Nitrogen-containing double fused ring compound and medical application thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to an NLRP3 inhibitor, a preparation method thereof and application of the NLRP3 inhibitor in medicine. The invention provides an NLRP3 inhibitor shown in a formula (IA) or (IB) as well as a composition and application of the NLRP3 inhibitor. The compound can be used for treating or preventing diseases or symptoms related to abnormal expression of an NLRP3 signaling pathway. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and relates to a nitrogen-containing bicyclic compound. Specifically, it relates to structural forms such as free bases, isomers, and pharmaceutically acceptable salts of such compounds. Further, the present invention also discloses a preparation method and pharmaceutical use of such nitrogen-containing bicyclic compounds, which can be used as NLRP3 inhibitors for treating diseases mediated by abnormal expression of the NLRP3 signaling pathway. Background Art

[0002] NLRP3 belongs to the NOD-like receptor protein family and is one of the most studied intracellular pattern recognition receptors in recent years. After recognizing pathogen-associated molecular patterns (PAMPs) or host-derived danger signal molecular patterns (DAMPs), it recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to assemble into an inflammasome, and at the same time releases activated inflammatory cytokines IL-1β and IL-18, causing an inflammatory response.

[0003] Inflammation is the body's defensive response to stimuli, including infectious inflammation and sterile inflammation. Inflammation is mainly manifested as redness, swelling, heat, pain, and dysfunction, usually caused by increased permeability of vascular endothelial cells and exudation of immune cells in plasma. After tissue repair, the inflammatory response will end quickly, but excessive cytokine production can lead to a cytokine storm, causing damage to the body. Inflammatory dysregulation is an important pathogenesis of many human diseases.

[0004] Abnormal activation of the NLRP3 inflammasome has been observed in many inflammations and inflammatory diseases, and the overproduction of IL-1β and IL-18 also participates in and promotes the occurrence and development of various diseases, including cryopyrin-associated periodic syndromes; sickle cell disease; autoimmune diseases such as systemic lupus erythematosus and psoriasis; liver diseases such as chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, and alcoholic liver disease; inflammatory arthritis-related diseases such as gout, chondrocalcinosis, osteoarthritis, and rheumatoid arthritis; kidney diseases such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, and diabetic nephropathy; neuroinflammation-related diseases such as brain infections, acute injuries, and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease; cardiovascular and metabolic-related diseases such as atherosclerosis, type I and type II diabetes and related complications (such as nephropathy, retinopathy), peripheral artery disease, acute heart failure, and hypertension; wound healing and scar formation; inflammatory skin diseases such as acne and hidradenitis suppurativa; asthma; sarcoidosis; age-related macular degeneration; cancer-related diseases such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes, myelofibrosis, lung cancer, colon cancer, etc.

[0005] Currently, there are no marketed drugs for NLRP3 inhibitors. The compound MCC950, which was the first to enter clinical research, had its trial terminated due to liver toxicity, but it has been used as a tool molecule in a large number of literatures to explore different indications or mechanisms. Existing compounds such as OLT-1177, Emlenoflast, RG6418, and DFV890 are in the clinical research stage for the clinical treatment of diseases such as acute gout attacks, knee osteoarthritis, Schnitzler syndrome, Cryopyrin-associated periodic syndromes, ulcerative colitis, and Parkinson's disease. Diseases that are essentially inflammatory or immune-related are usually difficult to diagnose or treat efficiently. Most treatment methods include treating symptoms, slowing the progression of the disease, changing lifestyle, and surgery as a last resort. There is an urgent need for more efficient and effective means to treat such diseases.

[0006] Therefore, developing NLRP3 inflammasome inhibitors has certain therapeutic potential for treating such diseases with inflammatory pathological characteristics. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a novel nitrogen-containing bicyclic compound that can be used as an NLRP3 inhibitor for the treatment of diseases.

[0008] To solve the above technical problems, the technical solutions provided by the present invention are as follows:

[0009] On the one hand, the present invention provides a nitrogen-containing bicyclic compound, which is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general formula (IA) or (IB):

[0010]

[0011] Among them, ring A is selected from

[0012] Ring B is selected from

[0013] R a1 、R a2 Each independently is selected from hydrogen or C 1-6 alkyl;

[0014] Ring C is selected from 3- to 8-membered heterocyclic groups; the 3- to 8-membered heterocyclic groups are optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, or C 1-6 alkoxy;

[0015] R 1 、R 2 、R 3 、R4 , R 5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group or 5- to 10-membered heteroaryl; the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group or 5- to 10-membered heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy;

[0016] R 6 is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group; the C 1-6 alkyl, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group.

[0017] In some embodiments, the compound is a compound, isomer or pharmaceutically acceptable salt thereof having the following general structural formula (IIB-1):

[0018]

[0019] wherein, R a1 is selected from hydrogen or C 1-6 alkyl;

[0020] Y is selected from -OR a2 or oxo group;

[0021] R a2 is selected from C 1-6 alkyl;

[0022] R 5 is selected from C 1-6 alkyl or hydroxy;

[0023] Ring C is selected from 3- to 6-membered heterocyclic group;

[0024] The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from N, O or S.

[0025] In some embodiments, the compound is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (IIB-1-1):

[0026]

[0027] wherein R a1 is selected from hydrogen or C 1-6 alkyl;

[0028] Ring C is selected from 3- to 6-membered heterocyclic groups;

[0029] The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from N, O, or S.

[0030] In some embodiments, the compound is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (IIB-1-2):

[0031]

[0032] wherein R 1 , R 5 are each independently selected from hydrogen, hydroxy, or C 1-6 alkyl.

[0033] In some embodiments, the compound is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (IIA):

[0034]

[0035] wherein Z is selected from C or N;

[0036] R 1 , R 3 , R 5 are each independently selected from hydrogen, C 1-6 alkyl, hydroxy, or halogen, and at least one of R 1 , R 3 , R 5 is hydroxy.

[0037] In some embodiments, the compound is a compound, isomer, or pharmaceutically acceptable salt thereof having the following general structural formula (IIA-1):

[0038]

[0039] wherein R 1 , R 3 are each independently selected from hydrogen, C 1-6 alkyl, or halogen.

[0040] In some embodiments, the compound is a compound, isomer or pharmaceutically acceptable salt thereof having the following general structural formula (IIA-1-1):

[0041]

[0042] Wherein, ring A is selected from

[0043] In some embodiments, the compound is a compound, isomer or pharmaceutically acceptable salt thereof having the following general structural formula (IIA-1-2):

[0044]

[0045] Wherein, ring A is selected from

[0046] The present invention also provides a nitrogen-containing bicyclic fused-ring compound, which is a compound, isomer or pharmaceutically acceptable salt thereof having the following structure:

[0047]

[0048]

[0049] On the other hand, the present invention provides a pharmaceutical composition comprising at least one compound, isomer or pharmaceutically acceptable salt thereof represented by formula (IA), (IB), (IIB-1), (IIB-1-1), (IIB-1-2), (IIA), (IIA-1), (IIA-1-1) or (IIA-1-2) as described above, and at least one pharmaceutically acceptable carrier or excipient.

[0050] On another aspect, the present invention provides the use of a compound, isomer or pharmaceutically acceptable salt thereof represented by formula (IA), (IB), (IIB-1), (IIB-1-1), (IIB-1-2), (IIA), (IIA-1), (IIA-1-1) or (IIA-1-2) as described above, or a pharmaceutical composition thereof, in the preparation of a drug for preventing and / or treating NLRP3-related diseases or disorders.

[0051] On another aspect, the present invention further provides a compound, isomer or pharmaceutically acceptable salt thereof represented by formula (IA), (IB), (IIB-1), (IIB-1-1), (IIB-1-2), (IIA), (IIA-1), (IIA-1-1) or (IIA-1-2) as described above, or a pharmaceutical composition thereof, for preventing and / or treating NLRP3-related diseases or disorders.

[0052] In another aspect, the present invention also provides a method for preventing and / or treating a disease, comprising administering to a patient in need an effective amount of a compound, isomer or pharmaceutically acceptable salt thereof represented by formula (IA), (IB), (IIB-1), (IIB-1-1), (IIB-1-2), (IIA), (IIA-1), (IIA-1-1) or (IIA-1-2) as described above, or a pharmaceutical composition thereof; the disease to be prevented and / or treated is an NLRP3-related disease or disorder.

[0053] In some embodiments, the NLRP3-related disease or disorder is selected from cancer diseases, inflammatory diseases or diseases accompanied by an inflammatory response;

[0054] The cancer diseases include, but are not limited to, myeloproliferative neoplasms, myeloid leukemia, lung cancer, nasopharyngeal carcinoma, laryngeal cancer, esophageal cancer, cholangiocarcinoma, oral cancer, head and neck cancer, mesothelioma, adrenocortical carcinoma, renal cancer, liver cancer, gastric cancer, colon cancer, rectal cancer, bone cancer, brain cancer, breast cancer, melanoma, pancreatic cancer, skin cancer, lymphoma, bladder cancer, small intestine cancer, soft tissue sarcoma, endometrial cancer, cervical cancer, osteosarcoma, prostate cancer or testicular cancer;

[0055] The inflammatory diseases or diseases accompanied by an inflammatory response include, but are not limited to:

[0056] 1) Auto-inflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever, Schnitzler syndrome, mevalonate kinase deficiency (MKD);

[0057] 2) Chronic pain, including neuropathic pain and non-neuropathic pain;

[0058] 3) Skin disorders such as contact hypersensitivity, bullous pemphigoid, sunburn, contact dermatitis, seborrheic dermatitis, hidradenitis suppurativa (HS), diabetic (foot) ulcers, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, acne, alopecia;

[0059] 4) Respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchitis, rhinitis, sinusitis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, sarcoidosis, adult respiratory distress syndrome, pneumonia;

[0060] 5) Joint disorders such as arthritis;

[0061] 6) Muscle disorders such as polymyositis, myasthenia gravis;

[0062] 7) Cardiovascular disorders such as hypertension, local anemia, reperfusion injury, vasculitis, pericarditis;

[0063] 8) Blood diseases, such as sickle cell disease;

[0064] 9) Central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, brain injury, multiple sclerosis, amyotrophic lateral sclerosis;

[0065] 10) Metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout;

[0066] 11) Liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH);

[0067] 12) Kidney diseases, such as acute kidney disease, hyperoxaluria, chronic kidney disease, nephrocalcinosis, glomerulonephritis, diabetic nephropathy;

[0068] 13) Gastrointestinal disorders, such as inflammatory bowel disease, pancreatitis;

[0069] 14) Ocular disorders, such as uveitis, allergic conjunctivitis;

[0070] 15) Graft-versus-host disease;

[0071] 16) Burns, sunburns, mechanical injuries.

[0072] In some embodiments, the neuropathic pain includes central neuropathic pain and peripheral neuropathic pain;

[0073] The central neuropathic pain includes, but is not limited to, neuropathic pain due to spinal cord injury, pain after stroke, pain in multiple sclerosis, pain in syringomyelia, pain in ischemic myelopathy, pain in compressive myelopathy, pain in post-radiation myelopathy, pain in Parkinson's disease, phantom limb pain, pain in myelitis;

[0074] The peripheral neuropathic pain includes, but is not limited to, postherpetic neuralgia, HIV neuropathy, diabetic peripheral neuropathy, chronic pain after trauma / surgery, neuropathy after chemo / radiotherapy, trigeminal neuralgia, glossopharyngeal neuralgia, stump pain, toxicant-induced neuropathy, sciatica, dorsal root neuralgia;

[0075] The non-neuropathic pain includes, but is not limited to, osteoarthritis pain, chronic low back pain, chronic visceral pain, cancer pain, fibromyalgia.

[0076] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear if it is not specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0077] The "compound" described in the present invention includes, but is not limited to, the following situations of the compound: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0078] The "compound" described in the present invention may be asymmetric. For example, it may have one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in the present invention can be isolated in optically active pure form or in racemic form. The optically active pure form can be obtained by methods such as resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0079] The "isomer" in the present invention refers to, unless otherwise indicated, stereoisomers or tautomers. Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers. Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on differences in the physicochemical properties of the components, for example by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers that can be interconverted through a low energy barrier with different energies. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through reorganization of some bonding electrons.

[0080] The "isotope" in the present invention refers to, unless otherwise specified, the compounds of the present invention can exist in isotopically labeled or enriched forms, containing one or more atoms whose atomic weights or mass numbers are different from those of the atoms found in the largest amounts in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used for isotope labeling are: hydrogen isotopes, including but not limited to 2 H and 3 H; carbon isotopes: including but not limited to13 C and 14 C; chlorine isotopes: including but not limited to 35 Cl and 37 Cl; fluorine isotopes: including but not limited to 18 F; iodine isotopes: including but not limited to 123 I and 125 I; nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O, 17 O and 18 O; sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues, especially 3 H and 13 C, because they are easy to label and convenient to detect, and are more widely used. Substitution with certain heavy isotopes, such as deuterium ( 2 H), can enhance metabolic stability, extend the half-life, and thus achieve the purpose of reducing the dose and providing a therapeutic advantage. Isotope-labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques in the same way as non-isotope-labeled compounds.

[0081] "Pharmaceutically acceptable" in the present invention refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0082] The "pharmaceutically acceptable salts" in the present invention refer to the salts of the compounds of the present invention. The compounds with specific substituents discovered in the present invention form salts with one of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodate, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and p-toluenesulfonic acid; or when containing relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, ammonium, or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkanesulfonates, arylsulfonates, organic acid salts, amino acid salts, etc.

[0083] In addition to the salt form, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to convert into the compounds of the present invention. In addition, the prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0084] The "solvate" in the present invention is selected from hydrates, ethanolates, methanolates, acetonates, etherates, or isopropanolates.

[0085] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0086] The term "hydroxy" refers to -OH.

[0087] The term "cyano" refers to -CN.

[0088] The term "amino" refers to -NH2.

[0089] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as C 1-6Alkyl, including but not limited to methyl, ethyl, propyl (including: 1-propyl or n-propyl, 2-propyl or isopropyl), butyl (including: 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl, 1,1-dimethylethyl or tert-butyl), pentyl (1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl), hexyl (1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl).

[0090] The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as C 1-6 Alkylamino, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0091] The term "alkoxy" refers to a straight-chain or branched-chain alkyl group connected through an oxygen atom, such as C 1-6 Alkoxy, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy), hexyloxy (n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 2,3-dimethylbutoxy, 2,2-dimethylbutoxy), etc.

[0092] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group that is straight-chain or branched-chain and composed of carbon atoms and hydrogen atoms and has at least one double bond. The alkenyl group can contain 2 - 20 carbon atoms, preferably 2 - 10 carbon atoms (i.e., C 2-10 alkenyl), more preferably 2 - 8 carbon atoms (i.e., C 2-8 alkenyl), still more preferably 2 - 6 carbon atoms (i.e., C 2-6 alkenyl), 2 - 5 carbon atoms (i.e., C 2-5 alkenyl), 2 - 4 carbon atoms (i.e., C 2-4 alkenyl), 2 - 3 carbon atoms (i.e., C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl). For example, "C 2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, etc.

[0093] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkynyl), more preferably 2-8 carbon atoms (C 2-8 alkynyl), still more preferably 2-6 carbon atoms (i.e., C 2-6 alkynyl), 2-5 carbon atoms (i.e., C 2-5 alkynyl), 2-4 carbon atoms (i.e., C 2-4 alkynyl), 2-3 carbon atoms (i.e., C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl). For example, "C 2-6 alkynyl" means that the group is an alkynyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentadiynyl, 1,5-hexadiynyl, etc.

[0094] The term "cycloalkyl" refers to a monocyclic or bicyclic alkyl group composed of carbon atoms and hydrogen atoms, such as C 3-8 cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0095] The term "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic ring having 6-16 carbon atoms and having a fully conjugated π-electron system, including but not limited to benzene ring, naphthalene ring, anthracene ring, etc., preferably benzene ring.

[0096] The term "aryl" refers to a fully carbon monocyclic or fused polycyclic group having 6-16 carbon atoms and having a fully conjugated π-electron system, including but not limited to phenyl, naphthyl, anthryl, etc., preferably phenyl.

[0097] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring hydrocarbon, which is a non-aromatic structure, containing 3-20 ring atoms, wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Bicyclic or polycyclic heterocycles include spiro, fused and bridged heterocycles. The bicyclic or polycyclic "heterocycle" includes the case where one ring is an aromatic ring and the other rings are non-aromatic rings, including spiro, fused and bridged heterocycles. The bicyclic heterocycle can contain one or more heteroatoms in one or two rings. In some embodiments, the heterocycle further includes a ring system in which the heterocycle as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the ring of the carbocycle or heterocycle; or, in some embodiments, the heterocycle further includes a ring system in which the heterocycle as defined above is fused with one or more aromatic / heteroaromatic rings, wherein the attachment point is on the ring of the aromatic / heteroaromatic ring or heterocycle; or, in some embodiments, a ring system in which the heterocycle as defined above is fused with one or more heterocycles as defined above, wherein the attachment point is on the ring of any heterocycle. In the above cases, the ring system of the heterocycle has the number of ring atoms of the ring system after fusion. In some embodiments, the heterocycle is optionally substituted, for example, unsubstituted (unsubstituted heterocycle) or substituted by one or more substituents (substituted heterocycle). Exemplary 3-membered heterocycles containing 1 heteroatom include (but are not limited to) aziridine, oxirane and thiirane. Exemplary 4-membered heterocycles containing 1 heteroatom include (but are not limited to) azetidine, oxetane and thietane. Exemplary 5-membered heterocycles containing 1 heteroatom include (but are not limited to) tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole and 2,5-pyrrolidinedione. Exemplary 5-membered heterocycles containing 2 heteroatoms include (but are not limited to) dioxolane, oxathiolane, dithiolane and 2-oxazolidone. Exemplary 5-membered heterocycles containing 3 heteroatoms include (but are not limited to) triazole, oxadiazole and thiadiazole. Exemplary 6-membered heterocycles containing 1 heteroatom include (but are not limited to) piperidine, tetrahydropyran, dihydropyridine and tetrahydrothiopyran. Exemplary 6-membered heterocycles containing 2 heteroatoms include (but are not limited to) piperazine, morpholine, thiomorpholine, etc. Exemplary 6-membered heterocycles containing 3 heteroatoms include (but are not limited to) triazane, oxadiazane, thiadiazane, oxathiazane and dioxazane. Exemplary 7-membered heterocycles containing 1 heteroatom include (but are not limited to) azepane, oxepane and thiepane. Exemplary 8-membered heterocycles containing 1 heteroatom include (but are not limited to) azocane, oxocane and thiooctane. Exemplary 5-membered heterocycles fused to a C6 aryl ring (herein also referred to as 5,6-bicyclic heterocycles) include but are not limited to dihydroindole, isoindoline, dihydrobenzofuran, dihydrobenzothiophene, benzoxazolinone. Exemplary 6-membered heterocycles fused to a C6 aryl ring (herein also referred to as 6,6-bicyclic heterocycles) include (but are not limited to) tetrahydroquinoline, tetrahydroisoquinoline.

[0098] The term "heterocyclic group" refers to a substituent generated on the basis of the foregoing heterocyclic definition. Exemplary 3-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and 2,5-dioxopyrrolidinyl. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include (but are not limited to) dioxolanyl, oxathiolanyl, dithiolanyl, and 2-oxooxazolidinyl. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include (but are not limited to) triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) piperidinyl, tetrahydropyranyl, dihydropyridyl, and tetrahydrothiopyranyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include (but are not limited to) piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include (but are not limited to) triazinyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include (but are not limited to) azocanyl, oxocanyl, and thioocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (herein also referred to as 5,6-bicyclic heterocyclic groups) include (but are not limited to) dihydroindolyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinone. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (herein also referred to as 6,6-bicyclic heterocyclic groups) include (but are not limited to) tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0099] The term "heteroaromatic ring" refers to an aromatic monocyclic, bicyclic or polycyclic ring system having a 5- to 16-membered structure, preferably a 5- to 14-membered structure, a 5- to 12-membered structure, a 5- to 10-membered structure, a 5- to 8-membered structure, more preferably a 5- to 6-membered structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. The bicyclic or polycyclic heteroaromatic rings include fused heteroaromatic rings. Examples of heteroaromatic rings include, but are not limited to, furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, thiadiazole, triazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, indazole, benzofuran, benzothiophene, benzopyridine, benzopyrimidine, benzopyrazine, benzimidazole, benzophthalazine, pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyridine.

[0100] The term "heteroaryl" refers to a substituent generated on the basis of the aforementioned definition of heteroaromatic ring. Examples of heteroaryl include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl.

[0101] The term "pharmaceutical composition" refers to a preparation of one or more compounds of the present invention or salts thereof and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (such as a human). The purpose of the pharmaceutical composition is to facilitate the administration and delivery to the organism.

[0102] In the present invention, "a", "one", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the pharmaceutical composition comprises "one or more" pharmaceutically acceptable excipients.

[0103] The term "pharmaceutically acceptable excipient" refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0104] The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable excipient, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0105] The administration routes of the compounds of the present invention, their prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions, include but are not limited to oral, rectal, transmucosal, enteral administration, or topical percutaneous, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0106] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. This effect can be therapeutic according to partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0107] The term "effective amount" means the amount of the compound of the present application that (i) treats or prevents a specific disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0108] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0109] Based on the target design of NLRP3 inhibitors, the present invention has developed a novel nitrogen-containing bicyclic fused ring compound. Relevant biological tests have shown that the representative compound exhibits significant inhibitory activity against IL-1β expression in both THP-1 and PBMC cells. Moreover, the compound has low hERG toxicity and good metabolic stability, showing great potential for clinical application. In addition, the synthetic route of the compound provided by the present invention is novel, safe, environmentally friendly, and has good production feasibility. Detailed implementation manners

[0110] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention. However, the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0111] In addition, all operations involving raw materials that are prone to oxidation or hydrolysis are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be directly used without further purification.

[0112] The starting materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or prepared by oneself. For the starting materials and common intermediates that need to be prepared by oneself, the preparation processes are described in detail as follows.

[0113] Compounds 1-8: (R)-1-Methylpiperidin-3-amine was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd. According to the quality inspection report provided by the raw material supplier, the purity (NMR) was 97%, and the specific rotation was 9.8417° (c = 1 g / 100 mL, CHCl3).

[0114] The following abbreviations are used in the embodiments:

[0115] MeOH(CH3OH): Methanol; Pd(OAc)2: Palladium(II) acetate; K2S2O8: Potassium persulfate; DCM: Dichloromethane; EA: Ethyl acetate; PE: Petroleum ether; Na2SO4: Sodium sulfate; NaOH: Sodium hydroxide; H2O: Water; MeNH2: Methylamine; HCl: Hydrochloric acid; HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA: N,N-Diisopropylethylamine; DMF: N,N-Dimethylformamide; I2: Iodine; DMSO: Dimethyl sulfoxide; m-CPBA: m-Chloroperoxybenzoic acid; NaCl: Sodium chloride; Na2S2O3: Sodium thiosulfate; NaHCO3: Sodium bicarbonate; n-BuOH: n-Butanol; BBr3: Boron tribromide; Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0); NH4Cl: Ammonium chloride; Dioxane: 1,4-Dioxane; NaH: Sodium hydride; MeI: Iodomethane; NaHSO3: Sodium bisulfite; K2CO3: Potassium carbonate; CS2: Carbon disulfide; BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); t-BuONa: Sodium tert-butoxide; xylenes: Xylenes; ACN: Acetonitrile; CuBr2: Copper(II) bromide; acetone: Acetone; Et3N: Triethylamine; POCl3: Phosphorus oxychloride; AcOH: Acetic acid; THF: Tetrahydrofuran; CuBr: Copper(I) bromide; KI: Potassium iodide; ZnI2: Zinc iodide; 1,10-Phen: 1,10-Phenanthroline; 1,2-Dichlorobenzene: 1,2-Dichlorobenzene; LC-MS: Liquid chromatography - mass spectrometry; NADPH: Nicotinamide adenine dinucleotide phosphate, reduced form; UDPGA: Uridine diphosphate glucuronic acid; PB: Phosphate buffer; CYP3A4: Cytochrome P450 3A4; UGT: UDP-glucuronosyltransferase. In the examples of the present invention, x mL × y represents repeating y times, each time x mL. For example, washing the organic phase with water (80 mL × 3 times) means washing with 80 mL of water each time and repeating 3 times.

[0116] Example 1: Synthesis of (R)-5-(4-chloro-2-hydroxy-6-methylphenyl)-6-methyl-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (Target Compound 1):

[0117]

[0118] Synthetic Route 1: Synthesis of Intermediate 1-2

[0119] Step 1: Synthesis of 4-chloro-2-methoxy-6-methylbenzaldehyde (1-2)

[0120] Weigh compound 1-1 (1.1 g, 7.09 mmol), 3-trifluoromethylaniline (457.0 mg, 2.84 mmol), MeOH (5.68 g, 177.22 mmol), Pd(OAc)₂ (159.0 mg, 0.71 mmol) and K₂S₂O₈ (3.83 g, 14.18 mmol) respectively and place them in a sealed tube. Add DCM (30 mL) as the solvent, seal it, and heat to 65 °C with stirring for 24 hours. Pour the reaction solution into water (100 mL), then add DCM (70 mL) for extraction. The organic phase is washed with dilute hydrochloric acid (2 M, 40 mL) and water (80 mL) respectively, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE:EA = 90:10) to obtain compound 1-2 (230.0 mg), which is a brown solid with a yield of 17.6%.

[0121] LC-MS (m / z): 185.0 [M+H] + 。

[0122] 1 ¹H-NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 2.45 (s, 3H).

[0123] Synthetic Route 2: Synthesis of the target compound (R)-5-(4-chloro-2-hydroxy-6-methylphenyl)-6-methyl-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (target compound 1)

[0124] Step 1: Synthesis of sodium 4-amino-2-(methylthio)thiazole-5-carboxylate (1-4)

[0125] Weigh compound 1-3: ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate (1.17 g, 5.38 mmol), add MeOH (9 mL), and then weigh NaOH solid (645.3 mg, 16.13 mmol) and dissolve it in water (6 mL) to form a solution. Add this solution to the reaction system, heat to 65 °C with stirring for 1 hour. Let it stand and cool, concentrate the reaction solution, and dry it to obtain compound 1-4 (1.14 g), which is a brown solid. The product is directly used in the next step without further purification.

[0126] LC-MS (m / z): 191.0 [M+H] + 。

[0127] Step 2: Synthesis of 4-amino-N-methyl-2-(methylthio)thiazole-5-carboxamide (1-5)

[0128] Compound 1-4 (1.14 g), methylamine hydrochloride (1.09 g, 16.13 mmol) and DIPEA (2.08 g, 16.13 mmol) were added to DMF (10 mL). After stirring well, HATU (3.06 g, 8.07 mmol) was weighed and added, and the mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction solution, and the mixture was extracted with DCM (80 mL). The organic phase was separated, and the organic phase was washed with water (80 mL × 3 times). Anhydrous Na2SO4 was added for drying, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 1-5 (240.0 mg), which was a brown solid product with a two-step yield of 21.9%.

[0129] LC-MS (m / z): 204.0 [M+H] + 。

[0130] Step 3: Synthesis of 5-(4-chloro-2-methoxy-6-methylphenyl)-6-methyl-2-(methylthio)thiazolo[4,5-d]pyrimidin-7(6H)-one (1-6) The preparation of compound 1-2 refers to Synthetic Route 1 of this example.

[0131] Compound 1-5 (240.0 mg, 1.18 mmol), compound 1-2 (222.0 mg, 1.19 mmol) and iodine (359.6 mg, 1.42 mmol) were weighed and placed in a sealed tube, dissolved in anhydrous DMSO (9 mL), and heated to 120 °C under nitrogen protection for 2 hours of sealed reaction. The reaction solution was poured into saturated NaCl (100 mL), and then extracted with EA (80 mL). The organic phase was separated and washed with saturated NaCl (80 mL × 3). The organic phase was separated again, anhydrous Na2SO4 was added for drying, filtered, concentrated, and purified by column chromatography (PE:EA = 50:50) to obtain compound 1-6 (208.0 mg), which was a brown solid product with a yield of 47.9%.

[0132] LC-MS (m / z): 368.0 [M+H] + 。

[0133] 1 1H-NMR (400 MHz, DMSO-d6) δ 7.18 - 7.16 (m, 1H), 7.14 - 7.12 (m, 1H), 3.79 (s, 3H), 3.23 (s, 3H), 2.81 (s, 3H), 2.12 (s, 3H).

[0134] Step 4: Synthesis of 5-(4-chloro-2-methoxy-6-methylphenyl)-6-methyl-2-(methylsulfonyl)thiazolo[4,5-d]pyrimidin-7(6H)-one (1-7)

[0135] Weigh compound 1-6 (193.0 mg, 0.53 mmol) and dissolve it in DCM (15 mL). Then weigh m-CPBA (241.4 mg, 1.05 mmol) and add it. Stir the reaction mixture at room temperature overnight. Add saturated aqueous NaHCO3 solution (40 mL) to the reaction solution, then add DCM (50 mL) for extraction. Separate the organic phase, add anhydrous Na2SO4 for drying, filter, concentrate, and purify by column chromatography (PE:EA = 50:50) to obtain compound 1-7 (198.0 mg), which is a white solid product with a yield of 94.3%.

[0136] LC-MS (m / z): 400.0 [M+H] +

[0137] 1 1H-NMR (600 MHz, DMSO-d6) δ 7.20 - 7.19 (m, 1H), 7.16 - 7.14 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.29 (s, 3H), 2.15 (s, 3H).

[0138] Step 5: Synthesis of (R)-5-(4-chloro-2-methoxy-6-methylphenyl)-6-methyl-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (1-9)

[0139] Weigh compound 1-7 (77.0 mg, 0.19 mmol), compound 1-8: 1-methyl-(R)-3-aminopiperidine (28.6 mg, 0.25 mmol), and DIPEA (74.6 mg, 0.58 mmol) respectively and dissolve them in n-butanol (5 mL). Protect with nitrogen replacement, heat to 85 °C and stir the reaction for 2 hours. Pour the reaction solution into water (100 mL), then add DCM (50 mL) for extraction. Separate the organic phase, add anhydrous Na2SO4 for drying, filter, concentrate, and purify by column chromatography (DCM:MeOH = 90:10) to obtain compound 1-9 (60.0 mg), which is a brown solid product with a yield of 71.8%.

[0140] LC-MS (m / z): 434.0 [M+H] + .

[0141] Step 6: Synthesis of (R)-5-(4-chloro-2-hydroxy-6-methylphenyl)-6-methyl-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (Target Compound 1)

[0142] Weigh compound 1-9 (60.0 mg, 0.138 mmol) and dissolve it in DCM (3 mL). Then add a DCM solution of BBr3 (1 M, 0.6 mL), and stir the reaction at room temperature for 1 hour. Add MeOH (1 mL) dropwise to quench the reaction. After concentrating the reaction solution, it is purified by reverse-phase chromatography (ACN: 0.1% formic acid aqueous solution = 85%) to obtain the target compound 1 (41.0 mg), which is a white solid product with a yield of 70.6%.

[0143] LC-MS (m / z): 420.0 [M+H] + 。

[0144] 1 1H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.95 - 8.60 (m, 1H), 6.95 - 6.89 (m, 1H), 6.87 - 6.82 (m, 1H), 3.98 - 3.79 (m, 1H), 3.20 (s, 3H), 2.89 - 2.75 (m, 1H), 2.25 - 2.17 (m, 3H), 2.15 - 2.10 (m, 1H), 2.07 (s, 3H), 2.07 (m, 2H), 1.88 - 1.78 (m, 1H), 1.76 - 1.65 (m, 1H), 1.61 - 1.44 (m, 1H), 1.41 - 1.30 (m, 1H).

[0145] Example 2: Synthesis of (R)-1-(4-chloro-2-hydroxyphenyl)-4-((1-methylpiperidin-3-yl)amino)pyrimidin-2(1H)-one (Target Compound 2)

[0146]

[0147] Step 1: Synthesis of ethyl 4-amino-2-(4-chloro-2-methylphenyl)thiazole-5-carboxylate (2-2)

[0148] Weigh out compound 1-3 (1.00 g, 4.58 mmol), (4-chloro-2-methylphenyl)boronic acid (1.01 g, 5.95 mmol), Pd(PPh3)4 (211.7 mg, 0.183 mmol) and copper(I) 3-methylsalicylate complex (1.47 g, 6.87 mmol) and dissolve them in THF (32 mL). Replace the air with nitrogen for protection, heat to 50 °C and stir the reaction for 2 days. After standing and cooling, add water (80 mL) and EA (80 mL) to the reaction solution, filter through diatomaceous earth placed in a funnel, and wash the filter cake with a small amount of EA. Collect the filtrate, transfer it to a separatory funnel, and separate the organic phase. Dry over anhydrous Na2SO4, filter, concentrate, and purify by column chromatography (using PE:EA = 80:20 as the eluent) to obtain compound 2-2 (570.0 mg), which is a brownish-yellow solid product with a yield of 41.9%.

[0149] LC-MS (m / z): 297.0 [M+H] + 。

[0150] 1 1H-NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.05 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0151] Step 2: Synthesis of 4-amino-2-(4-chloro-2-methylphenyl)thiazole-5-carboxylic acid (2-3)

[0152] Weigh out compound 2-2 (540.0 mg, 1.81 mmol) and dissolve it in MeOH (15 mL). Weigh out solid NaOH (728.0 mg, 18.19 mmol) and dissolve it in water (12 mL) to prepare a solution, and add this solution to the reaction system. Heat to 65 °C and stir the reaction for 7 hours. Stop heating, let it stand and cool. Add water (20 mL) to the reaction solution, and then gradually add dilute hydrochloric acid (2 M, 5 mL) to adjust the pH to 7. Filter the reaction solution, and wash the filter cake with a small amount of DCM. Dry the filter cake to obtain compound 2-3 (308.0 mg), which is a brownish-yellow solid with a yield of 63.0%.

[0153] LC-MS (m / z): 269.0 [M+H] + 。

[0154] Step 3: Synthesis of 4-amino-2-(4-chloro-2-methylphenyl)thiazole-5-carboxamide (2-4)

[0155] Weigh out compound 2-3 (308.0 mg, 1.15 mmol), DIPEA (741.0 mg, 5.73 mmol) and anhydrous NH4Cl (184.0 mg, 3.44 mmol) separately and dissolve them in DMF (4 mL). Stir well until homogeneous. Then weigh out HATU (654.0 mg, 1.72 mmol) and add it. Stir the reaction at room temperature for about 1.5 hours. Add water (70 mL) to the reaction solution, stir well, then add DCM (60 mL) for extraction. Separate the organic phase, wash the organic phase with water (50 mL×4), then add anhydrous Na2SO4 for drying, filter, concentrate, and purify by column chromatography (DCM:MeOH = 90:10 as the eluent) to obtain compound 2-4 (211.0 mg), which is a light yellow solid product with a yield of 68.7%.

[0156] LC-MS (m / z): 268.0 [M+H] + 。

[0157] Step 4: Synthesis of 5-chloro-2-(4-chloro-2-methylphenyl)thiazolo[4,5-d]pyrimidin-7(6H)-one (2-5)

[0158] In a sealed tube, first dissolve compound 2-4 (177.0 mg, 0.661 mmol) in anhydrous dioxane (8 mL), then add thiophosgene (380.0 mg, 3.31 mmol). Flush with nitrogen for protection. Stir the reaction at room temperature for 1 hour first, then heat to 105 °C and continue stirring for 1 hour. Stop heating and let it stand to cool. Filter the reaction solution directly, collect the filter cake, concentrate to obtain compound 2-5 (121.0 mg), which is a brownish yellow solid product with a yield of 58.6%.

[0159] LC-MS (m / z): 312.0 [M+H] + 。

[0160] Step 5: Synthesis of 2-(4-chloro-2-methylphenyl)-5-morpholinothiazolo[4,5-d]pyrimidin-7(6H)-one (Target compound 2)

[0161] Weigh out compound 2-5 (121.0 mg, 0.39 mmol), compound 2-6: morpholine (101.3 mg, 1.16 mmol) and DIPEA (250.4 mg, 1.938 mmol) separately and dissolve them in n-butanol (10 mL). Flush with nitrogen for protection. Heat to 100 °C and stir the reaction for 2 hours. Stop heating and let it stand to cool. Concentrate the reaction solution and purify by column chromatography (DCM:MeOH = 90:10 as the eluent) to obtain the target compound 2 (55.0 mg), which is a light yellow solid with a yield of 39.1%.

[0162] LC-MS (m / z): 363.0 [M+H] + 。

[0163] 1 H-NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.49 - 7.43 (m, 1H), 3.70 - 3.67 (m, 4H), 3.66 - 3.63 (m, 4H), 2.60 (s, 3H).

[0164] Example 3: Synthesis of (R)-1-(4-chloro-2-hydroxyphenyl)-4-((1-methylpiperidin-3-yl)amino)pyrimidin-2(1H)-one (Target Compound 3)

[0165]

[0166] Referring to the preparation method of Compound 2 in Reference Example 2, replace Compound 2-6 with Compound 2-7: pyrrolidine in Step 5, and the rest of the method is the same. The target compound 3 was prepared as a yellow solid with a reaction yield of 50.2%.

[0167] LC-MS (m / z): 347.0 [M+H] + 。

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.48 - 7.41 (m, 1H), 3.60 - 3.44 (m, 4H), 2.61 (s, 3H), 2.01 - 1.83 (m, 4H).

[0169] Examples 4 and 5: Synthesis of 2-(4-chloro-2-methylphenyl)-6-methyl-5-(pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one (Target Compound 4) and 2-(4-chloro-2-methylphenyl)-7-methoxy-5-(pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidine (Target Compound 5)

[0170]

[0171] Step 1: Synthesis of the target compounds 2-(4-chloro-2-methylphenyl)-6-methyl-5-(pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one (target compound 4) and 2-(4-chloro-2-methylphenyl)-7-methoxy-5-(pyrrolidin-1-yl)thiazolo[4,5-d]pyrimidine (target compound 5)

[0172] The preparation method of compound 3 refers to Example 3.

[0173] Dissolve compound 3 (150.0 mg, 0.43 mmol) in anhydrous DMF (5 mL), add NaH (26.0 mg, 0.65 mmol) under an ice-water bath. After maintaining the reaction for 20 minutes, add MeI (123.0 mg, 0.86 mmol), and carry out the reaction at room temperature for 0.5 hour. Quench the reaction solution with saturated NH4Cl, extract with EA (20 mL), wash the organic phase with water (10 mL × 3) and saturated NaCl (10 mL), dry with anhydrous Na2SO4, filter, concentrate, and purify by column chromatography to obtain the target compound 4 (102.0 mg), which is a yellow solid with a yield of 65.4%.

[0174] LC-MS (m / z): 361.0 [M+H] + 。

[0175] 1 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.4, 2.0 Hz, 1H), 3.63 - 3.53 (m, 4H), 3.47 (s, 3H), 2.60 (s, 3H), 1.95 - 1.87 (m, 4H).

[0176] Obtain the target compound 5 (15.0 mg), which is a yellow solid with a yield of 9.6%.

[0177] LC-MS (m / z): 361.0 [M+H] + 。

[0178] 1 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.4 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.51 - 7.43 (m, 1H), 4.07 (s, 3H), 3.67 - 3.50 (m, 4H), 2.63 (s, 3H), 2.11 - 1.87 (m, 4H).

[0179] Synthesis of Example 8: (R)-5-chloro-2-(7-methoxy-2-(1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-5-yl)-3-methylphenol (Target Compound 8)

[0180]

[0181] Step 1: Synthesis of 4-amino-2-(methylthio)thiazole-5-carboxamide (8-2)

[0182] Under an ice-water bath, 8-1: 4-amino-2-(methylthio)thiazole-5-carbonitrile (1.00 g, 5.84 mmol) was slowly added to concentrated sulfuric acid (5 mL), and the reaction was kept warm for 10 minutes. The reaction solution was slowly added dropwise to an ice-water mixture containing sodium carbonate, extracted twice with DCM (25 mL), the organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain Compound 8-2 (614.0 mg), with a yield of 55.6%.

[0183] LC-MS (m / z): 190.0 [M+H] + 。

[0184] Step 2: Synthesis of 5-(4-chloro-2-methoxy-6-methylphenyl)-2-(methylthio)thiazolo[4,5-d]pyrimidin-7(6H)-one (8-3)

[0185] In a sealed tube, 8-2 (605.0 mg, 3.20 mmol), 1-2 (593.0 mg, 3.20 mmol) and iodine (1.62 g, 6.40 mmol) were dissolved in DMSO (10 mL), and the reaction was carried out at 120 °C for 1 hour under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with EA (50 mL), washed successively with Na2S2O3 solution (25 mL), water (25 mL×3) and saturated brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated, and purified by column chromatography (MeOH:DCM = 5:95) to obtain Compound 8-3 (490.0 mg), with a yield of 43.4%.

[0186] LC-MS (m / z): 354.0 [M+H] + 。

[0187] Step 3: Synthesis of 5-(4-chloro-2-methoxy-6-methylphenyl)-2-(methylsulfonyl)thiazolo[4,5-d]pyrimidin-7(6H)-one (8-4)

[0188] 8-3 (490.0 mg, 1.39 mmol) was dissolved in DCM (20 mL), and m-CPBA (702.6 mg, 3.03 mmol) was added. The reaction was carried out at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was washed successively with Na2S2O3 solution (20 mL), aqueous NaHCO3 solution (20 mL), water (10 mL) and saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 4:96) to obtain the crude product of compound 8-4 (576.0 mg), which was used directly in the next step without further purification.

[0189] LC-MS (m / z): 386.0 [M+H] + 。

[0190] Step 4: Synthesis of (R)-5-(4-chloro-2-methoxy-6-methylphenyl)-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (8-5)

[0191] The crude product of 8-4 (576.0 mg, 1.39 mmol), 1-8 (190.5 mg, 1.67 mmol) and DIPEA (0.49 mL, 2.78 mmol) were dissolved in n-butanol (10 mL), and the reaction was carried out at 80 °C for 2.5 h. After the reaction mixture was cooled to room temperature, it was concentrated, and purified by column chromatography (MeOH:DCM = 5:95) to obtain compound 8-5 (394.0 mg), with a two-step yield of 67.5%.

[0192] LC-MS (m / z): 420.0 [M+H] + 。

[0193] Step 5: Synthesis of (R)-7-chloro-5-(4-chloro-2-methoxy-6-methylphenyl)-N-(1-methylpiperidin-3-yl)thiazolo[4,5-d]pyrimidin-2-amine (8-6)

[0194] 8-5 (84.0 mg, 0.20 mmol) was added to POCl3 (2 mL), and DIPEA (0.2 mL) was added. The reaction was carried out at 100 °C for 1 h. After the reaction mixture was cooled to room temperature, it was concentrated, and the concentrated solution was diluted with EA (20 mL), dropped into warm water (25 mL) for quenching, adjusted to pH > 8 with saturated aqueous sodium carbonate solution, and the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 4:96) to obtain compound 8-6 (81.0 mg), with a yield of 92.4%.

[0195] LC-MS (m / z): 438.0 [M+H] +。

[0196] Step 6: Synthesis of (R)-5-chloro-2-(7-chloro-2-((1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-5-yl)-3-methylphenol (8-7)

[0197] Dissolve 8-6 (81.0 mg, 0.18 mmol) in DCM (3 mL), add a DCM solution of BBr3 (2.0 M, 0.5 mL), and react at room temperature for 1 hour. Quench the reaction solution with MeOH in an ice-water bath, concentrate, and purify by column chromatography (MeOH:DCM:TEA = 2.5:96.5:1) to obtain the crude product of 8-7 (241.0 mg), which is directly used in the next step without purification.

[0198] LC-MS (m / z): 424.0 [M+H] + 。

[0199] Step 7: Synthesis of (R)-5-chloro-2-(7-methoxy-2-(1-methylpiperidin-3-yl)amino)thiazolo[4,5-d]pyrimidin-5-yl)-3-methylphenol (8)

[0200] Add the crude product of 8-7 (241.0 mg) to a methanol solution of sodium methoxide (5.0 M, 2 mL), and react at 60 °C for 1 hour. Adjust the reaction solution to pH about 5 with dilute hydrochloric acid in an ice-water bath, extract with DCM (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous Na2SO4, filter, concentrate, and purify by reverse-phase chromatography (ACN: 0.1% formic acid aqueous solution = 85%) to obtain the target compound 8 (25.7 mg), with a two-step yield of 33.1%.

[0201] LC-MS (m / z): 420.0 [M+H] + 。

[0202] 1 1H NMR (400 MHz, DMSO-d6) δ 10.80–10.22 (m, 1H), 9.70–9.54 (m, 1H), 6.93–6.84 (m, 2H), 4.46–4.26 (m, 1H), 4.05 (s, 3H), 3.94–3.80 (m, 1H), 3.43–3.35 (m, 1H), 3.01–2.73 (m, 5H), 2.42 (s, 3H), 2.19–2.06 (m, 1H), 2.02–1.75 (m, 2H), 1.64–1.38 (m, 1H).

[0203] Synthesis of Example 38: (R)-5-Chloro-2-(1-methyl-5-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (Target Compound 38)

[0204]

[0205] Step 1: Synthesis of 5-Bromo-2-(4-chloro-2-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (38-3)

[0206] Compound 38-1: 2,3-Diaminopyridine (2.00 g, 10.64 mmol), Compound 38-2: 4-Chloro-2-methoxybenzaldehyde (1.80 g, 10.67 mmol) and NaHSO3 (1.10 g, 10.61 mmol) were added to DMF (30 mL). The mixture was reacted at 130 °C for 6 hours. After the reaction was completed, when the reaction solution was cooled, the reaction solution was dropped into water (300 mL), filtered, the filter cake was washed with water (30 mL), the filter cake was collected and dried to obtain Compound 38-3 (3.60 g), which was a yellow solid with a yield of 99.9%.

[0207] LC-MS (m / z): 338.0 / 340.0 [M+H] + .

[0208] Step 2: Synthesis of 5-Bromo-2-(4-chloro-2-methoxyphenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (38-4)

[0209] Compound 38-3 (3.60 g, 10.61 mmol) and K2CO3 (4.40 g, 31.83 mmol) were weighed in a round-bottom flask, DMF (35 mL) was added, MeI (1.80 g, 9.55 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL), extracted with EA (70 mL×3), the combined organic phases were washed with saturated NaCl (20 mL×3), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to obtain Compound 38-4 (335.0 mg), which was a yellow solid with a yield of 9.0%.

[0210] LC-MS (m / z): 352.0 / 354.0 [M+H] + .

[0211] Step 3: Synthesis of (R)-2-(4-Chloro-2-methoxyphenyl)-1-methyl-N-(1-methylpiperidin-3-yl)-1H-imidazo[4,5-b]pyridin-5-amine (38-6)

[0212] Weigh compound 38-4 (210.0 mg, 0.60 mmol), compound 1-8 (1.40 g, 11.91 mmol), sodium tert-butoxide (114.0 mg, 1.19 mmol), BINAP (148.0 mg, 0.24 mmol) and Pd2(dba)3 (109.0 mg, 0.12 mmol) in a round-bottom flask, add xylene (4 mL), and microwave the mixture at 110 °C for 0.5 h under a nitrogen atmosphere. After the reaction, dilute the reaction mixture with distilled water (10 mL), extract with EA (25 mL × 3), combine the organic phases, wash with saturated NaCl (15 mL), dry over anhydrous Na2SO4, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain compound 38-6 (130.0 mg), which is a yellow solid with a yield of 56.8%.

[0213] LC-MS (m / z): 386.0 [M+H] + 。

[0214] Step 4: Synthesis of (R)-5-chloro-2-(1-methyl-5-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (Target compound 38)

[0215] Weigh compound 38-6 (210.0 mg, 0.31 mmol) in a round-bottom flask, add ultra-dry DCM (3 mL), add a DCM solution of BBr3 (1 M, 3.1 mL) at 0 °C, and stir the mixture at room temperature for 3 h. After the reaction, quench the reaction solution with a small amount of MeOH at 0 °C, rotary evaporate under reduced pressure, and purify by reverse-phase chromatography (ACN: 0.1% formic acid aqueous solution = 85%) to obtain the target compound 38 (9.8 mg), which is an off-white solid with a yield of 8.5%.

[0216] LC-MS (m / z): 372.0 [M+H] + 。

[0217] 11H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.83 - 7.58 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 4.12 - 3.96 (m, 1H), 3.82 (s, 3H), 3.08 - 2.92 (m, 1H), 2.81 - 2.63 (m, 1H), 2.29 (s, 3H), 2.25 - 2.10 (m, 1H), 2.09 - 1.94 (m, 1H), 1.92 - 1.79 (m, 1H), 1.81 - 1.69 (m, 1H), 1.67 - 1.46 (m, 1H), 1.38 - 1.17 (m, 1H).

[0218] Example 39: Synthesis of (R)-3,5-dimethyl-2-(1-methyl-5-((1-methylpiperidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (Target Compound 39)

[0219]

[0220] Referring to the preparation method of Target Compound 38 in Reference Example 38, only replace Compound 38-2 in Step 1 with Compound 39-1: 2-methoxy-4,6-dimethylbenzaldehyde, and the rest of the method is the same. The target compound 39 was prepared; the total yield of the four-step reaction was 4.0%, and it was a yellow solid.

[0221] LC-MS (m / z): 366.0 [M + H] + .

[0222] 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 - 9.09 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.63 (s, 2H), 6.46 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 4.08 - 3.89 (m, 1H), 3.44 (s, 3H), 3.04 - 2.82 (m, 1H), 2.71 - 2.54 (m, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.02 (s, 3H), 2.00 - 1.94 (m, 1H), 1.90 - 1.78 (m, 2H), 1.76 - 1.65 (m, 1H), 1.62 - 1.49 (m, 1H), 1.32 - 1.17 (m, 1H).

[0223] Example 40: Synthesis of (R)-5-chloro-2-(7-((1-methylpiperidin-3-yl)amino)imidazo[1,2-a]pyrimidin-2-yl)phenol (Target Compound 40)

[0224]

[0225] Synthetic Route 1: Synthesis of Intermediate 40-3

[0226] Step 1: Synthesis of 4-chloro-2-methoxyacetophenone (40-2)

[0227] Dissolve Compound 40-1: 4-chloro-2-hydroxyacetophenone (5.0 g, 29.31 mmol) and MeI (3.66 mL, 58.62 mmol) in DMF, add K2CO3 (6.07 g, 43.96 mmol), and react at room temperature for 3 hours. Dilute the reaction solution with water (100 ml), extract with EA (50 mL × 2), combine the organic phases, wash with water (50 mL × 3) and saturated NaCl (50 mL), dry over anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 50:50) to obtain Compound 40-2 (4.80 g), which is a white solid with a yield of 88.7%.

[0228] LC-MS (m / z): 185.0 [M+H] + 。

[0229] Step 2: Synthesis of 2-bromo-1-(4-chloro-2-methoxyphenyl)ethan-1-one (40-3)

[0230] Dissolve Compound 40-2 (4.53 g, 24.57 mmol) and CuBr2 (10.98 g, 49.14 mmol) in ACN (100 mL), and react at 90 °C for 3 hours. Wait for the reaction solution to cool to room temperature, dilute with EA (100 mL), filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE:EA = 90:10) to obtain Compound 40-3 (2.53 g), which is a white solid with a yield of 39.0%.

[0231] LC-MS (m / z): 263.0 / 265.0 [M+H] + 。

[0232] Synthetic Route 2: Synthesis of the Target Compound (R)-5-chloro-2-(7-((1-methylpiperidin-3-yl)amino)imidazo[1,2-a]pyrimidin-2-yl)phenol (Target Compound 40)

[0233] Step 1: (R)-N 4Synthesis of (1-Methylpiperidin-3-yl)pyrimidine-2,4-diamine (40-5)

[0234] Dissolve compound 40-4: 2-Amino-4-chloropyrimidine (648.0 mg, 5.00 mmol), compound 1-8 (856.5 mg, 7.50 mmol) and DIPEA (2.62 mL, 15.00 mmol) in n-butanol (10 mL), and react at 150 °C in a microwave for 1 hour. Wait for the reaction solution to cool to room temperature, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH:Et3N = 89:10:1) to obtain compound 40-5 (976.0 mg), which is a pale yellow solid with a yield of 94.1%.

[0235] LC-MS (m / z): 208.0 [M+H] + 。

[0236] Step 2: Synthesis of (R)-2-(4-Chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)imidazo[1,2-a]pyrimidin-7-amine (40-6)

[0237] The preparation of compound 40-3 refers to Synthetic Route 1 of this example.

[0238] Dissolve compound 40-5 (100.0 mg, 0.37 mmol), compound 40-3 (146.3 mg, 0.55 mmol) and DIPEA (143.5 mg, 1.11 mmol) in acetone (3 mL), and react at 65 °C for 2 hours. Wait for the reaction solution to cool to room temperature, dilute with EA (10 mL), wash with saturated aqueous NaHCO3 solution (10 mL), water (10 mL) and saturated NaCl (10 mL), dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH = 85:15) to obtain compound 40-6 (73.0 mg), which is a white solid with a yield of 53.0%.

[0239] LC-MS (m / z): 372.0 [M+H] + 。

[0240] Step 3: Synthesis of (R)-5-Chloro-2-(7-((1-methylpiperidin-3-yl)amino)imidazo[1,2-a]pyrimidin-2-yl)phenol (Target Compound 40)

[0241] Compound 40-6 (73.0 mg, 0.20 mmol) was dissolved in anhydrous DCM (2.5 mL), and a DCM solution of BBr3 (0.5 mL, 2.0 M) was added at room temperature. The reaction was carried out for 1.5 h. The reaction solution was quenched with MeOH, concentrated to dryness, and purified by reverse-phase chromatography (ACN: 0.1% aqueous formic acid solution = 85%) to obtain the target compound 40 (13.5 mg) as a white solid with a yield of 19.2%.

[0242] LC-MS (m / z): 358.0 [M+H] + 。

[0243] 1 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 7.2 Hz, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 2.0 Hz, 1H), 6.43 (d, J = 7.4 Hz, 1H), 4.18 - 4.03 (m, 1H), 2.91 - 2.82 (m, 1H), 2.63 - 2.56 (m, 1H), 2.25 (s, 3H), 2.20 - 2.13 (m, 1H), 2.10 - 1.95 (m, 1H), 1.87 - 1.68 (m, 2H), 1.63 - 1.51 (m, 1H), 1.41 - 1.27 (m, 1H).

[0244] Example 41: Synthesis of (R)-5-chloro-2-(5-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenol (target compound 41)

[0245]

[0246] Step 1: Synthesis of 3-(4-chloro-2-methoxyphenyl)-1H-1,2,4-triazol-5-amine (41-2)

[0247] Compound 41-1: Methyl 4-chloro-2-methoxybenzoate (2.00 g, 10.00 mmol), aminoguanidine hydrochloride (3.30 g, 30.00 mmol), K2CO3 (5.20 g, 37.60 mmol) and MeOH (80 mL) were placed in a sealed tube and reacted at 100 °C for 3 h. After the reaction solution was cooled to room temperature, it was concentrated, then DCM (50 mL) was added and stirred. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 41-2 (1.01 g) as a white solid with a yield of 45.0%.

[0248] LC-MS (m / z): 225.0 [M+H] + 。

[0249] Step 2: Synthesis of 5,7-dichloro-2-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (41-3)

[0250] Dissolve compound 41-2 (1.0 g, 4.45 mmol) and malonic acid (695.0 mg, 6.69 mmol) in POCl3 (10 mL), and react at 110 °C for 2 hours. After the reaction solution cools to room temperature, concentrate it. Dilute the residue with EA (20 mL), slowly add it dropwise to water (20 mL), adjust to alkaline with aqueous sodium carbonate solution, and separate the layers. Wash the organic phase with saturated NaCl (20 mL), dry it with anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 65:35) to obtain compound 41-3 (837.0 mg), which is a white solid with a yield of 57.1%.

[0251] LC-MS (m / z): 329.0 / 331.0 [M+H] + 。

[0252] Step 3: Synthesis of 5-chloro-2-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (41-4)

[0253] Add compound 41-3 (83.0 mg, 0.25 mmol) to a mixed solution of MeOH (1 mL) and THF (6 mL), add 1 drop of acetic acid, then add zinc-copper reagent (162.0 mg, 1.26 mmol), and react at room temperature for 16 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE:EA = 50:50) to obtain compound 41-4 (16.0 mg), which is a white solid with a yield of 21.5%.

[0254] LC-MS (m / z): 295.0 [M+H] + 。

[0255] Step 4: Synthesis of (R)-2-(4-chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-amine (41-5)

[0256] Compound 41-4 (16.0 mg, 0.05 mmol), compound 1-8 (19.0 mg, 0.16 mmol) and DIPEA (0.05 mL, 0.27 mmol) were dissolved in n-butanol (1 mL), and the mixture was reacted at 150 °C in a microwave for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 90:10) to obtain the crude product of compound 41-5 (24.0 mg), which was a white solid.

[0257] LC-MS (m / z): 373.0 [M+H] + 。

[0258] Step 5: Synthesis of (R)-5-chloro-2-(5-((1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenol (target compound 41)

[0259] The crude product of compound 41-5 (24.0 mg) was dissolved in anhydrous DCM (3 mL), and a DCM solution of BBr3 (0.2 mL, 2.0 M) was added at room temperature, and the reaction was carried out for 0.5 hour. The reaction solution was quenched with MeOH, concentrated to dryness, and the residue was separated and purified by thin-layer chromatography to obtain the target compound 41 (4.9 mg), which was a white solid, and the two-step yield was 25.2%.

[0260] LC-MS (m / z): 359.0 [M+H] + 。

[0261] 1 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.31 - 8.18 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 4.17 - 4.06 (m, 1H), 3.58 - 3.44 (m, 1H), 2.85 - 2.73 (m, 1H), 2.21 (s, 3H), 2.18 - 1.97 (m, 2H), 1.87 - 1.68 (m, 2H), 1.63 - 1.50 (m, 1H), 1.43 - 1.31 (m, 1H).

[0262] Example 42: Synthesis of (R)-5-chloro-2-(6-(1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-b]pyrazin-2-yl)phenol (target compound 42)

[0263]

[0264] Step 1: Synthesis of 6-chloro-2-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[1,5-b]pyridazine (42-2)

[0265] Dissolve compound 42-1: 4-chloro-2-methoxybenzonitrile (1.00 g, 5.97 mmol), 6-chloro-3-aminopyridazine (309.0 mg, 2.38 mmol), CuBr (34.0 mg, 0.24 mmol), 1,10-phenanthroline (43.0 mg, 0.24 mmol), ZnI2 (152.0 mg, 0.48 mmol), elemental iodine (605.0 mg, 2.38 mmol), KI (426.0 mg, 2.63 mmol) and K2CO3 (990.0 mg, 7.17 mmol) in ortho-dichlorobenzene (20 mL), and react at 130 °C for 22 hours. After the reaction solution is cooled to room temperature, filter, concentrate the filtrate, and purify by column chromatography (PE:EA = 50:50) to obtain compound 42-2 (42.0 mg), which is a white solid with a yield of 6.0%.

[0266] LC-MS (m / z): 295.0 [M+H] + 。

[0267] Step 2: Synthesis of (R)-2-(4-chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-amine (42-3)

[0268] Dissolve compound 42-2 (40.0 mg, 0.14 mmol), compound 1-8 (19.0 mg, 0.16 mmol) and DIPEA (52.0 mg, 0.41 mmol) in n-butanol (2 mL), and react in a microwave at 180 °C in two portions for a total of 7 hours. After the reaction solution is cooled to room temperature, concentrate under reduced pressure and purify by column chromatography (DCM:MeOH = 85:15) to obtain compound 42-3 (27.0 mg), which is a white solid with a yield of 53.8%.

[0269] LC-MS (m / z): 373.0 [M+H] + 。

[0270] Step 3: Synthesis of (R)-5-chloro-2-(6-(1-methylpiperidin-3-yl)amino)-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)phenol (target compound 42)

[0271] Compound 42-3 (27.0 mg, 0.07 mmol) was dissolved in anhydrous DCM (3 mL), and a DCM solution of BBr3 (0.5 mL, 2.0 M) was added at room temperature. The reaction was carried out for 1 hour. The reaction mixture was quenched with MeOH, concentrated to dryness, and the residue was purified by thin-layer chromatography to obtain the target compound 42 (7.0 mg) as a white solid, with a yield of 26.9%.

[0272] LC-MS (m / z): 359.0 [M+H] + 。

[0273] 1 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.06 - 8.00 (m, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 9.6 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.29 - 3.16 (m, 1H), 2.92 - 2.82 (m, 1H), 2.20 (s, 3H), 2.15 - 2.06 (m, 1H), 2.06 - 1.94 (m, 1H), 1.90 - 1.80 (m, 1H), 1.78 - 1.66 (m, 1H), 1.63 - 1.50 (m, 1H), 1.41 - 1.30 (m, 1H).

[0274] Example 48: Synthesis of (R)-2-(4-chloro-2-methylphenyl)-1-methyl-N-(1-methylpiperidin-3-yl)-1H-imidazo[4,5-b]pyridin-5-amine (target compound 48)

[0275]

[0276] Referring to Steps 1 - 3 of Reference Example 38, only compound 38-2 in Step 1 was replaced with compound 48-1: 4-chloro-2-methylbenzaldehyde, and the rest of the method was the same. The control compound 48 was prepared as a yellow solid, and the total yield of the three-step reaction was 4.7%.

[0277] LC-MS (m / z): 370.0 [M+H] + 。

[0278] 11H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.46 - 7.40 (m, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.54 (s, 3H), 3.05 - 2.93 (m, 1H), 2.75 - 2.62 (m, 1H), 2.24 (d, J = 2.8 Hz, 6H), 2.14 - 2.03 (m, 1H), 1.99 - 1.90 (m, 1H), 1.90 - 1.79 (m, 1H), 1.78 - 1.68 (m, 1H), 1.64 - 1.51 (m, 1H), 1.35 - 1.17 (m, 1H).

[0279] Biological activity test

[0280] Example 1: Inhibitory effect of the compound of the present invention on the release of IL-1β in THP-1 cells induced by PMA

[0281] THP-1 cells were purchased from Wuhan Punosai Life Science Co., Ltd. (product number CL-0233). The complete medium used was RPMI1640 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin double antibody (Pen-Strep), and β-mercaptoethanol at a final concentration of 0.05 mM. Cells were cultured according to the supplier's instructions, and the cell density was maintained in the logarithmic phase before the experiment. The cell density was adjusted to 1×10 5 cells / mL, and after induction with 100 ng / mL phorbol 12-myristate 13-acetate (PMA) for 16 h, they were stimulated with 100 ng / mL lipopolysaccharide (LPS) for 3 h. The compound of the present invention was dissolved in dimethyl sulfoxide (DMSO) and diluted 3-fold with the medium to the required concentration and added to a 96-well plate respectively. After 1 h, sodium nigericin at a final concentration of 10 μM was added to the culture plate with the drug and incubated for 1 h. The cell-free supernatant was collected, and the IL-1β level was evaluated according to the instructions of the ELISA detection kit (Invitrogen). The solvent was blank. EC 50 Fitted by the GraphPad software log(agonist) vs. response-Variable slope four-parameter method. The results are shown in Table 1.

[0282] Table 1 Inhibitory activity of the compound on the release of IL-1β in THP-1 cells

[0283]

[0284]

Note

[0285] Experimental conclusion: The results show that the compound of the present invention can significantly inhibit the pyroptosis of human THP-1 cells induced by PMA and the expression of IL-1β in these cells.

[0286] Example 2: Inhibitory effect of the compound of the present invention on the release of IL-1β in PBMC cells

[0287] Healthy human peripheral blood mononuclear cells (PBMC) were purchased from Miaoshun Biology (product number PB010C), and the complete medium used was RPMI 1640 medium containing FBS (10%) and Pen-Strep (1%). After inoculating PBMC at 1×10 5 cells / well into a 96-well plate, they were cultured overnight in an incubator, and then stimulated with LPS (final concentration 100 ng / mL) for 3 h. The derivative of the present invention was dissolved in DMSO and serially diluted 3-fold with the medium to the desired concentrations and added to the 96-well plate for continued culture for 1 h, and then adenosine triphosphate (ATP) with a final concentration of 5 mM was added for continued culture for 1 h. The cell-free supernatant was collected, and the IL-1β level was evaluated according to the instructions of the ELISA detection kit (Invitrogen). The vehicle was used as the blank. IC 50 Fitted by the GraphPad software log(agonist) vs. response-Variable slope four-parameter method. The results are shown in Table 2.

[0288] Table 2 Inhibitory activity of the compound on the release of IL-1β in PBMC cells

[0289] Compound <![CDATA[IC 50 (nΜ)]]> 1 58.3 3 1.4

[0290] Example 3: Inhibitory effect of the compound on the hERG ion channel

[0291] The inhibitory effect of the compound on the human hERG ion channel stably expressed in HEK293 cells was tested using the traditional patch clamp method. The compound was formulated at a concentration of 10 μM. Each cell was used as its own control. The compound was perfused using a perfusion system utilizing its own gravity. After the current was stabilized in each cell, the hERG current magnitude before and after adding the compound was compared, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 3.

[0292] Table 3 Blocking effect of the compound on the hERG current

[0293]

[0294]

[0295] Example 4: Detection of the Metabolic Stability of the Test Compound

[0296] 1 Preparation of Experimental Materials

[0297] 1.1 Incubation Buffer

[0298] Weigh a certain amount of anhydrous sodium dihydrogen phosphate into a centrifuge tube, add an appropriate amount of ultrapure water, vortex and mix well to prepare a sodium dihydrogen phosphate solution with a concentration of 0.1 mol / L for standby; weigh a certain amount of anhydrous disodium hydrogen phosphate into a centrifuge tube, add an appropriate amount of ultrapure water, vortex and mix well to prepare a disodium hydrogen phosphate solution with a concentration of 0.1 mol / L for standby; mix the sodium dihydrogen phosphate solution (0.1 mol / L) and the disodium hydrogen phosphate solution (0.1 mol / L) in a reagent bottle according to a ratio of 19:81 (v:v), mix well to obtain a PB buffer solution with a concentration of 100 mmol / L (the concentration is based on the phosphate ion concentration), and store it at 2 - 8 °C for standby.

[0299] 1.2 Initiating Factors (NADPH and UDPGA Mixed Solution)

[0300] Accurately weigh an appropriate amount of NADPH into a 1.5 mL centrifuge tube, add an appropriate amount of PB solution, vortex and mix well to prepare a NADPH solution with a concentration of 40 mmol / L, place it on ice for standby; accurately weigh an appropriate amount of UDPGA into a 1.5 mL centrifuge tube, add an appropriate amount of PB solution, vortex and mix well to prepare a UDPGA solution with a concentration of 40 mmol / L, place it on ice for standby; respectively transfer the same volume of NADPH and UDPGA solutions into the same centrifuge tube, vortex and mix well to prepare a mixed solution of NADPH and UDPGA (containing 20 mmol / L of NADPH and UDPGA), place it on ice for standby.

[0301] 1.3 Positive Substrate Working Solution (Testosterone and 7-Hydroxycoumarin Mixed Solution)

[0302] Accurately weigh an appropriate amount of testosterone reference substance, dissolve it in DMSO, vortex and mix well to dissolve it, prepare a testosterone stock solution with a concentration of 20 mmol / L, and store it in a -20 °C refrigerator; accurately weigh an appropriate amount of 7-hydroxycoumarin reference substance, dissolve it in DMSO, vortex and mix well to dissolve it, prepare a 7-hydroxycoumarin stock solution with a concentration of 20 mmol / L, and store it in a -20 °C refrigerator; respectively transfer the same volume of testosterone stock solution and 7-hydroxycoumarin stock solution into the same 1.5 mL centrifuge tube, and dilute it with 50% methanol-water to a mixed substrate working solution with a concentration of 20 μmol / L, and place it on ice for standby.

[0303] 1.4 Test Substrate Working Solution

[0304] Accurately weigh an appropriate amount of the test substance reference standard, dissolve it in DMSO, vortex to mix well until it is dissolved, and prepare a 10 mmol / L stock solution of the test substance, which is placed in a -20°C refrigerator for later use; transfer an appropriate amount of the test substance stock solution into a 1.5 mL centrifuge tube, and dilute it with a 50% methanol-water diluent to a 20 μmol / L substrate working solution, which is placed on ice for later use.

[0305] 2 Experimental methods

[0306] The experimental design is divided into three groups, namely the positive control group (PC), the negative control group (NC), and the experimental group. The test substance is incubated with human, rat, or mouse liver microsomes for a certain period of time under the conditions of NADPH and UDPGA (using the absence of NADPH and UDPGA as the negative control and setting a positive control), the reaction is terminated by adding a termination solution, and the remaining amount of the test substance in the sample is detected by an LC-MS / MS instrument. The concentrations of the test substance at different reaction times are compared with those at T0 to obtain the stability of the test substance in liver microsomes. Generally, the final protein concentration of liver microsomes in the reaction system is 1.0 mg / mL. All incubations are carried out in a 37°C water bath.

[0307] 2.1 Experimental grouping

[0308] Experimental group: The test substance is incubated with liver microsomes for 60 min or 120 min under the conditions of NADPH and UDPGA.

[0309] Negative control group (NC): The test substance is incubated with liver microsomes for 60 min or 120 min without any coenzymes.

[0310] Positive control group (PC): The probe substrates of CYP3A4 and UGT, testosterone and 7-hydroxycoumarin, are incubated with liver microsomes for 60 min or 120 min under the conditions of NADPH and UDPGA.

[0311] 2.2 Experimental procedures

[0312] (1) Take out an appropriate amount of liver microsomes of the required species and thaw them on ice, and gently shake to mix well.

[0313] (2) Experimental group and negative control group (NC): Take an appropriate amount of PB buffer, add an appropriate amount of the test substance substrate working solution, and then transfer an appropriate amount of liver microsomes into a 1.5 mL centrifuge tube, pipette 20 - 30 times to mix well, ensuring that the final concentration of liver microsomes is 1 mg / mL (if there are special requirements, the liver microsome concentration can be adjusted to 0.5 mg / mL).

[0314] (3) Positive control group (PC): Take an appropriate amount of PB buffer, add an appropriate amount of positive substrate working solution, and then transfer an appropriate amount of liver microsomes into a 1.5 mL centrifuge tube. Pipette 20 - 30 times to mix evenly, ensuring that the final concentration of liver microsomes is 1 mg / mL.

[0315] (4) Experimental group: Aliquot 90 μL of the solution in (2) respectively. After pre-incubating in a 37°C water bath for 5 min, add 10 μL of the starting factor at 20 mmol / L to initiate the reaction. After reaching the set incubation times, add an appropriate amount of pre-cooled methanol solution containing internal standard to terminate the reaction.

[0316] (n = 2)

[0317] (5) Negative control group (NC): Aliquot 90 μL of the solution in (2). After pre-incubating in a 37°C water bath for 5 min, add 10 μL of PB buffer. After reaching the set incubation times, add an appropriate amount of pre-cooled methanol solution containing internal standard to terminate the reaction. (n ≥ 2)

[0318] (6) Positive control group (PC): Aliquot 90 μL of the solution in (3). After pre-incubating in a 37°C water bath for 5 min, add 10 μL of the starting factor at 20 mmol / L to initiate the reaction. After reaching the set incubation times, add an appropriate amount of pre-cooled methanol solution containing internal standard to terminate the reaction. (n = 2)

[0319] (7) Vortex the above-prepared samples at 2500 rpm for 1 min, centrifuge at 17000 g and 4°C for 10 min, and take the supernatant for LC-MS / MS detection.

[0320] 3 Data processing and analysis

[0321] Quantify the stability samples using the standard curve to obtain the concentration of the test substance at each time point, and calculate the percentage of the remaining amount of the parent compound relative to the amount of the parent compound before incubation (0 min); alternatively, calculate the percentage of the remaining amount of the parent compound relative to the amount of the parent compound before incubation (0 min) by the ratio of the peak area of the test substance to the peak area of the internal standard. The data is calculated according to the following formula: Parent remaining percentage (Parent remaining, % of 0 min) = T x Amount of parent compound at T / Amount of parent compound at T0 × 100%; T x : Incubation time point at x min; T0: Incubation time point at 0 min. The results are shown in Table 4 and Table 5.

[0322] Table 4 In vitro metabolic stability of compound 8 in liver microsomes

[0323]

[0324] Table 5 In vitro metabolic stability of Compound 40 in liver microsomes

[0325]

Claims

1. A nitrogen-containing bifused ring compound, which is a compound having the following structural formula (IA) or (IB), an isomer or a pharmaceutically acceptable salt thereof: in, Ring A is selected from Ring B is selected from R a1 , R a2 are independently selected from hydrogen or C 1-6 alkyl; Ring C is selected from 3-8 membered heterocyclic groups; the 3-8 membered heterocyclic groups are optionally further substituted with one or more selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 1 , R 2 , R 3 , R 4 , R 5 Each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl may be optionally further substituted with one or more radicals selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent; R 6 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; 1-6 Alkyl, C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further substituted by one or more radicals selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 3-8 The cycloalkyl group or the 3- to 8-membered heterocyclic group is substituted.

2. The nitrogen-containing bifused ring compound according to claim 1, which is a compound having the following structural formula (IIB-1), an isomer or a pharmaceutically acceptable salt thereof: in, R a1 Selected from hydrogen or C 1-6 alkyl; Y is selected from -OR a2 or oxo; R a2 Selected from C 1-6 alkyl; R 5 Selected from C 1-6 Alkyl or hydroxyl; Ring C is selected from 3-6 membered heterocyclic groups; The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from N, O or S.

3. The nitrogen-containing bifused ring compound according to claim 1 or 2, characterized in that: A compound having the following general structural formula (IIB-1-1), an isomer or a pharmaceutically acceptable salt thereof: Among them, R a1 Selected from hydrogen or C 1-6 alkyl; Ring C is selected from 3-6 membered heterocyclic groups; The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from N, O or S.

4. The nitrogen-containing bifused ring compound according to claim 1, characterized in that: A compound having the following general structural formula (IIB-1-2), an isomer or a pharmaceutically acceptable salt thereof: Among them, R 1 , R 5 Each independently selected from hydrogen, hydroxyl or C 1-6 alkyl.

5. The nitrogen-containing bifused ring compound according to claim 1, characterized in that: A compound having the following general structural formula (IIA), an isomer or a pharmaceutically acceptable salt thereof: wherein Z is selected from C or N; R 1 , R 3 , R 5 are each independently selected from hydrogen, C 1-6 alkyl, hydroxyl or halogen, and R 1 , R 3 , R 5 At least one is a hydroxyl group.

6. The nitrogen-containing bifused ring compound according to claim 1 or 5, characterized in that: A compound having the following general structural formula (IIA-1), an isomer or a pharmaceutically acceptable salt thereof: Among them, R 1 , R 3 are each independently selected from hydrogen, C 1-6 Alkyl or halogen.

7. The nitrogen-containing bifused ring compound according to claim 1, characterized in that: A compound having the following general structural formula (IIA-1-1), an isomer or a pharmaceutically acceptable salt thereof: Wherein, ring A is selected from 8. The nitrogen-containing bifused ring compound according to claim 1 or 7, characterized in that: A compound having the following general structural formula (IIA-1-2), an isomer or a pharmaceutically acceptable salt thereof: Wherein, ring A is selected from 9. A nitrogen-containing bifused ring compound, which is a compound, isomer or pharmaceutically acceptable salt thereof having the following structure:

10. A pharmaceutical composition comprising the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient, and at least one pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a drug for preventing or treating a disease associated with NLRP3.

12. The use according to claim 11, characterized in that: The NLRP3-related disease is cancer, inflammatory disease or a disease accompanied by inflammatory response. The cancer diseases include, but are not limited to, myeloproliferative neoplasms, myeloid leukemia, lung cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, bile duct cancer, oral cancer, head and neck cancer, mesothelioma, adrenocortical carcinoma, kidney cancer, liver cancer, stomach cancer, colon cancer, rectal cancer, bone cancer, brain cancer, breast cancer, melanoma, pancreatic cancer, skin cancer, lymphoma, bladder cancer, small intestine cancer, soft tissue sarcoma, endometrial cancer, cervical cancer, osteosarcoma, prostate cancer or testicular cancer. The inflammatory diseases or diseases accompanied by inflammatory responses include, but are not limited to: 1) Autoinflammatory diseases, such as chillin-associated periodic syndrome (CAPS), familial Mediterranean fever, Schnitzler syndrome, and mevalonate kinase deficiency (MKD); 2) Chronic pain, including neuropathic pain and non-neuropathic pain; 3) Skin conditions, such as contact hypersensitivity, bullous pemphigoid, sunburn, contact dermatitis, seborrheic dermatitis, hidradenitis suppurativa (HS), diabetic (foot) ulcers, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, acne, and alopecia; 4) Respiratory system diseases, such as chronic obstructive pulmonary disease (COPD), asthma, bronchitis, rhinitis, sinusitis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, sarcoidosis, adult respiratory distress syndrome, pneumonia; 5) Joint diseases, such as arthritis; 6) Muscle diseases, such as polymyositis and myasthenia gravis; 7) Cardiovascular diseases, such as hypertension, ischemia, reperfusion injury, vasculitis, pericarditis; 8) Blood diseases, such as sickle cell disease; 9) Central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, brain injury, multiple sclerosis, amyotrophic lateral sclerosis; 10) Metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, and gout; 11) Liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH); 12) Kidney disease, such as acute kidney disease, hyperoxaluria, chronic kidney disease, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; 13) Gastrointestinal diseases, such as inflammatory bowel disease and pancreatitis; 14) Eye diseases, such as uveitis and allergic conjunctivitis; 15) Graft-versus-host disease; 16)Burns, sunburn, and mechanical injuries.

13. The use according to claim 12, characterized in that: The neuropathic pain includes central neuralgia and peripheral neuropathic pain; The central neuralgia includes, but is not limited to, spinal cord injury neuralgia, post-stroke pain, multiple sclerosis pain, syringomyelia pain, ischemic myelopathy pain, compressive myelopathy pain, post-radiation myelopathy pain, Parkinson's disease pain, phantom limb pain, and myelitis pain. The peripheral neuropathic pain includes, but is not limited to, post-herpetic neuralgia, HIV neuropathy, diabetic peripheral neuropathy, chronic pain after trauma / surgery, neuropathy after chemotherapy / radiotherapy, trigeminal neuralgia, glossopharyngeal neuralgia, residual limb pain, toxic contact neuropathy, sciatica, and dorsal root neuralgia; The non-neuropathic pain includes, but is not limited to, osteoarthritis pain, chronic low back pain, chronic visceral pain, cancer pain, and fibromyalgia.

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