Pyridazine compound and application thereof

Abstract

The invention discloses a pyridazine compound and application thereof, and belongs to the technical field of chemical medicines. The pyridazine compound as shown in the formula I provided by the invention can be used as an NLRP3 inhibitor, has high activity and excellent pharmacokinetic properties, and provides a new way for treating NLRP3 related diseases.

Description

Pyridazine compounds and uses thereof Technical Field

[0001] The present invention relates to a pyridazine compound and application thereof, belonging to the technical field of chemical medicine. Background Art

[0002] Inflammasomes are protein complexes that recognize intracellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Inflammasome assembly triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1 and converting the cytokine precursors pro-IL-1β and pro-IL-18 into mature, biologically active IL-1β and IL-18, respectively. These complexes regulate the expression of inflammation-related genes and produce various biological effects. As receptors of innate immunity, inflammasome activation protects against pathogen infection and stress injury, but uncontrolled activation can also amplify inflammatory effects and cause organ damage. Currently, research on the nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasomes is the most active.

[0003] The NLRP3 inflammasome is composed of a sensor (NLRP3), an adaptor (ASC, also known as PYCARD), and an effector (caspase 1). Classic NLRP3 inflammasome activation is activated by two signals co-stimulating the body. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting the nuclear translocation of NF-κB, inducing the production of precursors such as IL-1β and IL-18, and inducing post-translational modification of NLRP3. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. Upon activation, it aggregates with the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. The pro-caspase (pro-caspase-1) self-cleaves into its active form. Activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into their active forms and releasing them into the extracellular space. This recruits inflammatory cells and amplifies the inflammatory response. ASC speck-like proteins can also recruit and activate caspase-8, cleaving the pro-caspase forms of IL-1β and IL-18 into their mature forms, triggering pyroptosis. Non-classical NLRP3 inflammasome activation does not depend on TLR4 signaling pathway activation. It is caused by caspase-11 directly recognizing intracellular LPS, initiating NLRP3 inflammasome activation, promoting the activation and release of gasdermin D, and thus mediating cell death.

[0004] Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, neurological diseases, autoimmune diseases and / or autoinflammatory diseases, cancer, chronic metabolic diseases, and neurological diseases. For example, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease or ischemic stroke. NLRP3 is upstream of cytokines and can block inflammation at the root, so the development of new NLRP3 inflammasome inhibitors has high research value.

[0005] Summary of the Invention

[0006] The present invention creatively develops a class of pyridazine compounds that can act as NLRP3 inhibitors with high activity and excellent pharmacokinetic properties, providing a new approach for treating NLRP3-related diseases.

[0007] The present invention first provides a compound represented by Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0008] in,

[0009] X and Y are independently selected from C or N, and at most one of X and Y is selected from N;

[0010] When X or Y is selected from N, is a single bond; when X and Y are selected from C, is a double bond;

[0011] Ring A is the following group optionally substituted by 0-6 R8: 5-6 membered alkyl ring (the 5-6 membered alkyl ring must be a double bond), 5- to 6-membered alkyl heterocycle (the 5- to 6-membered alkyl heterocycle According to the above X and Y, it is determined to be a single bond or a double bond), a benzene ring (the benzene ring must be a double bond), 5- to 6-membered heteroaromatic ring (the 5- to 6-membered heteroaromatic ring According to the above X and Y, it is determined to be a single bond or a double bond), The connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R7 on the left, Y is connected to the pyridazine N in the middle, and L is connected on the right); in ring A, the 5- to 6-membered alkyl heterocyclic ring and the 5- to 6-membered heteroaromatic ring contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0012] R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0013] R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R2 and R4, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0014] R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S and O;

[0015] R5 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R5, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0016] Alternatively, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, a 5-6 membered heteroaromatic ring, The substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 a deuterated alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered fluorocycloalkyl group, or two of the above substituents attached to the same carbon atom to form a 3-6 membered alkyl ring; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are attached to form a ring, the 5-6 membered alkane heterocycle or 5-6 membered heteroaromatic ring contains 1-3 heteroatoms selected from at least one of N, S, and O;

[0017] L is selected from -(CH2) n1 -, -CH(CH3)(CH2) n1 -、-(CH2) n1 -CH(CH3)-, -(CH2) n1 O-, -O(CH2) n1 -, -OCH(CH3)(CH2) n1 -、-(CH2) n1 -NH-, -NH-(CH2) n1 -、-NH-CH(CH3)(CH2) n1-or-NHC(CH3)2(CH2) n1 -, n1 is an integer selected from 0-3 (the left end is connected to ring A, and the right end is connected to R6) (according to the embodiments of the present invention, when the C in L is connected to ring A, it is connected to the N on ring A; when the N or O in L is connected to ring A, it is connected to the C on ring A);

[0018] R6 is selected from hydrogen, deuterium, halogen, -CN, -OR 9a 、-SR 9a 、-NR 9b R 9c 、-C(=O)R 9a 、-OC(=O)R 9a 、-C(=O)OR 9a 、-C(=O)NR 9b R 9c 、-NR 9b C(=O)R 9c 、-SO2R 9a 、-SO2NR 9b R 9c 、-NR 9b SO2R 9c or 0-6 R 9d Substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; in R6, the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0019] R 9a 、R 9b and R 9c independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; R 9a 、R 9b and R 9c wherein the substituent is selected from the group consisting of: deuterium, halogen, -N(R 10a R 10b )、-C(O)N(R 10a R 10b ), -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkylmethylene, or 4- to 6-membered heterocycloalkylmethylene; R 9a 、R 9b and R 9c wherein the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkylmethylene groups in the substituents contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0020] Or, R 9b With R 9c Together with the atoms to which they are attached, they form a 3- to 6-membered alkyl heterocyclic ring substituted with 0-6 substituents; R 9b With R 9c When connected to the atoms to which they are attached to form a ring, the substituents are selected from: deuterium, halogen, -N(R 10a R 10b )、-C(O)N(R 10a R 10b ), -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R 9b With R 9c When connected to the atoms to which they are attached to form a ring, the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4- to 6-membered heterocycloalkyl group in the substituent group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0021] R 9d Selected from hydrogen, deuterium, halogen, -CN, -OR 10c 、-SR 10c 、-NR 10d R 10e 、-C(=O)R 10c 、-OC(=O)R 10c 、-C(=O)OR 10c 、-C(=O)NR 10d R 10e 、-NR 10d C(=O)R 10e 、-SO2R 10c 、-SO2NR 10d R 10e 、-NR 10d SO2R 10eor 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, C 1-6 Alkyl; R 9d wherein the substituent is selected from deuterium, halogen, -OH, -NR 10f R 10g 、-C(=O)NR 10f R 10g 、CN、C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 9d wherein the 5- to 10-membered heteroaryl group and the 3- to 8-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0022] R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl;

[0023] R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, -CONH2 or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-3-6 membered cycloalkyl, -(C=O)NH-C 1-6 Alkyl, -(C=O)NH-3 to 6-membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R7, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0024] R8 is selected from hydrogen, deuterium, halogen, -NH2, -OH, -CN, -CONH2 or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)NH-C 1-6 Alkyl, 3-6 membered cycloalkyl, -C(O)-3-6 membered cycloalkyl, -C(O)NH-3-6 membered cycloalkyl; in R8, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0025] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0026] In some embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0027] In some preferred embodiments of the present invention, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0028] In some more preferred embodiments of the present invention, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

[0029] In some embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0030] In some preferred embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0031] In some more preferred embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

[0032] In some embodiments of the present invention, R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, -CF3 or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O.

[0033] In some preferred embodiments of the present invention, R3 is selected from hydrogen, deuterium, F, Cl, Br, -CN, or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, F, Cl, -OH, -NH2, -CF3, -CN or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1-2 heteroatoms selected from at least one of N, S and O.

[0034] In some more preferred embodiments of the present invention, R3 is selected from hydrogen, deuterium, F, Cl, Br, CN, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.

[0035] In some embodiments of the present invention, R5 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0036] In some preferred embodiments of the present invention, R5 is selected from hydrogen, deuterium, F, Cl, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0037] In some more preferred embodiments of the present invention, R5 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

[0038] In some embodiments of the present invention, R2 and R3, R3 and R4, or R4 and R5 can form together with the atoms to which they are connected a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, a 5-6 membered heteroaromatic ring or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents. The substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorinated cycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle and 5-6 membered heteroaromatic ring contain 1-2 heteroatoms selected from at least one of N, S, and O.

[0039] In some preferred embodiments of the present invention, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from the group consisting of: deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorinated cycloalkyl, or two of the above substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.

[0040] In some more preferred embodiments of the present invention, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituents are selected from: deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.

[0041] In some embodiments of the present invention, the structural unit Selected from:

[0042] In some embodiments of the present invention, L is selected from a bond or -CH2-, -CH2CH2-, -CH2-CH(CH3)-, -CH2-C(CH3)2-, -CH(CH3)CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH(CH3)-, -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH(CH3)- or -NHC(CH3)2- (the left end is connected to ring A and the right end is connected to R6) (it can be seen from the embodiments of the present invention that when the C in L is connected to ring A, it is connected to the N on ring A; when the N or O in L is connected to ring A, it is connected to the C on ring A).

[0043] In some embodiments of the present invention, R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-3 substituents: C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -CONH2, -NH-C 1-3 Alkyl, -NHC(=O)-C 1-3 Alkyl, -NHC(=O)-3-6 membered cycloalkyl, -(C=O)NH-C 1-3 Alkyl, -(C=O)NH-3 to 6-membered cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl; in R7, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0044] In some preferred embodiments of the present invention, R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups substituted with 0-3 substituents: C 1-3 Alkyl, -OC 1-3 Alkyl, -CONH2, -(C=O)NH-C 1-3Alkyl, -(C=O)NH-3- to 4-membered cycloalkyl or 3- to 4-membered cycloalkyl; in R7, the substituent is selected from: deuterium, fluorine or -OH.

[0045] In some more preferred embodiments of the present invention, R7 is selected from hydrogen, deuterium, fluorine, chlorine, -OH, -NH2, -CN, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, methoxy, fluoromethoxy, cyclopropyl, fluorocyclopropyl, -CONH2, -CONHCH3, -CONHCD3 or -CONH-cyclopropyl.

[0046] In some embodiments of the present invention, R8 is selected from hydrogen, deuterium, fluorine, -NH2, -CONH2, -CN, or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -C(O)-3-4 membered cycloalkyl, -C(O)NH-C 1-4 Alkyl, -C(O)NH-3-4 membered cycloalkyl, 3-4 membered cycloalkyl; in R8, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN.

[0047] In some preferred embodiments of the present invention, R8 is selected from hydrogen, deuterium, fluorine or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -C(O)-3- to 4-membered cycloalkyl, 3- to 4-membered cycloalkyl; in R8, the substituent is selected from: deuterium, fluorine or -OH.

[0048] In some embodiments of the present invention, more preferably, R8 is selected from hydrogen, fluorine, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, -C(O)CH3, -C(O)CD3 or -C(O)-cyclopropyl.

[0049] In some embodiments of the present invention, Ring A is the following group optionally substituted by 0-3 R8: 5-6 membered alkyl ring (the 5-6 membered alkyl ring must be a double bond), 5- to 6-membered alkyl heterocycle (the 5- to 6-membered alkyl heterocycle According to the above X and Y, it is determined to be a single bond or a double bond), a benzene ring (the benzene ring must be a double bond), 5- to 6-membered heteroaromatic ring (the 5- to 6-membered heteroaromatic ring According to the above X and Y, it is determined to be a single bond or a double bond), The connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R7 on the left, Y is connected to the pyridazine N in the middle, and L is connected on the right); in ring A, the 5- to 6-membered alkyl heterocyclic ring and the 5- to 6-membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S, and O.

[0050] In some preferred embodiments of the present invention, Ring A The following groups optionally substituted by 0-2 R8:

[0051] (Ring A The connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R7 on the left, Y is connected to pyridazine N in the middle, and L is connected to the right).

[0052] In some embodiments of the present invention, the structural unit Selected from:

[0053] n2 is selected from integers of 0-2.

[0054] In some preferred embodiments of the present invention, the structural unit Selected from:

[0055] In some preferred embodiments of the present invention, the structural unit Selected from:

[0056] In some embodiments of the present invention, R6 is selected from the following structures:

[0057] R 11a Selected from hydrogen, deuterium, -C(=O)R 12a 、-C(=O)OR 12a 、-SO2R 12a or 6-10 membered aryl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl; R 11a wherein the substituent is selected from deuterium, fluorine, chlorine, -OH, -NR 12b R 12c 、-C(=O)NR 12b R 12c 、CN、C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 11awherein the 5- to 10-membered heteroaryl group or the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 12a 、R 12b and R 12c are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl;

[0058] R 11b Selected from hydrogen, deuterium, halogen, -CN, -OR 12a 、-NR 12d R 12e 、-C(=O)R 12a 、-C(=O)OR 12a 、-C(=O)NR 12d R 12e 、-NR 12d C(=O)R 12e 、-SO2R 12a 、-SO2NR 12d R 12e 、-NR 12d SO2R 12e or 6-10 membered aryl, 5-10 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, C 1-6 Alkyl; R 11a wherein the substituent is selected from deuterium, fluorine, chlorine, -OH, -NR 12b R 12c 、-C(=O)NR 12b R 12c 、CN、C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 11a wherein the 5- to 10-membered heteroaryl group or the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 12a 、R 12b 、R 12c 、R 12d and R 12e are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl;

[0059] R 11c 、R 11d independently selected from hydrogen, deuterium or C substituted by 0-3 substituents 1-4 Alkyl; R 11c 、R 11d wherein the substituent is selected from deuterium, fluorine, and chlorine.

[0060] In some preferred embodiments of the present invention, R 11a Selected from H, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl, 3-6 membered cycloalkyl substituted with hydroxyl, C 1-4 Alkanoyl, 3-6 membered cycloalkanoyl, C 1-4 Alkoxyacyl, 3-6 membered cycloalkoxyacyl, C 1-4 Alkanesulfonyl, 3-6 membered cycloalkanesulfonyl,

[0061] R 11b Selected from H, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, 3-6 membered cycloalkyl substituted with hydroxyl, C 1-4 Alkanoyl, 3-6 membered cycloalkanoyl, C 1-4 Alkoxyacyl, 3-6 membered cycloalkoxyacyl, C 1-4 Alkanesulfonyl, 3-6 membered cycloalkanesulfonyl, methylamino, dimethylamino,

[0062] R 11c 、R 11d Independently selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl.

[0063] In some embodiments of the present invention, R6 is selected from the following structures:

[0064] In some embodiments of the present invention, the structural unit Selected from:

[0065] The present invention also provides some specific compounds, which are selected from:

[0066] A Series:

[0067] B Series:

[0068] C Series:

[0069] D Series:

[0070] E Series:

[0071] F Series:

[0072] G Series:

[0073] H Series:

[0074] I Series:

[0075] J Series:

[0076] K Series:

[0077] L Series:

[0078] M Series:

[0079] N Series:

[0080] The present invention also provides some specific compounds, which are selected from:

[0081] A Series:

[0082] B Series:

[0083] C Series:

[0084] D Series:

[0085] E Series:

[0086] F Series:

[0087] G Series:

[0088] H Series:

[0089] I Series:

[0090] J Series:

[0091] K Series:

[0092] L Series:

[0093] M Series:

[0094] N Series:

[0095] In some embodiments of the present invention, the structural unit Selected from:

[0096] In some embodiments of the present invention, the structural unit Selected from:

[0097] In some embodiments of the present invention, the structural unit Selected from:

[0098] The present invention also provides some compounds, which are selected from:

[0099] A Series:

[0100] B Series:

[0101] C Series: M Series:

[0102] other:

[0103] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites or prodrugs as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0104] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining a compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0105] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0106] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0107] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0108] The present invention also relates to a pharmaceutical preparation comprising the compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, or a pharmaceutical composition of the present invention as an active ingredient. In some embodiments, the preparation is in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.

[0109] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0110] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0111] The second container is a container for accommodating the first container and optional package insert. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0112] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating NLRP3-related diseases.

[0113] The present invention provides a method for preventing or treating NLRP3-related diseases, comprising administering the compound of formula I or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.

[0114] The present invention provides a method for preventing or treating NLRP3-related diseases by combining the compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention with another treatment method, wherein the other treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0115] In some embodiments, the NLRP3-related disease includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine system disease or central nervous system disease.

[0116] In some embodiments, the NLRP3-associated disease comprises: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.

[0117] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy or immunotherapy to prevent or treat NLRP3-related diseases.

[0118] Beneficial effects of the present invention:

[0119] The present invention provides a class of pyridazine compounds and uses thereof. The compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.

[0120] Definition of Terms: Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are intended to be inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass "consisting of."

[0121] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0122] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form "about a to b," or equivalently, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0123] For example, the statement "C 1-6 " should be understood to include any sub-ranges therein and each point value, such as C 2-5 、C 1-4 、C 1-5 etc., as well as C1, C3, C6, etc. For example, the expression “C 3-10 ” should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, for example, C 3-9 、C 7-10 、C 7-9 、C 8-9 etc. and C3, C4, C8, C 10 etc. For another example, the expression "3-10 yuan" should be understood to include any sub-ranges and point values ​​therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 4-5 yuan, 4-6 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 6, 7, 10 yuan, etc. For another example, the expression "5-10 yuan" should also be understood in a similar manner, for example, it can include any sub-ranges and point values ​​contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 6-10 yuan, 7-8 yuan, etc., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

[0124] As used herein, unless otherwise specified, represents a single bond or a double bond.

[0125] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0126] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, isopropyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 C in "alkyl" 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms in a straight or branched chain.

[0127] In the present invention, unless otherwise specified, "cycloalkyl", "carbocycle" or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclononyl, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc. For example, "C3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 6, 7, 10 or 12). The cycloalkyl or cycloalkylene groups in the present invention are optionally substituted with one or more substituents described herein.

[0128] In the present invention, unless otherwise specified, "heterocycloalkyl", "heterocycloalkylene" or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example: cyclic, bridged or spirocyclic) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur. If the valence requirements are met, the heterocycloalkyl group can be connected to the rest of the molecule through any ring atom. For example, "3-8 membered heterocycloalkyl" refers to a heterocycloalkyl group with 3 to 8 ring atoms. Common heterocycloalkyl groups include (but are not limited to) oxirane, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, sulfolane, etc. The heterocycloalkyl, heterocycloalkylene or heterocycle in the present invention is optionally substituted with one or more substituents (for example, oxo) described herein.

[0129] In the present invention, unless otherwise specified, "haloalkyl" refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by halogen. For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CCl3, -C2Cl5, -CH2CF3, -CH2Cl, etc. The haloalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0130] In the present invention, unless otherwise specified, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 "Fluoroalkyl" refers to a C group optionally substituted by one or more (e.g. 1-3) fluorine atoms. 1-4Alkyl. It will be understood by those skilled in the art that when there are more than one fluorine atom substituent, the fluorine atoms may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CHF2, -CF3, -C2F5, -CH2CF3, etc. The fluoroalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0131] In the present invention, unless otherwise specified, "alkenyl" refers to a linear or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, "C 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. Common alkenyl groups include (but are not limited to) ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl group in the present invention is optionally substituted with one or more substituents described herein.

[0132] In the present invention, unless otherwise specified, "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, "C 2-4 "Alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in the present invention is optionally substituted with one or more substituents described herein.

[0133] In the present invention, unless otherwise specified, "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (such as bicyclic) aromatic group or aromatic ring having a conjugated π electron system. As used herein, the term "C6-10 aryl" refers to an aromatic group containing 6-10 carbon atoms. Examples include, but are not limited to, phenyl and naphthyl. The aryl or aromatic ring in the present invention is optionally substituted with one or more substituents described herein.

[0134] In the present invention, unless otherwise specified, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. A heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, in particular 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups include, for example, thienyl, furanyl, oxazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, triazolyl, thiadiazolyl, and the like; the term also encompasses situations in which the heteroaryl or heteroaromatic ring is optionally further fused to an aryl or heteroaryl ring to form a fused ring. The heteroaryl or heteroaromatic ring in the present invention is optionally substituted with one or more substituents as described herein.

[0135] In the present invention, unless otherwise specified, "oxo" means that it forms C=O together with the carbon atom to which it is attached.

[0136] In the present invention, unless otherwise specified, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), hydroxyl, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R", -C(O)NR'R", cyano, nitro, -S(O)2R', -OS(O)2OR', -OS(O)2R', -OP(O)(OR')(OR"); wherein R' and R" are independently selected from -H, C 1-8 Alkyl, C 1-8 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C (O) CH 3 , cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0137] The present invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes in the compounds of the present invention include, but are not limited to, hydrogen isotopes (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); chlorine isotopes (e.g. 37 Cl); iodine isotopes (e.g. 125 I); nitrogen isotopes (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); phosphorus isotopes (e.g. 32 P); and sulfur isotopes (e.g. 34 S).

[0138] As used herein, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to encompass various crystalline forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of the present invention. The term "solvate," as used herein, refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, they may only retain adventitious water or a mixture of water and a portion of adventitious solvent. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also encompassed by the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0139] In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0140] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed with acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed with bases that form pharmaceutically acceptable salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, hexanoates, octanoates, decanoates, undecylenates, glycolates, gluconates, oxalates, maleates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, 4-aminosalicylates, and naphthalene disulfonates. These salts can be prepared by methods known in the art. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, N-ethylpiperidine, and polyamine resins. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, choline and caffeine.

[0141] In the present invention, unless otherwise indicated, "ester" refers to an ester derived from a compound described herein, including physiologically hydrolyzable esters. The compounds of the present invention may themselves also be esters.

[0142] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.

[0143] As used herein, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present invention. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0144] In the present invention, "prodrug" refers to certain derivatives of the compounds of the present invention that can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo.

[0145] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0146] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.

[0147] As used herein, the terms "drug combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either in combination or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0148] In the present invention, unless otherwise specified, "tumor" includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

[0149] As used herein, unless otherwise indicated, "treating" or "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0150] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. DETAILED DESCRIPTION

[0151] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications shall be followed.

[0152] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0153] Table 1 Abbreviations and their meanings in the present invention

[0154] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10 -6 The units are given in ppm.

[0155] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0156] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0157] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0158] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0159] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0160] Intermediate int-1: 2-(2-methoxy-6-methyl-4-trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0161] Step 1: Int-1a (21.7 g, 90.8 mmol), LiOH.H2O (11.4 g, 272 mmol), Pd2(dba)3 (1.7 g, 1.82 mmol), and BippyPhos (1.8 g, 3.63 mmol) were weighed and added to a flask. Dioxane (220 mL) and water (22 mL) were then added. The atmosphere was purged with N2 three times and the reaction was refluxed at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through a layer of Celite, and then rinsed with EtOAc (100 mL). The filtrate was washed with 1M hydrochloric acid (50 mL). The organic phase was collected, dried over anhydrous Na2SO4, and purified by column chromatography (PE:EtOAc = 5:1, KMnO4 color development) under reduced pressure to obtain the target compound int-1b (14.1 g, 80.0 mmol, light yellow liquid, 88% yield). MS: [MH] + =175.0.

[0162] Step 2: Dissolve compound int-1b (14.0 g, 79.5 mmol) in toluene (280 mL) and cool to 0°C. Then, add NaH (6.36 g, 159 mmol, 60%) portionwise. After addition, stir at 0°C for 1 h. Then, add I2 (20.2 g, 79.5 mmol) portionwise to the suspension. After addition, stir at 0°C for 1 h. After completion of the reaction, quench with water, adjust the pH to 5 with 2M hydrochloric acid, extract with EtOAc, dry over anhydrous Na2SO4, filter, and the filtrate is evaporated to dryness under reduced pressure. Separate by column chromatography (PE:EtOAc = 5:1, KMnO4 for color development) to obtain the target compound int-1c (20.7 g, 68.5 mmol, light yellow solid, 86% yield). MS: [MH] - =301.

[0163] Step 3: Compound int-1c (20.7 g, 68.5 mmol) and K2CO3 (18.9 g, 137 mmol) were added to acetone (200 mL), followed by MeI (14.6 g, 103 mmol), and stirred at 25°C overnight. After the reaction was complete, the mixture was filtered, and silica gel was added to the filtrate. The mixture was concentrated to dryness under reduced pressure and separated by column chromatography (PE:EtOAc = 20:1, UV chromatographic analysis) to obtain the target compound int-1d (6.20 g, 19.6 mmol, white solid, 29% yield). 1 H NMR (400MHz, CDCl3) δ7.13(s,1H),6.82(s,1H),3.93(s,3H),2.53(s,3H).

[0164] Step 4: Compound int-1d (6.10 g, 19.3 mmol), 2-(dicyclohexylphosphino)biphenyl (0.676 g, 1.93 mmol), Pd(OAc)2 (0.433 g, 1.93 mmol), and Et3N (5.86 g, 57.9 mmol) were added to anhydrous dioxane (60 mL), followed by the addition of pinacol borane (4.94 g, 38.6 mmol). The mixture was refluxed at 110°C under nitrogen protection overnight. After the reaction was complete, silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure to dryness. The mixture was separated by column chromatography (PE:EtOAc = 20:1, KMnO4 color development) to obtain the target compound int-1 (4.9 g, 15.5 mmol, light yellow solid, 80% yield). 1 H NMR (400MHz, CDCl3) δ7.00(s,1H),6.83(s,1H),3.81(s,3H),2.39(s,3H),1.39(s,12H).

[0165] Intermediate int-2: (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid

[0166] Compound int-1 (3.16 g, 10 mmol) was dissolved in DCM (100 mL), and BBr3 (1 M, 20 mL) was added under nitrogen protection. The reaction was carried out at -10°C for one hour, and then quenched with MeOH. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH = 10:1) to obtain the target compound int-2 (1.19 g, 54% yield).

[0167] Intermediate int-3: 2-(4-methoxybenzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0168] Step 1: CuBr2 (146.5 g, 656 mmol) was added to EtOAc (250 mL) and stirred at 80°C for 10 minutes. Compound INT1a (25.0 g, 164 mmol) was then dissolved in chloroform (250 mL) and added to the suspension. The mixture was refluxed at 80°C overnight. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was slurried with EtOAc (500 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to afford the target compound int-3b (46.0 g, 148 mmol, light brown solid, 90% yield). MS: [M+H] + =309.0,311.0,313.0.

[0169] Step 2: Compound int-3b (45.0 g, 145 mmol) and Li2CO3 (26.8 g, 363 mmol) were added to DMF (450 mL) and stirred at 100°C for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was treated with aqueous hydrochloric acid (900 mL, 0.5 N) and extracted with EtOAc (400 mL × 2). The organic phase was washed with water (300 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to afford the target compound int-3c (31.0 g, 135 mmol, light brown solid, 93% yield). MS: [MH] - =227.0,229.0.

[0170] Step 3: Compound int-3c (15.0 g, 65.5 mmol) and K2CO3 (18.1 g, 131 mmol) were added to MeCN (150 mL), followed by Me2SO4 (9.9 g, 78.6 mmol). The mixture was stirred at 60°C overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. Silica gel (30 g) was added to the filtrate, which was then concentrated to dryness under reduced pressure. The target compound int-3d (13.7 g, 56.4 mmol, white solid, 86% yield) was obtained by column chromatography (PE:EtOAc = 10:1). 1 H NMR (400MHz, CDCl3) δ7.51-7.46(m,2H),7.45-7.42(m,2H),4.00(s,3H).

[0171] Step 4: Compound int-3d (13.7 g, 56.4 mmol), bis-pinacol boronate (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol), and Pd(PPh3)Cl2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL) and reacted at 90°C under nitrogen for 12 h. After the reaction, the mixture was filtered, and 30 g of silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and dried by spin-drying. Column chromatography (PE:EtOAc = 30:1) afforded the target compound int-3 (7.6 g, 26.2 mmol, colorless solid, 46% yield). 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 4.00 (s, 3H), 1.39 (s, 12H).

[0172] Intermediate int-4: 2-(1-(difluoromethylene)-4-methoxy-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0173] Step 1: Dissolve 3-bromo-2-hydroxybenzaldehyde (25.0 g, 104.65 mmol), CH3I (60.63 g, 373.14 mmol), and K2CO3 (34.38 g, 248.76 mmol) in DMF (200 mL) and heat to 50°C for 3 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure to obtain the target compound int-4b (yellow oily liquid, 22.5 g, yield: 84%). No further purification was required. MS / ESI [M+H]+ :215.1.

[0174] Step 2: Et3N (12.71 g, 125.58 mmol) was added dropwise to HOOH (14.45 g, 313.95 mmol) at 0°C. The mixture was allowed to react at room temperature for 30 minutes. A solution of int-4b (22.5 g, 104.65 mmol) and cycloisopropyl malonate (15.08 g, 104.65 mmol) in DMF (200 mL) was then added and the mixture was heated to 100°C and allowed to react overnight. Aqueous NaOH was added to the reaction mixture to adjust the pH to 9, and the mixture was extracted with ethyl acetate. HCl (3 M) was added to the aqueous phase to adjust the pH to 5, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA = 5:1) to afford the target compound int-4c (white solid, 20.3 g, yield: 75%). MS / ESI [M+H] + :259.1.

[0175] Step 3: Polyphosphoric acid (200 g) was heated to 90°C, and compound int-4c (20.3 g, 78.34 mmol) was added. After reacting for one hour, heating was stopped and aqueous solution was added. The solution was cooled to room temperature and extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=5:1) to obtain the target compound int-4d (yellow solid, 9.7 g, yield: 51.3%). MS / ESI [M+H] + :241.1.

[0176] Step 4: Compound int-4d (4.7 g, 19.50 mmol) and 2-(difluoromethanesulfonyl)pyridine (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL), cooled to -50°C, and a DMF solution of potassium tert-butoxide was added under nitrogen. The temperature was raised to -40°C and allowed to react for 3 hours. The mixture was quenched by adding saturated aqueous ammonium chloride (26 ml), followed by adding 3N HCl (26 ml). The mixture was warmed to room temperature and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=20:1) to obtain the target compound int-4e (yellow oily liquid, 1.92 g, yield: 35.8%). 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 7.7Hz, 1H), 7.11 (d, J = 7.7Hz, 1H), 3.75 (s, 3H), 3.01–2.95 (m, 2H), 2.76–2.65 (m, 2H).

[0177] Step 5: Under nitrogen protection, compound int-4e (1.92 g, 6.98 mmol), pinacol diboronate (2.66 g, 10.47 mmol), PdCl2(dppf) (0.57 g, 0.7 mmol), and potassium acetate (2.05 g, 20.94 mmol) were dissolved in 1,4-dioxane solution and refluxed at 100°C overnight. After the reaction was complete, the temperature was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=10:1) to obtain the target compound int-4 (yellow solid, 1.02 g, yield: 45.4%). 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 2.97–2.82 (m, 2H), 2.62–2.51 (m, 2H), 1.30 (s, 12H).

[0178] Intermediate int-5: 2-(4-methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0179] The preparation of 2-(4-methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was based on the intermediate int-3. MS / ESI[M+H] + :275.1.

[0180] Example 1: 2-(7-(2-hydroxypropyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0181] Step 1: Weigh the starting materials, compound 1 (1 eq, 25 g), trimethylsilyl acetylene (1.2 eq), triethylamine (2.5 eq), cuprous bromide (0.1 eq), and (PPh3)2PdCl2 (0.05 eq). Transfer all materials to a 2L three-necked flask, add toluene (500 mL), purge with nitrogen three times, and then allow to react at room temperature. After 1 hour, LC / MS confirms the reaction is complete. Add ethyl acetate (100 mL) to the reaction suspension, then filter through celite. Rinse the filter cake with 100 mL of ethyl acetate, combine the organic phases, and concentrate. Disperse the concentrated solid in 100 mL of ether, stir for 15 minutes, and filter. Drain the filter cake to obtain compound 2, which is used directly in the next reaction without further purification.

[0182] Step 2: Transfer the crude product from the previous step to a 1 L flask and add 400 mL of methanol to dissolve with stirring. Heat to 65°C and then add solid potassium carbonate (1 eq) in batches. After 1 h of reaction, complete reaction was confirmed by LC / MS. Filter the reaction suspension through celite and do not perform further processing.

[0183] Step 3: Heat the filtrate from the previous step to 65°C, then add 6N hydrochloric acid dropwise until the hydrochloric acid concentration of the system reaches 1N. After stirring at room temperature for 4 hours, LC / MS detection shows that the reaction is complete. The reaction solution is concentrated, the pH is adjusted to a weak base, and extracted with ethyl acetate. The combined organic phase is concentrated, then slurried with ether, filtered, and the filter cake is drained to obtain compound 4 (15.4 g).

[0184] Step 4: Transfer compound 4 (15.4 g, 1 eq) and potassium carbonate (2 eq) to a 1 L flask, add 400 mL of dioxane, and heat to 80°C. Then, add a solution of TsCl (1.1 eq) in dioxane dropwise. After 6 h of reaction, analyze by LC / MS. Filter the suspension through celite, and concentrate the filtrate. Disperse the concentrate in diethyl ether (100 mL), stir for 15 min, and filter to obtain compound 5.

[0185] Step 5: Compound 5 (15.4 g, 50 mmol), int-1 (17.4 g, 55 mmol, 1.1 equiv), potassium carbonate (13.8 g, 100 mmol, 2 equiv), and (dppf)PdCl2 (1.8 g, 2.5 mmol, 0.05 equiv) were added to a 500 mL three-necked flask. A solvent mixture of dioxane / ethanol / water (7:3:4) (200 mL total) was added. The atmosphere was purged with nitrogen three times, and the mixture was placed in an 80°C oil bath for 2 h. LC / MS analysis was performed. The reaction solution was concentrated and extracted with ethyl acetate. The organic phases were combined and concentrated, and the crude product was purified by column chromatography to obtain compound 6.

[0186] Step 6: Dissolve compound 6 in 100 mL of methanol / water (suspension system) and adjust the pH to approximately 14 by adding potassium hydroxide. Transfer the system to a 50°C oil bath and react for 1 hour. After the reaction cools to room temperature, add 300 mL of dichloromethane to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Disperse the solid in 50 mL of diethyl ether, continue stirring for 0.5 hour, and filter. Rinse the filter cake with a small amount of diethyl ether and dry to obtain compound 7.

[0187] Step 7: Compound 7 (308 mg, 1 mmol), cesium carbonate (650 mg, 2 mmol), and compound 8 (1.2 mmol) were added to 20 mL of acetonitrile and heated to 80°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, concentrated to remove the solvent, and extracted with dichloromethane. The organic phases were combined and dried, and then purified by column chromatography to obtain compound 8.

[0188] Step 8: Dissolve compound 8 obtained in an appropriate amount of dichloromethane, add boron tribromide solution (1M) dropwise to the system, react at room temperature for 1 hour, and then analyze by LC / MS. Quench the reaction solution in ice water, adjust the pH to a weak acidic state, extract with dichloromethane, concentrate, and purify by column chromatography to obtain compound A1. MS / ESI: [M+H] + =352.2. 1 H NMR (400MHz, DMSO) δ14.13(s,1H),8.78(s,1H),8.28(s,1H),8.08(s,1H),7.30(d,J=2 .4Hz,2H),6.73(d,J=2.4Hz,1H),5.03(d,J=5.0Hz,1H),4.45(dd,J=13.8,4.3Hz,1H), 4.33 (dd, J=13.8, 7.4Hz, 1H), 4.16 (p, J=5.9Hz, 1H), 2.35 (s, 3H), 1.12 (d, J=6.2Hz, 3H).

[0189] The synthesis methods of Examples 2 to 35, Examples 628 to 673 and Examples 686 to 689 were prepared by referring to Example 1 to obtain target compounds A2 to A85.

[0190] Table 2 Compounds A2 to A85 of the present invention

[0191] Example 3 Compound A3: 1H NMR(400MHz,Chloroform-d)δ8.02–7.95(m,1H),7.89(s,1H),7.20(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H),6.57(d,J=3.5Hz,1H),5.27–5.17 (m,1H),3.07(dd,J=11.5,3.8Hz,1H),2.76–2.63(m,2H),2.51(s,3H),2.36(s,3H),2.36–2.30(m,1H),2.17–1.99(m,2H),1.92–1.75(m,2H).

[0192] Example 5 Compound A5: 1 H NMR (400MHz, Chloroform-d) δ7.87 (s, 1H), 7.66 (d, J = 3.5Hz, 1H), 7.19 (d, J = 1.9Hz, 1H), 7.11 (d, J = 1.8Hz, 1H), 6.61 (d, J = 3.4Hz, 1H), 4.74 (ddd, J = 12. 3,10.0,4.2Hz,1H),4.06(td,J=10.0,4.3Hz,1H),2.46(s,3H),2.28–2.12( m,2H),2.04(qd,J=12.4,3.8Hz,1H),1.96–1.84(m,2H),1.61–1.44(m,3H).

[0193] Example 11 Compound A11: 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.08(d,J=3.5Hz,1H),7.80(s,1H),7.16(d,J=1.8Hz,1H),7.12(d,J=1.8 Hz,1H),6.62(d,J=3.5Hz,1H),5.75–5.67(m,1H),3.06(td,J=8.6,4.2Hz,1H),2.92(dd,J=9.9,3.7Hz,1H),2.85 (dd,J=9.9,6.8Hz,1H),2.63–2.54(m,1H),2.49–2.43(m,1H),2.39(s,3H),2.11–2.02(m,4H).

[0194] Example 12 Compound A12: 1H NMR (400MHz, Chloroform-d) δ7.91 (s, 1H), 7.75 (d, J = 3.4Hz, 1H), 7.21 (d, J = 1.9Hz, 1H), 7.15–7.10 (m, 1H), 6.57 (d, J = 3.4Hz, 1H), 4.72 (dd, J = 14. 1,4.8Hz,1H),4.33(dd,J=14.1,5.5Hz,1H),3.14–3.06(m,1H),2.90–2.8 3(m,1H),2.53(s,3H),2.38(s,3H),2.32–2.25(m,1H),1.72–1.52(m,4H). 19 F NMR (376MHz, Chloroform-d) δ-63.06.

[0195] Example 21 Compound A21: 1 H NMR (400MHz, DMSO): δ13.85 (s, 1H), 8.78 (s, 1H), 8.26, 8.8.26 (d, J = 8.4Hz, 1H), 7. 98(s,1H),7.30(d,J=3.2Hz,1H),6.78(d,J=3.2Hz,1H),5.50(s,2H),2.30(s,3H).

[0196] Example 22 Compound A22: 1 H NMR (400MHz, DMSO): δ9.44(s,1H),8.09(s,1H),8.05(d,J=2.5Hz,1H),6.72(d,J=2.6Hz,1H),6.59(d,J=15.4Hz,2H),5.02(d,J=5 .1Hz,1H),4.42(dd,J=13.6,4.7Hz,1H),4.31(dd,J=13.6,4.8Hz,1H),4.12-4.02(m,1H),2.31(s,3H),2.27(s,3H),1.19(s,3H).

[0197] Example 31 Compound A31: 1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J=3.4Hz,1H),7.22–7.18(m,1H),7.13–7.10(m,1H) ,6.59(d,J=3.4Hz,1H),4.65(dd,J=14.5,3.4Hz,1H),4.48(dd,J=14.6,7.1Hz,1H),4.05–3.98(m,1H), 3.91(ddd,J=11.5,3.3,1.6Hz,1H),3.65(td,J=11.5,2.5Hz,1H),2.88(dt,J=11.3,1.9Hz,1H),2.66(d q,J=11.4,1.9Hz,1H),2.50(s,3H),2.27(s,3H),2.13(td,J=11.5,3.4Hz,1H),1.85(t,J=10.7Hz,1H). 19 F NMR (376MHz, Chloroform-d) δ-63.05.

[0198] Example 33 Compound A33: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.81(d,J=3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.1 5–7.10(m,1H),6.60(d,J=3.5Hz,1H),5.22(tt,J=9.7,4.0Hz,1H),3.73–3.63(m,2H),3.24( dd,J=11.0,3.9Hz,1H),2.97–2.88(m,1H),2.73(t,J=10.2Hz,1H),2.65(q,J=5.2Hz,2H),2. 52(s,3H),2.38(t,J=10.4Hz,1H),2.27–2.18(m,1H),2.14–2.01(m,1H),1.98–1.81(m,2H).

[0199] Example 628 Compound A36: 1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.57(d,J=3.4Hz,1H),7.20(d,J=1.9Hz ,1H),7.12(d,J=1.9Hz,1H),6.59(d,J=3.4Hz,1H),4.47–4.35(m,2H),2.75(d,J=11 .1Hz,1H),2.67(d,J=11.2Hz,1H),2.50(s,3H),2.47–2.35(m,1H),2.26(s,3H),2. 10(t,J=11.2Hz,1H), 1.96(t,J=10.4Hz,1H), 1.80–1.57(m,3H), 1.23–1.11(m,1H).

[0200] Example 629 Compound A37: 1 H NMR (400MHz, Chloroform-d) δ7.92 (s, 1H), 7.70 (d, J= 3.5Hz,1H),7.22(d,J=1.8Hz,1H),7.13(d,J=1.8Hz,1H),6.61(d,J=3.4Hz, 1H),4.65(dd,J=14.6,3.4Hz,1H),4.42(dd,J=14.6,7.4Hz,1H),4.12–4.04 (m,1H),3.93(dd,J=11.5,2.6Hz,1H),3.83(dd,J=11.3,2.7Hz,1H),3.76–3 .68(m,2H),3.63–3.55(m,1H),3.33(dd,J=11.5,10.0Hz,1H),2.52(s,3H).

[0201] Example 630 Compound A38: 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.88(t,J=2.9Hz,1H),7.21(d,J=1.9Hz,1H),7.13(d,J=1.9Hz,1H),6.62(d,J=3.5Hz,1H),5.65–5.51(m,1H ),5.18–5.00(m,1H),3.00(dd,J=10.5,4.7Hz,1H),2.85(t,J=11.3Hz,1H), 2.77(dt,J=11.7,3.8Hz,2H),2.52(s,3H),2.42(s,3H),2.26–2.13(m,2H).

[0202] Example 631 Compound A39: 1H NMR(400MHz,Chloroform-d)δ7.95(d,J=3.5Hz,1H),7.90(s,1H),7.21(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H),6.54(d,J=3.5Hz ,1H),6.26–6.21(m,1H),5.96–5.91(m,1H),5.85–5.81(m,1H),3.39–3.30(m,1H),2.93–2.83(m,3H),2.51(s,3H),2.33(s,3H).

[0203] Example 632 Compound A40: 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J=3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H),6.5 8(d,J=3.4Hz,1H),4.64(t,J=6.5Hz,2H),3.04(t,J=6.5Hz,2H),2.66–2.60(m,4H),2.52(s,3H),1.83–1.77(m,4H).

[0204] Example 633 Compound A41: 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.70(d,J=3.4Hz,1H),7.22(d,J=1.9Hz,1H),7.12(d,J=1.8Hz,1H),6.59(d,J=3.4Hz ,1H),4.62(t,J=6.2Hz,2H),2.92(t,J=6.2Hz,2H),2.84(p,J=6.4Hz,1H),2.79–2.60(m,8H),2.51(s,3H),1.13(d,J=6.5Hz,6H).

[0205] Example 634 Compound A42: 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J=3.4Hz,1H),7.20(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H), 6.58(d,J=3.4Hz,1H), 4.61(t,J=6.3Hz,2H), 2.89(t,J=6.3Hz,2H), 2.71–2.41(m,13H), 1.10(t,J=7.2Hz,3H).

[0206] Example 635 Compound A43: 1 H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.71(d,J=3.5Hz,1H),7.19(d,J=1.9Hz,1H),7.11(d,J=1.9Hz, 1H), 6.58 (d, J = 3.4Hz, 1H), 4.60 (t, J = 6.2Hz, 2H), 2.88 (t, J = 6.2Hz, 2H), 2.71–2.34 (m, 11H), 2.29 (s, 3H).

[0207] Example 636 Compound A44: 1 H NMR (400MHz, DMSO-d6) δ7.88(s,1H),7.69(d,J=3.5Hz,1H),7.19(d,J=1.9Hz,1H),7.10(d,J=1.9Hz,1H),6.57(d,J=3.4Hz,1H),4.60(t,J=6.3Hz ,2H),3.68–3.56(m,2H),2.84(t,J=6.3Hz,2H),2.77(dt,J=10.2,1.8Hz ,2H),2.48(s,3H),1.88(dd,J=11.3,10.0Hz,2H),1.15(d,J=6.3Hz,6H).

[0208] Example 637 Compound A45: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J= 3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.12(d,J=2.0Hz,1H),6.58(d,J=3.4Hz,1H),4.67–4.48(m,2H),3.82–3.72(m,1H),3.67–3.55 (m,2H),3.30–3.11(m,2H),2.83(dt,J=11.6,2.9Hz,1H),2.70(dt,J=13.8,5.5Hz,1H),2.54–2.44(m,5H),0.82(d,J=6.3Hz,3H).

[0209] Example 638 Compound A46: 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=3.4Hz,1H),7.81(s,1H),7.24(d,J=1.8Hz,1H),7.13(d,J=1.7Hz,1H),6.61(d,J=3.4Hz,1H),4.47 –4.33(m,2H),3.04–2.86(m,3H),2.68–2.53(m,2H),2.35(tt,J=7.1,3.7Hz,1H),2.06(s,3H),1.76–1.64(m,2H),1.57–1.44(m,1H).

[0210] Example 639 Compound A47: 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=3.5Hz,1H),7.80(s,1H),7.18(d,J=1.9Hz,1H),7.15(s,1H),6.62(d,J=3.5Hz,1H),5.66–5.5 6(m,1H),3.28–3.22(m,2H),3.15(dd,J=11.6,4.9Hz,1H),3.07–3.02(m,1H),2.47–2.37(m,1H),2.17–2.09(m,1H),2.07(s,3H).

[0211] Example 640 Compound A48: 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 8.08 (d, J = 3.5Hz, 1H), 7.80 (s, 1H), 7.16 (d,J=1.8Hz,1H),7.12(d,J=1.8Hz,1H),6.62(d,J=3.5Hz,1H),5.75–5.67(m,1H ),3.06(td,J=8.6,4.2Hz,1H),2.92(dd,J=9.9,3.7Hz,1H),2.85(dd,J=9.9,6. 8Hz,1H),2.63–2.54(m,1H),2.49–2.43(m,1H),2.39(s,3H),2.11–2.02(m,4H).

[0212] Example 641 Compound A49: 1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.67(d,J=3.5Hz,1H),7.21(d,J=1.9Hz,1H),7.13(d,J=1.9 Hz, 1H), 6.60 (d, J = 3.4Hz, 1H), 4.75 (t, J = 5.1Hz, 1H), 4.61 (d, J = 5.1Hz, 2H), 3.46 (s, 6H), 2.52 (s, 3H).

[0213] Example 642 Compound A50: 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.94(d,J=3.3Hz,1H),7.81(s,1H),7.16(s,2H),6.5 9(d,J=3.2Hz,1H), 4.64(t,J=5.2Hz,2H), 3.83(t,J=5.2Hz,2H), 3.28(s,3H), 2.07(s,3H).

[0214] Example 643 Compound A51: 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),7.82(d,J=3.5Hz,1H),7.80(s,1H),7.14(d,J=1.8Hz,1H), 7.11(d,J=1.8Hz,1H),6.59(d,J=3.4Hz,1H),5.43(s,2H),3.17(s,3H),2.88(s,3H),2.05(s,3H).

[0215] Example 644 Compound A52: 1 H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.68(d,J=3.5Hz,1H),7.22–7.19(m,1H),7.13( d,J=1.8Hz,1H),6.61(d,J=3.4Hz,1H),4.67–4.62(m,2H),4.17–4.12(m,2H),2.50(s,3H).

[0216] Example 645 Compound A53: 1H NMR(400MHz,Chloroform-d)δ8.70(d,J=4.9Hz,2H),7.95(s,1H),7.75(d,J=3.5Hz,1H),7.24(t,J=4.9Hz,1H),7.20(d,J=1.9Hz,1H),7.12 (s, 1H), 6.70 (d, J = 3.5Hz, 1H), 5.96 (s, 2H), 2.53 (s, 3H).

[0217] Example 646 Compound A54: 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J=3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.12(d,J=2.0 Hz, 1H), 6.58 (d, J = 3.4Hz, 1H), 4.60 (t, J = 6.3Hz, 2H), 2.84 (t, J = 6.3Hz, 2H), 2.51 (s, 3H), 2.33 (s, 6H).

[0218] Example 647 Compound A55: 1 H NMR(400MHz,Chloroform-d)δ10.96(s,1H),7.94(s,1H),7.62(d,J=3.5Hz,1H),7.22(d, J=1.9Hz,1H),7.14(s,1H),6.69(d,J=3.5Hz,1H),5.30(s,2H),3.83(s,3H),2.53(s,3H).

[0219] Example 648 Compound A56: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.77(d,J=3.4Hz,1H),7.21(d,J=1.9Hz ,1H),7.12(d,J=1.9Hz,1H),6.59(d,J=3.4Hz,1H),4.75(dd,J=14.1,2.8Hz,1H),4 .44(dd,J=14.1,7.1Hz,1H),4.36(qd,J=7.0,2.8Hz,1H),3.95–3.87(m,1H),3.84– 3.76(m,1H),2.51(s,3H),2.17–2.08(m,1H),1.97–1.76(m,2H),1.69–1.58(m,1H).

[0220] Example 649 Compound A57: 1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J=3.4Hz,1H),7.22–7.18(m,1H),7.13–7.10(m,1H) ,6.59(d,J=3.4Hz,1H),4.65(dd,J=14.5,3.4Hz,1H),4.48(dd,J=14.6,7.1Hz,1H),4.05–3.98(m,1H), 3.91(ddd,J=11.5,3.3,1.6Hz,1H),3.65(td,J=11.5,2.5Hz,1H),2.88(dt,J=11.3,1.9Hz,1H),2.66(d q,J=11.4,1.9Hz,1H),2.50(s,3H),2.27(s,3H),2.13(td,J=11.5,3.4Hz,1H),1.85(t,J=10.7Hz,1H). 19 F NMR (376MHz, Chloroform-d) δ-63.05.

[0221] Example 650 Compound A58: 1 H NMR (400MHz, Chloroform-d) δ7.91 (s, 1H), 7.75 (d, J = 3.4Hz, 1H), 7.21 (d, J = 1.9Hz, 1H), 7.15–7.10 (m, 1H), 6.57 (d, J = 3.4Hz, 1H), 4.72 (dd, J = 14. 1,4.8Hz,1H),4.33(dd,J=14.1,5.5Hz,1H),3.14–3.06(m,1H),2.90–2.8 3(m,1H),2.53(s,3H),2.38(s,3H),2.32–2.25(m,1H),1.72–1.52(m,4H). 19 F NMR (376MHz, Chloroform-d) δ-63.06.

[0222] Example 651 Compound A59: 1H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.56(d,J=3.5Hz,1H),7.28(s,1H),7.16(d,J=1.8Hz,1H),7.09(d,J=1.8Hz,1H),6 .53(d,J=3.4Hz,1H),4.50(d,J=5.5Hz,2H),4.23(dt,J=11.2,5.4Hz,1H),2.35(s,3H),2.29–2.08(m,3H),1.96–1.86(m,1H). 19 F NMR (376MHz, Chloroform-d) delta-62.92.

[0223] Example 652 Compound A60: 1 H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.57(d,J=3.4Hz,1H),7.17(d,J=1.9Hz,1H),7.14(s,1H),7.10(d,J=1.2Hz,1H),6.56(d, J=3.4Hz,1H),4.59–4.45(m,2H),4.26(dt,J=10.9,5.5Hz,1H),2.39(s,3H),2.35–2.19(m,3H),2.21–2.09(m,1H),1.99–1.88(m,1H).

[0224] Example 653 Compound A61: 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=0.8Hz,1H),7.71(dd,J=14.9,3.5Hz,1 H),7.22(d,J=2.2Hz,1H),7.12(s,1H),6.59(t,J=3.6Hz,1H),5.16–4.91(m,1H ),3.92–3.77(m,2H),3.35–3.21(m,1H),3.15–3.08(m,1H),2.94–2.69(m,2H), 2.51(s,3H),2.33–2.17(m,2H),2.01–1.87(m,2H),1.05(dd,J=6.7,1.8Hz,3H).

[0225] Example 654 Compound A62: 1H NMR(400MHz,Chloroform-d)δ8.05(d,J=3.4Hz,1H),7.90(s,1H),7.21(d,J=1 .8Hz,1H),7.14–7.09(m,1H),6.57(d,J=3.5Hz,1H),5.29–5.19(m,1H),3.17( dd,J=11.1,3.8Hz,1H),2.97–2.84(m,2H),2.87–2.76(m,1H),2.61–2.52(m,1 H), 2.51 (s, 3H), 2.19–2.05 (m, 2H), 1.92–1.77 (m, 2H), 1.10 (d, J = 6.6Hz, 6H).

[0226] Example 655 Compound A63: 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.90(s,1H),7.21(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H),6.58(d,J=3.5Hz,1H),5.22(tt,J=8.4,4.2Hz,1H),2 .99(d,J=11.1Hz,1H),2.82(p,J=7.8Hz,1H),2.69–2.56(m,2H),2.52(s,3H) ,2.32–2.19(m,1H),2.17–1.99(m,4H),1.97–1.87(m,2H),1.85–1.64(m,4H).

[0227] Example 656 Compound A64: 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.91(s,1H),7.21(d,J=1.9Hz,1H), 7.12(d,J=1.9Hz,1H),6.60(d,J=3.5Hz,1H),5.27(tt,J=8.4,4.1Hz,1H),4.68( p,J=6.5Hz,4H),3.60(p,J=6.5Hz,1H),2.96(dd,J=11.0,3.7Hz,1H),2.68–2.5 5(m,2H),2.51(s,3H),2.35–2.29(m,1H),2.21–2.07(m,2H),1.94–1.79(m,2H).

[0228] Example 657 Compound A65: 1H NMR(400MHz,Chloroform-d)δ8.00(d,J=12.0Hz,1H),7.91(s,1H),7.21(d,J=1.9Hz, 1H),7.13(d,J=1.8Hz,1H),6.59(d,J=3.5Hz,1H),5.24(tt,J=8.7,3.7Hz,1H),4.00–3 .93(m,1H),3.92–3.83(m,1H),3.81–3.69(m,2H),3.25–3.00(m,2H),2.82(t,J=9.7H z,1H),2.69(q,J=8.3,6.4Hz,1H),2.52(s,3H),2.21–1.98(m,4H),1.95–1.80(m,3H).

[0229] Example 658 Compound A66: 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J=3.6Hz,1H),7.91(s,1H),7.22(d,J=1.9Hz,1H),7 .13(d,J=1.9Hz,1H),6.58(d,J=3.4Hz,1H),5.28–5.19(m,1H),4.04(dd,J=11.1,4.3Hz,2 H),3.38(tt,J=12.0,2.3Hz,2H),3.26–3.20(m,1H),2.92–2.80(m,2H),2.68–2.56(m,2H) ,2.53(s,3H),2.19–2.06(m,2H),1.91–1.81(m,2H),1.79–1.75(m,2H),1.70–1.63(m,2H).

[0230] Example 659 Compound A67: 1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.70(d,J=3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.12(dd,J=1.9,1.1Hz,1H),6.60(d,J=3.4Hz,1H), 4.64(dd,J=14.6,3.4Hz,1H),4.42(dd,J=14.6,7.3Hz,1H),4.11–4.04(m,1H),3.93(dd,J=11.5,2.6Hz,1H),3.83(d d,J=11.4,2.7Hz,1H),3.75–3.68(m,2H),3.59(td,J=11.8,2.8Hz,1H),3.33(dd,J=11.5,10.0Hz,1H),2.51(s,3H).

[0231] Example 660 Compound A68: 1 H NMR(400MHz,Chloroform-d)δ7.88(d,J=10.8Hz,1H),7.63–7.50(m,1H),7.18(d,J=2 .1Hz,1H),7.09(d,J=2.1Hz,1H),6.59(dd,J=14.2,3.4Hz,1H),4.47(dd,J=14.1,6.7 Hz,1H),4.36–3.99(m,2H),3.69–3.54(m,1H),3.29–2.68(m,2H),2.44(d,J=4.3Hz,3 H),2.33–2.21(m,1H),2.01(d,J=53.8Hz,3H),1.84–1.70(m,2H),1.55–1.30(m,2H).

[0232] Example 661 Compound A69: 1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.72(d,J=3.4Hz,1H),7.21(d,J=1.9Hz,1H),7.12(d, J=1.9Hz,1H),6.60(d,J=3.4Hz,1H),4.66(dd,J=14.5,3.5Hz,1H),4.49(dd,J=14.5,7.1Hz,1H),4 .06–3.99(m,1H),3.94–3.88(m,1H),3.66(td,J=11.4,2.5Hz,1H),2.88(dt,J=11.2,2.0Hz,1H),2 .71–2.64(m,1H),2.52(s,3H),2.28(s,3H),2.13(td,J=11.5,3.4Hz,1H),1.86(t,J=10.7Hz,1H).

[0233] Example 662 Compound A70: 1 H NMR(400MHz,Chloroform-d)δ10.94(s,1H),7.88(s,1H),7.75(d,J=3.5Hz,1H),7.1 7(d,J=1.9Hz,1H),7.10(d,J=2.0Hz,1H),6.60(d,J=3.5Hz,1H),5.08–4.96(m,1H),4 .00(dd,J=12.0,4.1Hz,1H),3.75–3.66(m,2H),3.23–3.13(m,1H),3.03(q,J=7.4Hz, 2H), 2.51–2.39 (m, 4H), 2.27–2.19 (m, 1H), 2.02–1.81 (m, 2H), 1.39 (t, J = 7.4Hz, 3H).

[0234] Example 663 Compound A71: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.77(d,J=3.5Hz,1H),7.20(d,J=1.9Hz, 1H),7.14–7.11(m,1H),6.61(d,J=3.5Hz,1H),5.07–4.96(m,1H),3.99(dd,J=12.0, 4.2Hz,1H),3.80–3.67(m,2H),3.24–3.14(m,1H),3.04–2.91(m,2H),2.56–2.45(m, 4H), 2.29–2.20 (m, 1H), 2.04–1.95 (m, 1H), 1.94–1.82 (m, 3H), 1.07 (t, J = 7.4Hz, 3H).

[0235] Example 664 Compound A72: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.73(d,J=3.5Hz,1H),7.22–7.19(m,1H),7.14–7.11(m,1H),6.62(d,J=3.5Hz,1H),5.18–5.07(m,1H),3. 99–3.91(m,1H),3.73–3.64(m,1H),3.54(dd,J=12.1,9.7Hz,1H),3.17–3. 08(m,1H),2.87(s,6H),2.50(s,3H),2.36–2.22(m,2H),2.02–1.84(m,2H).

[0236] Example 665 Compound A73: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.69(d,J=3.5Hz,1H),7.21(d,J=1 .9Hz,1H),7.12(d,J=1.9Hz,1H),6.61(d,J=3.5Hz,1H),5.19–5.10(m,1H),4. 04–3.98(m,1H),3.67(dt,J=13.2,4.0Hz,1H),3.29(dd,J=12.6,10.4Hz,1H), 3.01–2.93(m,1H),2.89(s,6H),2.51(s,3H),2.37–2.30(m,1H),2.28–2.19(m, 1H),1.99–1.83(m,2H).

[0237] Example 666 Compound A74: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.69(d,J=3.5Hz,1H),7.20(d,J=2.0H z,1H),7.12(d,J=1.9Hz,1H),6.60(d,J=3.5Hz,1H),5.03–4.92(m,1H),4.77(d,J =7.3Hz,1H),4.24(dd,J=13.3,3.9Hz,1H),4.03–3.89(m,2H),3.46(dd,J=13.2,9 .6Hz,1H),3.12–3.01(m,1H),2.49(s,3H),2.36–2.29(m,2H),1.95–1.77(m,2H).

[0238] Example 667 Compound A75: 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.99(d,J=3.4Hz,1H),7.76(s,1H),7.15–7.03(m,3 H), 6.76 (dd, J = 2.6, 1.5Hz, 1H), 6.63–6.51 (m, 3H), 5.56 (s, 2H), 2.80 (s, 6H), 2.01 (s, 3H).

[0239] Example 668 Compound A76: 1 H NMR (400MHz, Methanol-d4) δ8.64(s,1H),8.46(d,J=4.4Hz,1H),7.97(d,J=3.3Hz,1H),7.92–7.81(m,2H) ,7.40(dd,J=7.9,4.7Hz,1H),7.12(s,1H),7.06(s,1H),6.71(d,J=3.2Hz,1H),5.77(s,2H),2.10(s,3H).

[0240] Example 669 Compound A77: 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.72(d,J=3.5Hz,1H),7.21(d,J=1.9Hz,1H),7.15–7.09( m,1H),6.59(d,J=3.4Hz,1H),4.66(dd,J=14.5,3.2Hz,1H),4.46(dd,J=14.5,7.4Hz,1H),3.97–3.83 (m,2H),3.54(td,J=11.4,2.5Hz,1H),3.03(dt,J=11.2,2.0Hz,1H),2.83–2.73(m,1H),2.52(s,3H), 2.37(td,J=11.5,3.4Hz,1H), 2.10(t,J=10.7Hz,1H), 1.61(tt,J=6.5,3.8Hz,1H), 0.49–0.34(m,4H).

[0241] Example 670 Compound A78: 1 H NMR(400MHz,Methanol-d4)δ7.89(d,J=3.5Hz,1H),7.86(s,1H),7.12(d,J=1.8Hz,1H) ,7.06(d,J=1.7Hz,1H),6.65(d,J=3.5Hz,1H),4.50(s,2H),2.11(s,3H),1.24(s,6H).

[0242] Example 671 Compound A79: 1 H NMR(400MHz,Chloroform-d)δ8.52(s,1H),7.88(s,1H),7.69(d,J=3.5Hz,1H),7.20(d,J=1.9Hz,1H), 7.11(d,J=1.9Hz,1H),6.57(d,J=3.5Hz,1H),4.64(dd,J=14.5,3.3Hz,1H),4.45(dd,J=14.5,7.5Hz,1H ),4.14–4.06(m,1H),3.95–3.88(m,1H),3.75–3.65(m,1H),3.08(dt,J=11.4,2.1Hz,1H),2.89–2.76( m, 2H), 2.45 (s, 3H), 2.40 (dd, J = 11.5, 3.5Hz, 1H), 2.16 (t, J = 10.8Hz, 1H), 1.08 (dd, J = 6.6, 1.7Hz, 6H).

[0243] Example 672 Compound A80: 1 H NMR(400MHz,Chloroform-d)δ7.87–7.78(m,2H),7.09(d,J=15.0Hz,2H),6.60 (d,J=3.5Hz,1H),4.60(dd,J=14.4,3.9Hz,1H),4.54–4.45(m,1H),4.08–4.00 (m,1H),3.90–3.82(m,1H),3.65–3.55(m,2H),3.31–3.27(m,1H),2.99(d,J=1 1.3Hz,1H),2.80–2.74(m,1H),2.52(t,J=5.8Hz,2H),2.23(td,J=11.5,3.4Hz, 1H), 2.10 (s, 3H), 2.02 (t, J = 10.8Hz, 1H).

[0244] Example 673 Compound A81: 1H NMR (400MHz, Methanol-d4) δ7.97(d,J=3.6Hz,1H),7.84(d,J=2.1Hz,1H),7.11( d,J=1.7Hz,1H),7.05(d,J=1.8Hz,1H),6.67(d,J=3.5Hz,1H),4.40–4.30(m,1H) ,3.20–3.14(m,1H),3.01–2.94(m,1H),2.82(t,J=11.2Hz,1H),2.42(s,1H),2.3 8(s,3H),2.36–2.32(m,1H),2.21–2.13(m,1H),2.11(s,3H),1.92–1.83(m,1H).

[0245] Example 686 Compound A82: 1 H NMR (400MHz, Chloroform-d) δ7.92 (s, 1H), 7.80 (d, J = 3.5Hz, 1H), 7.22 (d, J = 1.8Hz, 1H), 7.13 (d, J = 1.9Hz, 1H), 6.62 (d, J = 3.5Hz, 1H), 5.15-4. 98(m,1H),3.96(dd,J=11.8,4.2Hz,1H),3.80-3.71(m,2H),3.23-3.14( m,1H),2.89(s,3H),2.51(s,3H),2.28-2.20(m,1H),2.07-1.86(m,3H).

[0246] Example 687 Compound A83: 1 H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.66(d,J=3.5Hz,1H),7.20(d,J=1.9Hz,1H ),7.11(d,J=1.9Hz,1H),6.59(d,J=3.5Hz,1H),5.48(dd,J=8.5,4.4Hz,1H),3.51(s,1 H),2.96-2.89(m,1H),2.69-2.63(m,1H),2.60(s,3H),2.49(s,3H),2.43(d,J=9.1Hz, 1H), 2.34-2.27 (m, 1H), 2.10-2.04 (m, 1H), 1.92-1.86 (m, 1H), 1.79 (d, J = 10.6Hz, 1H).

[0247] Example 688 Compound A84: 1H NMR (400MHz, Chloroform-d) δ7.91 (s, 1H), 7.57 (d, J = 3.4Hz, 1H), 7.21 (s, 1H), 7. 12(s,1H),6.60(d,J=3.4Hz,1H),4.46–4.39(m,2H),2.75(d,J=11.3Hz,1H),2.70– 2.63(m,1H),2.50(s,3H),2.46–2.36(m,1H),2.26(s,3H),2.10(t,J=11.0Hz,1H) ,1.97(t,J=10.4Hz,1H),1.81–1.69(m,2H),1.65–1.55(m,1H),1.23–1.11(m,1H).

[0248] Example 689 Compound A85: 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.99(d,J=3.6Hz,1H),7.73(s,1H),7.07(d,J=1.8Hz,1H),7.04(d,J=1.8Hz,1H),6.56(d,J=3.5Hz,1H) ,5.33–5.16(m,1H),3.50–3.39(m,1H),3.25–3.14(m,2H),2.78–2.63( m,1H),2.57(s,3H),2.16–1.99(m,2H),1.96(s,3H),1.93–1.84(m,2H).

[0249] Example 36: 2-(7-(2-Hydroxypropyl)-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0250] Step 1: Compound 9 (1.45 g, 10 mmol), NaHCO₃ (2.1 g, 25 mmol) and MeOH (20 mL) were added to a round-bottom flask, followed by the dropwise addition of Br₂ (0.57 mL, 11 mmol). The mixture was stirred at room temperature for 4 hours and then filtered. The filtrate was concentrated in vacuo, and EtOAc (100 mL) was added to the resulting residue, which was then washed sequentially with saturated aqueous NaHCO₃ (2×20 mL) and aqueous NaCl (1×20 mL). The organic phase was dried over MgSO₃, filtered, and concentrated. The crude product was purified by column chromatography to afford compound 10 (1.0 g, 45.5% yield). MS / ESI: [M+H] + =222.1.

[0251] The preparation of 2-(7-(2-hydroxypropyl)-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol was carried out according to Example 1. MS / ESI: [M+H] + =222.1.

[0252] The synthesis methods of Examples 37 to 85, Examples 674 to 683 and Example 690 were prepared by referring to Example 36 to obtain target compounds B2 to B61.

[0253] Table 3 Compounds B2 to B61 of the present invention

[0254] Example 39 Compound B4: 1 HNMR(DMSO-d6): δ10.42(s,1H),7.85(d,J=3.4Hz,1H),7.47(d,J=7.7Hz,1H),7.26-7. 30(m,2H),6.68(d,J=3.4Hz,1H),4.90(s,1H),4.39(s,2H),2.36(s,3H),1.12(s,6H).

[0255] Example 42 Compound B7: 1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.56(d,J=8.1Hz,1H),7.40(d,J=1.9Hz,1H),7.21(dd,J=8.2,1.9Hz,1H),6.62(d,J=3.5Hz,1 H),5.26–5.16(m,1H),3.18–3.09(m,1H),2.78(t,J=10.0Hz,2H),2.71(s,3H),2.43–2.35(m,4H),2.18–2.08(m,2H),1.91–1.82(m,2H).

[0256] Example 674 Compound B51: 1 H NMR(400MHz,Chloroform-d)δ7.39(d,J=3.6Hz,1H),7.01(s,1H),6.97(s,1H),6 .57(d,J=3.4Hz,1H),5.20–4.96(m,2H),2.29(s,3H),2.18(s,3H),1.94(s,3H).

[0257] Example 675 Compound B52: 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.70(d,J=5.5Hz,1H),7.47(s,2H),7.36(d,J=5.5Hz,1H),6.58(d,J=3.5Hz,1H),5.22–5.13(m,1H), 3.11–3.03(m,1H),2.74(s,3H),2.65(t,J=9.8Hz,1H),2.36(s,3H),2.3 4–2.28(m,1H),2.17–2.09(m,1H),2.08–1.93(m,2H),1.89–1.78(m,2H).

[0258] Example 676 Compound B53: 1 H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.56(d,J=8.1Hz,1H),7.40(d,J=1.9Hz,1H),7.21(dd,J=8.2,1.9Hz,1H),6.62(d,J=3.5Hz,1 H),5.26–5.16(m,1H),3.18–3.09(m,1H),2.78(t,J=10.0Hz,2H),2.71(s,3H),2.43–2.35(m,4H),2.18–2.08(m,2H),1.91–1.82(m,2H).

[0259] Example 677 Compound B54: 1 H NMR (400MHz, Chloroform-d) δ7.63 (d, J = 3.5Hz, 1H), 7.55(d,J=8.1Hz,1H),7.40–7.36(m,1H),7.20(dt,J=8.1,1.2Hz,1H),6.61(d,J=3.5Hz,1H),4.60(dd,J=14.5,3.4Hz,1H),4.38(dd,J=14.5,7 .3Hz,1H),3.96–3.84(m,2H),3.55(td,J=10.9,3.6Hz,1H),3.07–3.00(m,1H),2.88–2.75(m,2H),2.70(s,3H),2.56(dd,J=12.1,10.3Hz,1H).

[0260] Example 678 Compound B55: 1H NMR(400MHz,Chloroform-d)δ7.64(d,J=3.5Hz,1H),7.59–7.54(m,1H),7.38(d,J=1.9Hz,1H),7.23 –7.18(m,1H),6.62(d,J=3.4Hz,1H),4.60(dd,J=14.5,3.6Hz,1H),4.46(dd,J=14.5,6.9Hz,1H),4.0 2–3.92(m,1H),3.92–3.85(m,1H),3.62(td,J=11.4,2.5Hz,1H),2.82(dt,J=11.1,1.9Hz,1H),2.72 (s,3H),2.62(dq,J=11.5,1.9Hz,1H),2.24(s,3H),2.08(td,J=11.5,3.3Hz,1H),1.85–1.74(m,1H).

[0261] Example 679 Compound B56: 1 H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.63(d,J=2.2Hz,1H),7.36–7.27(m,2H),6.98(d,J=2.3Hz,1H),6.53(d,J=3.4Hz,1H),5.33–5.20( m,1H),3.83(s,3H),3.24(d,J=10.3Hz,1H),2.92–2.83(m,2H),2.46–2. 40(m,1H),2.38(d,J=6.5Hz,6H),2.21–2.13(m,2H),1.93–1.86(m,2H).

[0262] Example 680 Compound B57: 1H NMR (400MHz, Chloroform-d) δ7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.46 (s, 2H), 7.35 (d, J = 5. 4Hz,1H),6.59(d,J=3.5Hz,1H),4.61(dd,J=14.5,3.6Hz,1H),4.47(dd,J=14.5,6.8Hz,1H),4.04–3.9 6(m,1H),3.90(ddd,J=11.5,3.4,1.6Hz,1H),3.65(td,J=11.4,2.4Hz,1H),2.84(dt,J=11.2,1.9Hz,1 H), 2.74 (s, 3H), 2.66–2.59 (m, 1H), 2.25 (s, 3H), 2.10 (td, J = 11.4, 3.3Hz, 1H), 1.81 (t, J = 10.7Hz, 1H).

[0263] Example 681 Compound B58: 1 H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.71(d,J=8.7Hz,1H),7.56(d,J=2.2Hz,1H),7.11(dd,J= 8.7,0.9Hz,1H),7.05(dd,J=2.2,0.9Hz,1H),6.60(d,J=3.5Hz,1H),5.15(tt,J=8.7,4.1Hz,1H),3.1 3–3.03(m,1H),2.70(dt,J=19.8,10.3Hz,2H),2.41(ddd,J=8.6,5.5,3.1Hz,1H),2.36(s,3H),2.36– 2.26(m,1H),2.15–1.95(m,2H),1.83(dq,J=11.1,4.7Hz,2H),1.13–1.03(m,2H),0.87–0.79(m,2H).

[0264] Example 682 Compound B59: 1H NMR(400MHz,Chloroform-d)δ9.81(s,1H),7.76(d,J=3.4Hz,1H),7.66(d,J=8.1Hz,1H),7. 62(s,1H),7.24(t,J=2.7Hz,1H),7.18(dd,J=8.1,1.5Hz,1H),6.54(d,J=3.5Hz,1H),6.49(t ,J=2.6Hz,1H),5.50–5.36(m,1H),3.32(d,J=11.0Hz,1H),2.93–2.84(m,1H),2.78(d,J=9.8 Hz,1H),2.48(s,3H),2.45–2.37(m,1H),2.22(s,3H),2.17–2.07(m,2H),1.95–1.80(m,2H).

[0265] Example 683 Compound B60: 1 H NMR (400MHz, Methanol-d4) δ8.53(d,J=3.6Hz,1H),7.60(d,J=7.9Hz,1H),7.44(dd,J=7.9,1.5Hz,1H),7.37(d,J=1.4Hz,1H),7.21(d,J=3.6Hz,1H),5.40– 5.29(m,1H),3.96–3.81(m,1H),3.69–3.54(m,2H),3.20–3.07(m,1H),2.98( s,3H),2.60(s,3H),2.43–2.32(m,2H),2.30–2.21(m,1H),2.17–2.04(m,1H).

[0266] Example 690 Compound B61: 1 H NMR(400MHz, Methanol-d4)δ7.94(d,J=3.6Hz,1H),7.71(d,J=2.3Hz,1H),7.23–7.13( m,2H),7.03(dd,J=2.4,0.9Hz,1H),6.69(d,J=3.5Hz,1H),5.20–5.10(m,1H),3.23(dd ,J=10.9,3.9Hz,1H),2.92(d,J=11.5Hz,1H),2.63(t,J=10.7Hz,1H),2.44(s,3H),2.3 9(s,3H),2.31–2.22(m,1H),2.21–2.13(m,1H),2.13–2.02(m,1H),1.99–1.80(m,2H).

[0267] Example 86: 2-(1-(2-Hydroxypropyl)-1H-pyrazolo[3,4-c]pyridazin-5-yl)-3-methyl-5-(trifluoromethyl)phenol

[0268] Step 1: Add compound 19 (2 g, 1 eq.), hydrazine hydrate (4 eq.), and methanol to a reaction flask and heat to 60°C for 2 h. After the reaction is complete, cool to room temperature and filter. The filter cake is dried to obtain compound 20 (1.6 g, yield 82.1%). MS / ESI: [M+H] + =170.1.

[0269] Step 2: At 0°C, a 5 mL aqueous solution of sodium nitrite (814 mg, 2 eq.) was added dropwise to a 10 mL acetic acid solution of compound 20 (1.6 g). The mixture was allowed to react overnight after warming to room temperature. After the reaction was complete, the mixture was cooled to 0°C, filtered, and the filter cake was washed with cold water to obtain compound 21 (1 g, 44.2% yield, as a yellow solid). MS / ESI: [M+H] + =241.1.

[0270] Step 3: Compound 21 (1 g, 1.0 eq.), 0.1 M aqueous hydrochloric acid (60 ml), and DME (10 ml) were added to a reaction flask and heated to 80°C for 2 h. After the reaction was complete, the mixture was cooled to room temperature. Ethyl acetate was added and extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain compound 22 (260 mg, yellow solid). MS / ESI: [M+H] + =155.1; 1 HNMR (400MHz, DMSO-d6): δ14.70 (s, 1H), 8.53-8.29 (m, 2H).

[0271] Step 4: Compound 22 (200 mg, 1 eq.), compound 8 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and reacted at room temperature overnight. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 23 (210 mg, white solid). MS / ESI: [M+H] + =213.1.

[0272] Step 5: Compound 23 (200 mg, 1 eq.), intermediate int-1 (2 eq.), Pd(dppf)Cl2 (0.1 eq.), cesium carbonate (3 eq.), dioxane, and water were added to a reaction flask and reacted at 100°C overnight under nitrogen. After the reaction was complete, the mixture was filtered through Celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 24 (90 mg, white solid). MS / ESI: [M+H] + =367.1.

[0273] Step 6: Compound 24 (50 mg, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was allowed to proceed at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound C1 (30 mg). MS / ESI: [M+H] + =353.1. 1 H NMR(400MHz,CD3OD)δ8.84(s,1H),8.71(s,1H),7.26(s,1H),7.15(s,1H),4.76– 4.73(m,1H),4.50–4.43(m,1H),3.66(s,2H),2.24(s,3H),1.35(d,J=6.4Hz,3H).

[0274] The synthesis methods of Examples 87 to 135 and Example 684 were prepared by referring to Example 86 to obtain target compounds C2 to C51.

[0275] Table 4 Compounds C2 to C51 of the present invention

[0276] Example 90 Compound C5: 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.42(s,1H),8.18(s,1H),7.20(s,1H),7.14(s,1H),5.28-5.15(m,1H),3.17-3. 08(m,1H),2.91-2.81(m,1H),2.50-2.45(m,2H),2.27(s,3H),2.20-1.96(m,5H),1.93-1.85(m,1H),1.85-1.72(m,1H).

[0277] Example 99 Compound C14: 1H NMR (400 MHz, DMSO-d6) δ8.47 (s, 1H), 8.32 (s, 1H), 8.23 ​​(s, 1H), 7.22 (d, J = 11.2 Hz, 2H), 4.79-4.56 (m, 2H), 2.70-2.59 (m, 2H), 2.47-2.35 (m, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.08-1.91 (m, 2H), 1.78-1.61 (m, 2H), 1.58-1.46 (m, 1H), 1.18-1.06 (m, 1H).

[0278] Example 103 Compound C18: 1 H NMR (400MHz, CD3OD) δ8.22(s,1H),8.05(s,1H),7.03(s,1H),6.97(s,1H),4.85(d,J=7. 1Hz,2H),3.46-3.40(m,2H),3.22-3.19(m,2H),2.26(s,3H),2.12(s,1H),2.02(s,3H).

[0279] Example 104 Compound C19: 1HNMR (400 MHz, Chloroform-d): δ9.79 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 6.80 (s, 1H), 6.75 (s, 1H), 4.85 (dd, J = 14.2, 3.0 Hz, 1H), 4.69 (dd, J = 14.2, 7.8 Hz, 1H), 4.53–4.41 (m, 1H), 3.15 (s, 1H), 2.39 (s, 3H), 2.34 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H).

[0280] Example 684 Compound C51: 1 H NMR(400MHz,DMSO-d6)δ10.20(br s,1H),8.41(s,1H),8.16(s,1H),7.17(dd,J=22.8,1.6Hz,2H),4.81(d,J=6.4Hz,2H),2.89(d,J=6.4Hz,2H),2.21(s,6H),2.08(s,3H).

[0281] Example 136: 2-(1-(2-Hydroxypropyl)-4-methyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0282] Step 1: Compound 25 (5 g, 1 eq.), methyl 2-butynoate (1.1 eq.), and xylene were added to a sealed tube and reacted at 160°C overnight. The xylene was removed by concentration under reduced pressure, and the residue was purified by column chromatography to obtain compound 27 (2 g). MS / ESI: [M+H] + =211.0.

[0283] Step 2: Dissolve compound 27 (2 g) in anhydrous toluene, cool to 0°C, and add DIBAL-H toluene solution (1.5 M, 18 mL) dropwise. React at 0°C for 1 h. Quench the reaction with saturated ammonium chloride solution, extract three times with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and purify the residue by column chromatography to obtain compound 28 (610 mg). MS / ESI: [M+H] + =193.0.

[0284] Step 3: Under a nitrogen atmosphere, anhydrous dichloromethane (20 mL) and oxalyl chloride (1.0 mL, 11.25 mmol) were added to a 100 mL round-bottom flask. The mixture was cooled to -78°C. Anhydrous DMSO (1.1 mL, 15 mmol) was slowly added. The reaction was stirred for 30 minutes. A dichloromethane solution (5 mL) of compound 28 (1.2 g, 7.5 mmol) was slowly added. The reaction was stirred for approximately 3 hours until the reaction was complete as monitored by TLC (1:1 ethyl acetate / n-hexane). Triethylamine (4.3 mL, 30 mmol) was added to quench the reaction and stirred for 10 minutes, then warmed to room temperature. Water (50 mL) was added to the reaction mixture, which was then extracted with dichloromethane (2×25 mL). The organic phase was washed with saturated NaHCO3 solution (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 29 (0.8 g). MS / ESI:[M+H] + =191.1.

[0285] Step 4: Compound 29 (1.9 g, 10 mmol) and hydrazine monohydrate (60% aqueous solution, 10 mL) were added to 140 mL of water, the reaction temperature was raised to 100°C and stirred for 72 hours. The reaction mixture was cooled to room temperature and extracted with 20 mL of ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification gave compound 30 (1.2 g, yield 71%). MS / ESI: [M+H] + =169.1.

[0286] Step 5: Compound 30 (169 mg, 1 eq.), compound 8 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and allowed to react overnight at room temperature. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 31 (158 mg). MS / ESI: [M+H] + =227.1.

[0287] Step 6: Compound 31 (114 mg, 1 eq.), compound 32 (2 eq.), Pd(dppf)Cl2 (0.1 eq.), cesium carbonate (3 eq.), dioxane, and water were added to a reaction flask and reacted at 100°C overnight under nitrogen. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound D1 (52 mg, white solid). MS / ESI: [M+H] + =353.1.

[0288] The synthesis methods of Examples 137 to 200 were carried out by referring to Example 136 to obtain target compounds D2 to D65.

[0289] Table 5 Compounds D2 to D65 of the present invention

[0290] Example 201: 2-(7-(2-Hydroxypropyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0291] Step 1: Compound 1 (5.0 g, 24.0 mmol), compound 33 (4.41 g, 26.4 mmol) and DIEA (6.20 g, 1.82 mmol) were weighed and added into a flask, followed by addition of 25 mL of dimethyl sulfoxide, and the mixture was heated to 110°C and reacted overnight. The reaction mixture was cooled to room temperature and slowly added dropwise to 125 mL of water. A large amount of solid precipitated and was filtered. The filter cake was slurried with ethyl acetate (15 mL) for 0.5 h and filtered. The filter cake was dried to give the title compound 34 (5.5 g, 18.7 mmol, gray solid, yield 78%). 1H NMR (400 MHz, DMSO) δ 7.13 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.56-6.50 (m, 1H), 6.26 (s, 1H), 6.14 (s, 2H), 4.20 (d, J = 5.2 Hz, 2H), 3.82 (s, 3H), 3.75 (s, 3H); MS / ESI: [M+H] + =295.0.

[0292] Step 2: Add HCl / EtOAc (2.5 mL, 4.0 M) to compound 34 (500 mg, 1.70 mmol) and stir at room temperature for 1 h. A large amount of solid is formed, which is filtered and the filter cake is rinsed with EtOAc and dried under reduced pressure to yield the title compound 35 (440 mg, 2.43 mmol, as a gray solid).

[0293] Step 3: Compound 35 (340 mg, 1.56 mmol), DIEA (972 mg, 7.52 mmol), and trimethyl orthoformate (998 mg, 9.40 mmol) were weighed and added to DMF (3 mL). The mixture was heated to 110°C and stirred for 3 h. After the reaction was complete, the filtrate was filtered and collected to obtain the target compound 36, which was used directly in the next reaction.

[0294] Step 4: To a DMF solution of compound 36, K2CO3 (672 mg, 4.86 mmol) and bromoacetone (400 mg, 2.92 mmol) were added and allowed to react at room temperature overnight. After the reaction was complete, the reaction solution was poured into water (15 mL) and extracted with DCM / MeOH (15 mL × 3, v:v = 5:1). The organic phase was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 37 (100 mg, 0.475 mmol, light yellow solid, 20% yield). MS / ESI: [M+H] + =211.0.

[0295] Step 5: Compound 37 (200 mg, 1 eq.), intermediate int-1 (2 eq.), Pd(dppf)Cl2 (0.1 eq.), cesium carbonate (3 eq.), dioxane, and water were added to a reaction flask and reacted at 100°C under nitrogen overnight. After the reaction was complete, the mixture was filtered through Celite pad, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to yield compound 38 (85 mg, white solid). MS / ESI: [M+H] + =367.1.

[0296] Step 6: Compound 38 (50 mg, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was allowed to proceed at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound E1 (28 mg). MS / ESI: [M+H] + =353.1.

[0297] The synthesis methods of Examples 202 to 245 were similar to those of Example 201 to obtain target compounds E2 to E45.

[0298] Table 6 Compounds E2 to E45 of the present invention

[0299] Example 205 Compound E5: 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),8.24(s,1H),7.26(s,1H),7.13(s,1H),5.78–5.62(m,1H),3.09(dd,J=10.8,3.2Hz, 1H),2.84–2.72(m,2H),2.34(s,3H),2.31(s,3H),2.21(dd,J=11.0,6.0Hz,2H),2.09–1.94(m,2H),1.93–1.78(m,2H).

[0300] Example 246: 2-(7-(2-Hydroxypropyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0301] The preparation of 2-(7-(2-hydroxypropyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol was carried out according to Example 201. MS / ESI: [M+H] + =353.2.

[0302] The synthesis methods of Examples 247 to 295 were carried out by referring to Example 246 to obtain target compounds F2 to F50.

[0303] Table 7 Compounds F2 to F50 of the present invention

[0304] Example 296: 2-(7-(2-Hydroxypropyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0305] Step 1: Compound 25 (5 g, 1 eq.), compound 44 (1.1 eq.), and xylene were added to a sealed tube and reacted at 160°C overnight. The xylene was removed by concentration under reduced pressure, and the residue was purified by column chromatography to obtain compound 45 (2.3 g). MS / ESI: [M+H] + =292.1.

[0306] Step 2: Compound 45 (2.9 g, 10 mmol), potassium tert-butoxide (1.23 g, 11 mmol), and DMSO (20 mL) were added to a round-bottom flask and the reaction temperature was raised to 50°C with stirring for 6 hours. After the reaction was complete, the temperature was lowered to room temperature and extracted with water and ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 46 (1.8 g, yield 70.6%). MS / ESI: [M+H] + =256.1.

[0307] Step 3: Compound 46 (256 mg, 1 eq.), intermediate int-1 (2 eq.), Pd(dppf)Cl2 (0.1 eq.), cesium carbonate (3 eq.), dioxane, and water were added to a reaction flask and reacted at 100°C under nitrogen overnight. After the reaction was complete, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 47 (178 mg, white solid). MS / ESI: [M+H] + =410.2.

[0308] Step 4: Compound 47 (205 mg, 1 eq.), compound 8 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and reacted at room temperature overnight. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 48 (154 mg, white solid). MS / ESI: [M+H] + =310.1.

[0309] Step 5: Compound 48 (100 mg, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was continued at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound G1 (42 mg). MS / ESI: [M+H] + =354.1.

[0310] The synthesis methods of Examples 297 to 310 were similar to those of Example 296 to obtain target compounds G2 to G15.

[0311] Table 8 Compounds G2 to G15 of the present invention

[0312] Example 311: 2-(7-(2-Hydroxypropyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0313] The preparation of 2-(7-(2-hydroxypropyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol was carried out according to Example 296. MS / ESI: [M+H] + =354.1.

[0314] The synthesis methods of Examples 312 to 325 were similar to those of Example 311 to obtain target compounds H2 to H15.

[0315] Table 9 Compounds H2 to H15 of the present invention

[0316] Example 326: 2-(8-(2-Hydroxypropyl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0317] The preparation of 2-(8-(2-hydroxypropyl)-5,6,7,8-tetrahydropyrido[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol was carried out according to Example 296. MS / ESI: [M+H] + =368.2.

[0318] The synthesis methods of Examples 327-340 were similar to those of Example 326 to obtain target compounds I2-I15.

[0319] Table 10 Compounds I2-I15 of the present invention

[0320] Example 341: 2-(8-(2-Hydroxypropyl)-7,8-dihydro-6H-pyridazino[4,3-b][1,4]oxazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0321] Step 1: Compound 62 (1.82 g, 10 mmol), compound 63 (1.93 g, 12 mmol), NaH (60%, 0.48 g, 12 mmol), and DMF (20 mL) were added to a round-bottom flask and stirred at room temperature for 2 hours. Water and ethyl acetate were added for extraction. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 64 (1.2 g). MS / ESI: [M+H] + =308.0.

[0322] The preparation of 2-(8-(2-hydroxypropyl)-7,8-dihydro-6H-pyridazino[4,3-b][1,4]oxazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol was carried out according to Example 296. MS / ESI: [M+H] + =370.1.

[0323] The synthesis methods of Examples 342-360 were similar to those of Example 341 to obtain target compounds J2-J20.

[0324] Table 11 Compounds J2 to J20 of the present invention

[0325] Example 361: 1-((6-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[4,3-c]pyridazin-3-yl)amino)propan-2-ol

[0326] Step 1: Compound 69 (3.0 g, 1.0 eq.) was dissolved in 35 mL of ethanol, and hydrazine hydrate (1.4 g, 3.0 eq.) was added. The mixture was allowed to react at 20°C for 2 hours. TLC confirmed the complete reaction. After concentrating under reduced pressure to remove the solvent, compound 70 (1.2 g) was obtained, which was used directly in the next step. MS / ESI: [M+H] + =203.5.

[0327] Step 2: Compound 70 (2.4 g, 1.0 eq.) was dissolved in H2O:MeOH:THF = 1:1:1 (24 mL). LiOH (2.4 g, 5.3 eq.) was added to the reaction flask at 0°C and reacted at 0°C for 6 hours. TLC confirmed the complete reaction of the starting material. After concentrating under reduced pressure to remove the solvent, 30 mL of water was added, the pH was adjusted to 2 with 1N dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 71 (2.0 g). MS / ESI: [M+H] + =171.0.

[0328] Step 3: Dissolve compound 71 (2.0 g, 1.0 eq.) and DIEA (1.3 g, 1.1 eq.) in DMF (20 mL) and add iodomethane (1.4 g, 1.0 eq.) at 0°C. Allow to react overnight at room temperature. TLC monitors the reaction completion. The reaction solution is extracted three times with ethyl acetate and water. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography to yield compound 72 (1.2 g). MS / ESI: [M+H] + =185.0.

[0329] Step 4: Dissolve compound 72 (0.5 g, 1.0 eq.), intermediate int-1 (1.5 eq.), Pd(dppf)Cl2 (0.1 eq.), and Cs2CO3 (2.0 eq.) in 1,4-dioxane (10 mL) and water (1 mL). After replacing the nitrogen atmosphere, the mixture was reacted at 100°C for 12 hours. TLC confirmed the complete reaction of the starting materials. The reaction solution was extracted with ethyl acetate and water. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 73 (0.3 g). MS / ESI: [M+H] + =339.1.

[0330] Step 5: Dissolve compound 73 (350 mg) in POCl3 (3 mL) and react at 110°C for 12 hours. LCMS monitoring confirmed the formation of the target product and complete reaction of the starting materials. The reaction mixture was quenched by adding ice water, followed by addition of saturated aqueous sodium bicarbonate solution and extraction with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 74 (245 mg). MS / ESI: [M+H] + =357.1.

[0331] Step 6: Compound 74 (357 mg, 1 eq.), compound 75 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and reacted at room temperature overnight. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 76 (231 mg, white solid). MS / ESI: [M+H] + =396.2.

[0332] Step 7: Compound 76 (0.1 g, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was allowed to proceed at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to yield compound K1 (68 mg). MS / ESI: [M+H] + =382.2.

[0333] Example 362: 2-(3-((2-Hydroxypropyl)amino)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridazin-6-yl)-5-(trifluoromethyl)phenol

[0334] The preparation of 2-(3-((2-hydroxypropyl)amino)-1,7-dimethyl-1H-pyrazolo[4,3-c]pyridazin-6-yl)-5-(trifluoromethyl)phenol was carried out according to Example 361. MS / ESI: [M+H] + =382.2.

[0335] The synthesis methods of Examples 363 to 440 were similar to those of Examples 361 and 362 to obtain target compounds K3 to K80.

[0336] Table 12 Compounds K3 to K80 of the present invention

[0337] Example 436 Compound K76: 1 H NMR(400MHz,)δ8.34(s,1H),7.11(d,J=8.0Hz,2H),4.65(s,1H),3.18(s,3H),2.22-2.15( m,2H),2.15(s,3H),2.03-1.99(m,2H),1.78-1.73(m,2H),1.49-1.43(m,2H),1.12(s,3H).

[0338] Example 441: 2-(8-((2-Hydroxypropyl)amino)pyrimido[5,4-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0339] Step 1: Compound 69 (2.06 g, 10 mmol), compound 33 (2.0 g, 12 mmol), DIEA (15 mmol), and DMSO (20 mL) were added to a round-bottom flask and the reaction mixture was heated to 110°C and stirred for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 77 (2.2 g). MS / ESI: [M+H] + =306.1.

[0340] Step 2: Compound 77 (3.05 g, 10 mmol), trifluoroacetic acid (3 mL), and dichloromethane (20 mL) were added to a round-bottom flask and stirred at room temperature for 16 hours. After the reaction was complete, saturated sodium carbonate solution was added to adjust the pH to 8-9, and the mixture was extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 78 (1.6 g). MS / ESI: [M+H] + =188.1.

[0341] Step 3: Compound 78 (5.0 g), ammonium acetate (4.1 g), and triethyl orthoformate (30 mL) were added to a round-bottom flask. The reaction temperature was raised to 100°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with water and ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 80 (1.7 g). MS / ESI: [M+H] + =182.1.

[0342] Step 4: Dissolve compound 80 (0.5 g, 1.0 eq.), intermediate int-1 (1.5 eq.), Pd(dppf)Cl2 (0.1 eq.), and Cs2CO3 (2.0 eq.) in 1,4-dioxane (10 mL) and water (1 mL). After replacing the nitrogen atmosphere, the mixture was reacted at 100°C for 12 hours. TLC confirmed the complete reaction of the starting materials. The reaction solution was extracted with ethyl acetate and water. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 81 (0.3 g). MS / ESI: [M+H] + =337.1.

[0343] Step 5: Dissolve compound 81 (350 mg) in POCl3 (3 mL) and react at 110°C for 12 hours. LCMS analysis confirmed the formation of the target product and the complete reaction of the starting materials. The reaction mixture was quenched by adding ice water, followed by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 82 (187 mg). MS / ESI: [M+H] + =355.1.

[0344] Step 6: Compound 82 (357 mg, 1 eq.), compound 75 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and reacted at room temperature overnight. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 83 (231 mg, white solid). MS / ESI: [M+H] + =394.2.

[0345] Step 7: Compound 83 (0.1 g, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was continued at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound L1 (42 mg). MS / ESI: [M+H] + =380.2.

[0346] Example 442: 2-(8-((2-Hydroxypropyl)amino)-4-methylpyrimido[5,4-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0347] The preparation of 2-(8-((2-hydroxypropyl)amino)-4-methylpyrimido[5,4-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol was carried out according to Example 441. MS / ESI: [M+H] + =380.2.

[0348] Example 443: 3-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-8-((2-hydroxypropyl)amino)-5-methylpyrimido[5,4-c]pyridazin-6(5H)-one

[0349] Step 1: Compound 98 (1.87 g, 10 mmol) and 20 mL of 7N methanolic NH3 solution were added to a round-bottom flask. The reaction was stirred at room temperature for 1 hour. After completion, the solvent was concentrated and extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 103 (1.2 g). MS / ESI: [M+H]+ = 173.1.

[0350] Step 2: Compound 103 (1.72 g, 10 mmol), CDI (1.62 g, 10 mmol), and tetrahydrofuran (20 mL) were added to a round-bottom flask and the reaction mixture was heated to 60°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated to remove the solvent, and extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to yield compound 104 (1.32 g). MS / ESI: [M+H]+ = 199.0.

[0351] Step 3: Dissolve compound 104 (2.0 g, 1.0 eq.) and DIEA (1.3 g, 1.1 eq.) in DMF (20 mL) and add iodomethane (1.4 g, 1.0 eq.) at 0°C. Allow to react overnight at room temperature. TLC monitors the reaction completion. The reaction solution is extracted three times with ethyl acetate and water. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography to yield compound 105 (1.8 g). MS / ESI: [M+H]+ = 213.0.

[0352] Preparation of 2-(8-((2-hydroxypropyl)amino)-4-methylpyrimido[5,4-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol Using Compound 104 as the starting material, refer to Example 441. MS / ESI: [M+H] + =410.2.

[0353] The synthesis methods of Examples 444 to 530 were similar to those of Examples 441, 442 and 443 to obtain target compounds L4 to L90.

[0354] Table 13 Compounds L4 to L90 of the present invention

[0355] Example 512 Compound L72: 1H NMR (400 MHz, MeOD) δ7.68 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 4.53 (dq, J = 12.2, 3.9 Hz, 1H), 3.54 (s, 3H), 3.04–2.87 (m, 1H), 2.71–2.59 (m, 1H), 2.57–2.40 (m, 2H), 2.38 (s, 3H), 2.20 (s, 3H), 2.03–1.83 (m, 2H), 1.82–1.66 (m, 2H).

[0356] Example 531: 3-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(2-hydroxypropyl)-5,5-dimethyl-5,7-dihydro-6-pyrrolo[2,3-c]pyridazin-6-one

[0357] Step 1: Compound 62 (10 g, 54.6 mmol), compound 33 (9.1 g, 54.6 mmol), DIEA (21.1 g, 163.9 mmol), and isopropanol (150 mL) were placed in a reaction flask and stirred at 70°C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 200 mL of ethyl acetate and 200 mL of saturated aqueous ammonium chloride were added. The ethyl acetate phase was washed twice with 200 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 84 (17.0 g, 99.4%, orange-red solid). 1 H NMR (400MHz, Chloroform-d) δ7.13(d,J=8.4Hz,1H),6.62(s,1H),6.54-6.45(m,2H),5.55(t,1H),4.32(d,J=5.6Hz,2H),3.86(s,3H),3.82(s,3H).

[0358] Step 2: Compound 84 (2.5 g, 8.0 mmol), triethylamine (4.0 g, 40.0 mmol) and dichloromethane (50 mL) were placed in a reaction flask, and isobutyryl chloride (2.1 g, 20.0 mmol) was added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, 50 mL of saturated ammonium chloride and 30 mL of dichloromethane were added to the system, and the aqueous phase was further extracted with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 85 (4.1 g, crude product), which was used directly in the next step without further purification. 1 H NMR(400MHz,Chloroform-d)δ7.19(d,J=8.4Hz,1H),6.46(dd,J=8.4,2.4Hz,1H),6.41(d,J=2.4Hz,1H),5.30(s,1H),4.7 2(s,1H),4.61(d,J=14.4Hz,1H),4.22(d,J=14.4Hz,1H),3.81(s,3H),3.73(s,3H),1.26-1.22(m,6H),1.17-1.09(m,6H).

[0359] Step 3: Compound 85 (4.1 g, crude product), cesium carbonate (5.8 g, 17.7 mmol), and anhydrous DMF (50 mL) were placed in a reaction flask and stirred at 80°C for 2 h. After the reaction was complete, the filtrate was collected by filtration and dried, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1-0:1) to obtain compound 86 (2.7 g, 97.5%, white solid); LC-MS: ESI [M+H] + =316.1.

[0360] Step 4: Compound 86 (400 mg, 1.1 mmol), intermediate int-1 (544.8 mg, 1.7 mmol), Pd(dppf)Cl2 (84.0 mg, 0.1 mmol), cesium carbonate (1120.6 mg, 3.4 mmol), dioxane (15 mL), and water (3 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 12 h. After the reaction was complete, the mixture was cooled to room temperature and directly added to silica gel. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 87 (475 mg, 82.6% yield); LC-MS:ESI [M+H] + =470.2.

[0361] Step 5: Compound 87 (4.7 g, 10 mmol), trifluoroacetic acid (5 mL), and dichloromethane (40 mL) were added to a round-bottom flask and stirred at room temperature for 16 hours. After the reaction was complete, saturated sodium carbonate solution was added to adjust the pH to 8-9, and the mixture was extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound 88 (2.6 g). MS / ESI: [M+H] + =352.1.

[0362] Step 6: Compound 88 (352 mg, 1 eq.), compound 8 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and reacted at room temperature overnight. After the reaction was complete, the filtrate was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 89 (269 mg, white solid). MS / ESI: [M+H] + =410.1.

[0363] Step 7: Compound 89 (100 mg, 1 eq.) was added to a reaction tube, the atmosphere was replaced with nitrogen, anhydrous DCM was added, the temperature was cooled to -30°C, 0.4 mL of a 1 M boron tribromide solution in DCM was added dropwise, and the reaction was continued at -30°C for 3 h. The reaction was quenched with methanol, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound M1 (38 mg). MS / ESI: [M+H] + =396.1. 1 H NMR (400MHz, DMSO) δ10.27(s,1H),7.71(s,1H),7.15(s,1H),7.09(s,1H),4.95(d,J=5.2Hz,1H),4.29-4.13(m,1H),3 .84(dd,J=13.3,7.8Hz,1H),3.66(dd,J=13.4,5.3Hz,1H),2.13(s,3H),1.37(d,J=3.6Hz,6H),1.12(d,J=6.2Hz,3H).

[0364] Example 532: 2-(7-(2-Hydroxypropyl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0365] Compound M1 (0.1 g) and borane tetrahydrofuran solution (1 M / L, 2 mL) were added to a round-bottom flask and the reaction temperature was raised to 60°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound M2 (26 mg). MS / ESI: [M+H] + =382.2.

[0366] The synthesis methods of Examples 533 to 550 and Example 685 were similar to those of Example 531 and Example 532 to obtain target compounds M3 to M21.

[0367] Table 14 Compounds M3 to M21 of the present invention

[0368] Example 685 Compound M21: 1 H NMR (400MHz, DMSO-d6) δ10.36(br s,1H),7.83(s,1H),7.17(s,1H),7.11(s,1H),4.83(s,2H),2.30(s,3H),2.12(s,3H),1.42(s,6H).

[0369] Example 551: 2-(8-((2-Hydroxypropyl)amino)-4-methylpyrazolo[5,1-c][1,2,4]triazin-3-yl)-5-(trifluoromethyl)phenol

[0370] Step 1: Dissolve compound 90 (50.0 mg, 0.427 mmol) in 1 mL of 6M hydrochloric acid, cool to 0°C, and add solid sodium nitrite (32.0 mg, 0.470 mmol). Stir at 0°C for 0.5 h. Disperse 3-chloropentane-2,4-dione (57.2 mg, 0.427 mmol) and sodium acetate (58.1 mg, 0.427 mmol) in 0.8 mL / 0.8 mL of ethanol and water, cool to 0°C, and add the above reaction mixture directly to the mixture. Stir at 0°C for 2 h. After the reaction is complete, collect the solid by filtration, wash the filter cake with 2 mL of ethanol / water (1 / 2), and dry in vacuo to obtain compound 92 (71 mg, 75.5%, pale yellow solid). 1 H NMR(400MHz, DMSO-d6)δ12.94(br s,1H),10.67(s,1H),8.02(s,1H),2.47(s,3H); LC-MS:ESI[M+H] + =221.0.

[0371] Step 2: Compound 92 (71 mg, 0.323 mmol) was dissolved in 4 mL of acetic acid and stirred at 110°C for 3 h. After the reaction was complete, the solvent was directly dried to obtain compound 93 (60 mg, 92.3%, khaki solid), which was used directly in the next step without further purification. 1 H NMR(400MHz, DMSO-d6)δ8.72(s,1H),2.86(s,3H); LC-MS:ESI[M+H] + =203.0.

[0372] Step 3: Compound 93 (202 mg, 1 eq.), compound 75 (1.5 eq.), potassium carbonate (3 eq.), and acetonitrile (8 mL) were added to a reaction flask and allowed to react overnight at room temperature. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 94 (157 mg, white solid). MS / ESI: [M+H] + =242.1.

[0373] Step 4: Compound 94 (100 mg, 1 eq.), compound 32 (2 eq.), Pd(dppf)Cl2 (0.1 eq.), cesium carbonate (3 eq.), dioxane, and water were added to a reaction flask and reacted at 100°C overnight under nitrogen. After the reaction was complete, the mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound N1 (41 mg). MS / ESI: [M+H] + =368.1.

[0374] The synthesis methods of Examples 552 to 625 were similar to those of Example 551 to obtain target compounds N2 to N75.

[0375] Table 15 Compounds N2 to N75 of the present invention

[0376] Example 626: (R)-2-(5-chloro-7-((4-methylmorpholin-2-yl)methyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0377] Compound A69 (1 eq, 200 mg) was weighed into a 100 mL two-necked flask, and 20 mL of ultra-dry dichloromethane was added. The mixture was purged with nitrogen three times. NCS (1.2 eq, 79 mg) was added under an ice bath, and the mixture was allowed to react at room temperature. After 2 h, the reaction was complete as determined by LC / MS. The reaction was quenched with water and extracted three times with DCM (20 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and washed with silica gel. Column chromatography with DCM / MeOH (100:1 to 97:3) afforded the target compound O1. MS / ESI: [M+H] + =368.1. 1 H NMR (400MHz, Methanol-d4) δ7.94(d,J=9.2Hz,1H),7.86(d,J=7.4Hz,1H),7.14(d,J=1.7Hz,1H),7.08( d,J=1.8Hz,1H),4.70–4.60(m,1H),4.59–4.48(m,1H),4.06–3.95(m,1H),3.95–3.87(m,1H),3.59(td,J =11.6,2.4Hz,1H),2.92(dt,J=11.4,2.0Hz,1H),2.69(dq,J=11.8,1.9Hz,1H), 2.29(s,3H),2.17(dd,J=11.6,3.4Hz,1H),2.12(s,3H),1.92(t,J=10.9Hz,1H).

[0378] Example 627: (R)-2-(5-chloro-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0379] Preparation of (R)-2-(5-chloro-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Reference Example 626 to obtain the target compound O2. MS / ESI: [M+H] + =425.1. 1H NMR(400MHz,Chloroform-d)δ8.10(s,1H),7.90(s,1H),7.20(d,J=1.9Hz,1H),7.15–7.11(m,1H),5.31–5.22(m,1H),3.08–2.92(m,1H),2. 77(dd,J=10.5,6.7Hz,1H),2.62(s,1H),2.51(s,3H),2.49–2.44(m,1H),2.37(s,3H),2.07(dq,J=12.2,7.1,5.3Hz,2H),1.89–1.76(m,2H).

[0380] Biological activity test:

[0381] 1. Assay of NLRP3 inflammasome inhibitory activity in human monocytes

[0382] Reagents: THP-1 cells: Wuhan Punosai Life Science Technology Co., Ltd., PMA: Sigma-Aldrich, RPMI medium: Hyclone, LPS: Sigma-Aldrich, Opti-MEM medium: Gibco, Nigericin: Invivogen, Human IL-1β ELISA detection kit: 4A Biotech, reference compound MCC950: MedChemExpress (MCE).

[0383] Experimental method: THP-1 cells were cultured in RPMI medium containing PMA (10 μM) at a rate of 2×10 5 Cells were seeded into 48-well plates at a cell density of 100 μg / mL and induced overnight in a 37°C, 5% CO2 incubator. The next day, the medium was replaced with Opti-MEM medium containing 1 μg / mL LPS. Three hours later, the drug was added for 40 minutes. Nigericin (10 μM) was also added for 40 minutes. The cell supernatant was collected for ELISA analysis.

[0384] The experimental results are shown in Tables 16 and 17 below, where in Table 16, +++ means: the inhibition rate at 1 uM is greater than or equal to 90%, ++ means: the inhibition rate at 1 uM is greater than or equal to 50% and less than 90%, and + means: the inhibition rate at 1 uM is less than 50%.

[0385] Table 16 Inhibition rate of compounds on NLRP3 inflammasome at 1 uM concentration

[0386] Table 17 Compounds' half inhibition rate (IC) on NLRP3 inflammasome50 )

[0387] Experimental results: The compounds of the present invention have good inhibitory activity against NLRP3 inflammasome. In some embodiments, the compounds of the present invention have good inhibitory activity against NLRP3 inflammasome. 50 Less than or equal to 500nM, preferably less than or equal to 250nM, more preferably less than or equal to 100nM, more preferably less than or equal to 50nM, and the most preferred compound IC among the compounds shown in the present invention 50 Less than or equal to 5nM.

[0388] 2. Inhibition experiment of compounds on hERG potassium channels

[0389] Cell culture and treatment: CHO cells stably expressing hERG were cultured in a cell culture flask at 37°C in a 5% CO2 incubator. When the cell density reached 60-80%, the cell culture medium was removed, the cells were washed once with PBS, and then digested with Detachin. After digestion was complete, the cells were neutralized with culture medium, centrifuged, and the supernatant was removed. The cells were then resuspended in culture medium to adjust the cell density to 2-5×10 6 / mL for future use.

[0390] Compound Preparation: Dilute the compound stock solution with 100% DMSO. Add 10 μL of the compound stock solution to 20 μL of DMSO and serially dilute three-fold to six concentrations. Add 4 μL of each of the six concentrations to 396 μL of extracellular fluid, creating six intermediate 100-fold dilutions. Then, add 80 μL of each of the six intermediate concentrations to 320 μL of extracellular fluid, creating a five-fold dilution to the desired final concentration. The highest concentration tested was 40 μM, followed by six concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration has no effect on hERG potassium channels. Compound preparation was performed entirely on the Bravo instrument.

[0391] Electrophysiological recordings: Single-cell high-impedance sealing and whole-cell pattern formation were automated by the Qpatch instrument. After acquiring whole-cell recording mode, cells were clamped at -80 mV. A 50-millisecond pre-depolarization of -50 mV was applied before a 5-second depolarization of +40 mV. The cells then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage was applied every 15 seconds. After recording for 2 minutes, extracellular solution was added for 5 minutes. Drug administration then began. Compound concentrations were administered for 2.5 minutes at each test concentration, starting with the lowest tested concentration. After all concentrations were administered, the positive control compound, 3 μM Cisapride, was administered. At least three cells were tested for each concentration (n ≥ 3).

[0392] Data processing: GraphPad Prism 5.0 and Excel software were used for data analysis. 50 Calculated using GraphPad Prism 5 software by fitting the following equation:

[0393] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0394] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0395] Experimental results: In some embodiments, the compounds of the present invention have a weak inhibitory effect on hERG potassium ion channels. In some embodiments, the compounds of the present invention have a weak inhibitory effect on hERG potassium ion channels. 50 The hERG inhibition IC value of the compound shown in the present invention is greater than 10uM, the preferred compound is greater than 20uM, and the more preferred compound is greater than 30uM. 50 Greater than 40uM.

[0396] Table 18 Inhibition results of compounds on hERG potassium channels

[0397] Conclusion: Compound A69 and others of the present invention have weak inhibitory effects on hERG potassium channels.

[0398] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0399] Experimental purpose: To understand the pharmacokinetics of the compound.

[0400] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0401] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous and oral administration to Balb / c mice.

[0402] Sample preparation: Weigh the compound and dissolve it in DMSO, then add sodium chloride solution for injection to prepare the compound solution for administration.

[0403] Sample collection: 6 male Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), 3 were intravenously administered (IV) and 3 were gavage administered (PO). About 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, the supernatant plasma was collected, and frozen at -40 ° C for testing. The blood concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the concentration-time curve (AUC(0-t)), half-life (T 1 / 2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc. The results of the pharmacokinetic evaluation are shown in Table 19 below.

[0404] Table 19 Pharmacokinetic test results of the compound in Balb / c mice

[0405] Conclusion: Compounds A3, A69 and A82 of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance.

[0406] 4. Evaluation of the brain-blood ratio of compounds in vivo

[0407] Experimental purpose: To obtain the brain-to-blood ratio of the compound.

[0408] Experimental plan: The brain-to-blood ratio of the compound was investigated by monitoring the content of the compound in the mouse brain and plasma.

[0409] Experimental steps: Weigh the compound, add a small amount of DMSO, and then add sodium chloride solution for injection to make 1 mg mL -1 Compound solution, ready for administration. -1 Oral administration was performed, and whole blood and whole brain were collected 1 hour and 6 hours after administration (n=3). Whole blood was centrifuged at 3500rpm for 15 minutes, and the supernatant plasma was collected. The weight of the centrifuge tube was weighed as M1, the weight of the centrifuge tube containing the whole brain was weighed as M2, the weight of the centrifuge tube after adding water homogenate was weighed as M3, and the weight of the centrifuge tube after taking out 30μL of homogenate was weighed as M4. 30μL of plasma and 30μL of brain homogenate were taken into the centrifuge tube, and 120μL of 20ng·ml-1 The internal standard SAHA was precipitated with acetonitrile, vortexed for 30 seconds, centrifuged at 13,000 rpm for 15 minutes, and the supernatant was collected and placed in a sample vial for testing.

[0410] Standard curve range: 10~10000ng·ml -1 .

[0411] Drug content in brain = measured value × 0.03 × (M3-M1) / [(M2-M1) × (M3-M4)].

[0412] The results of the brain-to-blood ratios of the compounds are shown in Table 20 below.

[0413] Table 20 Results of brain-to-blood ratio test in mice after compound administration

[0414] Conclusion: Compounds A3, A69 and B52 of the present invention have higher brain-to-blood ratios at 1 hour and 6 hours, indicating that the compounds of the present invention have the potential to enter the brain.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: in, X and Y are independently selected from C or N, and at most one of X and Y is selected from N; When X or Y is selected from N, is a single bond; when X and Y are selected from C, is a double bond; Ring A is the following group optionally substituted by 0-6 R8: 5-6 membered alkyl ring, 5-6 membered alkyl heterocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, In ring A, the 5- to 6-membered alkyl heterocyclic ring and the 5- to 6-membered heteroaromatic ring contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R2 and R4, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl In R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; In R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S and O; R5 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R5, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Alternatively, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, a 5-6 membered heteroaromatic ring, substituted with 0-6 substituents, The substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 Deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-6 membered alkyl ring; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle, 5-6 membered heteroaromatic ring contains 1-3 heteroatoms selected from at least one of N, S, and O; L is selected from -(CH2) n1 -、-CH(CH3)(CH2) n1 -、-(CH2) n1 -CH(CH3)-, -(CH2) n1 O-, -O(CH2) n1 -、-OCH(CH3)(CH2) n1 -、-(CH2) n1 -NH-, -NH-(CH2) n1 -、-NH-CH(CH3)(CH2) n1 -or-NHC(CH3)2(CH2) n1 -, n1 is an integer selected from 0-3; R6 is selected from hydrogen, deuterium, halogen, -CN, -OR 9a 、-SR 9a 、-NR 9b R 9c 、-C(=O)R 9a 、-OC(=O)R 9a 、-C(=O)OR 9a 、-C(=O)NR 9b R 9c 、-NR 9b C(=O)R 9c 、-SO2R 9a 、-SO2NR 9b R 9c 、-NR 9b S02R 9c or 0-6 R 9d Substituted 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; in R6, the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 9a , R 9b and R 9c independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; R 9a , R 9b and R 9c In the above, the substituent is selected from the group consisting of: deuterium, halogen, -N(R 10a R 10b )、-C(O)N(R 10a R 10b )、-OH、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkylmethylene or 4- to 6-membered heterocycloalkylmethylene; R 9a , R 9b and R 9c wherein the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, 6- to 10-membered heterobridged ring The alkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4- to 6-membered heterocycloalkyl group and the 4- to 6-membered heterocycloalkyl methylene group in the substituent group contain 1 to 3 heteroatoms selected from at least one of N, S, and O; Or, R 9b With R 9c Together with the atoms to which they are attached, they form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; R 9b With R 9c When connected to the atoms to which they are attached to form a ring, the substituents are selected from: deuterium, halogen, -N(R 10a R 10b )、-C(O)N(R 10a R 10b )、-OH、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R 9b With R 9c When connected to the atoms to which they are attached to form a ring, the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4- to 6-membered heterocycloalkyl group in the substituent group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 9d Selected from hydrogen, deuterium, halogen, -CN, -OR 10c 、-SR 10c 、-NR 10d R 10e 、-C(=O)R 10c 、-OC(=O)R 10c 、-C(=O)OR 10c 、-C(=O)NR 10d R 10e 、-NR 10d C(=O)R 10e 、-SO2R 10c 、-SO2NR 10d R 10e 、-NR 10d S02R 10e or a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 3- to 8-membered heterocycloalkyl group, a 3- to 8-membered cycloalkyl group, a C 1-6 Alkyl; R 9d In the above, the substituent is selected from deuterium, halogen, -OH, -NR 10f R 10g 、-C(=O)NR 10f R 10g , CN, C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 9d In the above, the 5- to 10-membered heteroaryl group and the 3- to 8-membered heterocycloalkyl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl; R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, -CONH2 or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, -NHC(=O)-C 1-6 alkyl, -NHC(=O)-3- to 6-membered cycloalkyl, -(C=O)NH-C 1-6 Alkyl, -(C=O)NH-3- to 6-membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R7, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R8 is selected from hydrogen, deuterium, halogen, -NH2, -OH, -CN, -CONH2 or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)NH-C 1-6 Alkyl, 3-6 membered cycloalkyl, -C(O)-3-6 membered cycloalkyl, -C(O)NH-3-6 membered cycloalkyl; in R8, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.

2. The compound according to any one of claim 1, characterized in that: R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkane The substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

3. The compound according to any one of claims 1 to 2, characterized in that: R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

4. The compound according to any one of claims 1 to 3, characterized in that: R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, -CF3 or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O; Preferably, R3 is selected from hydrogen, deuterium, F, Cl, Br, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, F, Cl, -OH, -NH2, -CF3, -CN or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1-2 heteroatoms selected from at least one of N, S and O; More preferably, R3 is selected from hydrogen, deuterium, F, Cl, Br, CN, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.

5. The compound according to any one of claims 1 to 4, characterized in that: R5 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or optionally substituted by 0-6 substituents. Lower group: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R5 is selected from hydrogen, deuterium, F, Cl, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R5 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

6. The compound according to any one of claims 1 to 5, characterized in that: R2 and R3, R3 and R4, or R4 and R5 may form, together with the atoms to which they are connected, a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, a 5-6 membered heteroaromatic ring or a The substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle and 5-6 membered heteroaromatic ring contain 1-2 heteroatoms selected from at least one of N, S and O; Preferably, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from: deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorinated cycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; More preferably, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituents are selected from: deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.

7. The compound according to any one of claims 1 to 6, characterized in that: Structural unit Selected from:

8. The compound according to any one of claims 1 to 7, characterized in that: L is selected from a bond or -CH2-, -CH2CH2-, -CH2-CH(CH3)-, -CH2-C(CH3)2-, -CH(CH3)CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH(CH3)-, -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH(CH3)- or -NHC(CH3)2-.

9. The compound according to any one of claims 1 to 8, characterized in that: R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-3 Alkyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -CONH2, -NH-C 1-3 Alkyl, -NHC(=O)-C 1-3 alkyl, -NHC(=O)-3- to 6-membered cycloalkyl, -(C=O)NH-C 1-3 Alkyl, -(C=O)NH-3- to 6-membered cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl; in R7, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R7 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups substituted by 0-3 substituents: C 1-3 Alkyl, -OC 1-3 Alkyl, -CONH2, -(C=O)NH-C 1-3 Alkyl, -(C=O)NH-3-4-membered cycloalkyl or 3-4-membered cycloalkyl; in R7, the substituent is selected from: deuterium, fluorine or -OH; More preferably, R7 is selected from hydrogen, deuterium, fluorine, chlorine, -OH, -NH2, -CN, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, methoxy, fluoromethoxy, cyclopropyl, fluorocyclopropyl, -CONH2, -CONHCH3, -CONHCD3 or -CONH-cyclopropyl.

10. The compound according to any one of claims 1 to 9, characterized in that: R8 is selected from hydrogen, deuterium, fluorine, -NH2, -CONH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -C(O)-3- to 4-membered cycloalkyl, -C(O)NH-C 1-4 Alkyl, -C(O)NH-3-4-membered cycloalkyl, 3-4-membered cycloalkyl; in R8, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R8 is selected from hydrogen, deuterium, fluorine or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -C(O)-3-4-membered cycloalkyl, 3-4-membered cycloalkyl; in R8, the substituent is selected from: deuterium, fluorine or -OH; More preferably, R8 is selected from hydrogen, fluorine, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, Cyclopropyl, fluorocyclopropyl, -C(O)CH3, -C(O)CD3 or -C(O)-cyclopropyl.

11. The compound according to any one of claims 1 to 10, characterized in that: Ring A is the following group optionally substituted by 0-3 R8: 5-6 membered alkyl ring, 5-6 membered alkyl heterocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, In ring A, the 5- to 6-membered alkyl heterocyclic ring and the 5- to 6-membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S, and O; Preferably, Ring A The following groups optionally substituted by 0-2 R8:

12. The compound according to any one of claims 1 to 11, characterized in that: Structural unit Selected from: n2 is an integer selected from 0 to 2; Preferably, the structural unit Selected from:

13. The compound according to any one of claims 1 to 12, characterized in that: R6 is selected from the following structures: R 11a Selected from hydrogen, deuterium, -C(=O)R 12a 、-C(=O)OR 12a 、-SO2R 12a or a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, a C 1-6 Alkyl; R 11a In the above, the substituent is selected from deuterium, fluorine, chlorine, -OH, -NR 12b R 12c 、-C(=O)NR 12b R 12c , CN, C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 11a wherein the 5- to 10-membered heteroaryl group or the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 12a , R 12b and R 12c are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl; R 11b Selected from hydrogen, deuterium, halogen, -CN, -OR 12a 、-NR 12d R 12e 、-C(=O)R 12a 、-C(=O)OR 12a 、-C(=O)NR 12d R 12e 、-NR 12d C(=O)R 12e 、-SO2R 12a 、-SO2NR 12d R 12e 、-NR 12d S02R 12e or a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 3- to 6-membered heterocycloalkyl group, a 3- to 6-membered cycloalkyl group, a C 1-6 Alkyl; R 11a In the above, the substituent is selected from deuterium, fluorine, chlorine, -OH, -NR 12b R 12c 、-C(=O)NR 12b R 12c , CN, C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered cycloalkyl; R 11a wherein the 5- to 10-membered heteroaryl group or the 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 12a , R 12b , R 12c , R 12d and R 12e are independently selected from hydrogen, C 1-4 Alkyl, N,N-dimethyl substituted C 1-4 Alkyl, 3-6 membered cycloalkyl; R 11c , R 11d independently selected from hydrogen, deuterium or C substituted by 0-3 substituents 1-4 Alkyl; R 11c , R 11d wherein the substituent is selected from deuterium, fluorine, and chlorine; Preferably, R 11a Selected from H, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, hydroxyl-substituted 3- to 6-membered cycloalkyl, C 1-4 Alkanoyl, 3-6-membered cycloalkanoyl, C 1-4 Alkoxyacyl, 3-6-membered cycloalkoxyacyl, C 1-4 Alkanesulfonyl, 3-6-membered cycloalkanesulfonyl, R 11b is selected from H, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 deuterated alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, 3- to 6-membered cycloalkyl substituted with hydroxyl, C 1-4 Alkanoyl, 3-6-membered cycloalkanoyl, C 1-4 Alkoxyacyl, 3-6-membered cycloalkoxyacyl, C 1-4 Alkanesulfonyl, 3-6-membered cycloalkanesulfonyl, methylamino, dimethylamino, R 11c , R 11d Independently selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl.

14. The compound according to any one of claims 1 to 13, characterized in that: R6 is selected from the following structures:

15. The compound according to any one of claims 1 to 14, characterized in that: Structural unit Selected from:

16. The compound according to any one of claims 1 to 15, characterized in that: The compound is selected from: A Series: B Series: C Series: D Series: E Series: F Series: G Series: H Series: I Series: J Series: K Series: L Series: M Series: N Series:

17. The compound according to any one of claims 1 to 15, characterized in that: The compound is selected from: A Series: B Series: C Series: D Series: E Series: F Series: G Series: H Series: I Series: J Series: K Series: L Series: M Series: N Series:

18. The compound according to claim 1, characterized in that: Structural unit Selected from:

19. The compound according to claim 1, characterized in that: Structural unit Selected from:

20. The compound according to claim 1, characterized in that: Structural unit Selected from:

21. The compound according to claim 1, characterized in that: The compound is selected from: A Series: B Series:

22. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

23. Use of the compound according to any one of claims 1 to 21 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 22 in the preparation of a medicament for preventing and / or treating NLRP3-related diseases.

24. The use according to claim 23, characterized in that: The NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases.

25. The use according to claim 23, characterized in that: The NLRP3-related diseases include: cryptopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / type II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing myelitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease or ischemic stroke.

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