6 membered heterocyclic groups optionally substituted with one or more substituents, said substituents being selected from deuterium, halogens, -OR 8a -NR 8a R 8b -CN,C 1-4 Alkyl and C 3-6 cycloalkyl; R 8a and R 8b Independently selected from hydrogen, deuterium, and C 1-4 Alkyl, C 3-6 Cycloalkyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein, R8 is or .

16. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein, R8 is selected from C14, which is optionally substituted with one or more substituents. 3-6 cycloalkyl groups, wherein the substituents are selected from deuterium, halogens, -OH, -NH2, -CN, and C. 1-4 alkyl.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein, R8 is selected from: , , and ; R 10e R 10f R 10e’ R 10f’ Independently selected from hydrogen, deuterium, halogens, -OH and C 1-4 alkyl; Or R8 is selected from: , , and ; R 10e R 10e’ Independently selected from hydrogen, deuterium, halogens, -OH and C 1-4 alkyl.

18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein, R8 is selected from: , , , , and .

19. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein, R8 is selected from .

20. The compound shown in Formula I or a pharmaceutically acceptable salt thereof, selected from: 。 21. A pharmaceutical composition comprising the compound of any one of claims 1-2, 20, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

22. Use of the compound or pharmaceutically acceptable salt thereof of any one of claims 1-2 or 20, or the pharmaceutical composition of claim 21, in the preparation of a medicament for treating diseases related to NLRP3 activity.

23. Use of the compound or pharmaceutically acceptable salt thereof of any one of claims 1-2 or 20, or the pharmaceutical composition of claim 21, in the preparation of a medicament for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and / or autoinflammatory diseases.

Images