Pyridazinone derivative and medical application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to pyridazinone derivatives as shown in a formula (I), and prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof. The compound is an NLRP3 inhibitor and can be used for treating NLRP3-mediated diseases, including one or more of tumor, pathogen infection and / or alopecia. The series of compounds can obviously inhibit pyroptosis of human THP-1 cells after PMA induced differentiation and expression of IL-1beta in the cells; the compound provided by the invention can obviously inhibit pyroptosis of human PBMC cells and expression of IL-1beta in the cells, and part of the compound is obviously superior to a positive control drug MCC950; the clinical application prospect is relatively great.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to pyridazinone derivatives represented by formula (I) and their prodrugs, isomers, solvates or pharmaceutically acceptable salts. Such compounds are NLRP3 inhibitors and can be used to treat NLRP3-mediated diseases, including one or more of tumors, pathogen infection and / or alopecia. Background Art

[0002] NLRP3 belongs to the NOD-like receptor protein family and is the most studied intracellular pattern recognition receptor 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 inflammasomes, and simultaneously releases activated inflammatory cytokines IL-1β and IL-18, causing an inflammatory response.

[0003] Inflammation is the body's defense response to stimulation, including infectious inflammation and aseptic inflammation. Inflammation is mainly manifested as redness, swelling, heat, pain and dysfunction, usually due to increased permeability of vascular endothelial cells and infiltration of immune cells in plasma. The inflammatory response will end quickly after tissue repair, but excessive cytokine production will lead to an inflammatory storm and cause damage to the body. Inflammatory disorders are an important pathogenesis of many human diseases.

[0004] Abnormal NLRP3 inflammasome activation has been observed in many inflammatory diseases, and excessive production of IL-1β and IL-18 has also been involved in and promoted the occurrence and development of various diseases, including pyrogenic protein-associated periodic syndrome; sickle cell disease; autoimmune diseases such as systemic lupus erythematosus and psoriasis; liver diseases such as chronic liver disease, viral hepatitis, nonalcoholic 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; neuroinflammatory diseases such as brain infection, acute injury and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease; cardiovascular and metabolic diseases such as atherosclerosis, type I and type II diabetes and related complications (e.g. nephropathy, retinopathy), peripheral arterial 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 syndrome, myelofibrosis, lung cancer, colon cancer, etc.

[0005] Diseases that are inflammatory or immune in nature are often difficult to diagnose or treat effectively. Most treatments involve treating symptoms, slowing the progression of the disease, lifestyle changes, and surgery as a last resort. More efficient and effective treatments are needed.

[0006] Therefore, developing NLRP3 inflammasome inhibitors to target such diseases with inflammatory pathological features has certain therapeutic potential. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a pyridazinone derivative with a novel structure, which can be used as an NLRP3 inhibitor for the treatment of diseases.

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

[0009] It is a pyridazinone derivative represented by formula (I), and its prodrug, isomer, solvate or pharmaceutically acceptable salt:

[0010]

[0011] in:

[0012] R 1 independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -OR 3 、-SR 3 、-CN、-C(O)OR 3 、-NHC(O)OR 3 、-NHC(O)NR 3 R 4 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 ;

[0013] Preferably, R 1 Independent

[0014] Where R a independently selected from H, C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -C(O)OR 3 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 , the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 Preferably, R a Independently -CH3, -CH2CH3, -CH(CH3)2,

[0015] R b are independently selected from H, halogen, -CN, -OR 3 、-NR 3 R 4 , C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 The aryl or 5-10 membered heteroaryl is substituted by one or more substituents independently selected from the group consisting of H, halogen or -OR 3 Preferably, R b independently H, F, Cl, -OH, -CH3, -OCH3, -CF3, -OCH2CF3, -OCHF2, -NH2, -NH(CH3), -N(CH3)2, -NHC(O)CH3, -C(O)OH or -C(O)OCH3.

[0016] R c , R d are independently selected from H, halogen, -OR 3 、-NR 3 R 4, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R c independently H, F, Cl, -CH3, -OCH3, -CF3, -OCF3, -OCHF2 or -N(CH3)2.

[0017] R e independently selected from H, halogen, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -OR 3 、-NR 3 R 4 、-C(O)OR 3 、-OC(O)NR 3 R 4 、-NHC(O)NR 3 R 4 、-NHC(O)OR 3 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 or -C(O)R 3 The C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is substituted by one to three OR 3 or halogen substituted; preferably, R e independently H, F, Cl, -OH, -CH3, -OCH3, -CF3, -OCH2CF3, -OCHF2, -NH2, -NHS(O)2CH3, -NHC(O)CH3, -CH2C(O)OH, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2 or

[0018] More preferably, R 1 Independent

[0019] R 2 independently selected from H, halogen, -CN, -NR 3 R 4 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 4, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, -OR 3 or -NR 3 R 4 Preferably, R 2 are independently ethyl, isopropyl, cyclopropyl,

[0020] R 3 , R 4 independently selected from H, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen, -OR 3 Preferably, R 3 , R 4 Each of the groups is independently methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, difluoroethyl, methoxyethyl, trifluoromethoxyethyl or cyclopropyl.

[0021] R 6 , R 7 are independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C6 heteroalkyl or R 6 , R 7 The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C3-C6 cycloalkyl or 3-6 membered heterocyclic group is b Substituted; preferably, R 6 , R 7 are independently H, F, methyl, ethyl, trifluoroethyl, methoxyethyl, or R 6 , R 7 The cyclopropyl, ethylene oxide, cyclobutyl, cyclopentyl,

[0022] Ring A may be present or absent. When ring A is present, the pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts have the structure of formula (II):

[0023]

[0024] in,

[0025] Y and Z are independently selected from N or C, and X is independently selected from S, CR3 , N or NR 4 , and at least one of X, Y, and Z is the above-mentioned heteroatom;

[0026] Ring A is independently selected from C4-C8 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl, the C4-C8 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -CN, oxo, -OR 3 、-NR 3 R 4 、-C(O)OR 3 or -C(O)NR 3 R 4 ;

[0027] Preferably, Independent

[0028] When ring A is absent, the pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts have the structure of formula (II):

[0029]

[0030] in,

[0031] W is N or C, Y is CR 5 , X, Z are independently selected from S, N, NR a or CR e , and S and N do not appear at the same time;

[0032] Independently selected from Preferably, Ring A is independently

[0033] R 5 independently selected from H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic group, -OR 3 、-NR 3 R 4 or -C(O)NR 3 R 4 The C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C6-C 10Aryl, 3-6 membered heterocyclyl are optionally substituted by one or more substituents independently selected from the following: H, halogen, -CN, oxo, -OR 3 、-C(O)OR 3 or -C(O)NR 3 R 4 Preferably, R 5 are independently Br, I, ethyl, isopropyl, tert-butyl, cyclopropyl, -CF3,

[0034] Preferably, it is a pyridazinone derivative represented by formula (II-1) and its prodrug, isomer, solvate or pharmaceutically acceptable salt:

[0035]

[0036] R 1 Selected from

[0037] R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

[0038] Preferably, it is a pyridazinone derivative represented by formula (II-1-1) and its prodrug, isomer, solvate or pharmaceutically acceptable salt:

[0039]

[0040] R 1 Selected from

[0041] R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

[0042] Preferably, it is a pyridazinone derivative represented by formula (II-2) and its prodrug, isomer, solvate or pharmaceutically acceptable salt:

[0043]

[0044] R 1 Selected from

[0045] R2 Selected from ethyl, isopropyl, cyclopropyl,

[0046] R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

[0047] Preferably, it is a pyridazinone derivative represented by formula (II-3) and its prodrug, isomer, solvate or pharmaceutically acceptable salt:

[0048]

[0049] R 1 Selected from

[0050] R 2 Selected from ethyl, isopropyl, cyclopropyl,

[0051] R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

[0052] The pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof of the present invention are preferably selected from the following structures:

[0053]

[0054]

[0055] The term "isomer" includes all stereoisomers, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0056] The term "pharmaceutically acceptable salt" refers to a complex of a compound that does not significantly irritate the organism to which it is administered and does not eliminate the biological activity and properties of the compound. When the derivative of the present invention contains a relatively acidic functional group, it can be obtained by reacting the compound having an acidic group described herein with a base in a suitable inert solvent to form a salt. Pharmaceutically acceptable base addition salts are shown by the following specific examples: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, ammonium salts; salts thereof with organic bases such as methylamine, dicyclohexylamine, N-methyl-D-glucamine and tris(hydroxymethyl)methylamine; salts thereof with basic amino acids such as arginine, lysine, ornithine, histidine. When the derivatives of the present invention contain relatively basic functional groups, they can be obtained by reacting the compounds having basic groups described herein with an acid in a suitable inert solvent to form a salt. Pharmaceutically acceptable acid addition salts are shown by the following specific examples: salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, carbonic acid, sulfuric acid, nitric acid and phosphoric acid; salts of organic acids such as 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, ascorbic acid; Salts of hemic acid, benzenesulfonic acid, benzoic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthalene, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, pamoic acid, pantothenic acid, phenylacetic acid, polygalactonic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, para-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid and p-toluenesulfonic acid.

[0057] The term "prodrug" means that the prodrug of the pyridazinone derivatives described herein is easily chemically changed under physiological conditions to be converted into the pyridazinone derivatives of the present invention. In addition, the prodrug can be converted into the pyridazinone derivatives of the present invention by chemical or biochemical methods in an in vivo environment.

[0058] The term "pharmaceutical composition" refers to a mixture of one or more pyridazinone derivatives or salts thereof of the present invention and a formulation generally accepted in the art that facilitates delivery of biologically active compounds to an organism (e.g., human) such as a carrier, stabilizer, diluent, dispersant, suspending agent and / or thickener. The purpose of the pharmaceutical composition is to facilitate delivery to an organism.

[0059] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0060] The term "alkyl" refers to a straight or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C1-C6 alkyl, including but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl).

[0061] The term "alkoxy" refers to a straight or branched alkyl group connected by an oxygen atom, such as C1-C6 alkoxy, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), pentoxy (including n-pentoxy, isopentoxy, neopentoxy), hexoxy (n-hexyloxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy).

[0062] The term "alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds which may be straight or branched. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl and 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl- -2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,2-dimethyl-1-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl- 2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,2-dimethyl-1-butenyl, 1,3-dimethyl-1-butenyl, 2,3-dimethyl-1-butenyl, 3,3-dimethyl-1-butenyl, 1-ethyl-1-butenyl, 2-ethyl-1-butenyl, 1,1- Dimethyl-2-butenyl, 1,2-dimethyl-2-butenyl, 1,3-dimethyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 2-ethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-3-butenyl, 3-ethyl-3-butenyl.

[0063] The term "alkynyl" refers to a hydrocarbon group that may be straight or branched and has one or more carbon-carbon triple bonds. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1,3-butadiynyl.

[0064] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group having a conjugated π electron system, wherein the ring of the monocyclic group is aromatic and at least one of the fused rings of the bicyclic or tricyclic group is aromatic, such as tetrahydronaphthyl. Examples of aryl groups also include phenyl, naphthyl and the like. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C 1-4alkyl) substituted.

[0065] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicyclic alkyl, including but not limited to spirocyclic alkyl, cyclo (condensed ring) alkyl or bridged cycloalkyl (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl). In the present invention, the cycloalkyl group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl group are optionally oxo (i.e., forming C=O).

[0066] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more (e.g., 1, 2, 3, or 4) identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen, or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally oxidized (e.g., to form C=O, S(=O) or S(=O)2). The ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic (but not necessarily a ring containing a heteroatom), such as Examples of heteroaryl groups also include, but are not limited to, pyridyl, furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl.

[0067] The term "heterocyclyl" refers to a monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, wherein the heteroatoms are selected from O, N, or S, and the carbon atoms and heteroatoms on the heterocyclyl are optionally oxidized (e.g., forming C=O, S(=O) or S(=O)2). Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxane, dithianyl, thiomorpholinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl,

[0068] The administration routes of the pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts or their pharmaceutical compositions of the present invention include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0069] The purpose of the present invention also includes providing the pyridazinone derivatives represented by formula (I) of the present invention and their prodrugs, isomers, solvates or pharmaceutically acceptable salts or pharmaceutical compositions thereof for regulating the activity of NLRP3, and preparing them into drugs for the purpose of treating diseases.

[0070] The use of the pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts for treating diseases can be used to prevent or treat inflammatory diseases or diseases accompanied by inflammatory reactions.

[0071] The pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts of the present invention can be used to treat diseases and can also be used to prevent or treat cancer.

[0072] The aforementioned inflammatory diseases or diseases accompanied by inflammatory responses include, but are not limited to, chronic liver disease, liver fibrosis, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, myelofibrosis, sickle cell disease, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (e.g., heart failure, retinopathy, diabetic foot), peripheral arterial disease, acute heart failure and hypertension, hyperoxaluria, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, hemodialysis-related inflammation, diabetic nephropathy, interstitial Cystitis, colorectalitis, polymyositis, dermatomyositis, brain infection, acute craniocerebral injury, chronic migraine, neuropathic pain, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, mechanical wound healing, burns, scar formation, acne, suppurative hidradenitis, pyoderma gangrenosum, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, keratitis, uveitis, glaucoma, COVID-19 and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis, age-related macular degeneration, and pyrroprotein-associated periodic syndrome.

[0073] The aforementioned cancers 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, and testicular cancer.

[0074] Preparation of compounds

[0075] The specific embodiments included below are for illustration and should not be construed as limiting the scope of the invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0076] The present invention also provides a method for preparing compounds of formula (II) and formula (III), including but not limited to the following method:

[0077] Preparation route 1: Preparation of series I to III compounds

[0078]

[0079] The bicyclic aromatic ester IA substituted with an appropriate ortho-primary amine is subjected to a Sandmeyer reaction (route A) to generate an ortho-halogen substituted intermediate IC, or the appropriate intermediate IB is subjected to a halogenation reaction using route B to obtain intermediate IC; intermediate IC undergoes a halogen-metal exchange with a Grignard reagent or an organic lithium reagent, and then reacts with an appropriate acid anhydride to generate an ortho-acyl substituted bicyclic aromatic ester ID, or the appropriate compound IB is reacted with an appropriate acid anhydride under organic lithium or magnesium metal strong base conditions using route C to generate intermediate ID, or compound IB is reacted with an appropriate acid anhydride or acyl chloride under Friedel-Crafts reaction conditions to generate intermediate ID; intermediate ID reacts with hydrazine hydrate to form a tricyclic pyridazinone intermediate IE, intermediate IE is substituted with an appropriate halogenated acetate to obtain intermediate IF, intermediate IF is hydrolyzed to obtain the corresponding acid intermediate IG, and then intermediate IG is reacted with an appropriate amine R 1 -NH2 is condensed to obtain IA series compounds.

[0080] When the amine intermediate B is selected from 10-2, the series I compounds can be further aminated to obtain series II compounds; the series I compounds can be further hydrolyzed to obtain series III compounds; the series III compounds can also undergo amide condensation with amine compounds in the presence of an amide condensation agent to obtain series II compounds.

[0081] When the amine intermediate B is selected from tert-butyl 3-aminopiperidine-1-carboxylate, IG and R 1 -NH2 is condensed to obtain I-prol1, I-prol1 is deprotected to generate I-prol2, and I-prol2 undergoes different substitution reactions to generate IB~IF series compounds.

[0082] Preparation route 2: Preparation of IV series compounds:

[0083]

[0084] The bicyclic aromatic diester IV-A with appropriate ortho-substitution is reacted with hydrazine hydrate to form a tricyclic pyridazine dione intermediate IV-B, the intermediate IV-B is brominated to form a dibromide intermediate IV-C, the intermediate IV-C is hydroxylated to form a pyridazinone intermediate IV-D, the intermediate IV-D is substituted with an appropriate halogenated acetate to obtain an intermediate IV-E, and the intermediate IV-E is reacted with HNR 3 R 4 Amination reaction occurs to generate intermediate IV-F, which is hydrolyzed to obtain intermediate IV-G, which is then reacted with an appropriate amine R 1 -NH2 is condensed to obtain IV series compounds.

[0085] Preparation route 3: Preparation of V series compounds

[0086]

[0087] Compound VA reacts with an appropriate acid anhydride under strong organic lithium or magnesium base conditions to generate intermediate VB; intermediate VII-B reacts with hydrazine hydrate to obtain intermediate VC; intermediate VC is substituted to generate ester intermediate VD, intermediate VD is hydrolyzed to obtain carboxylic acid intermediate VE, intermediate VE reacts with an appropriate amine R 1 -NH2 is condensed to obtain V series compounds.

[0088] Preparation route 4: Preparation of VI series compounds

[0089]

[0090] wherein compound VI-A is condensed with hydrazine hydrate to form hydrazone intermediate VI-B, intermediate VI-B is substituted to form intermediate VI-D, intermediate VI-D is cyclized under alkaline conditions to form intermediate VI-E (route D); or route E is used to condense compound VI-A with carbazate to form hydrazone intermediate VI-C, intermediate VI-C is intramolecularly cyclized under alkaline conditions to form intermediate VI-E; intermediate VI-E is substituted to form ester intermediate VI-F, intermediate VI-F is hydrolyzed to form carboxylic acid intermediate VI-G, intermediate VI-G is reacted with an appropriate amine R 1 -NH2 is condensed to obtain VIA series compounds.

[0091] When the amine intermediate B is selected from tert-butyl 3-aminopiperidine-1-carboxylate, VI-G and R 1 -NH2 is condensed to obtain VI-prol1, VI-prol1 is deprotected to generate VI-prol2, and VI-prol2 undergoes different substitution reactions to generate VIB series compounds.

[0092] Compared with the prior art, the present invention has the following beneficial effects:

[0093] ① In vitro activity tests showed that the compounds of the present invention can significantly inhibit the pyroptosis of human THP-1 cells after PMA-induced differentiation and the expression of IL-1β in the cells.

[0094] ② In vitro activity tests showed that the compounds of the present invention can significantly inhibit pyroptosis of human PBMC cells and the expression of IL-1β in the cells, and some compounds are significantly better than the positive control drug MCC950.

[0095] ③ Through the inhibitory effect on hERG ion channels, the compounds of this patent have lower cardiac toxicity.

[0096] In conclusion, the compounds of the present application have good activity data and great prospects for clinical application. DETAILED DESCRIPTION

[0097] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but 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.

[0098] In addition, all operations involving raw materials that are easily oxidized or hydrolyzed 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 used directly without further purification.

[0099] The reaction starting materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or prepared by themselves. The preparation process of the starting materials and common intermediates that need to be prepared by themselves is described in detail as follows:

[0100] Explanation of the solvent or material abbreviations used:

[0101] NaNO2: sodium nitrite; H2SO4: sulfuric acid; i PrMgCl·LiCl: isopropylmagnesium chloride lithium chloride complex; KI: potassium iodide; THF: tetrahydrofuran; ( iPrCO)2O: isobutyric anhydride; N2H4·H2O: hydrazine hydrate; C2H5OH: ethanol; NaOH: sodium hydroxide; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; HCl: hydrochloric acid; EA: ethyl acetate; K2CO3: potassium carbonate; MeI: iodomethane; NH4Cl: ammonium chloride; Fe: iron powder; TBAB: tetrabutylammonium bromide; CH3CN: acetonitrile; BocNH2 : tert-butyl carbamate; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Cs2CO3: cesium carbonate; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dioxane: 1,4-dioxane; LHMDS: lithium bis(trimethylsilyl)amide; LiOH·H2O: lithium hydroxide monohydrate; NH3 / MeOH: amine / methanol solution; MeOH: methanol; Me2NH·HCl: dimethylamine hydrochloride; HCl / EA: hydrogen chloride in ethyl acetate; EtI: ethyl iodide; Na BH3CN: sodium cyanoborohydride; EtOH / H2O: ethanol / water solution; TFAA: trifluoroacetic anhydride; TEA: triethylamine; DMAD: dimethyl butynedioate; K2S2O8: potassium persulfate; PBr5: phosphorus pentabromide; AcOH: glacial acetic acid; DCM: dichloromethane; Me2NH: dimethylamine; DMSO: dimethyl sulfoxide; NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; CCl4: carbon tetrachloride; PPA: polyphosphoric acid; SEM-Cl: (2-(chloromethoxy)ethyl)trimethylsilane; TB AF: tetrabutylammonium fluoride; AlCl3: aluminum chloride; DCE: 1,2-dichloroethane; DABCO: 1,4-diazabicyclo[2.2.2]octane; Ac2O: acetic anhydride; DMAP: 4-dimethylaminopyridine; Ph2O: diphenyl ether; Br2: liquid bromine; KI: potassium iodide; CuI: cuprous iodide; NaOAc: sodium acetate; PtO2: platinum dioxide; H2: hydrogen; POCl3: phosphorus oxychloride; TEA: triethylamine; BF3·Et2O: boron trifluoride ether complex; Py: pyridine; MeONa: sodium methoxide; i PrMgBr: isopropylmagnesium bromide; DMP: Dess-Martin periodinane; DHP: 3,4-dihydro-2H-pyran; TsOH·H2O: p-toluenesulfonic acid monohydrate; Pd(PPh3)4: tetrakistriphenylphosphine palladium; Pd / C: palladium on carbon; EtBr: ethyl bromide; KOH: potassium hydroxide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II); TMPMgCl·LiCl: 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex; THP: 2-tetrahydropyranyl; t Bu: tert-butyl.

[0102] 1. Synthesis of common intermediate A-2

[0103]

[0104] Add a mixed solution of concentrated sulfuric acid (1 mL) and water (10 mL) to compound A-1: ​​3-aminobenzo[b]thiophene-2-carboxylic acid methyl ester (700.0 mg, 3.38 mmol), and stir thoroughly at 0°C. Then, dissolve NaNO2 (699.0 mg, 10.13 mmol) in water (4 mL), and add this solution dropwise to the reaction system, and continue stirring at 0°C for 40 minutes after the addition. Solid potassium iodide (2.80 g, 16.88 mmol) was dissolved in water (5 mL) and added dropwise to the reaction system. After the addition, the mixture was stirred at 0°C for 30 minutes and then stirred at room temperature. After the reaction, the reaction solution was poured into a saturated aqueous sodium carbonate solution (80 mL), and EA (60 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 3-iodobenzo[b]thiophene-2-carboxylic acid methyl ester (A-2) (380.0 mg) with a yield of 35.0% as a white solid.

[0105] 1 H NMR (400MHz, Chloroform-d) δ8.04-7.94(m,1H),7.89-7.79(m,1H),7.59-7.47(m,2H),4.0(s,3H).

[0106] 2. Synthesis of Common Intermediate A-5

[0107]

[0108] Step 1: Synthesis of methyl 3-isobutyrylbenzo[b]thiophene-2-carboxylate (A-3)

[0109] Compound A-2 (300.0 mg, 0.94 mmol) was dissolved in anhydrous THF (5 mL) at -10°C and replaced with nitrogen for protection. i PrMgCl·LiCl (1.3M THF solution, 0.94 mL) was added dropwise into the reaction system. After the reaction was kept warm for 1 hour, isobutyric anhydride (298.00 mg, 1.88 mmol) was added dropwise. After 30 minutes after the addition, the temperature was raised to room temperature and stirred. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) for quenching, and EA (30 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound A-3 (78.0 mg) with a yield of 31.5% as a brown solid.

[0110] LC-MS (m / z): 263.0 [M+H] + .

[0111] 1 H NMR(600MHz,Chloroform-d)δ7.86(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.53-7.46( m,1H),7.46-7.40(m,1H),3.93(s,3H),3.25(hept,J=7.2Hz,1H),1.24(d,J=7.2Hz,6H).

[0112] Step 2: Synthesis of 1-isopropylbenzo[4,5]thieno[2,3-d]pyridazin-4(3H)-one (A-4)

[0113] Compound A-3 (78.0 mg, 0.30 mmol) and hydrazine hydrate (0.5 mL) were dissolved in ethanol (2.5 mL), and the mixture was heated to reflux and stirred for 5 hours after nitrogen replacement protection. The mixture was allowed to stand and cooled, and concentrated by rotary evaporation. Water (30 mL) was added to the reaction solution, and then DCM (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound A-4 (80.0 mg) as a white solid. Compound A-4 was used directly in the next step without further purification.

[0114] LC-MS (m / z): 245.0 [M+H] + .

[0115] Step 3: Synthesis of ethyl 2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetate (A-5)

[0116] The compound A-4 in the previous step was dissolved in DMF solution (4 mL), anhydrous cesium carbonate (160.0 mg, 0.49 mmol) and α-bromoEA (82.0 mg, 0.49 mmol) were added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (60 mL) and stirred thoroughly, and then EA (30 mL × 2) was added to extract twice, the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound A-5 (90.0 mg) as a colorless oily product. The yield of steps 2 and 3 was 83.3%.

[0117] LC-MS (m / z): 331.0 [M+H] + .

[0118] 3. Synthesis of Common Intermediate A

[0119]

[0120] Compound A-5 (90.0 mg, 0.27 mmol) was dissolved in THF (2 mL), and then 1 M sodium hydroxide solution (1 mL) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (30 mL), and then dilute hydrochloric acid (2 M) was added dropwise to adjust the pH to 2-3, and then DCM (30 mL) was added for extraction, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was dried to obtain the common intermediate A (70.0 mg) with a yield of 85.1%, as a white solid.

[0121] LC-MS (m / z): 303.0 [M+H] + .

[0122] 4. Synthesis of common intermediate 15-2

[0123]

[0124] Step 1: Synthesis of (R)-tert-butyl 3-(2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamido)piperidine-1-carboxylate (15-1)

[0125] Common intermediate A was prepared by referring to the preparation method of common intermediate A.

[0126] The common intermediate A (160.0 mg, 0.53 mmol), compound B-12: (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (111.0 mg, 0.56 mmol) and DIPEA (205.0 mg, 1.59 mmol) were dissolved in DMF (4 mL), stirred evenly, and HATU (302.0 mg, 0.79 mmol) was added. After the reaction was completed at room temperature, water (50 mL) was poured into the reaction solution and EA (50 mL) was added for extraction. The organic phase was separated, and the organic phase was washed with water (50 mL×4), washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain intermediate 15-1 (279.0 mg) as a white solid. Intermediate 15-1 was directly used in the next step without further purification.

[0127] LC-MS (m / z): 485.0 [M+H] + .

[0128] Step 2: Synthesis of (R)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (15-2)

[0129] Compound 15-1 (279.0 mg) was dissolved in EA (3 mL), and HCl / EA solution (1.2 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was directly dried by rotary evaporation to remove the solvent to obtain compound 15-2 (242.4 mg), which was used directly in the next step without further purification.

[0130] LC-MS (m / z): 385.0 [M+H] + .

[0131] Example 1: Preparation of 2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (1)

[0132]

[0133] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0134] Common intermediate A (70.0 mg, 0.23 mmol), compound B-1: 4-aminopyrimidine (24.0 mg, 0.25 mmol), DIPEA (90.0 mg, 0.69 mmol) and HATU (132.0 mg, 0.35 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 1 (60.0 mg) with a yield of 68.3% as a white solid.

[0135] LC-MS (m / z): 380.0 [M+H] + .

[0136] 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.94(d,J=1.6Hz,1H),8.67(d,J=6.0Hz,1H),8.50-8.44(m,1H),8.38 -8.30(m,1H),8.03-7.97(m,1H),7.78-7.68(m,2H),5.16(s,2H),3.95-3.84(m,1H),1.37(d,J=6.8Hz,6H).

[0137] Example 2: Preparation of 2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acetamide (2)

[0138]

[0139] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0140] The common intermediate A (148.0 mg, 0.49 mmol), intermediate B-2 (96.0 mg, 0.59 mmol), and DIPEA (174.0 mg, 1.35 mmol) were dissolved in DMF solution (3 mL), and HATU (373.0 mg, 0.98 mmol) was added. The reaction was reacted at room temperature. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (20 mL×3), and the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was slurried three times with EA (2 mL), filtered, and the solid was collected to obtain the target compound 2 (70.50 mg) with a yield of 32.2% as a white solid.

[0141] MS (m / z): 448.0 [M+H] + .

[0142] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),10.34(s,1H),8.52-8.43(m,1H),8.38-8.30(m,1H),7.77-7.68(m,2H),7.47(s, 1H),7.15(d,J=8.4Hz,1H),7.02(d,J=8.4Hz,1H),5.03(s,2H),3.97-3.82(m,1H),3.25(s,3H),1.38(d,J=6.8Hz,6H).

[0143] Wherein, compound B-2 can be obtained by commercial purchase or self-production. If it is obtained by self-production, the following preparation route can be referred to:

[0144]

[0145] Step 1: Synthesis of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (B-2-2)

[0146] Compound B-2-1: 5-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (1.0 g, 5.58 mmol), potassium carbonate (2.32 g, 16.79 mmol), iodomethane (0.72 g, 5.07 mmol) were added to DMF solution (50 mL) and reacted at room temperature. After the reaction was completed, water (20 mL) was added to the reaction mixture for dilution, and the mixture was extracted with EA (30 mL×3). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography to obtain compound B-2-2 with a yield of 22.7% as a light yellow solid.

[0147] MS (m / z): 235.0 [M+CH3CN+H] + .

[0148] Step 2: Synthesis of 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (B-2)

[0149] Compound B-2-2 (240.0 mg, 1.24 mmol) was dissolved in ethanol (4 mL) and added with saturated ammonium chloride solution (4 mL) and iron powder (626.0 mg, 11.18 mmol), and reacted at 60°C for 3 hours. The mixture was diluted with water (10 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound B-2 (96.0 mg) with a yield of 47.5% as a light yellow solid.

[0150] MS (m / z): 164.0 [M+H] + .

[0151] Example 3: Preparation of N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (3)

[0152]

[0153] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0154] Common intermediate A (60.0 mg, 0.20 mmol), compound B-3: 1,2,4-triazolo[4,3-a]pyridine-6-amine (32.0 mg, 0.24 mmol), DIPEA (77.0 mg, 0.60 mmol) and HATU (113.2 mg, 0.30 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 3 (37.0 mg) with a yield of 44.5% as a white solid.

[0155] LC-MS (m / z): 419 [M+H] + .

[0156] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.41(m,1H),8.54-8.42(m,2H),8.40-8.29(m,1H),7.91-7.86(m,1H), 7.79-7.69(m,2H),7.65(dd,J=9.6,2.0Hz,1H),5.13(s,2H),3.91(hept,J=6.8Hz,1H),1.39(d,J=6.8Hz,6H).

[0157] Example 4: Preparation of 2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)acetamide (4)

[0158]

[0159] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0160] Compound B-4 (83.0 mg, 0.51 mmol), common intermediate A (163.0 mg, 0.54 mmol) and DIPEA (266.0 mg, 2.05 mmol) were dissolved in DMF solution (4 mL), HATU (293.0 mg, 0.77 mmol) was added, and the reaction was carried out at room temperature. After the reaction, the reaction solution was poured into water (60 mL), extracted with EA (60 mL×2), and the organic phases were combined, washed with saturated brine (50 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography gave the target compound 4 (69.0 mg) with a yield of 32.8% as a white solid.

[0161] LC-MS (m / z): 410.0 [M+H] + .

[0162] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.51-8.41(m,1H),8.38-8.26(m,1H),7.95(d,J=10.0Hz,1H),7.77 -7.67(m,2H),6.99(d,J=10.0Hz,1H),5.06(s,2H),3.97-3.81(m,1H),3.60(s,3H),1.37(d,J=6.4Hz,6H).

[0163] Among them, compound B-4 can be obtained by commercial purchase or self-production. If it is obtained by self-production, the following preparation route can be referred to:

[0164]

[0165] Step 1: Synthesis of 6-chloro-2-methylpyridazin-3(2H)-one (B-4-2)

[0166] Compound B-4-1: 6-chloropyridazine-3(2H)-one (800.0 mg, 6.13 mmol), K2CO3 (1.69 g, 12.26 mmol), TBAB (395.0 mg, 1.23 mmol), CH3I (1.22 g, 8.58 mmol) were added to CH3CN (12 mL), and the mixture was sealed and reacted for 6 hours at 80°C. After cooling, the mixture was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with EA (15 mL×3), the organic phase was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound B-4-2 (660.0 mg) with a yield of 74.5% as a yellow solid.

[0167] LC-MS (m / z): 145.0 [M+H] + .

[0168] 1 H NMR (400MHz, DMSO-d6) δ7.56 (d, J = 10.0 Hz, 1H), 7.04 (d, J = 10.0 Hz, 1H), 3.61 (s, 3H).

[0169] Step 2: Synthesis of tert-butyl (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)carbamate (B-4-3)

[0170] Compound B-4-2 (453.0 mg, 3.13 mmol), BocNH2 (440.0 mg, 3.76 mmol), Pd2(dba)3 (143.0 mg, 0.16 mmol), Cs2CO3 (3.06 g, 9.40 mmol) and Xantphos (181.0 mg, 0.31 mmol) were added to 1,4-dioxane (10 mL), replaced with nitrogen, and heated to 100 ° C. Stirring for 5 hours. The reaction solution was poured into water (50 mL), extracted with EA (40 mL × 2), the organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain intermediate B-4-3 (320.0 mg) with a yield of 37.1% as a yellow solid.

[0171] LC-MS (m / z): 226.0 [M+H] + .

[0172] 1 H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 7.74 (d, J = 9.9Hz, 1H), 6.94 (d, J = 9.9Hz, 1H), 3.53 (s, 3H), 1.45 (s, 9H).

[0173] Step 3: Synthesis of 6-amino-2-methylpyridazin-3(2H)-one hydrochloride (B-4)

[0174] Compound B-4-3 (320.0 mg, 1.42 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 8 mL) and stirred overnight at room temperature. The reaction solution was filtered, washed with a little EA, and the filter cake was dried under reduced pressure to obtain compound B-4 (220.0 mg) with a yield of 95.8% as an off-white solid.

[0175] LC-MS (m / z): 126.0 [M+H] + .

[0176] Example 5: Preparation of N-(Benzo[d]oxazol-2-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (5)

[0177]

[0178] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0179] Common intermediate A (70.0 mg, 0.23 mmol), compound B-5: benzo[d]oxazol-2-amine (28.0 mg, 0.21 mmol), DIPEA (90.0 mg, 0.69 mmol) and HATU (132.0 mg, 0.35 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 5 (14.0 mg) with a yield of 16.8% as a white solid.

[0180] LC-MS (m / z): 419.0 [M+H] + .

[0181] 1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.53-8.43(m,1H),8.39-8.29(m,1H),7.79-7.69(m,2H),7.67 -7.56(m,2H),7.38-7.24(m,2H),5.26(s,2H),3.94-3.87(m,1H),1.38(d,J=6.8Hz,6H).

[0182] Example 6: Preparation of N-(6-fluoro-2-oxo-1,2-dihydropyridin-4-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (6)

[0183]

[0184] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0185] Compound B-6: 4-amino-6-fluoropyridin-2(1H)-one (58.0 mg, 0.45 mmol) was placed in a reaction flask, nitrogen replacement protection, and then anhydrous DMF (2 mL) was added with a syringe to stir and dissolve, and the temperature was controlled with an ice-water bath. LHMDS (1.0 M THF solution, 0.81 mL, 0.81 mmol) was added dropwise with a syringe, and the reaction was continued under stirring in an ice-water bath for 15 minutes. Common intermediate A (107.0 mg, 0.32 mmol) was dissolved in anhydrous THF (2.5 mL), and added dropwise with a syringe to the reaction system, and then the reaction was continued under stirring in an ice-water bath for 30 minutes, and the ice-water bath was removed, and the reaction was continued under stirring at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution for quenching, and the solution was extracted with EA (40 mL×2). The organic phases were combined, washed with water (30 mL×3) and saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to obtain the target compound 6 (10 mg) with a yield of 7.5% as a white solid.

[0186] LC-MS (m / z): 413.0 [M+H] + .

[0187] 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.89(s,1H),8.52-8.42(m,1H),8.38-8.30(m,1H),7.77 -7.69(m,2H),6.76(s,1H),6.74(s,1H),5.07(s,2H),3.96-3.84(m,1H),1.37(d,J=6.8Hz,6H).

[0188] Example 7: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (7)

[0189]

[0190] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0191] Common intermediate A (70.0 mg, 0.23 mmol), compound B-7: cis-3-amino-1-methylcyclobutanol hydrochloride (38.5 mg, 0.28 mmol), DIPEA (90.0 mg, 0.69 mmol) and HATU (132.0 mg, 0.35 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 7 (32.0 mg) with a yield of 35.8% as a white solid.

[0192] LC-MS (m / z): 386.0 [M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d6) δ8.49-8.41(m,1H),8.36(d,J=7.2Hz,1H),8.34-8.29(m,1H),7.78-7.66(m,2H),5.0(s, 1H), 4.77 (s, 2H), 3.94-3.70 (m, 2H), 2.33-2.18 (m, 2H), 2.02-1.90 (m, 2H), 1.36 (d, J = 6.8Hz, 6H), 1.22 (s, 3H).

[0194] Example 8: Preparation of N-((1r,1r)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (8)

[0195]

[0196] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0197] Referring to the preparation method of target compound 7 in Example 7, only compound B-7 was replaced by compound B-8: trans-3-amino-1-methylcyclobutanol hydrochloride. The rest of the method was the same to prepare target compound 8 with a yield of 99.5% as a white solid.

[0198] LC-MS (m / z): 386.0 [M+H] + .

[0199] 1H NMR (400MHz, DMSO-d6) δ8.49-8.41(m,1H),8.37(d,J=7.2Hz,1H),8.37-8.28(m,1H),7.76-7.66(m,2H),4.85(s,1H),4.77(s,2 H), 4.27 (h, J = 7.6Hz, 1H), 3.87 (hept, J = 6.4Hz, 1H), 2.34-2.16 (m, 2H), 2.00-1.85 (m, 2H), 1.36 (d, J = 6.4Hz, 6H), 1.27 (s, 3H).

[0200] Example 9: Preparation of (3-hydroxy-3-methylbutyl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (9)

[0201]

[0202] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0203] Common intermediate A (42.0 mg, 0.14 mmol), compound B-9: 4-amino-2-methyl-butan-2-ol (18.0 mg, 0.17 mmol), DIPEA (54.0 mg, 0.42 mmol) and HATU (80.0 mg, 0.21 mmol) were added to DMF (2 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (30 mL), and EA (30 mL) was added for extraction. The organic phase was then washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 9 (38.0 mg) with a yield of 70.6% as a white solid.

[0204] MS (m / z): 388.0 [M+H] + .

[0205] 1 H NMR (400MHz, DMSO-d6) δ8.49-8.42(m,1H),8.37-8.29(m,1H),8.02(t,J=5.6Hz,1H),7.76-7.67(m,2H),4.77(s ,2H),4.30(s,1H),3.92-3.81(m,1H),3.22-3.12(m,2H),1.58-1.51(m,2H),1.36(d,J=6.8Hz,6H),1.09(s,6H).

[0206] Example 10: Preparation of methyl 3-(2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamido)bicyclo[1.1.1]pentane-1-carboxylate (10)

[0207]

[0208] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0209] Common intermediate A (70.0 mg, 0.23 mmol), compound B-10 (44.4 mg, 0.25 mmol), DIPEA (90.0 mg, 0.69 mmol) and HATU (132.0 mg, 0.35 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 10 (90.0 mg) with a yield of 91.3% as a white solid.

[0210] MS (m / z): 426.0 [M+H] + .

[0211] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.48-8.42(m,1H),8.37-8.29(m,1H),7.76-7.66( m,2H),4.75(s,2H),3.92-3.81(m,1H),3.61(s,3H),2.25(s,6H),1.36(d,J=6.8Hz,6H).

[0212] Among them, compound B-10 can be obtained by commercial purchase or self-production. If it is obtained by self-production, the following preparation route can be referred to:

[0213]

[0214] Compound B-10-1: 3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (200.0 mg, 0.83 mmol) was dissolved in EA (2 mL), and then HCl / EA solution (4M, 2 mL) was added, and the reaction was stirred at room temperature overnight. The reaction solution was directly filtered, and the obtained filter cake was washed with a small amount of EA, and the filter cake was dried to obtain intermediate B-10: 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid methyl ester hydrochloride (164.0 mg), which was a white solid. Intermediate B-10 was directly used in the next step without further purification.

[0215] MS (m / z): 142.0 [M+H] + .

[0216] Example 11: Preparation of 3-(2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide)bicyclo[1.1.1]pentane-1-carboxylic acid (11)

[0217]

[0218] Referring to the preparation method of target compound 10 in Example 10, target compound 10 was prepared.

[0219] The target compound 10 (63.0 mg, 0.15 mmol) was added to THF (2 mL), water (1 mL) and LiOH·H2O (18.9 mg, 0.45 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (10 mL) was added to dilute, and EA (10 mL×3) was extracted, the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target compound 11 (20.0 mg) with a yield of 32.8% as a white solid.

[0220] MS (m / z): 412.0 [M+H] + .

[0221] 1 H NMR(400MHz,DMSO-d6)δ12.81-12.14(m,1H),δ8.84(s,1H),8.49-8.42(m,1H),8.36-8.29(m ,1H),7.76-7.67(m,2H),4.75(s,2H),3.92-3.81(m,1H),2.19(s,6H),1.36(d,J=6.4Hz,6H).

[0222] Example 12: Preparation of 3-(2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide)bicyclo[1.1.1]pentane-1-carboxamide (12)

[0223]

[0224] Referring to the preparation method of target compound 10 in Example 10, target compound 10 was prepared.

[0225] The target compound 10 (30.0 mg, 0.07 mmol) and NH3 / MeOH (7.0 M, 5 mL) were added to a sealed tube and reacted at 100°C for 6 hours. The reaction solution was concentrated to dryness, slurried with a mixed solution of EA (1 mL) and MeOH (1 mL) at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to obtain the target compound 12 (18.0 mg) with a yield of 62.0% as a gray-green solid.

[0226] MS (m / z): 411.0 [M+H] + .

[0227] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.51-8.41(m,1H),8.38-8.28(m,1H),7.75-7.67(m,2H), 7.29(s,1H),6.97(s,1H),4.75(s,2H),3.97-3.81(m,1H),2.14(s,6H),1.36(d,J=6.8Hz,6H).

[0228] Example 13: Preparation of 3-(2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide)-N,N-dimethylbicyclo[1.1.1]pentane-1-carboxamide (13)

[0229]

[0230] Referring to the preparation method of target compound 11 in Example 11, target compound 11 was prepared.

[0231] The target compound 11 (39.0 mg, 0.08 mmol), dimethylamine hydrochloride (8.0 mg, 0.10 mmol) and DIPEA (0.04 mL, 0.24 mmol) were added to DMF (2 mL), and HATU (46.7 mg, 0.12 mmol) was added. The mixture was allowed to react at room temperature. After the reaction, the reaction solution was poured into water (6 mL), filtered, and the filter cake was purified by column chromatography to obtain the target compound 13 (30.0 mg) with a yield of 83.3% as a white solid.

[0232] MS (m / z): 439.0 [M+H] + .

[0233] 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.49-8.42(m,1H),8.36-8.28(m,1H),7.77-7.66(m,2H), 4.76(s,2H),3.94-3.80(m,1H),3.01(s,3H),2.79(s,3H),2.28(s,6H),1.36(d,J=6.8Hz,6H).

[0234] Example 14: Preparation of 2-(1-isopropyl-4-oxybenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (14)

[0235]

[0236] Referring to the preparation method of common intermediate A, common intermediate A was prepared.

[0237] Common intermediate A (60.0 mg, 0.20 mmol), compound B-11: tetrahydro-2H-pyran-4-amine (24.0 mg, 0.24 mmol), DIPEA (77.0 mg, 0.60 mmol) and HATU (113.2 mg, 0.30 mmol) were added to DMF solution (3 mL). After completion of the reaction at room temperature, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 14 (54.0 mg) with a yield of 72.0% as a white solid.

[0238] MS (m / z): 386.0 [M+H] + .

[0239] 1 H NMR (400MHz, DMSO-d6) δ8.50-8.42(m,1H),8.36-8.29(m,1H),8.19(d,J=7.6Hz,1H),7.76-7.66(m,2H),4.8 0(s,2H),3.92-3.74(m,4H),3.41-3.30(m,2H),1.78-1.66(m,2H),1.53-1.39(m,2H),1.36(d,J=6.4Hz,6H).

[0240] Example 15: Preparation of (R)-N-(1-ethylpiperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (15)

[0241]

[0242] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0243] Compound 15-2 (242.4 mg, 0.58 mmol) was dissolved in DMF (4 mL), stirred evenly, and then anhydrous potassium carbonate (278.0 mg, 2.02 mmol) and iodoethane (153.0 mg, 0.98 mmol) were weighed and added. After reaction at room temperature, water (50 mL) was added to the reaction solution, and then EA (50 mL×2) was added for extraction. The organic phases were combined, washed with saturated brine (50 mL×4), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 15 (101.0 mg) with a yield of 42.5% as a white solid.

[0244] LC-MS (m / z): 413.0 [M+H] + .

[0245] 1 H NMR(400MHz, DMSO-d6)δ8.46-8.40(m,1H),8.34-8.30(m,1H),8.07-8.05(d,J=8.0Hz,1H), 7.74-7.69(m,2H),4.84-4.76(m,2H),3.90-3.84(m,1H),3.78-3.70(m,1H),2.78-2.71(m, 1H),2.64-2.57(m,1H),2.38-2.27(m,2H),2.0-1.91(m,1H),1.87-1.80(m,1H),1.73-1.66 (m,2H),1.50-1.45(m,1H),1.36(d,J=6.4Hz,6H),1.26-1.21(m,1H),0.97(t,J=7.2Hz,3H).

[0246] Example 16: Preparation of (S)-N-(1-ethylpiperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (16)

[0247]

[0248] With reference to the preparation method of common intermediate A, common intermediate A was prepared.

[0249] Referring to the preparation of the common intermediate 15-2, only the compound B-12 in step 1: (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester was replaced with B-13: (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester to prepare compound 16-2. Compound 16-2 was subjected to ethylation reaction to prepare the target compound 16 (this step of reaction was referred to Example 15, only compound 15-2 was replaced with compound 16-2, and the rest of the method was the same), and the total yield of the three-step reaction was 30.8%, and it was a white solid.

[0250] LC-MS (m / z): 413.0 [M+H] + .

[0251] 1 H NMR (400MHz, DMSO-d6) δ8.46-8.40(m,1H),8.34-8.30(m,1H),8.06(d,J=8.0Hz,1H),7.74 -7.69(m,2H),4.84-4.76(m,2H),3.90-3.84(m,1H),3.78-3.70(m,1H),2.78-2.71(m,1H),2.64-2.57(m,1H),2.38-2.27(m,2H),2.0-1.9 1(m,1H),1.87-1.80(m,1H),1.73-1.66(m,2H),1.50-1.45(m,1H),1.37-1.35(d,J=6.4Hz,6H),1.26-1.21(m,1H),0.97(t,J=7.2Hz,3H).

[0252] Example 17: Preparation of (R)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(1-(oxetane-3-yl)piperidin-3-yl)acetamide (17)

[0253]

[0254] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0255] (R)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (84.0 mg, 0.20 mmol) and oxetane-3-one (26.0 mg, 0.36 mmol) were dissolved in MeOH (2.5 mL) and stirred at room temperature for 30 minutes. Then, NaBH3CN (25.0 mg, 0.40 mmol) was added. After the reaction at room temperature was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (40 mL), and DCM (40 mL) was added for extraction. The organic phase was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 17 (61.0 mg) with a yield of 69.4% as a white solid.

[0256] MS (m / z): 441.0 [M+H] + .

[0257] 1 H NMR (400MHz, DMSO-d6) δ8.48-8.41(m,1H),8.35-8.28(m,1H),8.09(d,J=8.0Hz,1H),7. 76-7.66(m,2H),4.81(s,2H),4.55-4.47(m,2H),4.44-4.34(m,2H),3.92-3.81(m,1H), 3.80-3.73(m,1H),3.45-3.36(m,1H),2.61-2.54(m,1H),2.47-2.39(m,1H),1.93-1.84 (m,1H),1.82-1.66(m,3H),1.56-1.44(m,1H),1.36(d,J=6.8Hz,6H),1.32-1.21(m,1H).

[0258] Example 18: Preparation of (R)-N-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (18)

[0259]

[0260] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0261] Compound 15-2 (84.0 mg, 0.20 mmol) and 2,2-dimethylpropylene oxide (144.0 mg, 2.0 mmol) were added to a mixed solvent of ethanol (2 mL) and water (1 mL), potassium carbonate (31.0 mg, 0.20 mmol) was added, and the mixture was placed in a sealed tube at 100°C for 0.5 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and the target compound 18 (43.0 mg) was obtained by reverse preparation purification with a yield of 47.2% as a white solid.

[0262] MS (m / z): 457.0 [M+H] + .

[0263] 1 H NMR(400MHz,DMSO-d6)δ8.49-8.40(m,1H),8.36-8.26(m,1H),8.16(s,1H),7.93( d,J=8.0Hz,1H),7.77-7.66(m,1H),4.89-4.70(m,2H),4.20-3.98(m,1H),3.94-3 .72(m,2H),2.88-2.77(m,1H),2.71-2.61(m,1H),2.28-2.07(m,4H),1.71-1.61( m,2H),1.54-1.41(m,1H),1.36(d,J=6.4Hz,6H),1.29-1.16(m,1H),1.01(s,6H).

[0264] Example 19: Preparation of (R)-N-(1-(cyanomethyl)piperidin-3-yl)-2-(1-isopropyl-4-oxybenzo[4,5]thiophene[2,3-d]pyridazin-3(4H)-yl)acetamide (19)

[0265]

[0266] Step 1: Synthesis of (R)-N-(1-(2-amino-2-oxoethyl)piperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thienyl[2,3-d]pyridazin-3(4H)-yl)acetamide (19-1)

[0267] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0268] Compound 15-2 (84.0 mg, 0.20 mmol) and bromoacetamide (55.0 mg, 0.40 mmol) were dissolved in DMF (2 mL), potassium carbonate (83.0 mg, 0.60 mmol) was added, and the reaction was allowed to complete at room temperature. The reaction solution was diluted with EA (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 19-1 (67.0 mg) with a yield of 76.1% as a white solid.

[0269] MS (m / z): 442.0 [M+H] + .

[0270] Step 2: Synthesis of (R)-N-(1-(cyanomethyl)piperidin-3-yl)-2-(1-isopropyl-4-oxybenzo[4,5]thiophene[2,3-d]pyridazin-3(4H)-yl)acetamide (19)

[0271] Intermediate 19-1 (47.0 mg, 0.10 mmol) and TFAA (0.03 mL, 0.20 mmol) were added to anhydrous DCM (2 mL), and triethylamine (0.04 mL, 0.30 mmol) was added under an ice-water bath, and the reaction was kept warm for 1 hour. The reaction solution was directly concentrated and purified by reverse preparation to obtain the target compound 19 (8.30 mg) with a yield of 19.8% as a white solid.

[0272] MS (m / z): 424.0 [M+H] + .

[0273] 1 H NMR(400MHz, DMSO-d6)δ8.49-8.41(m,1H),8.37-8.28(m,1H),8.16(d,J=8.0Hz,1H),7.77-7.66(m,2H),4.81(s,2H),3.99-3.64(m,4H),2.82-2.7 3(m,1H),2.66-2.57(m,1H),2.27-2.12(m,1H),2.10-2.0(m,1H),1.79-1 .67(m,2H),1.60-1.45(m,1H),1.36(d,J=6.4Hz,6H),1.32-1.15(m,1H).

[0274] Example 20: Preparation of (R)-N-(1-cyclopropylmethylpiperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (20)

[0275]

[0276] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0277] The preparation method of the target compound 17 in reference example 17 was used, except that oxetane-3-one was replaced with cyclopropanecarboxaldehyde. The rest of the method was the same, and the target compound 20 was prepared with a yield of 64.7% as a white solid.

[0278] MS (m / z): 439.0 [M+H] + .

[0279] 1 H NMR (400MHz, DMSO-d6) δ8.49-8.40(m,1H),8.37-8.28(m,1H),8.05(d,J=8.0Hz,1H),7.77-7.65(m, 2H),4.86-4.75(m,2H),3.96-3.81(m,1H),3.81-3.68(m,1H),2.90-2.80(m,1H),2.74-2.64(m,1H) ,2.17(d,J=6.4Hz,2H),2.08-1.98(m,1H),1.96-1.83(m,1H),1.78-1.62(m,2H),1.56-1.40(m,1H) ,1.36(d,J=6.8Hz,6H),1.3-1.17(m,1H),0.90-0.71(m,1H),0.50-0.36(m,2H),0.11-0.00(m,2H).

[0280] Example 21: Preparation of (R)-N-(1-cyclobutylpiperidin-3-yl)-2-(1-isopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (21)

[0281]

[0282] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0283] Referring to the preparation method of target compound 17 in Example 17, only oxetane-3-one was replaced by cyclobutanone. The rest of the method was the same to prepare target compound 21 with a yield of 40.9% as a white solid.

[0284] MS (m / z): 439.0 [M+H] + .

[0285] 1H NMR (400MHz, DMSO-d6) δ8.50-8.42(m,1H),8.37-8.29(m,1H),7.98(d,J=8.0Hz,1H) ,7.77-7.66(m,2H),4.87-4.74(m,2H),3.96-3.79(m,1H),3.77-3.64(m,1H),2.75-2 .57(m,2H),2.50-2.37(m,1H),1.99-1.86(m,2H),1.83-1.74(m,1H),1.74-1.60(m, 5H), 1.59-1.50 (m, 2H), 1.48-1.40 (m, 1H), 1.36 (d, J = 6.8Hz, 6H), 1.30-1.17 (m, 1H).

[0286] Example 22: Preparation of (R)-2-(1-isopropyl-4-oxybenzo[4,5]thiophene[2,3-d]pyrazine-3(4H)-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)acetamide (22)

[0287]

[0288] Referring to the preparation of common intermediate 15-2, common intermediate 15-2 was prepared.

[0289] Intermediate 15-2 (84.0 mg, 0.20 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (93.0 mg, 0.40 mmol) and DIPEA (0.17 mL, 1.00 mmol) were dissolved in DMF (2 mL) and allowed to react overnight at room temperature. The reaction solution was diluted with EA (10 mL), washed with water (5 mL*3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 22 (59.0 mg) with a yield of 63.4% as a white solid.

[0290] LC-MS (m / z): 467.0 [M+H] + .

[0291] 1H NMR(600MHz,DMSO-d6)δ8.47-8.41(m,1H),8.35-8.29(m,1H),8.05(d,J=8.4Hz,1H),7.75-7.6 7(m,2H),4.87-4.72(m,2H),3.86(hept,J=6.6Hz,1H),3.78-3.66(m,1H),3.19(q,J=10.2Hz,2 H),2.96-2.90(m,1H),2.77(d,J=11.4Hz,1H),2.36-2.28(m,1H),2.19(t,J=10.2Hz,1H),1.78 -1.70(m,1H),1.70-1.62(m,1H),1.55-1.43(m,1H),1.36(d,J=6.6Hz,6H),1.28-1.15(m,1H).

[0292] Example 23: Preparation of 2-(1-ethyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (23)

[0293]

[0294] Step 1: Synthesis of methyl 3-propionylbenzo[b]thiophene-2-carboxylate (23-1)

[0295] Referring to the preparation method of common intermediate A-2, common intermediate A-2 was prepared.

[0296] Compound A-2: 3-iodobenzo[b]thiophene-2-carboxylic acid methyl ester (0.50 g, 1.57 mmol) was dissolved in anhydrous THF (3 mL) at -10°C and replaced with nitrogen for protection. i PrMgCl·LiCl (1.3M THF solution, 1.57 mL) was added dropwise into the reaction system. After the addition, the reaction was continued with stirring for 30 minutes. Propionic acid glycoside (1.81 mL, 2.36 mmol) was added. After stirring for 30 minutes, the temperature was raised to room temperature for reaction for 16 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) for quenching. EA (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 23-1 (0.14 g) with a yield of 35.9% as a yellow oily liquid.

[0297] LC-MS (m / z): 249.0 [M+H] + .

[0298] Step 2: Synthesis of 1-ethylbenzo[4,5]thieno[2,3-d]pyridazin-4(3H)-one (23-2)

[0299] Compound 23-1 (0.14 g, 0.56 mmol) and hydrazine hydrate (1.0 mL) were dissolved in ethanol (5 mL), and the mixture was heated to reflux and stirred for 5 hours after nitrogen replacement protection. The mixture was allowed to stand and cooled, and the ethanol was removed by rotary evaporation. Water (60 mL) was added to the reaction solution, and then DCM (60 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound 23-2 (125.0 mg) with a yield of 96.3% as a white solid.

[0300] LC-MS (m / z): 231.0 [M+H] + .

[0301] Step 3: Synthesis of ethyl 2-(1-ethyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetate (23-3)

[0302] Compound 23-2 (125.0 mg, 0.54 mmol) was dissolved in DMF solution (7 mL), anhydrous cesium carbonate (288.0 mg, 0.88 mmol) and ethyl α-bromoacetate (148.0 mg, 0.88 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (60 mL) and stirred thoroughly, and then EA (30 mL × 2) was added and extracted twice, the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 23-3 (102.0 mg) with a yield of 58.2% as a white solid.

[0303] LC-MS (m / z): 317.0 [M+H] + .

[0304] Step 4: Synthesis of 2-(1-ethyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetic acid (23-4)

[0305] Compound 23-3 (100.0 mg, 0.32 mmol) was dissolved in THF (2 mL), and 1 M sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was poured into water (30 mL), and dilute hydrochloric acid (2 M) was added dropwise to adjust the pH to 2-3, and then DCM (30 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was dried to obtain compound 23-4 (75.0 mg) with a yield of 82.3% as a white solid.

[0306] LC-MS (m / z): 289.0 [M+H] + .

[0307] Step 5: Synthesis of 2-(1-ethyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (23)

[0308] Compound 23-4 (73.0 mg, 0.25 mmol), B-1 (26.0 mg, 0.27 mmol), DIPEA (98.0 mg, 0.75 mmol) and HATU (144.0 mg, 0.38 mmol) were added to DMF solution (3 mL) and reacted at room temperature. After the reaction, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 23 (21.3 mg) with a yield of 23.0% as a white solid.

[0309] MS (m / z): 366.0 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.94(s,1H),8.67(d,J=5.6Hz,1H),8.53-8.43(m,1H),8.38-8.27 (m,1H),8.03-7.95(m,1H),7.80-7.65(m,2H),5.17(s,2H),3.28(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H).

[0311] Example 24: Preparation of 2-(1-(difluoromethyl)-4-oxybenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (24)

[0312]

[0313] Referring to the preparation method of common intermediate A-2, common intermediate A-2 was prepared.

[0314] Referring to the preparation method of target compound 23 in Example 23, only the isobutyric anhydride in step 1 was replaced by difluoroacetic anhydride, and the rest of the method was the same to prepare target compound 24; the total yield of the five-step reaction was 2.4%, and the product was a white solid.

[0315] MS (m / z): 388.0 [M+H] +.

[0316] 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),8.95(d,J=1.2Hz,1H),8.69(d,J=6.0Hz,1H),8.49(d,J=7.6Hz,1H) ,8.42-8.36(m,1H),7.99(dd,J=5.6,1.2Hz,1H),7.83-7.73(m,2H),7.37(t,J=52.8Hz,1H),5.27(s,2H).

[0317] Example 25: Preparation of 2-(1-cyclopropyl-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)acetamide (25)

[0318]

[0319] Referring to the preparation method of common intermediate A-2, common intermediate A-2 was prepared.

[0320] The preparation of the compound described in Example 25 refers to the synthesis method described in Example 23, except that the isobutyric anhydride in step 1 is replaced by cyclopropanecarboxylic anhydride, and B-1 in step 5 is replaced by B-7; the total yield of the five-step reaction is 7.6%, and the product is a white solid.

[0321] MS (m / z): 385.0 [M+H] + .

[0322] 1 H NMR (400MHz, DMSO-d6) δ8.79 (d, J = 7.2Hz, 1H), 8.37-8.28 (m, 2H), 7.76-7.67 (m, 2H), 5.0 (s, 1H), 4.73 (s, 2H), 3.84-3. 71(m,1H),2.69-2.58(m,1H),2.28-2.20(m,2H),1.99-1.91(m,2H),1.22(s,3H),1.16-1.10(m,2H),1.02-0.96(m,2H).

[0323] Example 26: Preparation of 2-(1-isopropyl-4-oxopyrido[1',2':1,5]pyrazolo[3,4-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (26)

[0324]

[0325] Step 1: Synthesis of dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (26-2)

[0326] Compound 26-1: 1-aminopyridinium iodide (1.0 g, 4.50 mmol) and dimethyl butynedioate (0.96 g, 6.80 mmol) were dissolved in anhydrous DMF (10 mL), anhydrous potassium carbonate (0.87 g, 6.30 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was diluted with water (20 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with water (20 mL × 4) and saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 26-2 (516.0 mg) with a yield of 49.1%, as a brown oily liquid.

[0327] MS (m / z): 235.0 [M+H] + .

[0328] Step 2: Synthesis of methyl pyrazolo[1,5-a]pyridine-2-carboxylate (26-3)

[0329] A mixture of compound 26-2 (516.0 mg, 2.20 mmol) and concentrated sulfuric acid (10 mL) was placed at 80 ° C for 4 hours. The reaction solution was cooled, MeOH (10 mL) was added in an ice-water bath, and then the temperature was raised to 70 ° C for 1 hour. The reaction solution was diluted with water (50 mL) in an ice-water bath, extracted with EA (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 26-3 (276.0 mg) with a yield of 71.1%, as a brown oily liquid.

[0330] MS (m / z): 177.0 [M+H] + .

[0331] Step 3: Synthesis of 3-isobutyrylpyrazolo[1,5-a]pyridine-2-carboxylic acid (26-4)

[0332] Add 2 drops of concentrated sulfuric acid to a mixture of compound 26-3 (276.0 mg, 1.50 mmol) and isobutyric anhydride (2.76 mL), and place the reaction solution at 180 ° C for 4 hours. The reaction solution was cooled to room temperature, diluted with EA (20 mL), washed with sodium carbonate aqueous solution (20 mL × 2) and saturated brine (20 mL), and concentrated to dryness under reduced pressure. Add water (30 mL) and potassium hydroxide (3 g) to the concentrate, raise the temperature to 60 ° C for 1 hour. The reaction solution was adjusted to pH less than 5 with 2N dilute hydrochloric acid, extracted with EA (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 26-4 (217.0 mg) with a yield of 62.3%, as a gray solid.

[0333] MS (m / z): 233.0 [M+H] + .

[0334] Step 4: Synthesis of 1-isopropylpyrido[1',2':1,5]pyrazolo[3,4-d]pyridazin-4(3H)-one (26-5)

[0335] Compound 26-4 (217.0 mg, 0.93 mmol) was dissolved in anhydrous ethanol (5 mL), hydrazine hydrate (80%, 76.0 mg, 1.90 mmol) was added, and the mixture was reacted at 80°C for 3 hours. The reaction solution was concentrated to obtain compound 26-5 (212.0 mg) with a yield of 99.5% as a gray solid.

[0336] MS (m / z): 229.0 [M+H] + .

[0337] Step 5: Synthesis of tert-butyl 2-(1-isopropyl-4-oxopyrido[1',2':1,5]pyrazolo[3,4-d]pyridazine-3(4H)-acetate (26-6)

[0338] Compound 26-5 (212.0 mg, 0.93 mmol) and tert-butyl bromoacetate (363.0 mg, 1.86 mmol) were dissolved in DMF (5 mL), anhydrous cesium carbonate (606 mg, 1.86 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was diluted with EA (20 mL), washed with water (15 mL × 3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 26-6 (217.0 mg) with a yield of 68.2% as a colorless oily liquid.

[0339] MS (m / z): 343.0 [M+H] + .

[0340] Step 6: Synthesis of 2-(1-isopropyl-4-oxopyrido[1',2':1,5]pyrazolo[3,4-d]pyridazin-3(4H)-yl)acetic acid (26-7)

[0341] Compound 26-6 (217.0 mg, 0.63 mmol) was dissolved in 1,4-dioxane (5 mL), and hydrogen chloride dissolved in 1,4-dioxane (4.0 M, 5 mL) was added, and the mixture was reacted at 50°C for 4 hours. The reaction solution was concentrated to dryness to obtain compound 26-7 (234.0 mg) as a light brown solid. Compound 48-7 was used directly in the next step without further purification.

[0342] MS (m / z): 287.0 [M+H] + .

[0343] Step 7: Synthesis of 2-(1-isopropyl-4-oxopyrido[1',2':1,5]pyrazolo[3,4-d]pyridazin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (26)

[0344] Compound 26-7 (97.0 mg), B-1 (34.0 mg, 0.36 mmol) and DIPEA (116.0 mg, 0.90 mmol) were dissolved in DCM (5 mL), HATU (228.0 mg, 0.60 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase to obtain compound 26 (60.5 mg) as a white solid. The yield of steps 6 and 7 was 63.8%.

[0345] MS (m / z): 364.0 [M+H] + .

[0346] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),9.18(d,J=6.8Hz,1H),8.93(s,1H),8.66(d,J=6.0Hz,1H),8.32(d,J=8.8Hz,1H),8. 0(d,J=5.6Hz,1H),7.80-7.75(m,1H),7.52(t,J=6.8Hz,1H),5.08(s,2H),3.60(hept,J=6.8Hz,1H),1.34(d,J=6.8Hz,6H).

[0347] Example 27: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-(2-hydroxypropan-2-yl)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetamide (27)

[0348]

[0349] Step 1: Synthesis of ethyl 2-(1-(2-bromopropan-2-yl)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetate (27-1)

[0350] Referring to the preparation method of common intermediate A-5, common intermediate A-5 was prepared.

[0351] Compound A-5 (299.0 mg, 0.90 mmol), NBS (209.0 mg, 1.18 mmol), AIBN (6.0 mg, 0.036 mmol) were dissolved in CCl4 (10 mL), replaced with nitrogen for protection, heated to 77 ° C, stirred and reacted overnight. After standing and cooling, concentrated, and purified by column chromatography, compound 27-1 (330.0 mg) was obtained with a yield of 89.1% as a colorless oily product.

[0352] LC-MS (m / z): 409.0 / 411.0 [M+H] + .

[0353] Step 2: Synthesis of 2-(1-(2-hydroxypropan-2-yl)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetic acid (27-2)

[0354] Compound 27-1 (323.0 mg, 0.79 mmol) and LiOH (56.7 mg, 2.37 mmol) were added with THF (10 mL) and water (5 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (50 mL) was added to dilute, and EA was extracted (25 mL×3). The combined organic phases were washed with saturated sodium chloride (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain compound 27-2 (120.0 mg) with a yield of 47.7% as a white solid.

[0355] LC-MS (m / z): 319.0 [M+H] + .

[0356] 1H NMR (400MHz, DMSO-d6) δ9.41-9.36(m,1H),8.25-8.21(m,1H),7.67-7.58(m,2H),5.87(s,1H),4.70(s,2H),1.64(s,6H).

[0357] Step 3: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-(2-hydroxypropan-2-yl)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetamide (27)

[0358] Compound 27-2 (116.0 mg, 0.36 mmol) was dissolved in DMF (5 mL), and compound B-7 (64.5 mg, 0.47 mmol), DIPEA (148.0 mg, 1.15 mmol) and HATU (296.9 mg, 0.78 mmol) were added in sequence, and reacted at room temperature. After the reaction was completed, distilled water (25 mL) was added for dilution, and EA (20 mL × 3) was used for extraction. The organic phases were combined and washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound 27 (77.0 mg) with a yield of 52.6% as a white solid.

[0359] MS (m / z): 402.0 [M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6) δ9.41-9.37(m,1H),8.39(d,J=4.8Hz,1H),8.27-8.22(m,1H),7.69-7.60(m,2H),5.88(s, 1H),5.0(s,1H),4.76(s,2H),3.82-3.74(m,1H),2.28-2.22(m,2H),1.99-1.93(m,2H),1.63(s,6H),1.22(s,3H).

[0361] Example 28: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetamide (28)

[0362]

[0363] Step 1: Synthesis of methyl 3-isobutyryl-1H-indole-2-carboxylate (28-2)

[0364] PPA (52.0 mg) and isobutyric acid (151.0 mg, 1.71 mmol) were added to acetonitrile (2 mL) and stirred to dissolve. TFAA (360.0 mg, 1.71 mmol) was added and stirred at room temperature for 15 minutes. Compound 28-1: 1H-indole-2-carboxylic acid methyl ester (100.0 mg, 0.57 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was added dropwise to a sodium carbonate aqueous solution (50 mL) to quench, extracted with EA (40 mL), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 28-2 (100.0 mg) with a yield of 71.4% as a white solid.

[0365] LC-MS (m / z): 246.0 [M+H] + .

[0366] Step 2: Synthesis of methyl 3-isobutyryl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (28-3)

[0367] Weigh compound 28-2 (50.0 mg, 0.20 mmol) and SEM-Cl (44.0 mg, 0.27 mmol) respectively and dissolve in anhydrous DMF (4 mL), stir and react at room temperature for 10 minutes, add anhydrous potassium carbonate (150.0 mg, 1.08 mmol), continue to stir and react at room temperature overnight. Pour the reaction solution into water (50 mL) to quench, then add EA (40 mL) to extract, separate the organic phase, wash with saturated brine (50 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 28-3 (62.0 mg) with a yield of 40.5% as a colorless oil.

[0368] LC-MS (m / z): 376.0 [M+H] + .

[0369] Step 3: Synthesis of 1-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-3,5-dihydro-4H-pyridazin[4,5-b]indol-4-one (28-4)

[0370] Compound 28-3 (62.0 mg, 0.16 mmol) and hydrazine hydrate (80%, 0.2 mL) were dissolved in anhydrous ethanol (2 mL) and heated to reflux for 3 hours. After stopping the heating and cooling, the solvent ethanol was dried by rotary evaporator, water (50 mL) was added, and EA (40 mL) was used for extraction. The organic phase was separated and washed with saturated brine (40 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound 28-4 (70.0 mg) as a white solid. Compound 28-4 was used directly in the next step without further purification.

[0371] LC-MS (m / z): 358.0 [M+H] + .

[0372] Step 4: Synthesis of ethyl 2-(1-isopropyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetate (28-5)

[0373] Compound 28-4 (70.0 mg) and anhydrous potassium carbonate (54.0 mg, 0.39 mmol) were added to a DMF solution (4 mL), and ethyl α-bromoacetate (43.0 mg, 0.25 mmol) was added, and the reaction was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and it was extracted with EA (40 mL), and the organic phase was separated, washed with saturated brine (50 mL × 3), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 28-5 (47.0 mg) as a colorless oil. The yield of steps 3 and 4 was 54.1%.

[0374] LCMS (m / z): 444.0 [M+H] + .

[0375] Step 5: Synthesis of 2-(1-isopropyl-4-oxo-5-(2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetic acid (28-6)

[0376] Compound 28-5 (47.0 mg, 0.11 mmol) was dissolved in THF (3 mL), and LiOH·H2O (30.0 mg, 0.72 mmol) was weighed and dissolved in water (1 mL) to prepare a solution, which was added to the reaction system and stirred at room temperature. After the reaction was completed, water (30 mL) was added to the reaction solution, and then 2M dilute hydrochloric acid was added to adjust the pH to about 3, and extracted with EA (40 mL). The organic phase was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 28-6 (35.0 mg) with a yield of 76.5% as a white solid.

[0377] LC-MS (m / z): 416.0 [M+H] + .

[0378] Step 6: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetamide (28-7)

[0379] Compound 28-6 (35.0 mg, 0.08 mmol) was dissolved in DMF (1 mL), and compound B-7 (12.8 mg, 0.09 mmol), DIPEA (32.7 mg, 0.25 mmol) and HATU (48.0 mg, 0.13 mmol) were added in sequence, and reacted at room temperature. After the reaction was completed, distilled water (15 mL) was added for dilution, and EA (10 mL × 3) was used for extraction. The organic phases were combined and washed with saturated sodium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 28-7 (33.0 mg) with a yield of 78.8% as a white solid.

[0380] LCMS (m / z): 499.0 [M+H] + .

[0381] Step 7: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetamide (28)

[0382] Compound 28-7 (33.0 mg, 0.07 mmol) was dissolved in THF (3 mL), TBAF (287.0 mg, 1.09 mmol) was added, and the mixture was heated to reflux and reacted overnight. The heating was stopped, and the mixture was allowed to stand and cool, and THF was removed by rotary evaporation, and water (70 mL) was added and stirred thoroughly, and the mixture was extracted with DCM / MeOH (10:1, 30 mL×2), and the organic phase was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain the target compound 28 (8.80 mg) with a yield of 36.6% as a white solid.

[0383] LC-MS (m / z): 369.0 [M+H] + .

[0384] 1H NMR(400MHz, DMSO-d6)δ12.80(s,1H),8.28(d,J=7.2Hz,1H),8.12-8.06(m,1H),7.68-7.64(m,1H),7.56-7.49(m,1H),7.40-7.33(m,1H), 4.99(s,1H),4.76(s,2H),3.85-3.75(m,1H),3.73-3.62(m,1H),2.30-2.21(m,2H),2.02-1.88(m,2H),1.36(d,J=6.8Hz,6H),1.22(s,3H).

[0385] Example 29: Preparation of 2-(1-isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)-N-(pyrimidin-4-yl)acetamide (29)

[0386]

[0387] Step 1: Synthesis of methyl 1-methyl-1H-indole-2-carboxylate (29-2)

[0388] Compound 29-1: 1H-indole-2-carboxylic acid methyl ester (1.50 g, 8.56 mmol) was dissolved in acetonitrile (40 mL), and anhydrous potassium carbonate (1.30 g, 9.42 mmol) and iodomethane (2.48 g, 17.47 mmol) were added respectively, sealed in a sealed tube, heated to 60 ° C and stirred overnight. After stopping heating and standing to cool, the reaction solution was poured into water (100 mL) and stirred, and most of the acetonitrile solvent was removed by rotary evaporator, and EA (60 mL) was added for extraction. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29-2 (1.0 g) with a yield of 61.7% as a white solid.

[0389] LC-MS (m / z): 190.0 [M+H] + .

[0390] 1 H NMR (600MHz, DMSO-d6) δ7.77-7.72(m,1H),7.67-7.63(m,1H),7.44-7.38(m,1H),7.33(s,1H),7.22-7.17(m,1H),4.09(s,3H),3.92(s,3H).

[0391] Step 2: Synthesis of methyl 3-isobutyryl-1-methyl-1H-indole-2-carboxylate (29-3)

[0392] First weigh anhydrous aluminum chloride (423.0 mg, 3.17 mmol), replace with nitrogen for protection, and use an ice-salt bath to control the temperature at about -5 ° C. Then weigh isobutyryl chloride (338.0 mg, 3.17 mmol) and dissolve it in DCE solution (3 mL), and add it dropwise to the reaction system with a syringe, and continue to control the temperature and stir for 15 minutes. Dissolve compound 29-2 (300.0 mg, 1.59 mmol) in DCE solution (4 mL), add it dropwise to the reaction system, and after the addition, gradually warm to room temperature and continue to stir the reaction for 2 hours. Add water (40 mL) to the reaction solution to quench, extract with DCM (30 mL), separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain compound 29-3 (200.0 mg) with a yield of 48.6%, which is a colorless oily product.

[0393] LC-MS (m / z): 260.0 [M+H] + .

[0394] 1 H NMR(600MHz,Chloroform-d)δ7.80(d,J=8.4Hz,1H),7.42-7.35(m,2H),7.29-7.23 (m,1H),3.96(s,3H),3.94(s,3H),3.24(hept,J=6.6Hz,1H),1.23(d,J=6.6Hz,6H).

[0395] Step 3: Synthesis of 1-isopropyl-5-methyl-3,5-dihydro-4H-pyridazin[4,5-b]indol-4-one (29-4)

[0396] Dissolve compound 29-3 (200.0 mg, 0.77 mmol) in ethanol (4 mL), add hydrazine hydrate (80%, 1 mL), replace with nitrogen, and heat to reflux for 5 hours. Stop heating, let stand and cool to room temperature, use a rotary evaporator to dry most of the solvent, then add water (40 mL) and stir thoroughly, then add DCM (40 mL) to extract, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude compound 29-4 (210.0 mg) as a white solid. Compound 29-4 is used directly in the next step without further purification. .

[0397] LC-MS (m / z): 242.0 [M+H] + .

[0398] Step 4: Synthesis of ethyl 2-(1-isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetate (29-5)

[0399] Compound 29-4 (210.0 mg) was dissolved in DMF (4.5 mL), and then anhydrous cesium carbonate (425.0 mg, 1.31 mmol) and ethyl α-bromoacetate (189.0 mg, 1.13 mmol) were weighed and added to the reaction system. The reaction was carried out at room temperature. After the reaction was completed, the reaction solution was poured into water (80 mL), and EA (40 mL) was added for extraction. The organic phase was separated, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 29-5 (160.0 mg) as a colorless oil. The yield of steps 3 and 4 was 56.1%.

[0400] LC-MS (m / z): 328.0 [M+H] + .

[0401] 1 H NMR(400MHz,DMSO-d6)δ8.17-8.10(m,1H),7.84-7.78(m,1H),7.68-7.59(m,1H),7.49-7.40(m,1H),4.95(s,2 H), 4.29 (s, 3H), 4.18 (q, J = 8.0Hz, 2H), 3.71 (hept, J = 6.8Hz, 1H), 1.36 (d, J = 6.8Hz, 6H), 1.23 (t, J = 8.0Hz, 3H).

[0402] Step 5: Synthesis of 2-(1-isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazin[4,5-b]indol-3-yl)acetic acid (29-6)

[0403] First, compound 29-5 (160.0 mg, 0.49 mmol) was dissolved in THF (3 mL), and then sodium hydroxide solid (78.0 mg, 1.96 mmol) was weighed and dissolved in water (2 mL) to prepare a solution, which was added to the reaction system and stirred at room temperature for 6 hours. The reaction solution was poured into water (40 mL), and dilute hydrochloric acid was added to adjust the pH to less than 4, and then EA (40 mL) was added for extraction, and the organic phase was separated, washed with saturated brine (40 mL), dried with anhydrous sodium sulfate, and the solvent was dried to obtain compound 29-6 (135.0 mg) with a yield of 92.7%, as a white solid.

[0404] LC-MS (m / z): 300.0 [M+H] + .

[0405] Step 6: Synthesis of 2-(1-isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indol-3-yl)-N-(pyrimidin-4-yl)acetamide (29)

[0406] First, compound 29-6 (135.0 mg, 0.45 mmol), compound B-1 (47.0 mg, 0.50 mmol) and DIPEA (175.0 mg, 1.35 mmol) were weighed and dissolved in DMF solution (4 mL), stirred evenly at room temperature, HATU (257.0 mg, 0.68 mmol) was added, and the reaction was carried out at room temperature. After the reaction was completed, the reaction solution was poured into water (80 mL) and EA (50 mL) was added for extraction. The organic phase was separated, washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 29 (93.0 mg) with a yield of 54.8% as a white solid.

[0407] LC-MS (m / z): 377.0 [M+H] + .

[0408] 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.93(s,1H),8.70-8.64(m,1H),8.17-8.11(m,1H),8.03-7.98(m,1H),7.84-7. 78(m,1H),7.68-7.59(m,1H),7.49-7.41(m,1H),5.11(s,2H),4.29(s,3H),3.77-3.66(m,1H),1.36(d,J=8.0Hz,6H).

[0409] Example 30: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(5-isopropyl-8-hydroxythiazolo[3',2':1,5]pyrrolo[2,3-d]pyridazin-7(8H)-yl)acetamide (30)

[0410]

[0411] Step 1: Synthesis of ethyl 2-(hydroxy(thiazol-2-yl)methyl)acrylate (30-2)

[0412] Compound 30-1: thiazole-2-carboxaldehyde (4.0 g, 35.36 mmol), DABCO (4.16 g, 37.12 mmol) and ethyl acrylate (8.85 g, 88.39 mmol) were dissolved in DMF solution (40 mL) and stirred at room temperature for 2 hours. The reaction solution was poured into water (400 mL), extracted with EA (200 mL × 2), the organic phases were combined, washed with saturated brine (200 mL × 4), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30-2 (1.89 g) with a yield of 25.1% as a brown oil.

[0413] LC-MS (m / z): 214.0 [M+H] + .

[0414] 1 H NMR (400MHz, DMSO-d6) δ7.73-7.68(m,1H),7.68-7.62(m,1H),6.59(d,J=5.6Hz,1H),6.26-6. 22(m,1H),5.95-5.90(m,1H),5.72(d,J=5.6Hz,1H),4.19-4.03(m,2H),1.15(t,J=7.2Hz,3H).

[0415] Step 2: Synthesis of ethyl 2-(acetoxy(thiazol-2-yl)methyl)acrylate (30-3)

[0416] Compound 30-2 (1.89 g, 8.86 mmol), Ac2O (1.20 g, 11.75 mmol) and DMAP (217.0 mg, 1.77 mmol) were dissolved in DCM (40 mL) and stirred at room temperature for 2 hours. The reaction solution was washed with water (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30-3 (1.60 g) with a yield of 70.7% as a light yellow oil.

[0417] LC-MS (m / z): 256.0 [M+H] + .

[0418] Step 3: Synthesis of ethyl pyrrolo[2,1-b]thiazole-6-carboxylate (30-4)

[0419] Compound 30-3 (2.21 g, 8.66 mmol) was dissolved in diphenyl ether (20 mL), replaced with nitrogen, and heated to 250°C for 30 minutes. After cooling, silica gel powder was directly added to the reaction solution, and purified by column chromatography to obtain compound 30-4 (790.0 mg) with a yield of 64.7% as a red oil.

[0420] LC-MS (m / z): 196.0 [M+H] + .

[0421] 1 H NMR(600MHz,DMSO-d6)δ7.92(d,J=1.2Hz,1H),7.84-7.79(m,1H),6.59-6.58 (m, 1H), 7.21 (d, J = 2.8Hz, 1H), 4.21 (q, J = 4.8Hz, 2H), 1.27 (t, J = 4.8Hz, 3H).

[0422] Step 4: Synthesis of ethyl 5-isobutyrylpyrrolo[2,1-b]thiazole-6-carboxylate (30-5)

[0423] Compound 30-4 (456.0 mg, 2.34 mmol) was dissolved in isobutyryl chloride (10 mL), and then anhydrous sodium acetate (766.0 mg, 9.34 mmol) was added, and the mixture was heated to 50°C and stirred overnight. After standing and cooling, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (30 mL) and stirred thoroughly for neutralization, and then EA (40 mL × 2) was added for extraction, and the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30-5 (70.0 mg) with a yield of 11.3% as a colorless oil.

[0424] LC-MS (m / z): 266.0 [M+H] + .

[0425] Step 5: Synthesis of 5-isopropylthiazolo[3',2':1,5]pyrrolo[2,3-d]pyridazin-8(7H)-one (30-6)

[0426] Compound 30-5 (70.0 mg, 0.26 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (80%, 0.5 mL) was added. The mixture was replaced with nitrogen and heated to reflux for 2 hours. The heating was stopped, and the mixture was allowed to cool to room temperature. Most of the solvent was dried by rotary evaporation, and then water (10 mL) was added and stirred thoroughly. DCM (5 mL×2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 30-6 (31 mg) with a yield of 50.3% as a colorless oil.

[0427] LC-MS (m / z): 234.0 [M+H] + .

[0428] Step 6: Synthesis of ethyl 2-(5-isopropyl-8-hydroxythiazolo[3',2':1,5]pyrrolo[2,3-d]pyridazin-7(8H)-yl)acetate (30-7)

[0429] Compound 30-6 (31.0 mg, 0.13 mmol) and anhydrous potassium carbonate (36.0 mg, 0.26 mmol) were added to a DMF solution (3 mL), and ethyl α-bromoacetate (27.7 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with EA (40 mL). The organic phase was separated and washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 30-7 (32.0 mg) with a yield of 75.4% as a colorless oil.

[0430] LC-MS (m / z): 320.0 [M+H] + .

[0431] Step 7: Synthesis of 2-(5-isopropyl-8-hydroxythiazolo[3',2':1,5]pyrrolo[2,3-d]pyridazin-7(8H)-yl)acetic acid (30-8)

[0432] Compound 30-7 (32.0 mg, 0.10 mmol) was dissolved in THF (3 mL), and LiOH·H2O (27.5 mg, 0.65 mmol) was weighed and dissolved in water (1 mL) to prepare a solution, which was added to the reaction system and stirred at room temperature. After the reaction was completed, water (30 mL) was added to the reaction solution, and then 2M dilute hydrochloric acid was added to adjust the pH to about 3, and extracted with EA (40 mL). The organic phase was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 30-8 (26.0 mg) with a yield of 89.1% as a white solid.

[0433] LC-MS (m / z): 292.0 [M+H] + .

[0434] Step 8: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(5-isopropyl-8-hydroxythiazolo[3',2':1,5]pyrrolo[2,3-d]pyridazin-7(8H)-yl)acetamide (30)

[0435] Compound 30-8 (26.0 mg, 0.09 mmol) was dissolved in DMF solution (1 mL), and compound B-7 (13.5 mg, 0.10 mmol), DIPEA (34.6 mg, 0.27 mmol) and HATU (53.0 mg, 0.14 mmol) were added in sequence, and reacted at room temperature. After the reaction was completed, distilled water (15 mL) was added for dilution, and EA was used for extraction (10 mL × 3). The organic phases were combined and washed with saturated sodium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound 30 (5.0 mg) with a yield of 14.9% as a white solid.

[0436] LC-MS (m / z): 375.0 [M+H] + .

[0437] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=4.4Hz,1H),8.17(d,J=7.2Hz,1H),7.50(d,J=4.4Hz,1H),6.95(s,1H),4.96(s,1H),4.6 6(s,2H),3.82-3.72(m,1H),3.65-3.54(m,1H),2.27-2.18(m,2H),2.01-1.89(m,2H),1.28(d,J=6.8Hz,6H),1.21(s,3H).

[0438] Example 31: Preparation of 2-(1-isopropyl-4-oxopyridazine[4,5-a]indolizine-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (31)

[0439]

[0440] Step 1: Synthesis of indolizine-2-carboxylic acid ethyl ester (31-2)

[0441] A mixture of compound 31-1: pyridine-2-carboxaldehyde (4.70 mL, 0.05 mol), ethyl acrylate (9.70 mL, 0.11 mol) and DABCO (0.67 g, 6.0 mmol) was stirred at room temperature for 16 hours, and then acetic anhydride (25 mL) was added and the temperature was raised to 120°C for 2 hours. When the reaction liquid reached room temperature, the reaction liquid was concentrated and purified by column chromatography to obtain compound 31-2 (2.37 g) with a yield of 25.0%, which was a green oily liquid.

[0442] MS (m / z): 190.0 [M+H] + .

[0443] Step 2: Synthesis of ethyl 1-bromoindolizine-2-carboxylate (31-3)

[0444] Compound 31-2 (1.0 g, 5.29 mmol) was dissolved in anhydrous DCM (20 mL), and a DCM solution (9.5 mL) of liquid bromine (0.23 mL, 4.75 mmol) was added dropwise at -78 ° C, and the mixture was kept warm for 30 minutes. The reaction solution was quenched with water, warmed to room temperature, and separated. The organic phase was washed with saturated sodium thiosulfate aqueous solution (15 mL), water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 31-3 (0.68 g) with a yield of 48.6%, as a brown oily liquid.

[0445] MS (m / z): 268.0 / 270.0 [M+H] + .

[0446] Step 3: Synthesis of 1-iodoindolizine-2-carboxylic acid ethyl ester (31-4)

[0447] Compound 31-3 (459.0 mg, 1.71 mmol), potassium iodide (853.0 mg, 5.14 mmol) and cuprous iodide (979.0 mg, 5.14 mmol) were added to anhydrous DMF (5 mL), and the mixture was reacted at 120°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with EA (20 mL). The filtrate was washed with water (15 mL × 4) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 31-4 (416.0 mg) with a yield of 77.2%, which was a brown oily liquid and stored at -20°C under nitrogen protection.

[0448] MS (m / z): 316.0 [M+H] + .

[0449] Step 4: Synthesis of ethyl 1-isobutyrylindoleazine-2-carboxylate (31-5)

[0450] Compound 31-4 (416.0 mg, 1.32 mmol) was dissolved in anhydrous THF (3 mL) at -10°C and replaced with nitrogen for protection. iPrMgCl·LiCl (1.3M THF solution, 1.32 mL) was added dropwise into the reaction system. After the addition was completed, the reaction was continued to stir for 30 minutes. Isobutyric anhydride (0.33 mL, 1.98 mmol) was added. After the addition was completed, the temperature was raised to room temperature for reaction. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (20 mL) for quenching. EA (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 31-5 (68.0 mg) with a yield of 19.9% ​​as a yellow oily liquid.

[0451] MS (m / z): 260.0 [M+H] + .

[0452] Step 5: Synthesis of 1-isopropylpyridazino[4,5-a]indolizin-4(3H)-one (31-6)

[0453] Compound 31-5 (68.0 mg, 0.26 mmol) and hydrazine hydrate (1.0 mL) were dissolved in ethanol (5 mL), and the mixture was heated to reflux and stirred for 5 hours after nitrogen replacement protection. The mixture was allowed to stand and cooled, and the solvent was removed under reduced pressure. Water (30 mL) was added to the residue, and then DCM (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 31-6 (61.0 mg) as a white solid. Compound 31-6 was used directly in the next step without further purification.

[0454] MS (m / z): 228.0 [M+H] + .

[0455] Step 6: Synthesis of ethyl 2-(1-isopropyl-4-oxopyridazinyl[4,5-a]indolizin-3(4H)-yl)acetate (31-7)

[0456] Compound 31-6 (61.0 mg) was dissolved in DMF solution (7 mL), anhydrous cesium carbonate (144.0 mg, 0.44 mmol) and ethyl α-bromoacetate (74.0 mg, 0.44 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (30 mL) and stirred thoroughly, and then EA (15 mL × 2) was added to extract twice, the organic phases were combined, and then the organic phases were washed with water (25 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 31-7 (14.0 mg) as an off-white solid, and the yield of steps 5 and 6 was 17.3%.

[0457] MS (m / z): 314.0 [M+H] + .

[0458] Step 7: Synthesis of 2-(1-isopropyl-4-oxopyridazin[4,5-a]indolizin-3(4H)-yl)acetic acid (31-8)

[0459] Compound 31-7 (14.0 mg, 0.04 mmol) and LiOH·H2O (5.0 mg, 0.12 mmol) were added to THF / water (2 mL / 1 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried under reduced pressure to obtain compound 31-8 (21.0 mg) as an off-white solid after reaction. Compound 31-8 was used directly in the next step without further purification.

[0460] MS (m / z): 286.0 [M+H] + .

[0461] Step 8: Synthesis of 2-(1-isopropyl-4-oxopyridazinyl[4,5-a]indolizin-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (31)

[0462] Compound 31-8 (21.0 mg), compound B-1 (8.4 mg, 0.09 mmol), DIPEA (28.5 mg, 0.22 mmol) and HATU (42.0 mg, 0.11 mmol) were added to DMF solution (3 mL). After completion of the reaction at room temperature, the reaction solution was poured into water (20 mL), and EA (20 mL) was added for extraction. The organic phase was then washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. After purification, the target compound 31 (13.0 mg) was obtained as a yellow solid. The yield of step 7 and step 8 was 48.1%.

[0463] MS (m / z): 363.0 [M+H] + .

[0464] 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.92(s,1H),8.73(d,J=7.2Hz,1H),8.66(d,J=6.0Hz,1H),8.40(s,1H),8.07(d,J=9.2Hz,1H) ,8.0(dd,J=6.0,1.2Hz,1H),7.31-7.22(m,1H),7.15(t,J=7.2Hz,1H),5.0(s,2H),3.60(hept,J=6.8Hz,1H),1.33(d,J=6.8Hz,6H).

[0465] Example 32: Preparation of 2-(4-isopropyl-1-oxopyridazine[4,5-b]indolizine-2(1H)-yl)-N-(pyrimidin-4-yl)acetamide (32)

[0466]

[0467] Synthesis Scheme 1: Synthesis of Ethyl Indolizine-2-Carboxylate (31-2)

[0468] Compound 31-2 was prepared by referring to the synthesis of compound 31-2 in Example 31.

[0469] Synthesis Scheme 2: Synthesis of 2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizine-2(1H)-yl)-N-(pyrimidin-4-yl)acetamide (32)

[0470] Step 1: Synthesis of ethyl 3-isobutyrylindoleazine-2-carboxylate (32-1)

[0471] Compound 31-2 (567.0 mg, 3.0 mmol) and sodium acetate (246.0 mg, 3.0 mg) were added to isobutyryl chloride (3 mL) and reacted at 50 ° C for 24 hours. When the reaction solution reached room temperature, the reaction was quenched with MeOH, diluted with EA (20 mL), washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain compound 32-1 (157.0 mg) with a yield of 20.2% as a colorless oily liquid.

[0472] MS (m / z): 260.0 [M+H] + .

[0473] 1H NMR(400MHz,Chloroform-d)δ9.65(d,J=7.2Hz,1H),7.54(d,J=8.8Hz,1H),7.18-7.06(m,1H),6.96-6.87(m,1 H), 6.85 (s, 1H), 4.44 (q, J = 7.2Hz, 2H), 3.57 (hept, J = 6.8Hz, 1H), 1.44 (t, J = 7.2Hz, 3H), 1.23 (d, J = 6.8Hz, 6H).

[0474] Step 2: Synthesis of 4-isopropylpyridazino[4,5-b]indolizin-1(2H)-one (32-2)

[0475] Compound 32-1 (157.0 mg, 0.58 mmol) and hydrazine hydrate (1.0 mL) were dissolved in ethanol (5 mL), and the mixture was heated to reflux and stirred for 5 hours after nitrogen replacement protection. The mixture was allowed to stand and cooled, and the solvent was removed under reduced pressure. Water (60 mL) was added to the reaction solution, and then DCM (60 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 32-2 (71.0 mg) with a yield of 54.2% as a white solid.

[0476] MS (m / z): 228.0 [M+H] + .

[0477] Step 3: Synthesis of ethyl 2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)acetate (32-3)

[0478] Compound 32-2 (70.0 mg, 0.31 mmol) was dissolved in DMF (7 mL), and anhydrous potassium carbonate (85.6 mg, 0.62 mmol) and ethyl α-bromoacetate (74.0 mg, 0.44 mmol) were added and stirred at room temperature. After the reaction was completed, the reaction solution was poured into water (30 mL) and stirred thoroughly, and then EA (15 mL × 2) was added and extracted twice. The organic phases were combined, and then the organic phases were washed with water (25 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography. After purification, compound 32-3 (90.0 mg) was obtained with a yield of 92.8% as a colorless oily liquid.

[0479] MS (m / z): 314.0 [M+H] + .

[0480] Step 4: Synthesis of 2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)acetic acid (32-4)

[0481] Compound 32-3 (90.0 mg, 0.29 mmol) and LiOH·H2O (36.5 mg, 0.87 mmol) were added to THF / water (2 mL / 1 mL), and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried under reduced pressure to obtain compound 32-4 (85.0 mg) as a white solid, which was used directly in the next step without further purification.

[0482] MS (m / z): 286.0 [M+H] + .

[0483] Step 5: Synthesis of 2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)-N-(pyrimidin-4-yl)acetamide (32)

[0484] Compound 32-4 (85.0 mg), compound B-1 (34.0 mg, 0.36 mmol), DIPEA (115.5 mg, 0.89 mmol) and HATU (170.0 mg, 0.45 mmol) were added to DMF solution (3 mL). After the reaction was completed at room temperature, the reaction solution was poured into water (30 mL), and EA (30 mL) was added for extraction. The organic phase was then washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 32 (78.0 mg) as a light yellow solid. The yield of step 4 and step 5 was 71.6%.

[0485] MS (m / z): 363.0 [M+H] + .

[0486] 1 H NMR (600MHz, DMSO-d6) δ11.30(s,1H),8.93(d,J=1.2Hz,1H),8.76(d,J=7.2Hz,1H),8.66(d,J=6.0Hz,1H),8.05-7.96(m,1H),7.8 7-7.79(m,1H),7.27-7.18(m,1H),7.08(s,1H),7.04-6.98(m,1H),5.07(s,2H),3.80(hept,J=6.6Hz,1H),1.33(d,J=6.6Hz,6H).

[0487] Example 33: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)acetamide (33)

[0488]

[0489] Synthesis Scheme 1: Synthesis of 2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)acetic acid (32-4)

[0490] Referring to the synthesis of compound 32-4 in Example 32, that is, steps 1 to 4 in synthesis scheme 1 and synthesis scheme 2 in Example 32, compound 32-4 was prepared.

[0491] Synthesis Scheme 2: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxopyridazino[4,5-b]indolizin-2(1H)-yl)acetamide (33)

[0492] The target compound 33 (54.2 mg) was prepared as a white solid in the same manner as in step 5 of synthesis scheme 2 of reference example 32, except that B-1 was replaced by B-7. The yield was 38.1%.

[0493] MS (m / z): 369.0 [M+H] + .

[0494] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.2Hz,1H),8.21(d,J=7.2Hz,1H),7.80(d,J=9.2Hz,1H),7.19(dd,J=9.2,6.4Hz,1H),7.05(s,1H),7. 03-6.94(m,1H),4.97(s,1H),4.70(s,2H),3.86-3.70(m,2H),2.29-2.18(m,2H),2.03-1.87(m,2H),1.32(d,J=6.4Hz,6H),1.22(s,3H).

[0495] Example 34: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxopyridazino[4,5-a]indolizin-3(4H)-yl)acetamide (34)

[0496]

[0497] Synthesis Scheme 1: Synthesis of 2-(1-isopropyl-4-oxo-pyridazinyl[4,5-a]indolizin-3(4H)-yl)acetic acid (31-8)

[0498] Referring to the synthesis of compound 31-8 in Example 31, ie, steps 1 to 7 in Example 31, compound 31-8 was prepared.

[0499] Synthesis Scheme 2: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxopyridazino[4,5-a]indolizin-3(4H)-yl)acetamide (34)

[0500] Referring to the preparation method of step 7 of Example 32, only B-1 was replaced by B-7; the target compound 34 (15.4 mg) was prepared in a yield of 20.2% as a white solid.

[0501] MS (m / z): 369.0 [M+H] + .

[0502] 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=7.2Hz,1H),8.36(s,1H),8.16(d,J=7.2Hz,1H),8.05(d,J=9.2Hz,1H),7.30-7.19(m,1H),7.17-7.07(m,1H ),4.96(s,1H),4.63(s,2H),3.85-3.72(m,1H),3.63-3.50(m,1H),2.2 8-2.19(m,2H),2.04-1.88(m,2H),1.32(d,J=6.6Hz,6H),1.22(s,3H).

[0503] Example 35: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazine[4,5-b]indolizine-2(1H)-yl)acetamide (35)

[0504]

[0505] Synthesis Scheme 1: Synthesis of Ethyl Indolizine-2-Carboxylate (31-2)

[0506] Compound 31-2 was prepared by referring to the synthesis of compound 31-2 in Example 31.

[0507] Synthesis Scheme 2: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazin[4,5-b]indolizine-2(1H)-yl)acetamide (35)

[0508] Step 1: Synthesis of ethyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (35-2)

[0509] Compound 31-2 (1.60 g, 8.46 mmol) was dissolved in MeOH (20 mL), and platinum dioxide (192.0 mg, 0.85 mmol) was added. The reaction solution was reacted at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily liquid compound 35-2 (1.67 g), which was used directly in the next step without further purification.

[0510] LC-MS (m / z): 194.0 [M+H] + .

[0511] Step 2: Synthesis of ethyl 3-isobutyryl-5,6,7,8-tetrahydroindolizine-2-carboxylate (35-3)

[0512] Compound 35-2 (0.39 g) was dissolved in anhydrous THF (3 mL) at -78 °C, and n-butyl lithium (0.85 mL, 2.2 M, 1.86 mmol) was slowly added dropwise. After 30 minutes, isobutyric anhydride (491.0 mg, 3.10 mmol) was slowly added dropwise. The reaction solution was slowly warmed to room temperature under nitrogen protection and reacted for 16 hours. The reaction solution was poured into ammonium chloride solution (25 mL) and water (25 mL) for dilution, extracted with EA (30 mL × 3), the combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound 35-3 (84.0 mg) as a yellow oily liquid. The yield of step 1 and step 2 was 16.2%.

[0513] LC-MS (m / z): 264.0 [M+H] + .

[0514] 1 H NMR (400MHz, DMSO-d6) δ6.20 (s, 1H), 4.19 (q, J = 7.2Hz, 2H), 3.88 (t, J = 6.0Hz, 2H), 3.35-3.27 (m, 1H), 2.73(t,J=6.4Hz,2H),1.88-1.81(m,2H),1.76-1.69(m,2H),1.24(t,J=7.2Hz,3H),1.10-1.0(m,6H).

[0515] Step 3: Synthesis of 4-isopropyl-6,7,8,9-tetrahydropyridazine[4,5-b]indolizine-1(2H)-one (35-4)

[0516] Compound 35-3 (84.0 mg, 0.32 mmol) was dissolved in hydrazine hydrate (2 mL, 80%) at room temperature. The reaction solution was reacted at 80°C for 5 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and EA was extracted (20 mL×3). The combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 35-4 (65 mg) with a yield of 88.1% as a white solid.

[0517] LC-MS (m / z): 232.0 [M+H] + .

[0518] Step 4: Synthesis of ethyl 2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazin[4,5-b]indolizine-2(1H)-yl)acetate (35-5)

[0519] Compound 35-4 (65.0 mg, 0.28 mmol) was dissolved in DMF (5 mL), anhydrous potassium carbonate (116.0 mg, 0.84 mmol) and ethyl α-bromoacetate (148.0 mg, 0.88 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (60 mL) and stirred thoroughly, and then EA (30 mL × 2) was added to extract twice, the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain yellow oily liquid 35-5 (35.0 mg) with a yield of 39.2%.

[0520] LC-MS (m / z): 318.0 [M+H] + .

[0521] Step 5: Synthesis of 2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazin[4,5-b]indolizine-2(1H)-yl)acetic acid (35-6)

[0522] Compound 35-5 (35.0 mg, 0.11 mmol) and LiOH·H2O (11.40 mg, 0.27 mmol) were added to THF / water (1 mL / 1 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried under reduced pressure. Compound 35-6 (20.0 mg) was obtained as a white solid, which was used directly in the next step without further purification.

[0523] LC-MS (m / z): 290.0 [M+H] + .

[0524] Step 6: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazin[4,5-b]indolizine-2(1H)-yl)acetamide (35)

[0525] Compound 35-6 (20.0 mg), B-7 (10.5 mg, 0.08 mmol), DIPEA (26.8 mg, 0.21 mmol) and HATU (39.4 mg, 0.10 mmol) were added to DMF (3 mL) and stirred at room temperature overnight. The reaction solution was poured into water (20 mL), and EA (20 mL) was added for extraction. The organic phase was then washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain N-((1s, 3s)-3-hydroxy-3-methylcyclobutyl)-2-(4-isopropyl-1-oxo-6,7,8,9-tetrahydropyridazine[4,5-b]indolizine-2(1H)-yl)acetamide (20.40 mg) as a white solid. The yield of step 5 and step 6 was 49.8%.

[0526] MS (m / z): 373.0 [M+H] + .

[0527] 1H NMR (400MHz, DMSO-d6) δ8.13(d,J=7.6Hz,1H),6.39(s,1H),4.97(s,1H),4.59(s,2H),4.36(t,J=6.0Hz,2H),3.81-3.71( m,1H),3.58-3.50(m,1H),2.96-2.85(m,2H),2.26-2.17(m,2H),2.04-1.89(m,4H),1.82-1.73(m,2H),1.25-1.20(m,9H).

[0528] Example 36: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-7,8,9,10-tetrahydropyridazine[4,5-a]indolizine-3(4H)-yl)acetamide (36)

[0529]

[0530] Synthesis Scheme 1: Synthesis of ethyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (35-2)

[0531] First refer to the synthesis of compound 31-2 in Example 31 to prepare compound 31-2, and then refer to the synthesis of 35-2 in Example 35 to prepare compound 35-2.

[0532] Synthesis Scheme 2: Synthesis of 2-(1-isopropyl-4-oxo-7,8,9,10-tetrahydropyridazine[4,5-a]indolizine-3(4H)-yl)acetic acid (36-4)

[0533] Step 1: Synthesis of ethyl 1-isobutyryl-5,6,7,8-tetrahydroindolizine-2-carboxylate (36-1)

[0534] Aluminum trichloride (689.96 mg, 5.17 mmol) was dissolved in anhydrous DCE (10 mL) at 0°C, and isobutyryl chloride (413.52 mg, 3.88 mmol) was slowly added dropwise. After 30 minutes, a DCE solution (5 mL) of compound 35-2 (0.50 g, 2.59 mmol) was slowly added dropwise. The reaction solution was slowly warmed to room temperature under nitrogen protection and reacted for 16 hours. The reaction solution was poured into ammonium chloride solution (25 mL) and water (25 mL) for dilution, extracted with EA (30 mL × 3), and the combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography gave compound 36-1 (0.40 g) with a yield of 58.7% as a colorless oily liquid.

[0535] MS (m / z): 264.0 [M+H] + .

[0536] 1 H NMR (400MHz, DMSO-d6) δ7.31 (s, 1H), 4.17 (q, J = 6.8Hz, 2H), 3.96 (t, J = 6.0Hz, 2H), 3.30 (p, J = 6.8Hz, 1H), 2.68(t,J=6.4Hz,2H),1.90-1.80(m,2H),1.76-1.67(m,2H),1.24(t,J=7.2Hz,3H),0.98(d,J=6.8Hz,6H).

[0537] Step 2: Synthesis of 1-isopropyl-7,8,9,10-tetrahydropyridazine[4,5-a]indolizine-4(3H)-one (36-2)

[0538] Compound 36-1 (0.37 g, 1.41 mmol) was dissolved in hydrazine hydrate (5 mL, 80%) at room temperature. The reaction solution was reacted at 80°C for 5 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and EA was extracted (20 mL×3). The combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 36-2 (0.29 g) with a yield of 88.6% as a white solid.

[0539] MS (m / z): 232.0 [M+H] + .

[0540] Step 3: Synthesis of ethyl 2-(1-isopropyl-4-oxo-7,8,9,10-tetrahydropyridazine[4,5-a]indolizine-3(4H)-yl)acetate (36-3)

[0541] Compound 36-2 (0.29 g, 1.25 mmol) was dissolved in DMF solution (10 mL), anhydrous potassium carbonate (345.0 mg, 2.5 mmol) and ethyl α-bromoacetate (42.0 mg, 0.25 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (60 mL) and stirred thoroughly, and then EA (30 mL × 2) was added to extract twice, the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 36-3 (45.0 mg) with a yield of 11.3%, as a yellow oily liquid.

[0542] MS (m / z): 318.0 [M+H] + .

[0543] Step 4: Synthesis of 2-(1-isopropyl-4-oxo-7,8,9,10-tetrahydropyridazine[4,5-a]indolizine-3(4H)-yl)acetic acid (36-4)

[0544] Compound 36-3 (45.0 mg, 0.14 mmol) and LiOH·H2O (17.6 mg, 0.42 mmol) were added to THF / water (1 mL / 1 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried under reduced pressure. Compound 36-4 (30.0 mg) was obtained after the reaction, with a yield of 73.1%, as a yellow oily liquid.

[0545] MS (m / z): 290.0 [M+H] + .

[0546] Step 5: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-7,8,9,10-tetrahydropyridazin[4,5-a]indolizine-3(4H)-yl)acetamide (36)

[0547] Compound 36-4 (30 mg, 0.10 mmol), compound B-7 (14.5 mg, 0.11 mmol), DIPEA (38.3 mg, 0.30 mmol) and HATU (59.1 mg, 0.15 mmol) were added to DMF (3 mL) and stirred at room temperature overnight. The reaction solution was poured into water (20 mL), and EA (20 mL) was added for extraction. The organic phase was then washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 36 (5.20 mg) with a yield of 13.4% as a white solid.

[0548] MS (m / z): 373.0 [M+H] + .

[0549] 1 H NMR(400MHz,DMSO-d6)δ8.0(d,J=7.8Hz,1H),7.47(s,1H),4.94(s,1H),4.48(s,2H),4.19(t,J=6.0Hz,2H),3.7 8-3.74(m,1H),3.23-3.17(m,1H),3.09-3.05(m,2H),2.23-2.19(m,2H),1.94-1.87(m,6H),1.21-1.18(m,9H).

[0550] Example 37: Preparation of 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)-N-(pyrimidin-4-yl)acetamide (37)

[0551]

[0552] Step 1: Synthesis of methyl 3-isobutyryl-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylate (37-2)

[0553] Compound 37-1: 5,6-dihydro-4H-cyclopentane[b]thiophene-2-carboxylic acid methyl ester (200.0 mg, 1.02 mmol) was added to the flask and the atmosphere was replaced with nitrogen. TMPMgCl·LiCl solution (1 M, 1.2 mL) was added under ice bath and stirred for 30 minutes. After sufficient stirring, isobutyric anhydride (283.0 mg, 1.53 mmol) was added under ice bath and continued to stir. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with water (15 mL×2), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography to obtain compound 37-2 (243.0 mg) with a yield of 89.5% as a colorless oil.

[0554] MS (m / z): 253.0 [M+H] + .

[0555] Step 2: Synthesis of 1-isopropyl-7,8-dihydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-4(6H)-one (37-3)

[0556] Compound 37-2 (70.0 mg, 0.28 mmol), hydrazine hydrate (1 mL) and ethanol (1 mL) were placed in a flask and stirred at room temperature overnight. After the reaction was completed, EA (15 mL × 2) was added for extraction, the organic phases were combined, washed with water (15 mL), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 37-3 (74.0 mg) as a white solid. Compound 37-3 was used directly in the next step without further purification.

[0557] MS (m / z): 235.0 [M+H] + .

[0558] Step 3: Synthesis of ethyl 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)acetate (37-4)

[0559] The compound 37-3 (74.0 mg) from the previous step, ethyl α-bromoacetate (50.0 mg, 0.30 mmol), potassium carbonate (95.65 mg, 0.69 mmol) and DMF (2 mL) were added to a flask and stirred at room temperature. After the reaction was completed, EA (15 mL × 2) was added for extraction. The organic phases were combined, washed with water (15 mL), washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 37-4 (78.0 mg). The yield of steps 2 and 3 was 86.9%, which was a yellow oil.

[0560] MS (m / z): 321.0 [M+H] + .

[0561] Step 4: Synthesis of 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)acetic acid (37-5)

[0562] Compound 37-4 (78.0 mg, 0.24 mmol), 1N sodium hydroxide aqueous solution (2 mL), THF (2 mL) were added to the flask and stirred at room temperature for 2 hours. After the reaction was completed, the pH was adjusted to less than 6, and EA (15 mL × 2) was added for extraction. The organic phases were combined, washed with water (15 mL), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 37-5 (67.0 mg) with a yield of 95.5% as a yellow oil.

[0563] MS (m / z): 293.0 [M+H] + .

[0564] Step 5: Synthesis of 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)-N-(pyrimidin-4-yl)acetamide (37)

[0565] Compound 37-5 (76.0 mg, 0.26 mmol), compound B-1 (43.0 mg, 0.31 mmol), DIPEA (100.8 mg, 0.78 mmol) and HATU (148.3 mg, 0.39 mmol) were added to a DMF solution (3 mL) and stirred at room temperature overnight. The reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)-N-(pyrimidin-4-yl)acetamide (38.0 mg) with a yield of 39.6% as a white solid.

[0566] MS (m / z): 370.0 [M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.92(d,J=1.2Hz,1H),8.66(d,J=5.6Hz,1H),7.98(dd,J=5.6,1. 1Hz, 1H), 5.05 (s, 2H), 3.42-3.31 (m, 1H), 3.14-2.97 (m, 4H), 2.61-2.51 (m, 2H), 1.24 (d, J = 6.8Hz, 6H).

[0568] Example 38: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)acetamide (38)

[0569]

[0570] Synthesis Scheme 1: Synthesis of 2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)acetic acid (37-5) Refer to the preparation method of 37-5 in Example 37, i.e., steps 1 to 4, to prepare compound 37-5.

[0571] Synthesis Scheme 2: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[4,5]thieno[2,3-d]pyridazin-3-yl)acetamide (38)

[0572] Referring to the preparation method of step 5 of Example 37, only B-1 was replaced by B-7. The rest of the preparation method was the same to prepare the target compound 38 (348.0 mg) with a yield of 62.2% as a white solid.

[0573] MS (m / z): 376.0 [M+H] + .

[0574] 1 H NMR(600MHz,DMSO-d6)δ8.26(d,J=7.2Hz,1H),4.97(s,1H),4.66(s,2H),3.76(h,J=7.8Hz,1H),3.32-3.2 2(m,1H),3.08-2.97(m,4H),2.58-2.50(m,2H),2.27-2.18(m,2H),1.99-1.89(m,2H),1.27-1.16(m,9H).

[0575] Example 39: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-6,7,8,9-tetrahydro-6,9-methylbenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (39)

[0576]

[0577] Step 1: Synthesis of 3-chlorobicyclo[2.2.1]hept-2-ene-2-carbaldehyde (39-2)

[0578] First, weigh anhydrous DMF (1.30 g, 17.81 mmol), replace with nitrogen for protection, and cool in an ice-water bath. Then weigh phosphorus oxychloride (2.20 g, 14.52 mmol) and dissolve in DCE (4 mL), and add dropwise to the reaction system. Then continue to stir and react for 45 minutes under ice-water bath temperature control. Remove the ice-water bath and continue to stir and react at room temperature for 30 minutes. Weigh compound 39-1: bicyclo[2.2.1]heptane-2-one (800.0 mg, 7.26 mmol) and dissolve in DCE (2 mL), and add dropwise to the reaction system. After the addition is complete, replace with nitrogen for protection again, heat to 80°C and stir to react overnight. After standing and cooling, the reaction solution was slowly poured into a saturated aqueous sodium bicarbonate solution (100 mL) to quench, and then DCM (50 mL) was added for extraction. The organic phase was separated, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 39-2 (220.0 mg) with a yield of 19.4% as a colorless oily product.

[0579] Step 2: Synthesis of ethyl 2-((3-formylbicyclo[2.2.1]hept-2-en-2-yl)thio)acetate (39-3)

[0580] Compound 39-2 (207.0 mg, 1.32 mmol), ethyl α-mercaptoacetate (159.0 mg, 1.32 mmol) and triethylamine (267.0 mg, 2.64 mmol) were weighed and dissolved in DCE (6 mL), replaced with nitrogen, heated to 60 ° C and stirred overnight. After standing and cooling, the reaction solution was directly decompressed to remove the solvent, and the obtained crude compound 39-3 was directly used in the next step.

[0581] LC-MS (m / z): 241.0 [M+H] + .

[0582] Step 3: Synthesis of ethyl 4,5,6,7-tetrahydro-4,7-methylbenzo[b]thiophene-2-carboxylate (39-4)

[0583] The crude compound 39-3 was dissolved in anhydrous ethanol (4 mL), triethylamine (78.0 mg, 0.77 mmol) was added, and the mixture was replaced with nitrogen for protection, and heated to reflux for 7 hours. The reaction solution was poured into water (60 mL), and EA (50 mL) was added for extraction, and the organic phase was separated, washed with saturated brine (25 mL), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 39-4 (108.0 mg) with a yield of 36.7%, as a light red oily product.

[0584] LC-MS (m / z): 223.0 [M+H] + .

[0585] 1 H NMR (400MHz, Chloroform-d) δ7.56 (s, 1H), 4.33 (q, J = 7.2Hz, 2H), 3.59-3.55 (m, 1H), 3.46-3 .42(m,1H),2.05-1.88(m,3H),1.70-1.63(m,1H),1.37(t,J=7.2Hz,3H),1.17-1.06(m,2H).

[0586] Step 4: Synthesis of ethyl 3-isobutyryl-4,5,6,7-tetrahydro-4,7-methylbenzo[b]thiophene-2-carboxylate (39-5)

[0587] Compound 39-4 (108.0 mg, 0.49 mmol) was added to the flask and replaced with nitrogen. TMPMgCl·LiCl solution (1M, 0.6 mL) was added under ice bath, and the mixture was stirred for 30 minutes. After sufficient stirring, isobutyric anhydride (142.0 mg, 0.75 mmol) was added under ice bath, and stirring was continued overnight. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (15 mL × 2), the organic phases were combined, washed with water (15 mL × 2), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound 39-5 (53.0 mg) with a yield of 37.3%, as a colorless oily product.

[0588] LC-MS (m / z): 293.0 [M+H] + .

[0589] Step 5: Synthesis of 1-isopropyl-6,7,8,9-tetrahydro-6,9-methylbenzo[4,5]thieno[2,3-d]pyridazin-4(3H)-one (39-6)

[0590] Compound 39-5 (53.0 mg, 0.18 mmol) and hydrazine hydrate (0.5 mL) were dissolved in ethanol (3 mL), and the mixture was heated to reflux and stirred for 3 hours after nitrogen replacement protection. After standing and cooling, the ethanol was removed by rotary evaporation. Water (20 mL) was added to the reaction solution, and then DCM (20 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 39-6 (50.0 mg) as a white solid. Compound 39-6 was used directly in the next step without further purification.

[0591] LC-MS (m / z): 261.0 [M+H] + .

[0592] Step 6: Synthesis of ethyl 2-(1-isopropyl-4-oxo-6,7,8,9-tetrahydro-6,9-methylbenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetate (39-7)

[0593] Compound 39-6 (50.0 mg) was dissolved in DMF (5 mL), and anhydrous potassium carbonate (78.7 mg, 0.57 mmol) and ethyl α-bromoacetate (47.0 mg, 0.28 mmol) were added and stirred at room temperature. After the reaction was completed, the reaction solution was poured into water (30 mL) and stirred thoroughly, and EA (15 mL × 2) was added and extracted twice. The organic phases were combined, and then washed with water (25 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 39-7 (30.0 mg) as a colorless oil. The yield of step 5 and step 6 was 45.1%.

[0594] LC-MS (m / z): 347.0 [M+H] + .

[0595] Step 7: Synthesis of 2-(1-isopropyl-4-oxo-6,7,8,9-tetrahydro-6,9-methylbenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetic acid (39-8)

[0596] Compound 39-7 (30.0 mg, 0.09 mmol) and LiOH·H2O (11.40 mg, 0.27 mmol) were added to THF / water (1 mL / 1 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain compound 39-8 (35.0 mg) as a white solid. Compound 39-7 was used directly in the next step without further purification.

[0597] LC-MS (m / z): 319.0 [M+H] + .

[0598] Step 8: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(1-isopropyl-4-oxo-6,7,8,9-tetrahydro-6,9-methylbenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetamide (39)

[0599] The compound 39-8 (35.0 mgl) from the previous step, compound B-7 (16.6 mg, 0.12 mmol), DIPEA (42.6 mg, 0.33 mmol), and HATU (62.7 mg, 0.16 mmol) were added to a DMF solution (3 mL) and stirred at room temperature. After the reaction was completed, the reaction solution was poured into water (30 mL), and EA (30 mL) was added for extraction. The organic phase was then washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 39 (10.9 mg) as a white solid. The yield of step 7 and step 8 was 31.4%.

[0600] MS (m / z): 402.0 [M+H] + .

[0601] 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=7.2Hz,1H),4.97(s,1H),4.66(q,J=15.6Hz,2H),3.79-3.70(m,3H),3.45-3.33(m,1H),2.27-2.18(m ,2H),2.04-1.99(m,3H),1.99-1.90(m,2H),1.74(d,J=8.8Hz,1H),1.33-1.24(m,6H),1.21(s,3H),1.16-1.08(m,1H),1.08-1.0(m,1H).

[0602] Example 40: Preparation of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(9-isopropyl-6-oxo-2,3,4,6-tetrahydro-7H-pyrano[2',3':4,5]thieno[2,3-d]pyridazin-7-yl)acetamide (40)

[0603]

[0604] Step 1: Synthesis of 5-chloro-3,4-dihydro-2H-pyran (40-2)

[0605] First, weigh anhydrous DMF (350.0 mg, 4.79 mmol), replace with nitrogen for protection, and cool in an ice-water bath. Then weigh phosphorus oxychloride (735.0 mg, 4.79 mmol) and dissolve it in DCM (2 mL), and add it dropwise to the reaction system. Then continue to stir and react for 1 hour under ice-water bath temperature control. Weigh compound 40-1: dihydro-2H-pyran-3(4H)-one (400.0 mg, 3.99 mmol) and dissolve it in DCM (1 mL), and add it dropwise to the reaction system. After the addition is complete, continue to stir and react for 2 hours under ice-water bath temperature control. Remove the ice-water bath and continue to stir and react at room temperature for 30 minutes. After standing and cooling, the reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (60 mL) to quench, and then DCM (60 mL) was added for extraction. The organic phase was separated, washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 40-2 (347.0 mg) with a yield of 73.2%. It was a red oil and was used directly in the next step without further purification.

[0606] Step 2: Synthesis of ethyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate (40-3)

[0607] Compound 40-2 (347.0 mg, 2.93 mmol), ethyl α-mercaptoacetate (480.0 mg, 1.32 mmol) and triethylamine (1 mL) were dissolved in DCM (5 mL), replaced with nitrogen, heated to 40°C and stirred overnight. After standing and cooling, the reaction solution was concentrated and purified by column chromatography to obtain compound 40-3 (135.0 mg) with a yield of 21.7% as a colorless oily product.

[0608] LC-MS (m / z): 213.0 [M+H] + .

[0609] 1 H NMR (400MHz, Chloroform-d) δ7.26(s,1H),4.34-4.28(m,2H),4.19-4.15(m,2H),2.81-2.76(m,2H),2.09-2.02(m,2H),1.39-1.31(m,3H).

[0610] Step 3: Synthesis of ethyl 3-isobutyryl-6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate (40-4)

[0611] Compound 40-3 (120.0 mg, 0.57 mmol) was added to the flask and nitrogen was replaced. TMPMgCl·LiCl solution (1M, 0.7 mL) was added under ice bath, and the mixture was stirred for 30 minutes. After sufficient stirring, isobutyric anhydride (159.0 mg, 0.86 mmol) was added under ice bath, and stirring was continued overnight. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (15 mL×2), the organic phases were combined, washed with water (15 mL×2), washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound 40-4 (91.0 mg) with a yield of 57.0% as a colorless oily product.

[0612] LC-MS (m / z): 283.0 [M+H] + .

[0613] Step 4: Synthesis of 9-isopropyl-3,4-dihydro-2H-pyrano[2',3':4,5]thieno[2,3-d]pyridazin-6(7H)-one (40-5)

[0614] Compound 40-4 (86.0 mg, 0.30 mmol) and hydrazine hydrate (1 mL) were dissolved in ethanol (5 mL), and the mixture was heated to reflux and stirred for 5 hours after nitrogen replacement protection. After standing and cooling, the ethanol was removed by rotary evaporation. Water (60 mL) was added to the reaction solution, and then DCM (60 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 40-5 (75.0 mg) as a white solid. Compound 40-5 was used directly in the next step without further purification.

[0615] LC-MS (m / z): 251.0 [M+H] + .

[0616] Step 5: Synthesis of ethyl 2-(9-isopropyl-6-oxo-2,3,4,6-tetrahydro-7H-pyrano[2',3':4,5]thieno[2,3-d]pyridazin-7-yl)acetate (40-6)

[0617] The compound 40-5 (75.0 mg) of the previous step was dissolved in a DMF solution (5 mL), and anhydrous potassium carbonate (124.0 mg, 0.90 mmol) and ethyl α-bromoacetate (75.7 mg, 0.45 mmol) were added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was poured into water (30 mL) and stirred thoroughly, and then EA (15 mL × 2) was added to extract twice, and the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 40-6 (75.0 mg) as a colorless oil. The yield of steps 4 and 5 was 73.2%.

[0618] LC-MS (m / z): 337.0 [M+H] + .

[0619] Step 6: Synthesis of 2-(9-isopropyl-6-oxo-2,3,4,6-tetrahydro-7H-pyrano[2',3':4,5]thieno[2,3-d]pyridazin-7-yl)acetic acid (40-7) Compound 40-6 (75.0 mg, 0.23 mmol) and LiOH·H2O (28.0 mg, 0.66 mmol) were added to THF / water (2 mL / 1 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2N hydrochloric acid, water (10 mL) was added to dilute, and EA was extracted (15 mL×3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. Compound 40-7 (70.0 mg) was obtained as a white solid, and compound 40-7 was used directly in the next step without further purification.

[0620] LC-MS (m / z): 309.0 [M+H] + .

[0621] Step 7: Synthesis of N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-2-(9-isopropyl-6-oxo-2,3,4,6-tetrahydro-7H-pyrano[2',3':4,5]thieno[2,3-d]pyridazin-7-yl)acetamide (40)

[0622] Compound 40-7 (70.0 mg), compound B-7 (34.4 mg, 0.25 mmol), DIPEA (88.0 mg, 0.68 mmol), and HATU (129.5 mg, 0.34 mmol) were added to DMF solution (3 mL) and stirred at room temperature. After the reaction was completed, the reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 40 (64.0 mg) as a white solid. The yield of step 6 and step 7 was 73.3%.

[0623] LC-MS (m / z): 392.0 [M+H] + .

[0624] 1 H NMR (400MHz, DMSO-d6) δ8.25 (d, J = 7.2Hz, 1H), 4.97 (s, 1H), 4.65 (s, 2H), 4.34-4.27 (m, 2H), 3.82-3.71 (m, 1H), 3.62-3. 51(m,1H),2.95-2.87(m,2H),2.27-2.18(m,2H),2.07-2.04(m,2H),1.98-1.89(m,2H),1.23-1.20(m,6H),1.19(s,3H).

[0625] Example 41: Preparation of 2-(7-bromo-1-isopropyl-4-oxopyrrolo[1,2-d][1,2,4]triazine-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (41)

[0626]

[0627] Step 1: Synthesis of 1-(4-bromo-1H-pyrrol-2-yl)-2-methylpropan-1-one (41-2)

[0628] Compound 41-1: 1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)-2-methylpropan-1-one (2.35 g, 6.80 mmol) was dissolved in DCM (40 mL), BF3·Et2O (1.70 mL, 13.60 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. When the reaction was complete as monitored by LC-MS, the reaction solution was quenched with aqueous sodium bicarbonate solution, the liquids were separated, and the aqueous phase was extracted with DCM (20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was redissolved in a mixed solvent of ethanol (40 mL) and water (10 mL), potassium carbonate (4.0 g) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure to remove the solvent, the concentrate was diluted with (20 mL), extracted with EA (30 mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 41-2 (1.0 g) with a yield of 68.0% as a white solid.

[0629] LC-MS (m / z): 216.0 / 218.0 [M+H] + .

[0630] Step 2: Synthesis of 4-bromo-2-(1-hydrazono-2-methylpropyl)-1H-pyrrole (41-3)

[0631] A mixture of compound 41-2 (0.56 g, 2.60 mmol) and hydrazine hydrate (80%, 8 mL) was placed at 90°C for 8 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was diluted with EA (25 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 41-3 (0.31 g) with a yield of 52.2% as a white solid.

[0632] LC-MS (m / z): 230.0 / 232.0 [M+H] + .

[0633] Step 3: Synthesis of 4-bromo-2-(1-(2-(isopropylcarbonyl)hydrazono)-2-methylpropyl)-1H-pyrrole-1-carboxylic acid isopropyl ester (41-4)

[0634] Compound 41-3 (0.31 g, 1.35 mmol) and pyridine (0.27 mL, 3.40 mmol) were dissolved in DCM (10 mL), and isopropyl chloroformate (0.37 mL, 2.70 mmol) was added dropwise under an ice-water bath, and the reaction solution was left to react at room temperature overnight. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated and purified by column chromatography to obtain compound 41-4 (166.0 mg) with a yield of 30.6% as a white solid.

[0635] LC-MS (m / z): 402.0 / 404.0 [M+H] + .

[0636] Step 4: Synthesis of 7-bromo-1-isopropylpyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (41-5)

[0637] Compound 41-4 (166.0 mg, 0.41 mmol) and sodium methoxide (111.0 mg, 2.05 mmol) were dissolved in MeOH (8 mL), and the reaction solution was placed in a sealed tube and reacted at 100° C. for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was quenched with saturated aqueous ammonium chloride solution (0.5 mL), concentrated, and the concentrate was purified by column chromatography to obtain compound 41-5 (102.0 mg) with a yield of 96.9% as a white solid.

[0638] LC-MS (m / z): 256.0 / 258.0 [M+H] + .

[0639] Step 5: Synthesis of tert-butyl 2-(7-bromo-1-isopropyl-4-oxypyrrolo[1,2-d][1,2,4]triazine-3(4H)-yl)acetate (41-6)

[0640] 7-Bromo-1-isopropylpyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (102.0 mg, 0.40 mmol) and tert-butyl bromoacetate (156.0 mg, 0.80 mmol) were dissolved in DMF (5 mL), cesium carbonate (130.0 mg, 0.40 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed as monitored by LC-MS, the reaction solution was diluted with EA (20 mL), washed with water (15 mL×3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 41-6 (148.0 mg) with a yield of 99.9% as a white solid.

[0641] LC-MS (m / z): 314.0 / 316.0 [M- t Bu+H] + .

[0642] Step 6: Synthesis of 2-(7-bromo-1-isopropyl-4-oxopyrrolo[1,2-d][1,2,4]triazine-3(4H)-yl)acetic acid (41-7)

[0643] Compound 41-6 (148.0 mg, 0.40 mmol) was dissolved in 1,4-dioxane (4 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 4 mL) was added, and the mixture was reacted at 50°C for 7 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated to obtain a crude compound 41-7 (126.0 mg) as a brown solid, which was used directly in the next step without further purification.

[0644] LC-MS (m / z): 314.0 / 316.0 [M+H] + .

[0645] Step 7: Synthesis of 2-(7-bromo-1-isopropyl-4-oxopyrrolo[1,2-d][1,2,4]triazine-3(4H)-yl)-N-(pyrimidin-4-yl)acetamide (41)

[0646] Compound 41-7 (41.0 mg), compound B-1 (15.0 mg, 0.16 mmol) and DIPEA (0.06 mL, 0.39 mmol) were dissolved in DCM (4 mL), HATU (99.0 mg, 0.26 mmol) was added, and the mixture was allowed to react overnight at room temperature. After the reaction was complete as monitored by LC-MS, the reaction solution was diluted with DCM (20 mL), washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse preparation to obtain the target compound 41 (11.0 mg) as a white solid. The yield of steps 6 and 7 was 21.6%.

[0647] LC-MS (m / z): 391.0 / 393.0 [M+H] + .

[0648] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.92(s,1H),8.67(d,J=6.0Hz,1H),8.07-7.93(m ,2H),7.23-7.19(m,1H),4.96(s,2H),3.20(hept,J=6.8Hz,1H),1.25(d,J=6.8Hz,6H).

[0649] Example 42: Preparation of 2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(pyrimidin-4-yl)acetamide (42)

[0650]

[0651] Step 1: Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde (42-2)

[0652] Compound 42-1: 2-imidazole carboxaldehyde (5.0 g, 52.04 mmol) was dissolved in THF (50 mL), triethylamine (31.59 g, 312.21 mmol) was added, and the mixture was stirred for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (11.28 g, 67.65 mmol) was added under an ice-water bath, and the mixture was returned to room temperature for 4 hours after the addition. The reaction solution was quenched with water (50 mL), extracted with EA three times (50 mL × 3), and the combined organic phase was washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain compound 42-2 (8.03 g) with a yield of 68.2% as an off-white solid.

[0653] LC-MS (m / z): 227.0 / 229.0 [M+H] + .

[0654] Step 2: Synthesis of 2-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)propan-1-ol (42-3)

[0655] Compound 42-2 (8.03 g, 35.48 mmol) was dissolved in dry THF (80 mL), the atmosphere was replaced with nitrogen, and then dropwise added under an ice-water bath. i PrMgBr (141.90 mL, 141.90 mmol) was added dropwise and the mixture was returned to room temperature for 16 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was quenched with a saturated aqueous solution of ammonium chloride, the mixture was added with water (150 mL), extracted with EA three times (80 mL × 3), the combined organic phase was washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 42-3 (9.5 g) as an off-white solid. Compound 42-3 was used directly in the next step without further purification.

[0656] LC-MS (m / z): 271.0 / 273.0 [M+H] + .

[0657] Step 3: Synthesis of 2-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)propan-1-one (42-4)

[0658] Compound 42-3 (9.5 g, 35.48 mmol) was dissolved in THF (50 mL), and Dess-Martin periodinane (15.30 g, 36.10 mmol) was added in an ice-water bath, and the mixture was allowed to react at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution (100 mL) was added dropwise during the reaction, and the mixture was stirred for 20 minutes. A 15% sodium thiosulfate aqueous solution (100 mL) was added, and the mixture was stirred for 20 minutes to quench the mixture. The mixture was filtered, and the filter cake was washed with EA (50 mL). The filtrate was extracted with EA three times (50 mL × 3), and the combined organic phase was washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain compound 42-4 (4.17 g) as an off-white solid. The yield of steps 2 and 3 was 43.8%.

[0659] LC-MS (m / z): 269.0 / 271.0 [M+H] + .

[0660] Step 4: Synthesis of 1-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2-methylpropan-1-one (42-5)

[0661] Compound 42-4 (3.0 g, 11.18 mmol) was dissolved in THF (30 mL), N-bromosuccinimide (2.59 g, 14.53 mmol) was added, and the mixture was stirred for 3 hours. When the reaction was complete as monitored by LC-MS, the mixture was quenched with water (60 mL), extracted with EA three times (30 mL × 3), and the combined organic phase was washed once with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 42-5 (2.71 g) with a yield of 69.8% as an off-white solid.

[0662] LC-MS (m / z): 347.0 / 349.0 [M+H] + .

[0663] Step 5: Synthesis of 1-(4-bromo-1H-imidazol-2-yl)-2-methylpropan-1-one (42-6)

[0664] Compound 42-5 (2.71 g, 7.80 mmol) was dissolved in DCM (40 mL), and BF3·Et2O complex (908.0 mg, 15.60 mmol) was added and allowed to react at room temperature for 1 hour. The reaction solution was quenched with sodium bicarbonate aqueous solution, separated, and the aqueous phase was extracted with DCM (20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was redissolved in a mixed solvent of ethanol (40 mL) and water (10 mL), potassium carbonate (4.0 g) was added, and stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, the concentrate was diluted with water (20 mL), extracted with EA (30 mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 42-6 (1.23 g) with a yield of 72.7%, an off-white solid.

[0665] LC-MS (m / z): 217.0 / 219.0 [M+H] + .

[0666] Step 6: Synthesis of (Z)-ethyl 2-(1-(4-bromo-1H-imidazol-2-yl)-2-methylpropylidene)hydrazine-1-carboxylate (42-7)

[0667] Compound 42-6 (0.50 g, 2.30 mmol), ethyl carbazate (479 mg, 4.60 mmol), and 2 drops of acetic acid were added to ethanol (10 mL) and reacted at 85°C for 16 hours. The reaction solution was quenched with water (20 mL), extracted with EA three times (10 mL×3), and the combined organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain compound 42-7 (0.60 g) with a yield of 43.0% as an off-white solid.

[0668] LC-MS (m / z): 303.0 / 305.0 [M+H] + .

[0669] Step 7: Synthesis of 2-bromo-8-isopropylimidazole[1,2-d][1,2,4]triazine-5(6H)-one (42-8)

[0670] Compound 42-7 (0.50 g, 1.65 mmol) and sodium methoxide (111.0 mg, 2.05 mmol) were dissolved in MeOH (8 mL), and the reaction solution was placed in a sealed tube and reacted at 100° C. for 30 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution (0.5 mL), concentrated, and the concentrate was purified by column chromatography to obtain compound 42-8 (0.41 g) with a yield of 96.7% as an off-white solid.

[0671] LC-MS (m / z): 257.0 / 259.0 [M+H] + .

[0672] Step 8: Synthesis of tert-butyl 2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetate (42-9)

[0673] Compound 42-8 (0.41 g, 1.56 mmol) and tert-butyl bromoacetate (607.0 mg, 3.11 mmol) were dissolved in DMF (5 mL), cesium carbonate (1.52 g, 4.67 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was diluted with EA (20 mL), washed with water (15 mL × 3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 42-9 (568.0 mg) with a yield of 98.1% as an off-white solid.

[0674] LC-MS (m / z): 371.0 / 373.0 [M- t Bu+H] + .

[0675] Step 9: Synthesis of 2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid (42-10)

[0676] Compound 42-9 (120.0 mg, 0.32 mmol) was dissolved in 1,4-dioxane (4 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 4 mL) was added, and the mixture was reacted at 60° C. for 4 hours. The reaction solution was concentrated to obtain compound 42-10 (89.0 mg) with a yield of 88.3% as an off-white solid.

[0677] LC-MS (m / z): 315.0 / 317.0 [M+H] + .

[0678] Step 10: Synthesis of 2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(pyrimidin-4-yl)acetamide (42)

[0679] The crude compound 42-10 (89.0 mg, 0.28 mmol), compound B-1 (40.0 mg, 0.42 mmol) and DIPEA (86.0 mg, 0.85 mmol) were dissolved in DCM (4 mL), HATU (215.0 mg, 0.56 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with DCM (20 mL), washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse preparation to obtain the target compound 42 (7.50 mg) with a yield of 6.8% as a white solid.

[0680] LC-MS (m / z): 392.0 / 394.0 [M+H] + .

[0681] 1 H NMR (600MHz, DMSO-d6) δ11.29(s,1H),8.92(s,1H),8.68(d,J=6.0Hz,1H),8.36(s, 1H), 7.99 (d, J = 6.0Hz, 1H), 5.03 (s, 2H), 3.39-3.32 (m, 1H), 1.31 (d, J = 6.6Hz, 6H).

[0682] Example 43: Preparation of (R)-2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,5-d][1,2,4]triazine-6(5H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (43)

[0683]

[0684] Synthesis Scheme 1: Synthesis of 2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid (42-10)

[0685] Referring to the preparation method of compound 42-10 in Example 42, ie, steps 1 to 9, compound 42-10 was prepared.

[0686] Synthesis Scheme 2: Synthesis of (R)-2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,5-d][1,2,4]triazine-6(5H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (43)

[0687] Step 1: Synthesis of (R)-tert-butyl 3-(2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamido)piperidine-1-carboxylate (43-1)

[0688] Compound 42-10 (287.0 mg, 0.91 mmol), compound B-13 (364.0 mg, 1.82 mmol) and DIPEA (470.0 mg, 3.64 mmol) were dissolved in DCM (4 mL), HATU (692.0 mg, 1.82 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with EA (20 mL), washed with water (15 mL × 3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 43-1 (312.0 mg) with a yield of 70.0% as a white solid.

[0689] LC-MS (m / z): 497.0 / 499.0 [M- t Bu+H] + .

[0690] Step 2: Synthesis of (R)-2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (43-2)

[0691] Compound 43-1 (312.0 mg, 0.63 mmol) was dissolved in 1,4-dioxane (6 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 4 mL) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated to obtain compound 43-2 (355.0 mg) as a white solid, which was used directly in the next step without further purification.

[0692] LC-MS (m / z): 397.0 / 399.0 [M+H] + .

[0693] Step 3: Synthesis of (R)-2-(2-bromo-8-isopropyl-5-oxoimidazolo[1,5-d][1,2,4]triazine-6(5H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (43)

[0694] The crude compound 43-2 (355 mg), ethyl bromide (195 mg, 1.79 mmol), potassium carbonate (741 mg, 5.36 mmol) were placed in DMF (13 mL) and reacted at room temperature for 3 hours. The reaction solution was diluted with EA (20 mL), washed with water (15 mL × 3) and saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse preparation to obtain the target compound 43 (45.0 mg) as a white solid. The yield of step 2 and step 3 was 16.8%.

[0695] LC-MS (m / z): 425.0 [M+H]+ .

[0696] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.0(d,J=8.0Hz,1H),4.66(s,2H),3.83-3 .70(m,1H),3.42-3.22(m,1H),2.80-2.73(m,1H),2.70-2.61(m,1H),2.43-2.28 (m,2H),1.97(t,J=10.8Hz,1H),1.84(t,J=10.0Hz,1H),1.76-1.62(m,2H),1.5 4-1.41(m,1H),1.30(d,J=6.8Hz,6H),1.26-1.10(m,1H),0.98(t,J=7.2Hz,3H).

[0697] Example 44: Preparation of 2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (44)

[0698]

[0699] Step 1: Synthesis of 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (44-2)

[0700] Compound 44-1: 3,5-dibromo-1H-pyrazole (2.26 g, 10.0 mmol) and TsOH·H2O (95.0 mg, 0.50 mmol) were dissolved in DCM (10 mL), and 3,4-dihydro-2H-pyran (1.82 mL, 20.0 mmol) was added under an ice-water bath, and the mixture was allowed to react at room temperature. After the reaction, the reaction solution was diluted with DCM (20 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL), water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 44-2 (2.58 g) with a yield of 83.2% as a colorless oily liquid.

[0701] LC-MS (m / z): 227.0 [M+H-THP] + .

[0702] Step 2: Synthesis of 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-methylpropan-1-one (44-3)

[0703] Compound 44-2 (2.26 g, 7.30 mmol) was dissolved in anhydrous THF (30 mL) and added dropwise under an ice-water bath. i PrMgCl in THF solution (2.0M, 4.40mL, 8.70mmol) was heated for 30 minutes. Isobutyric anhydride (1.80mL, 11.0mmol) was added to the reaction solution, and the reaction solution was gradually warmed to room temperature for 3 hours. The reaction solution was quenched with aqueous ammonium chloride solution (20mL), extracted with EA (30mL×2), the organic phases were combined, washed with water (20mL) and saturated brine (20mL), dried with sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 44-3 (2.01g) with a yield of 91.4%, as a colorless oily liquid.

[0704] LC-MS(m / z):217.0 / 219.0[M+H-THP] + .

[0705] Step 3: Synthesis of 1-(3-bromo-1H-pyrazol-5-yl)-2-methylpropan-1-one (44-4)

[0706] Compound 44-3 (2.01 g, 6.67 mmol) was dissolved in HCl / EA (1.0 M, 20 mL) and allowed to react at room temperature overnight. The pH was adjusted to greater than 8 with saturated sodium carbonate aqueous solution, and the liquid was separated. The aqueous phase was extracted with EA (20 mL). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was slurried with EA (5 mL) and petroleum ether (10 mL), filtered, and compound 44-4 (783.0 mg) was obtained with a yield of 54.0% as a white solid.

[0707] LC-MS (m / z): 217.0 / 219.0 [M+H] + .

[0708] Step 4: Synthesis of ethyl 2-(1-(3-bromo-1H-pyrazol-5-yl)-2-methylpropylidene)hydrazine-1-carboxylate (44-5)

[0709] Compound 44-4 (0.78 g, 3.60 mmol) and ethyl hydrazinecarboxylate (0.75 g, 7.20 mmol) were dissolved in anhydrous ethanol (20 mL), 2 drops of acetic acid were added, and the reaction solution was placed at 80°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography to obtain compound 44-5 (676.0 mg) with a yield of 62.0% as a white solid.

[0710] LC-MS (m / z): 303.0 / 305.0 [M+H] + .

[0711] Step 5: Synthesis of ethyl 2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetate (44-6)

[0712] Compound 44-5 (0.51 g, 1.67 mmol) was dissolved in DMF solution (18 mL), cesium carbonate (0.54 g, 1.67 mmol) was added, and the reaction solution was placed at 50 ° C for overnight reaction. The reaction solution was cooled to room temperature, α-bromoethyl acetate (0.33 g, 3.60 mmol) was added, and the reaction was placed at room temperature for overnight reaction. The reaction solution was diluted with water (20 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with water (20 mL × 3) and saturated brine (20 mL), dried with sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 44-6 (0.50 g) with a yield of 87.8% as a white solid.

[0713] LC-MS (m / z): 343.0 / 345.0 [M+H- t Bu] + .

[0714] Step 6: Synthesis of 2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetic acid (44-7)

[0715] Compound 44-6 (0.50 g, 1.47 mmol) was dissolved in THF (10 mL), and an aqueous solution (5 mL) of LiOH·H2O (74.0 mg, 1.76 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was adjusted to a pH of less than 4 with dilute hydrochloric acid, extracted with EA (20 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse preparation to obtain compound 44-7 (187.0 mg) with a yield of 40.4% as a white solid.

[0716] LC-MS (m / z): 315.0 / 317.0 [M+H] + .

[0717] Step 7: Synthesis of 2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(pyrimidin-4-yl)acetyl (44)

[0718] Compound 44-7 (63.0 mg, 0.20 mmol), B-1 (22.8 mg, 0.24 mmol), DIPEA (77.5 mg, 0.60 mmol) and HATU (114.0 mg, 0.30 mmol) were added to a DMF solution (3 mL) and stirred overnight at room temperature. The reaction solution was poured into water (10 mL), and EA (10 mL) was added for extraction. The organic phase was then washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 44 (38.0 mg) with a yield of 48.7% as a white solid.

[0719] LC-MS (m / z): 392.0 / 394.0 [M+H] + .

[0720] 1 H NMR (600MHz, DMSO-d6) δ11.31(s,1H),8.92(s,1H),8.68(d,J=6.0Hz,1H),7.99(d,J=6 .0Hz,1H),7.45(s,1H),5.02(s,2H),3.20(hept,J=6.6Hz,1H),1.26(d,J=6.6Hz,6H).

[0721] Example 45: Preparation of 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (45)

[0722]

[0723] Synthesis Scheme 1: Synthesis of 1-(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-methylpropan-1-one (44-3)

[0724] Referring to the preparation method of compound 44-3 in Example 44, ie, step 1 to step 2, compound 44-3 was prepared.

[0725] Synthesis Scheme 2: Synthesis of 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (45)

[0726] Step 1: Synthesis of 2-methyl-1-(3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)propan-1-one (45-1)

[0727] Compound 44-3 (2.33 g, 7.40 mmol), isopropenylboronic acid pinacol ester (1.87 g, 11.10 mmol), Pd(PPh3)4 (855.0 mg, 0.74 mmol) and cesium carbonate (6.02 g, 18.50 mmol) were added to a mixed solution of 1,4-dioxane (60 mL) and water (6 mL), and the reaction solution was placed at 100 ° C for overnight reaction under nitrogen protection. The reaction solution was filtered, the filtrate was diluted with EA (60 mL), washed with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 45-1 (1.57 g) with a yield of 80.9% as a colorless oily liquid.

[0728] LC-MS (m / z): 179.0 [M+H-THP] + .

[0729] Step 2: Synthesis of 1-(3-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-methylpropan-1-one (45-2)

[0730] Compound 45-1 (1.57 g, 6.0 mmol) was dissolved in EA (20 mL), 10% Pd / C (containing 45% water, 0.29 g) was added, and after replacement with hydrogen, the mixture was allowed to react overnight at room temperature. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain compound 45-2 (1.45 g) with a yield of 92.1% as a colorless oily liquid.

[0731] LC-MS (m / z): 181.0 [M+H-THP] + .

[0732] Step 3: Synthesis of 1-(3-isopropyl-1H-pyrazol-5-yl)-2-methylpropan-1-one (45-3)

[0733] Compound 45-2 (1.45 g, 5.50 mmol) was dissolved in 1,4-dioxane (15 mL), and hydrogen chloride / 1,4-dioxane solution (4.0 M, 5 mL) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was adjusted to alkalinity with sodium bicarbonate solution, extracted with EA (20 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 45-3 (802.0 mg) with a yield of 81.0%, as a white solid.

[0734] LC-MS (m / z): 181.0 [M+H] + .

[0735] Step 4: Synthesis of ethyl 2-(1-(3-isopropyl-1H-pyrazol-5-yl)-2-methylpropyl)hydrazine-1-carboxylate (45-4)

[0736] Compound 45-3 (396.0 mg, 2.20 mmol) and ethyl hydrazinecarboxylate (457.6 mg, 4.40 mmol) were dissolved in anhydrous ethanol (20 mL), 2 drops of acetic acid were added, and the reaction solution was placed at 80° C. to react overnight. The reaction solution was concentrated and purified by column chromatography to obtain compound 45-4 (518.0 mg) with a yield of 88.5% as a white solid.

[0737] LC-MS (m / z): 267.0 [M+H] + .

[0738] Step 5: Synthesis of tert-butyl 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-acetate (45-5)

[0739] Compound 45-4 (518.0 mg, 1.95 mmol) was dissolved in DMF solution (15 mL), and anhydrous cesium carbonate solid (0.96 g, 2.90 mmol) and tert-butyl α-bromoacetate (565.5 mg, 2.90 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (80 mL) and stirred thoroughly, and then EA (40 mL × 2) was added to extract twice, and the organic phases were combined, and then the organic phases were washed with water (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 45-5 (547.0 mg) with a yield of 84.0%, as a colorless oily liquid.

[0740] LC-MS (m / z): 335.0 [M+H] + .

[0741] Step 6: Synthesis of 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetic acid (45-6)

[0742] Compound 45-5 (547.0 mg, 1.64 mmol) was added to HCl / EA solution (4.0 M, 10 mL) and reacted at 50°C for 3 hours. The reaction solution was concentrated to dryness to obtain compound 45-6 (550.0 mg) as a white solid, which was used directly in the next step without further purification.

[0743] LC-MS (m / z): 278.0 [M+H] + .

[0744] Step 7: Synthesis of 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (45)

[0745] Compound 45-6 (56.0 mg), B-1 (23.0 mg, 0.24 mmol), DIPEA (78.0 mg, 0.60 mmol) and HATU (115.0 mg, 0.30 mmol) were added to DMF (3 mL) and stirred at room temperature overnight. The reaction solution was poured into water (60 mL), and EA (60 mL) was added for extraction. The organic phase was then washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 45 (28.0 mg) with a yield of 47.2% as a white solid.

[0746] LC-MS (m / z): 356.0 [M+H] + .

[0747] 1 H NMR (600MHz, DMSO-d6) δ11.30(s,1H),8.92(s,1H),8.67(d,J=6.0Hz,1H),7.98(d,J=6.0Hz,1 H),7.07(s,1H),5.0(s,2H),3.27-3.08(m,2H),1.31(d,J=7.2Hz,6H),1.27(d,J=7.2Hz,6H).

[0748] Example 46: Preparation of (R)-2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide

[0749]

[0750] Synthesis Scheme 1: Synthesis of 2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetic acid (44-7)

[0751] Referring to the preparation method of compound 44-7 in Example 44, ie, step 1 to step 6, compound 44-7 was prepared.

[0752] Synthesis Scheme 2: Synthesis of (R)-2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (46)

[0753] Step 1: Synthesis of (R)-tert-butyl 3-(2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetamido)piperidine-1-carboxylate (46-1)

[0754] Referring to the synthesis method described in step 7 of Example 44, only B-1 was replaced by B-13 to obtain compound 46-1 with a yield of 86.4% as a yellow solid.

[0755] MS (m / z): 397.0 / 399.0 [M+H-Boc] + .

[0756] Step 2: Synthesis of (R)-2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (46-2)

[0757] Compound 46-1 (172.0 mg, 0.35 mmol) was dissolved in EA (3 mL), and HCl / EA solution (1.2 mL) was added and stirred at room temperature. After the reaction was completed, the reaction solution was directly dried by a rotary evaporator to remove the solvent to obtain compound 46-2 (112.0 mg) with a yield of 81.7% as a white solid.

[0758] MS (m / z): 397.0 / 399.0 [M+H] + .

[0759] Step 3: Synthesis of (R)-2-(2-bromo-4-isopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (46)

[0760] Compound 46-2 (104.0 mg, 0.26 mmol) and bromoethane (57.0 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), anhydrous potassium carbonate (108.0 mg, 0.78 mmol) was added, and the mixture was allowed to react at room temperature for 4 hours. The reaction solution was diluted with EA (20 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase preparation to obtain compound 46 (45.0 mg) with a yield of 40.9% as a white solid.

[0761] MS (m / z): 425.0 / 427.0 [M+H] + .

[0762] 1H NMR (400MHz, DMSO-d6) δ8.05 (d, J = 8.0Hz, 1H), 7.41 (s, 1H), 4.65 (s, 2H), 3.82-3. 69(m,1H),3.18(hept,J=6.8Hz,1H),2.84-2.75(m,1H),2.74-2.68(m,1H),2.45- 2.31(m,2H),2.01(t,J=11.2Hz,1H),1.88(t,J=10.0Hz,1H),1.75-1.62(m,2H),1 .55-1.39(m,1H),1.25(d,J=6.8Hz,6H),1.22-1.12(m,1H),0.99(t,J=7.2Hz,3H).

[0763] Example 47: Preparation of (R)-2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (47)

[0764]

[0765] Synthesis Scheme 1: Synthesis of 2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetic acid (45-6)

[0766] Referring to the preparation method of compound 45-6 in Example 45, compound 45-6 was prepared.

[0767] Synthesis Scheme 2: Synthesis of (R)-2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (47)

[0768] Step 1: Synthesis of tert-butyl (R)-3-(2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)acetamido)piperidine-1-carboxylate

[0769] Referring to the preparation method of step 7 of Example 45, only B-1 was replaced by B-13, and compound 47-1 (343.00 mg) was obtained from compound 45-6 (167.0 mg, 0.60 mmol) as a yellow oily liquid. Compound 47-1 was directly used in the next step without further purification.

[0770] MS (m / z): 361.0 [M+H-Boc] + .

[0771] Step 2: Synthesis of (R)-2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(piperidin-3-yl)acetamide hydrochloride (47-2)

[0772] Compound 47-1 (343.0 mg) was dissolved in EA (4 mL), HCl / EA solution (4.0 M, 2 mL) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was concentrated to dryness to obtain compound 47-2 (373.0 mg) as a white solid, which was used directly in the next step without further purification.

[0773] MS (m / z): 361.0 [M+H] + .

[0774] Step 3: Synthesis of (R)-2-(2,4-diisopropyl-7-oxopyrazolo[1,5-d][1,2,4]triazine-6(7H)-yl)-N-(1-ethylpiperidin-3-yl)acetamide (47)

[0775] Compound 47-2 (373.0 mg) and bromoethane (131.0 mg, 1.20 mmol) were added to acetonitrile (6 mL), anhydrous potassium carbonate (249.0 mg, 1.80 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was diluted with EA (15 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse preparation to obtain compound 47 (92.0 mg) as a white solid. The total yield of the three-step reaction from step 1 to step 3 was 39.4%.

[0776] MS (m / z): 389.0 [M+H] + .

[0777] 1 H NMR(600MHz,DMSO-d6)δ8.18(s,1H),8.04(d,J=7.8Hz,1H),7.02(s,1H),4.67-4.58(m, 2H),3.82-3.71(m,1H),3.23-3.07(m,2H),2.83-2.76(m,1H),2.72-2.65(m,1H),2.46-2 .32(m,2H),2.08-1.95(m,1H),1.94-1.81(m,1H),1.76-1.65(m,2H),1.54-1.42(m,1H) ,1.31(d,J=6.6Hz,6H),1.26(d,J=6.6Hz,6H),1.24-1.18(m,1H),0.99(t,J=7.2Hz,3H).

[0778] Example 48: Preparation of 2-(1-(dimethylamino)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)acetamide (48)

[0779]

[0780] Step 1: Synthesis of dimethyl benzo[b]thiophene-2,3-dicarboxylate (48-2)

[0781] Compound 48-1: diphenyl disulfide (6.0 g, 27.49 mmol), dimethyl butynedioate (13.7 g, 96.83 mmol), K2S2O8 (16.4 g, 60.67 mmol), TBAB (887.0 mg, 2.75 mmol) were weighed into a round-bottom flask, and DCE (120 mL) was added, and the mixture was stirred at 90°C for 24 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, the organic phase was evaporated to dryness, and purified by column chromatography to obtain compound 48-2 (6.75 g) with a yield of 49.1% as a yellow solid.

[0782] MS (m / z): 251.0 [M+H] + .

[0783] Step 2: Synthesis of 1-hydroxybenzo[4,5]thieno[2,3-d]pyridazin-4(3H)-one (48-3)

[0784] Compound 48-2 (8.9 g, 35.56 mmol) was weighed into a round-bottom flask, ethanol (250 mL) was added, hydrazine hydrate (33 mL) was added, and the mixture was stirred at 90°C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0°C and filtered, the solid was collected and dried to obtain compound 48-3 (6.86 g) with a yield of 88.4% as a white solid.

[0785] MS (m / z): 219.0 [M+H] + .

[0786] Step 3: Synthesis of 1,4-dibromobenzo[4,5]thiophene[2,3-d]pyridazine (48-4)

[0787] Compound 48-3 (5.40 g, 24.75 mmol) and PBr5 (22.40 g, 51.97 mmol) were weighed in a round-bottom flask, and DCE (100 mL) was added. The mixture was stirred at 90°C for 48 hours. After the reaction was completed, the reaction mixture was diluted with distilled water (30 mL), extracted with DCM (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried under reduced pressure. The crude compound 48-4 (4.20 g) was obtained with a yield of 61.8% as a yellow solid.

[0788] MS (m / z): 345.0 [M+H] + .

[0789] Step 4: Synthesis of 1-bromobenzo[4,5]thieno[2,3-d]pyridazin-4(3H)-one (48-5)

[0790] The crude compound 48-4 (4.2 g, 12.33 mmol) was weighed in a round-bottom flask, glacial acetic acid (100 mL) was added, and the mixture was stirred at 80°C for 24 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL), extracted with EA (50 mL × 3), the combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried under reduced pressure. The residue was purified by column chromatography to obtain compound 48-5 (2.40 g) with a yield of 69.8% as a yellow solid.

[0791] MS (m / z): 281.0 / 283.0 [M+H] + .

[0792] Step 5: Synthesis of ethyl 2-(1-bromo-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)acetate (48-6)

[0793] Compound 26-5 (2.40 g, 8.54 mmol), ethyl α-bromoacetate (2.85 g, 17.08 mmol), potassium carbonate (1.77 g, 12.81 mmol) were weighed in a round-bottom flask, and DMF (20 mL) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with distilled water (15 mL), extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography to obtain compound 48-6 (0.37 g) with a yield of 11.8% as a white solid.

[0794] MS (m / z): 367.0 / 369.0 [M+H] + .

[0795] Step 6: Synthesis of ethyl 2-(1-(dimethylamino)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetate (48-7)

[0796] Compound 48-6 (50.0 mg, 0.14 mmol), dimethylamine (2.0 M THF solution, 1.40 mL, 2.73 mmol), DIPEA (88.0 mg, 0.69 mmol) were weighed in a sealed tube, DMSO (2 mL) was added, and the mixture was stirred at 120 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (5 mL), extracted with EA (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 48-7 (35.0 mg) with a yield of 77.8% as a white solid.

[0797] MS (m / z): 332.0 [M+H] + .

[0798] Step 7: Synthesis of 2-(1-(dimethylamino)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)yl)acetic acid (48-8)

[0799] Compound 48-7 (30.0 mg, 0.09 mmol) was weighed into a round-bottom flask, THF (1 mL), water (1 mL) and LiOH·H2O (11.40 mg, 0.27 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was distilled under reduced pressure to remove THF, the pH was adjusted to 2-3 with 2M hydrochloric acid, water (5 mL) was added to dilute, and EA was extracted (15 mL×3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain compound 48-8 (22.0 mg) with a yield of 81.5% as a white solid.

[0800] MS (m / z): 304.0 [M+H] + .

[0801] Step 8: Synthesis of 2-(1-(dimethylamino)-4-oxobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)acetamide (48)

[0802] Compound 48-8 (22.0 mg, 0.07 mmol) was dissolved in DMF (1 mL), and B-7 (12.0 mg, 0.09 mmol), DIPEA (37.0 mg, 0.22 mmol) and HATU (49.0 mg, 0.15 mmol) were added in sequence, and reacted at room temperature. After the reaction was completed, distilled water (5 mL) was added for dilution, and EA (15 mL × 3) was used for extraction. The organic phases were combined and washed with saturated sodium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound 48 (15.0 mg) with a yield of 53.6% as a white solid.

[0803] MS (m / z): 387.0 [M+H] + .

[0804] 1 H NMR (600MHz, DMSO-d6) δ8.49-8.42(m,1H),8.35-8.26(m,2H),7.75-7.65(m,2H),4.98(s,1H),4. 68(s,2H),3.78(d,J=7.8Hz,1H),2.81(s,6H),2.30-2.16(m,2H),2.01-1.86(m,2H),1.21(s,3H).

[0805] Example 49: Preparation of 2-(7-(2-hydroxypropan-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)-N-(pyrimidin-4-yl)acetamide (49)

[0806]

[0807] Step 1: Synthesis of ethyl 2-isobutyrylthiophene-3-carboxylate (49-2)

[0808] Compound 49-1: Thiophene-3-carboxylic acid ethyl ester (0.78 g, 5.0 mol) was dissolved in anhydrous THF (30 mL). Under nitrogen protection, TMPMgCl·LiCl (1.0 M THF solution, 6 mL, 6.0 mmol) was added in an ice-water bath and the mixture was kept warm for 1 hour. Isobutyric anhydride (1.24 mL, 7.50 mmol) was added in an ice-water bath and the temperature was gradually raised to room temperature for overnight reaction. The reaction solution was quenched with saturated aqueous ammonium chloride solution, EA (50 mL) was added, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 49-2 (0.80 g) with a yield of 71.3% as a colorless oily liquid.

[0809] MS (m / z): 227.0 [M+H]+ .

[0810] Step 2: Synthesis of 7-isopropylthieno[2,3-d]pyridazin-4(5H)-one (49-3)

[0811] Compound 49-2 (0.80 g, 3.50 mmol) was dissolved in anhydrous ethanol (10 mL), hydrazine hydrate (80%, 2 mL) was added and reacted at 80°C for 1.5 hours. The reaction solution was diluted with EA (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 49-3 (0.60 g) with a yield of 88.4% as a white solid.

[0812] MS (m / z): 195.0 [M+H] + .

[0813] Step 3: Synthesis of ethyl 2-(7-isopropyl-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate (49-4)

[0814] Compound 49-3 (194.0 mg, 1.0 mmol) and ethyl α-bromoacetate (167.0 mg, 3.0 mmol) were dissolved in DMF (5 mL), anhydrous cesium carbonate (651 mg, 2.0 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction solution was diluted with EA (20 mL), washed with water (15 mL × 3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 49-4 (255.0 mg) with a yield of 91.1% as a white solid.

[0815] MS (m / z): 281.0 [M+H] + .

[0816] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=5.2Hz,1H),7.63(d,J=5.2Hz,1H),4.98(s,2H),4. 27(q,J=7.2Hz,2H),3.16(hept,J=7.2Hz,1H),1.41(d,J=7.2Hz,6H),1.31(t,J=7.2Hz,3H).

[0817] Step 4: Synthesis of ethyl 2-(7-(2-bromopropan-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate (49-5)

[0818] Compound 49-4 (100.0 mg, 0.36 mmol) was dissolved in dichloromethane (3 mL), N-bromosuccinimide (63.0 mg, 0.36 mmol) was added, and the mixture was reacted at 60° C. for 6 hours. The reaction solution was concentrated and purified by column chromatography to obtain compound 49-5 (38.0 mg) with a yield of 29.5% as a white solid.

[0819] MS (m / z): 359.0 / 361.0 [M+H] + .

[0820] 1 H NMR (400MHz, Chloroform-d) δ7.78 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 4.98 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.28 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H).

[0821] Step 5: Synthesis of 2-(7-(2-hydroxypropan-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetic acid (49-6)

[0822] Compound 49-5 (38.0 mg, 0.11 mmol) was dissolved in THF (2 mL), and an aqueous solution (2 mL) of LiOH·H2O (17.0 mg, 0.40 mmol) was added, and the mixture was allowed to react at room temperature for 3 hours. The pH was adjusted to less than 4 with 2N aqueous hydrochloric acid solution, and the mixture was extracted with EA (10 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 49-6 (28.0 mg) with a yield of 84.8% as a white solid.

[0823] MS (m / z): 269.0 [M+H] + .

[0824] Step 6: Synthesis of 2-(7-(2-hydroxypropan-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)-N-(pyrimidin-4-yl)acetamide (49)

[0825] Compound 49-6 (28.0 mg, 0.08 mmol), B-1 (10.0 mg, 0.10 mmol) and DIPEA (0.04 mL, 0.25 mmol) were dissolved in dichloromethane (2 mL), HATU (64.0 mg, 0.17 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound 49 (25.40 mg) with a yield of 77.0% as a white solid.

[0826] MS (m / z): 346.0 [M+H] + .

[0827] 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.92(s,1H),8.66(d,J=5.6Hz,1H),8.10(d,J=5.2Hz ,1H),7.98(d,J=5.6Hz,1H),7.62(d,J=5.2Hz,1H),5.96(s,1H),5.05(s,2H),1.51(s,6H).

[0828] Example 50: Preparation of 2-(2,4-diisopropyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (50)

[0829]

[0830] Step 1: Synthesis of 5-(propyl-1-en-2-yl)thiophene-2-carboxylic acid methyl ester (50-2)

[0831] Compound 50-1: 5-bromothiophene-2-carboxylic acid methyl ester (1.0 g, 4.52 mmol), isopropenylboronic acid pinacol ester (1.53 g, 9.10 mmol), cesium carbonate (3.69 g, 11.32 mmol), Pd(dppf)Cl2 (33.0 mg, 0.05 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added, and the mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 50-2 (814.0 mg) with a yield of 98.8% as a white solid.

[0832] MS (m / z): 183.0 [M+H] +.

[0833] Step 2: Synthesis of methyl 5-isopropylthiophene-2-carboxylate (50-3)

[0834] Compound 50-2 (814.0 mg, 4.46 mmol) was dissolved in MeOH (10 mL), 10% Pd / C (containing 45% water, 181.0 mg) was added, and the mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 50-3 (607.0 mg) with a yield of 73.8% as a light yellow oil.

[0835] MS (m / z): 185.0 [M+H] + .

[0836] Step 3: Synthesis of methyl 3-isobutyryl-5-isopropylthiophene-2-carboxylate (50-4)

[0837] Compound 50-3 (0.30 g, 1.62 mmol) was dissolved in ultra-dry THF (3 mL), cooled to 0°C in an ice-water bath, and TMPMgCl·LiCl THF solution (2.0 mL, 1.96 mmol) was added under a nitrogen atmosphere. After the reaction was kept warm for 1 hour, isobutyric anhydride (413.0 mg, 2.61 mmol) was added at 0°C, and the system was slowly warmed to room temperature and continued to react for 16 hours after stabilization. The reaction solution was quenched with saturated ammonium chloride solution (3 mL), diluted with water (10 mL), extracted with EA (15 mL×3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography gave compound 50-4 (0.19 g) with a yield of 46.0%, as an orange oily liquid.

[0838] MS (m / z): 255.0 [M+H] + .

[0839] Step 4: Synthesis of 2,4-diisopropylthiophene[2,3-d]pyridazin-7(6H)-one (50-5)

[0840] Compound 50-4 (0.19 g, 0.75 mmol) was dissolved in anhydrous ethanol (2 mL), hydrazine hydrate (80%, 0.2 mL) was added, and the mixture was reacted in an oil bath at 80°C for 1 hour. Anhydrous ethanol was removed by distillation under reduced pressure, and the mixture was diluted with distilled water (10 mL), extracted with EA (15 mL×3), and the combined organic phases were washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and dried to obtain compound 50-5 (135.0 mg) with a yield of 76.7% as a pink solid.

[0841] MS (m / z): 237.0 [M+H]+ .

[0842] Step 5: Synthesis of ethyl 2-(2,4-diisopropyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetate (50-6)

[0843] Compound 50-5 (135.0 mg, 0.57 mmol) was dissolved in DMF (3 mL), anhydrous potassium carbonate (158.0 mg, 1.14 mmol) and ethyl α-bromoacetate (287.0 mg, 1.72 mmol) were added, and stirred at room temperature for 16 hours. Diluted with distilled water (10 mL), extracted with EA (15 mL×3), the combined organic phases were washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 50-6 (164.0 mg) with a yield of 89.1%, as a yellow oily liquid.

[0844] MS (m / z): 323.0 [M+H] + .

[0845] Step 6: Synthesis of 2-(2,4-diisopropyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetic acid (50-7)

[0846] Compound 50-6 (164.0 mg, 0.51 mmol) was dissolved in THF (2 mL), and LiOH·H2O (43.0 mg, 1.03 mmol) was dissolved in water (2 mL) and added, and reacted at room temperature for 1 hour. THF was removed by distillation under reduced pressure, diluted with water (5 mL), adjusted to pH less than 4 with 2N hydrochloric acid, extracted with EA (15 mL×3), combined organic phases were washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain compound 50-7 (129.0 mg) with a yield of 86.6% as a light yellow solid.

[0847] MS (m / z): 295.0 [M+H] + .

[0848] Step 7: Synthesis of 2-(2,4-diisopropyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)-N-(pyrimidin-4-yl)acetamide (50)

[0849] Compound 50-7 (129.0 mg, 0.44 mmol) was dissolved in DMF solution (3 mL), and B-1 (50.0 mg, 0.53 mmol), DIPEA (170 mg, 1.32 mmol) and HATU (334.0 mg, 0.88 mmol) were added in sequence, and stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL), extracted with EA (15 mL × 3), and the organic phases were combined and washed with distilled water (15 mL × 3), saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound 50 (23.10 mg) was obtained by reverse preparation and purification, with a yield of 14.3%, as a white solid.

[0850] MS (m / z): 372.0 [M+H] + .

[0851] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.92(s,1H),8.66(d,J=6.0Hz,1H),7.98(d,J=6.0Hz,1 H),7.50(s,1H),5.05(s,2H),3.45-3.29(m,2H),1.38(d,J=6.8Hz,6H),1.27(d,J=6.8Hz,6H)

[0852] Example 51: Preparation of 2-(2,7-diisopropyl-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)-N-(pyrimidin-4-yl)acetamide (51)

[0853]

[0854] Step 1: Synthesis of 5-(propylene-1-en-2-yl)thiophene-3-carboxylic acid methyl ester (51-2)

[0855] Compound 51-1: 5-bromothiophene-3-carboxylic acid methyl ester (328.0 mg, 1.48 mmol), isopropenylboronic acid pinacol ester (499.0 mg, 2.97 mmol), cesium carbonate (1.21 g, 3.71 mmol), Pd(dppf)Cl2 (108.0 mg, 0.15 mmol), 1,4-dioxane (15 mL) and water (3 mL) were added, and the mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL×2), the organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain compound 51-2 (157.0 mg) with a yield of 58.4%, as a colorless oily liquid.

[0856] MS (m / z): 183.0 [M+H] + .

[0857] Step 2: Synthesis of 5-isopropylthiophene-3-carboxylic acid methyl ester (51-3)

[0858] Compound 51-2 (157.0 mg, 0.85 mmol) was dissolved in MeOH (10 mL), 10% Pd / C (containing 45% water, 28.0 mg) was added, and the mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 51-3 (115.0 mg) with a yield of 72.8%, which was a colorless oily liquid.

[0859] MS (m / z): 185.0 [M+H] + .

[0860] Step 3: Synthesis of methyl 2-isobutyryl-5-isopropylthiophene-3-carboxylate (51-4)

[0861] Compound 51-3 (115.0 mg, 0.61 mmol) was dissolved in ultra-dry THF (5 mL), cooled to 0°C in an ice-water bath, and TMPMgCl·LiCl THF solution (0.81 mL, 0.91 mmol) was added under a nitrogen atmosphere. After the reaction was kept warm for 1 hour, isobutyric anhydride (0.16 mL, 0.94 mmol) was added at 0°C, and the system was slowly warmed to room temperature and continued to react for 16 hours after stabilization. The reaction solution was quenched with saturated ammonium chloride solution (3 mL), diluted with water (10 mL), extracted with EA (15 mL×3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography gave compound 51-4 (76.0 mg) with a yield of 47.8%, as a colorless oily liquid.

[0862] MS (m / z): 255.0 [M+H] + .

[0863] Step 4: Synthesis of 2,7-diisopropylthieno[2,3-d]pyridazin-4(5H)-one (51-5)

[0864] Compound 51-4 (152.0 mg, 0.60 mmol) was dissolved in anhydrous ethanol (4 mL), hydrazine hydrate (80%, 1 mL) was added, and the mixture was reacted in an oil bath at 80°C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filter cake was dried under reduced pressure to obtain compound 51-5 (148.0 mg) as a white solid, which was used directly in the next step without further purification.

[0865] MS (m / z): 237.0 [M+H]+ .

[0866] Step 5: Synthesis of ethyl 2-(2,7-diisopropyl-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetate (51-6)

[0867] Compound 51-5 (135.0 mg) was dissolved in DMF (3 mL), anhydrous potassium carbonate (158.0 mg, 1.14 mmol) and ethyl α-bromoacetate (287.0 mg, 1.72 mmol) were added, and stirred at room temperature for 16 hours. Diluted with distilled water (10 mL), extracted with EA (15 mL×3), the combined organic phases were washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 51-6 (164.0 mg) as a yellow oily liquid. The yield of steps 4 and 5 was 92.9%.

[0868] MS (m / z): 323.0 [M+H] + .

[0869] Step 6: Synthesis of 2-(2,7-diisopropyl-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetic acid (51-7)

[0870] Compound 51-6 (68.0 mg, 0.21 mmol) was dissolved in THF (2 mL), and LiOH·H2O (18.0 mg, 0.42 mmol) was dissolved in water (2 mL) and added, and reacted at room temperature for 1 hour. THF was removed by distillation under reduced pressure, diluted with water (5 mL), adjusted to pH less than 4 with 2N hydrochloric acid, extracted with EA (15 mL×3), combined organic phases were washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain compound 51-7 (64.0 mg) as a white solid, which was used directly in the next step without further purification.

[0871] MS (m / z): 295.0 [M+H] + .

[0872] Step 7: Synthesis of 2-(2,7-diisopropyl-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)-N-(pyrimidin-4-yl)acetamide (51)

[0873] Compound 51-7 (64.0 mg) was dissolved in DMF (3 mL), and B-1 (25.0 mg, 0.26 mmol), DIPEA (0.11 mL, 0.65 mmol) and HATU (165.0 mg, 0.44 mmol) were added in sequence, and stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL), extracted with EA (15 mL × 3), and the organic phases were combined and washed with distilled water (15 mL × 3), saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound 51 (43.0 mg) was obtained by reverse preparation and purification as a white solid. The yield of steps 6 and 7 was 55.1%.

[0874] MS (m / z): 372.0 [M+H] + .

[0875] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.92(s,1H),8.66(d,J=6.0Hz,1H),7.98(d,J=6.0Hz,1H),7.43(s,1 H), 5.04 (s, 2H), 3.44-3.34 (m, 1H), 3.11 (hept, J = 6.8Hz, 1H), 1.37 (d, J = 6.8Hz, 6H), 1.31 (d, J = 6.8Hz, 6H).

[0876] Example 52: Inhibitory effect of the derivatives of the present invention on IL-1β release in THP-1 cells after PMA-induced differentiation

[0877] THP-1 cells were purchased from Wuhan Pronocell Life Science Co., Ltd. The complete culture medium used was RPMI1640 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin and a final concentration of 0.05 mM β-mercaptoethanol. Cells were cultured according to the supplier's instructions, and the cell density was maintained in the logarithmic phase before the experiment began. The cell density was adjusted to 1×10 5 / mL, add phorbol 12-myristate 13-acetate (PMA) with a final concentration of 100ng / mL to induce for 16h, and then stimulate with lipopolysaccharide (LPS) with a concentration of 100ng / mL for 3h. The derivative of the present invention was dissolved in dimethyl sulfoxide (DMSO), diluted 3 times with culture medium to the required concentration and added to 96-well plates respectively. After 1h, nigericin sodium with a final concentration of 10μM was added to the administered culture plate and incubated for 1h. The cell-free supernatant was collected and the IL-1β level was evaluated according to the instructions of the ELISA detection kit (Hangzhou Lianke Biotechnology Co., Ltd.). The solvent is blank. EC 50The results are shown in Table 1.

[0878] Table 1. Inhibitory activity of compounds on IL-1β release in THP-1 cells

[0879]

[0880]

Note

[0881] Example 53: Inhibitory effect of the derivatives of the present invention on IL-1β release in PBMC cells

[0882] Peripheral blood mononuclear cells (PBMCs) from healthy individuals were purchased from Sai Li Biotechnology. The complete culture medium used was RPMI1640 culture medium containing 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin / streptomycin (Pen / Strep). PBMCs were cultured at 1×10 5 After inoculating 100 cells / well into a 96-well plate, the cells were cultured overnight in an incubator, and then lipopolysaccharide (LPS) was added for stimulation for 3 hours. The derivative of the present invention was dissolved in dimethyl sulfoxide (DMSO), diluted 3 times with culture medium to the required concentration, and added to the 96-well plate for continued culture for 1 hour, and then adenosine triphosphate (ATP) was added for continued culture for 1 hour. The cell-free supernatant was collected and the IL-1β level was evaluated according to the instructions of the ELISA detection kit (Hangzhou Lianke Biotechnology Co., Ltd.). The solvent was blank. EC 50 The results are shown in Table 2 using the four-parameter method of log(agonist) vs. response—Variable slope using GraphPad software.

[0883] Table 2. Inhibitory activity of compounds on IL-1β release in PBMC cells

[0884]

[0885]

Note

[0886] Example 54: Inhibitory effect of compounds on hERG ion channels

[0887] The inhibitory effect of the compound on the human hERG ion channel stably expressed in HEK293 cells was tested using conventional patch clamp. The compound was prepared at a concentration of 10 μM. Each cell was used as a control. The compound was perfused using a perfusion system that utilized its own gravity. After the current of each cell stabilized, the hERG current size before and after the addition of the compound was compared, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 3.

[0888] Table 3. Blocking rate of compounds on hERG ion channels

[0889]

Claims

1. The present invention particularly provides a pyridazinone derivative represented by formula (I) and a prodrug, isomer, solvate or a pharmaceutically acceptable salt thereof: in: R 1 independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -OR 3 、-SR 3 、-CN、-C(O)OR 3 、-NHC(O)OR 3 、-NHC(O)NR 3 R 4 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 ; R 2 independently selected from H, halogen, -CN, -NR 3 R 4 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 4 , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, -OR 3 or -NR 3 R 4 ; R 3 , R 4 independently selected from H, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; Ring A may be present or absent, W is N or C, and Y is N, C or CR 5 , X, Z are independently selected from S, N, NR a or CR b , wherein at least one of W, X, Y, and Z is the above-mentioned heteroatom and S and N do not appear at the same time; R a independently selected from H, C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -C(O)OR 3 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 , the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R b are independently selected from H, halogen, -CN, -OR 3 、-NR 3 R 4 , C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 The aryl or 5-10 membered heteroaryl is substituted by one or more substituents independently selected from the group consisting of H, halogen or -OR 3 ; R 5 independently selected from H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 4-6 membered heteroaryl, -OR 3 、-NR 3 R 4 、-C(O)R 3 or -C(O)NR 3 R 4 The C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl, 4-6 membered heterocyclyl, C6-C 10 The aryl or 4-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -CN, oxo, -OR 3 、-NR 3 R 4 、-C(O)OR 3 or -C(O)NR 3 R 4 ; R 6 , R 7 are independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C6 heteroalkyl or R 6 , R 7 The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C3-C6 cycloalkyl or 3-6 membered heterocyclic group is b replace.

2. The pyridazinone derivatives and their prodrugs, isomers, solvates or pharmaceutically acceptable salts according to claim 1 have the structure of formula (II): in, Y and Z are independently selected from N or C; X is independently selected from S, CR 3 , N or NR 4 , and at least one of X, Y, and Z is the above-mentioned heteroatom; Ring A is independently selected from C4-C8 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl, the C4-C8 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally substituted by one or more substituents independently selected from the following: H, halogen, -CN, oxo, -OR 3 、-NR 3 R 4 、-C(O)OR 3 or -C(O)NR 3 R 4 ; R 1 independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -OR 3 、-SR 3 、-CN、-C(O)OR 3 、-NHC(O)OR 3 、-NHC(O)NR 3 R 4 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 ; R 2 independently selected from H, halogen, -CN, -NR 3 R 4 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 4 , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, -OR 3 or -NR 3 R 4 ; R 3 , R 4 Each of the following is independently selected from H, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R 6 , R 7 are independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C6 heteroalkyl or R 6 , R 7 The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C3-C6 cycloalkyl or 3-6 membered heterocyclic group is b replace; R b are independently selected from H, halogen, -CN, -OR 3 、-NR 3 R 4 , C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 The aryl or 5-10 membered heteroaryl is substituted by one or more substituents independently selected from the group consisting of H, halogen or -OR 3 .

3. The pyridazinone derivative and its prodrug, isomer, solvate or pharmaceutically acceptable salt according to claim 1, wherein the compound has the structure of formula (III): in, W is N or C, X and Z are independently selected from S, N, NR a or CR e , and S and N do not appear at the same time; Independently selected from R 1 independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, -OR 3 、-SR 3 、-CN、-C(O)OR 3 、-NHC(O)OR 3 、-NHC(O)NR 3 R 4 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 ; R 2 independently selected from H, halogen, -CN, -NR 3 R 4 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 4 , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, C1-C6 heteroalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, -OR 3 or -NR 3 R 4 ; R 3 , R 4 Each of the following is independently selected from H, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R 6 , R 7 are independently selected from H, halogen, cyano, C1-C4 alkyl, C1-C6 heteroalkyl or R 6 , R 7 The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C3-C6 cycloalkyl or 3-6 membered heterocyclic group is b replace; R b are independently selected from H, halogen, -CN, -OR 3 、-NR 3 R 4 , C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 The aryl or 5-10 membered heteroaryl is substituted by one or more substituents independently selected from the group consisting of H, halogen or -OR 3 ; R a independently selected from H, C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -C(O)OR 3 、-C(O)NR 3 R 4 、-C(O)R 3 、-S(O)2R 3 or -S(O)2NR 3 R 4 , the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R 3 is selected from H, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C4 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 ; R e independently selected from H, halogen, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -OR 3 、-NR 3 R 4 、-C(O)OR 3 、-OC(O)NR 3 R 4 、-NHC(O)NR 3 R 4 、-NHC(O)OR 3 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 or -C(O)R 3 The C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is substituted by one to three OR 3 or halogen substituted; preferably, R e independently H, F, Cl, -OH, -CH3, -OCH3, -CF3, -OCH2CF3, -OCHF2, -NH2, -NHS(O)2CH3, -NHC(O)CH3, -CH2C(O)OH, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2 or 4. The pyridazinone derivative according to any one of claims 1 to 3, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that R 1 Select from Where R a As defined above; preferably, R a Selected from H, -CH3, -CH2CH3, -CH(CH3)2, R b As defined above; preferably, R b Independently selected from H, F, Cl, -CH3, -OCH3, -CF3, -OCF3, -OCHF2, phenyl or -N(CH3)2; R c , R d are independently selected from H, halogen, -OR 3 、-NR 3 R 4 , C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; the C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is substituted by one or more substituents independently selected from the following: H, halogen or -OR 3 Preferably, R c are independently H, F, Cl, -CH3, -OCH3, -CF3, -OCF3, -OCHF2 or -N(CH3)2; R e independently selected from H, halogen, C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -OR 3 、-NR 3 R 4 、-C(O)OR 3 、-OC(O)NR 3 R 4 、-NHC(O)NR 3 R 4 、-NHC(O)OR 3 、-NHS(O)2R 3 、-NR 3 R 4 、-C(O)NR 3 R 4 or -C(O)R 3 The C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is substituted by one to three OR 3 or halogen substituted; preferably, R e independently H, F, Cl, -OH, -CH3, -OCH3, -CF3, -OCH2CF3, -OCHF2, -NH2, -NHS(O)2CH3, -NHC(O)CH3, -CH2C(O)OH, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(CH3)2 or m and n are 0, 1, 2, 3 or 4.

5. The pyridazinone derivative according to any one of claims 1 to 4, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that R 1 Further selected from 6. The pyridazinone derivative according to any one of claims 1 to 5, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that R 2 Preferably selected from ethyl, isopropyl, cyclopropyl, 7. The pyridazinone derivatives and prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6, characterized in that R 5 Preferably selected from Br, I, ethyl, isopropyl, tert-butyl, cyclopropyl, -CF3, -CHF2, 8. The pyridazinone derivatives and prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof according to any one of claims 1 to 7, characterized in that R 6 , R 7 are independently preferably selected from H, F, methyl, ethyl, trifluoroethyl, methoxyethyl, or R 6 , R 7 The cyclopropyl, ethylene oxide, cyclobutyl, cyclopentyl, 9. The pyridazinone derivatives and prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof according to claim 1 or 2, characterized in that Select from 10. The pyridazinone derivatives and prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof according to claim 1 or 3, characterized in that Select from 11. The pyridazinone derivative according to any one of claims 1 to 10, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, having the structure of formula (II-1): R 1 Selected from R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

12. The pyridazinone derivative according to any one of claims 1 to 11, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, having the structure of formula (II-1-1): R 1 Selected from R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

13. The pyridazinone derivative according to any one of claims 1 to 12, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, having the structure of formula (II-2): R 1 Selected from R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

14. The pyridazinone derivative according to any one of claims 1 to 13, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, having the structure of formula (II-3): R 1 Selected from R 2 Selected from ethyl, isopropyl, cyclopropyl, R 6 , R 7 Each is independently selected from H, F, methyl, ethyl, trifluoroethyl or methoxyethyl.

15. The pyridazinone derivatives and their prodrugs, isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts according to any one of claims 1 to 14, characterized in that Preferably selected from the following structures:

16. A pharmaceutical composition comprising at least one active ingredient as described in any one of claims 1 to 15 and at least one pharmaceutically acceptable carrier or excipient.

17. A method for preparing a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16 for use in preventing or treating a disease associated with NLRP3.

18. The use according to claim 17, characterized in that The medicine is used for preventing or treating inflammatory diseases or diseases accompanied by inflammatory reactions.

19. The use according to claim 17, characterized in that The medicine is used for preventing or treating cancer.

20. The use according to claim 18, characterized in that The inflammatory diseases or diseases accompanied by inflammatory responses include, but are not limited to, chronic liver disease, liver fibrosis, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, myelofibrosis, sickle cell disease, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (e.g., heart failure, retinopathy, diabetic foot), peripheral arterial disease, acute heart failure and hypertension, hyperoxaluria, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, hemodialysis-related inflammation, diabetic nephropathy, interstitial Cystitis, colorectalitis, polymyositis, dermatomyositis, brain infection, acute craniocerebral injury, chronic migraine, neuropathic pain, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, mechanical wound healing, burns, scar formation, acne, suppurative hidradenitis, pyoderma gangrenosum, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, keratitis, uveitis, glaucoma, COVID-19 and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis, age-related macular degeneration or pyrrocytic protein-related periodic syndrome.

21. The use according to claim 19, characterized in that 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.

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