URAT1 inhibitor, and preparation method therefor and use thereof

Abstract

A URAT1 inhibitor represented by formula (I), and a preparation method therefor and a use thereof. The inhibitor has an efficient inhibitory effect on URAT1, and can be used as a drug for treating diseases such as gout and hyperuricemia.

Description

URAT1 inhibitors and their preparation methods and uses Technical Field

[0001] The present invention relates to a URAT1 (uric acid transporter 1) inhibitor, a preparation method and use thereof, and in particular to a URAT1 inhibitor that can be used to treat diseases such as gout and hyperuricemia, a preparation method and use thereof. Background Art

[0002] Gout is a multi-gene hereditary disease caused by both environmental and genetic factors. Due to reduced uric acid excretion and purine metabolism disorders, blood uric acid levels increase, and a large amount of urate crystals are deposited in the joints and surrounding tissues, triggering an acute inflammatory response. Later, joint disorders or deformities occur. When urate is deposited in the kidneys, gouty nephropathy will occur, which is often complicated by cardiovascular and cerebrovascular diseases and is life-threatening. Gout is divided into primary gout (genetic, enzyme deficiency, etc.), secondary gout (chronic hemolytic anemia, hyperparathyroidism, various kidney diseases, etc.) and idiopathic gout. The pathogenesis of gout is still unclear, but hyperuricemia (HUA) is the most important biochemical basis of gout.

[0003] Hyperuricemia, as the "fourth high" after diabetes, hypertension, and hyperlipidemia, is the second largest metabolic disease after diabetes, but it has not been paid much attention or discussed by the Chinese people. Data from the "2021 China Hyperuricemia and Gout Trend White Paper" show that in recent years, hyperuricemia in my country has shown a significant upward trend and a younger trend. The overall prevalence of hyperuricemia in my country is 13.3%, with approximately 177 million patients. The overall incidence of gout is 1.1%, with approximately 14.66 million patients. Another data shows that nearly 60% of patients with hyperuricemia and gout in my country are young people aged 18-35.

[0004] The reabsorption and resecretion of uric acid in the kidney are primarily coordinated by two distinct classes of uric acid transporters. The first class, the uric acid reabsorption proteins, includes URAT1, glucose transporter 9 (GLUT9), organic anion transporter 4 (OAT4), and organic anion transporter 10 (OAT10). These proteins work together to maintain serum uric acid levels. UART1, a 12-transmembrane organic anion transporter encoded by the SLC22A12 gene, was first discovered on the apical membrane of human renal proximal tubular epithelial cells in 2002 by Enomoto et al. Compared to other transporters, URAT1 has a higher affinity and transport efficiency for urate. Approximately 90% of uric acid in the kidney is reabsorbed back into cells by URAT1. Therefore, inhibition of URAT1 could inhibit uric acid reabsorption and treat diseases such as gout and hyperuricemia.

[0005] Currently, while URAT1 inhibitors available on the market can control elevated uric acid levels to a certain extent, their efficacy is suboptimal and they are often associated with severe adverse reactions such as liver and kidney damage, limiting their clinical application. Therefore, there is an urgent need to develop URAT1 inhibitors with improved efficacy and minimal toxicity.

[0006] Summary of the Invention

[0007] In one aspect, the present invention provides a URAT1 inhibitor represented by formula (I),

[0008] or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts,

[0009] in,

[0010] X 1 Selected from O, S, Se, NR 5 、CHR 5 , SO, SO2 or S(O)=NR 5 , where R 5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or C1-C6 alkanoyl;

[0011] X 2 、X 3 、X 4 、X 5 Each independently selected from N or CR 6 , where R 6 is independently selected at each occurrence from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy;

[0012] A, B, Y, and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, nitro, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl-substituted C1-C6 alkoxy, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R8 R 8’ R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-substituted C1-C6 alkyl; 9 C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-substituted C1-C6 alkyl;

[0013] R 1 、R 2 、R 3 or R 4 Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, optionally substituted 3-membered to 6-membered heterocyclic group, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-membered or 6-membered heteroaryl, 3-membered to 6-membered heterocyclyl are optionally substituted by a group selected from the group consisting of H, halogen, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted C1~C6 alkyl, CO2R 8 or CONR 8 R 8’ ;or

[0014] R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 carbocyclic ring or an optionally substituted 3- to 6-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by a group selected from the group consisting of H, halogen, OR 5 、C1~C6 alkyl、NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted C1~C6 alkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 Do not form a cycloalkyl group or a heterocyclic group at the same time;

[0015] Q is selected from CH2, CO, SO or SO2.

[0016] In one aspect, the present invention provides a method for preparing a URAT1 inhibitor represented by formula (I).

[0017] In one aspect, the present invention provides a method for preventing and / or treating URAT1-mediated diseases using a URAT1 inhibitor represented by formula (I).

[0018] In one aspect, the present invention provides a method for preventing and / or treating diseases such as gout and / or hyperuricemia using a URAT1 inhibitor represented by formula (I).

[0019] Compared with the prior art, the beneficial effect of the present invention is that the URAT1 inhibitor disclosed in the present invention has a good inhibitory effect on URAT1, and while showing high efficiency in reducing uric acid levels, it also shows a small toxic and side effect effect. DETAILED DESCRIPTION

[0020] definition

[0021] As used in this specification, the following words and phrases generally have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0022] As used herein, the term "alkyl" refers to a monovalent group having a straight or branched saturated hydrocarbon chain of 1 to 6 carbon atoms, more typically 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. This term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0023] As used herein, the term "alkenyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms (more typically 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, or 2 carbon atoms) and having carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The term is exemplified by groups such as vinyl (i.e., -CH=CH2), propen-1-yl (i.e., -CH=CHCH3), propen-3-yl (or allyl, i.e., -CH2CH=CH2), propen-2-yl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and the like.

[0024] As used herein, the term "alkynyl" refers to a linear or branched unsaturated hydrocarbon chain monovalent group having 2 to 6 carbon atoms (more typically 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, or 2 carbon atoms) and having carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds). The term is exemplified by groups such as ethynyl (i.e., -C≡CH), propargyl (i.e., -CH2C≡CH), propynyl (i.e., -C≡CCH3), and the like.

[0025] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0026] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0027] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein. This term is exemplified by groups such as trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, and the like.

[0028] As used herein, the term "carbocycle" refers to a saturated or partially unsaturated, monocyclic non-aromatic carbocyclic ring system containing 3-6 ring carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, and cyclopentadiene.

[0029] As used herein, the term "cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms as ring atoms. Examples of cycloalkyl include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0030] As used herein, the term "heterocyclyl" or "heterocycle" refers to a monocyclic saturated or partially unsaturated group having 3 to 6 ring atoms in the ring, wherein, in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and / or sulfur. Examples of heterocyclyl or heterocyclic groups include, but are not limited to, aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, oxirane, oxetane, tetrahydrofuranyl, tetrahydropyranyl, thiirane, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, piperazinyl, morpholinyl, dioxanyl, thioxanyl, dithianyl, dihydropyridinyl, etc.

[0031] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a given compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be acid addition salts and / or base addition salts. Acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, etc.; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, lactate, nicotinate, lauryl sulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucuronate, oleate, palmitate, stearate, pamoate, trifluoroacetate, phenylacetate, mandelate or ferulate, etc. Base addition salts can be formed with inorganic or organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts and the like; salts derived from organic bases include salts formed with various primary, secondary and tertiary amines, for example, ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, arginine, piperazine, piperidine, morpholine, tromethamine, choline and the like.

[0033] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0034] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0035] As used herein, the term "prodrug" refers to compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. Additionally, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir together with an appropriate enzyme or chemical reagent, the prodrug can be slowly converted to a compound of the present invention.

[0036] Any formula or structure given herein, including Formula I or any formula disclosed herein, also represents unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically labeled" or "isotopically enriched analogs." An isotopically labeled compound has a structure as depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotope-labeled compounds of the present invention, for example, compounds into which a radioactive isotope (e.g. 3 H. 13 C and 14 C). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0037] In one embodiment, the present invention provides a URAT1 inhibitor as shown in (I) or a stereoisomer, solvate, prodrug, isotope label, and pharmaceutically acceptable salt thereof, wherein X 1 、X2 、X 3 、X 4 、X 5 、R 1 、R 2 、R 3 、R 4 , A, B, Y, Z, Q are as defined herein.

[0038] In one embodiment, X 1 Selected from O, S, NR 5 、CHR 5 , SO, SO2 or S(O)=NR 5 , where R 5 Selected from H, C1-C3 alkyl, C2-C3 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted C1-C3 alkyl or C1-C3 alkanoyl.

[0039] In one embodiment, X 1 Selected from O, S, SO, SO2 or S(O)=NR 5 , where R 5 Selected from H, C1-C3 alkyl, C3-C6 cycloalkyl.

[0040] In one embodiment, X 1 Selected from O, S, SO, SO2 or S(O)=NR 5 , where R 5 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0041] In one embodiment, X 1 Selected from O, S, SO, SO2 or S(O)=NH.

[0042] In one embodiment, X 2 、X 3 、X 4 、X 5 Each independently selected from N or CR 6 , where R 6 Each occurrence is independently selected from H, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy.

[0043] In one embodiment, X 2 、X 3 、X 4 、X 5 Each independently selected from N or CR 6 , where R 6and independently at each occurrence selected from H, F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, 2,2,2-trifluoroethoxy, and 1,1,-difluoroethoxy.

[0044] In one embodiment, X 2 、X 3 、X 4 、X 5 are each independently selected from N or CH.

[0045] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C3 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl-substituted C1-C3 alkoxy, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or C1-C3 alkyl substituted with C3-C6 cycloalkyl; 9 Selected from C1~C3 alkyl, C1~C3 haloalkyl, C3~C6 cycloalkyl, or C1~C3 alkyl substituted with C3~C6 cycloalkyl.

[0046] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-; 9 Selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-.

[0047] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, CO2CH3, CO2C2H5, CONH2 or CONHCH3.

[0048] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, and nitro.

[0049] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 and independently at each occurrence selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,-difluoroethoxy, cyano, and nitro.

[0050] In one embodiment, Y and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, cyano, nitro.

[0051] In one embodiment, A and B are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C3 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl-substituted C1-C3 alkoxy, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or C1-C3 alkyl substituted with C3-C6 cycloalkyl; 9 C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, or C1-C3 alkyl substituted with C3-C6 cycloalkyl;

[0052] In one embodiment, A and B are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-; 9Selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-.

[0053] In one embodiment, A and B are each independently selected from CR 7 , where R 7 and independently at each occurrence selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, COCH3, SO2CH3, SO2CF3, CO2CH3, CO2C2H5, CONH2 or CONHCH3.

[0054] In one embodiment, A and B are each independently selected from CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, and nitro.

[0055] In one embodiment, A and B are each independently selected from CR 7 , where R 7 and independently at each occurrence selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy, cyano, and nitro.

[0056] In one embodiment, A and B are each independently selected from CR 7 , where R 7 Each occurrence is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyano, and nitro.

[0057] In one embodiment, R 1 、R 2 、R 3 or R 4Each is independently selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 3- to 6-membered heterocyclyl, wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 3- to 6-membered heterocyclyl is optionally substituted by a group selected from the following: H, halogen, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C1~C3 alkyl substituted by C3~C6 cycloalkyl, CO2R 8 or CONR 8 R 8’ ;or

[0058] R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 carbocyclic ring or an optionally substituted 3- to 6-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by a group selected from the group consisting of H, halogen, C1-C6 alkyl, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C1~C3 alkyl substituted by C3~C6 cycloalkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 A carbocyclic ring or a heterocyclic ring cannot be formed at the same time.

[0059] In one embodiment, R 1 、R 2 、R 3 or R 4 each independently selected from H, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, dioxanyl, morpholinyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, thienyl, thiazolyl, optionally substituted with a group selected from H, halogen, OR 5 NR 8 R8’ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3~C6 cycloalkyl-CH2-, CO2R 8 or CONR 8 R 8’ ;or

[0060] R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, oxetane ring, tetrahydropyrrole ring, piperidine ring, tetrahydrofuran ring, tetrahydropyran ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydrothiazole ring, dioxane ring, morpholine ring, which is optionally substituted by a group selected from the following: H, halogen, C1-C3 alkyl, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted C1~C3 alkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 The above-mentioned carbocyclic ring or heterocyclic ring is not formed at the same time.

[0061] In one embodiment, R 1 、R 2 、R 3 or R 4 Each is independently selected from H, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or

[0062] R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

[0063] In one embodiment, R 1 、R 2 、R 3 or R 4 are each independently selected from H; or

[0064] R 1and R 2 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

[0065] In one embodiment, R 1 、R 2 、R 3 or R 4 are each independently selected from H; or

[0066] R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cyclopropane ring, R 3 and R 4 Selected from H.

[0067] In one embodiment, Q is selected from CO or SO2.

[0068] In one embodiment, Q is selected from CO.

[0069] In one embodiment, the URAT1 inhibitor represented by formula (I) is a compound represented by formula (II) or formula (II')

[0070] or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 、R 3 、R 4 , A, B, Y, Z, Q are as defined herein.

[0071] In one embodiment, the URAT1 inhibitor represented by formula (I) is a compound represented by formula (III) or formula (III')

[0072] or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 , A, B, Y, Z, Q are as defined herein.

[0073] In one embodiment, the URAT1 inhibitor represented by formula (I) is a compound represented by formula (IV) or formula (IV')

[0074] or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R2 , A, B, Y, and Z are as defined herein.

[0075] In one embodiment, the URAT1 inhibitor represented by formula (I) is a compound represented by formula (V-1), formula (V-2) and / or formula (V-3)

[0076] or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 、R 7 As defined herein.

[0077] In one embodiment, the URAT1 inhibitor represented by formula (I) is a compound represented by formula (VI-1), (VI-2), (VI-3), (VI-4), (VI-5) and / or (VI-6)

[0078] or a solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof, wherein X 1 、R 7 As defined herein.

[0079] In one embodiment, the compound represented by formula (I) is selected from any one of the following compounds:

[0080] or a solvate, prodrug, isotope label, or pharmaceutically acceptable salt thereof.

[0081] The present invention provides a pharmaceutical composition comprising a compound of the present invention or a stereoisomer thereof, a solvate, a prodrug, an isotope label, a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art and include diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, colorants, flavorings, sweeteners, and the like. Depending on the route of administration of the drug, such as oral administration, parenteral administration, and rectal administration, the pharmaceutical composition of the present invention can be prepared in solid form (including but not limited to tablets, capsules, pills, granules, powders, powders, suppositories) or liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricants, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binders, such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, etc.; d) disintegrants, such as starch, alginic acid, agar, corn starch; e) stabilizers, such as antioxidants such as ascorbic acid; f) glidants, such as silicon dioxide; g) flavorings, such as mint, methyl salicylate; sweeteners, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier generally includes one or more of the following: a) a diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) an antioxidant, such as ascorbic acid or sodium bisulfite; c) a buffer, such as acetate, phosphate, etc.

[0082] The present invention also provides a method for preventing and / or treating a disease mediated by URAT1, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomers, solvates, prodrugs, isotope-labeled substances, or pharmaceutically acceptable salts, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomers, solvates, prodrugs, isotope-labeled substances, or pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier. The present invention also provides a method for preventing and / or treating diseases such as gout and hyperuricemia, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or its stereoisomers, solvates, prodrugs, isotope-labeled substances, or pharmaceutically acceptable salts, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomers, solvates, prodrugs, isotope-labeled substances, or pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier.

[0083] In some embodiments, the therapeutically effective amount is from about 1 mg to about 1500 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 750 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 500 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 400 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 300 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 200 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 100 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 50 mg. In some embodiments, the therapeutically effective amount is from about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount is from about 5 mg to about 25 mg.

[0084] The present invention provides a use of a URAT1 inhibitor represented by formula (I) in the preparation of a medicament for preventing and / or treating a disease mediated by URAT1. The present invention also provides a use of a URAT1 inhibitor represented by formula (I) in the preparation of a medicament for preventing and / or treating a disease such as gout and / or hyperuricemia.

[0085] General synthetic method

[0086] Compounds of the present invention can be prepared using methods disclosed herein and their modified approaches and methods well known in the art. Typical embodiments of compounds of the present invention can be synthesized using the general reaction scheme of the following arbitrary methods. It will be apparent from the description herein that corresponding different products can be obtained by replacing reaction raw materials with other materials having similar structures. Reaction raw materials are typically obtained from commercial sources or synthesized using disclosed methods.

[0087] Reaction Scheme I

[0088] When X 1 Represents SO, X 2 、X 3 、X 4 and X 5 Represents CH, R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cyclopropyl group, R 3 and R 4 represents H, Q represents CO, and the synthetic route of formula IA is:

[0089] Wherein, Y, Z, A and B are as defined in the text.

[0090] Specifically, compound b first reacts with a chlorinating agent to form an acyl chloride compound, which is then reacted with compound a to prepare compound c, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or thionyl chloride; preferably, the chlorinating agent is selected from thionyl chloride; the solvent used is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, tetrahydrofuran or a mixed solvent composed of the above solvents; preferably, the solvent is selected from tetrahydrofuran; the reaction temperature is -5°C to 25°C; preferably, the reaction temperature is 0°C.

[0091] Compound d is prepared by reacting compound c with an oxidant, wherein the oxidant used is selected from m-chloroperbenzoic acid or hydrogen peroxide; preferably, the oxidant is selected from m-chloroperbenzoic acid; the solvent used is selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or a mixed solvent of any two thereof; preferably, the solvent used is selected from N,N-dimethylformamide; the reaction temperature is -5°C to 25°C; preferably, the reaction temperature is 0°C.

[0092] Compound IA is prepared by reacting compound d with a demethylation agent, wherein the demethylation agent is selected from lithium chloride, aluminum chloride, boron tribromide, hydrobromic acid, hydroiodic acid or pyridine hydrochloride; preferably, the demethylation agent is selected from lithium chloride; the solvent is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a mixed solvent composed of the above solvents; preferably, the solvent is selected from N,N-dimethylformamide; the reaction temperature is 100°C to 140°C; preferably, the reaction temperature is 130°C.

[0093] Reaction Scheme II

[0094] When X 1 represents SO2, X 2 、X 3 、X 4 and X 5 Represents CH, R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cyclopropyl group, R 3 and R 4 represents H, Q represents CO, and the synthetic route of formula IB is:

[0095] wherein Y, Z, A and B are as defined herein.

[0096] Specifically, compound e is prepared by reacting compound c with an oxidant, and the oxidant used is selected from meta-chloroperbenzoic acid or hydrogen peroxide; preferably, the oxidant used is selected from meta-chloroperbenzoic acid; the solvent used is selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or a mixed solvent of any two; preferably, the solvent used is selected from N,N-dimethylformamide; the reaction temperature is 0°C to 30°C; preferably, the reaction temperature is 25°C.

[0097] Compound IB is prepared by reacting compound e with a demethylation reagent, wherein the demethylation reagent is selected from lithium chloride, aluminum chloride, boron tribromide, hydrobromic acid or hydroiodic acid; preferably, the demethylation reagent is selected from lithium chloride; the solvent is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, isopropanol, ethanol or a mixed solvent composed of the above solvents; preferably, the solvent is selected from N,N-dimethylformamide; the reaction temperature is 100°C to 140°C; preferably, the reaction temperature is 130°C.

[0098] Reaction Scheme III

[0099] When X 1 represents O=S=NH, X 2 、X 3 、X 4 and X 5 Represents CH, R 1 、R 2 、R 3 and R 4 Represents H;

[0100] Q represents CO, and the synthetic route of formula IC is:

[0101] wherein Y, Z, A and B are as defined herein.

[0102] Specifically, compound b first reacts with a chlorinating agent to form an acyl chloride compound, which is then reacted with compound f to prepare compound g, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or thionyl chloride; preferably, the chlorinating agent is selected from thionyl chloride; the solvent used is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, tetrahydrofuran or a mixed solvent composed of the above solvents; preferably, the solvent used is selected from tetrahydrofuran; the reaction temperature is -5°C to 25°C; preferably, the reaction temperature is 0°C.

[0103] Compound h is prepared by reacting compound g with an ammonia source and iodobenzenediacetic acid, wherein the ammonia source is selected from ammonia gas, ammonium carbamate or ammonium carbonate; preferably, the ammonia source is selected from ammonium carbamate; the solvent used is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, isopropanol, tetrahydrofuran, ethanol or a mixed solvent composed of the above solvents; preferably, the solvent used is selected from methanol; the reaction temperature is 0°C to 30°C; preferably, the reaction temperature is 25°C.

[0104] Compound IC is prepared by reacting compound h with a demethylation reagent, wherein the demethylation reagent is selected from lithium chloride, aluminum chloride, boron tribromide, hydrobromic acid, or hydroiodic acid; preferably, the demethylation reagent is selected from lithium chloride; the solvent is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, isopropanol, ethanol, or a mixed solvent of the above solvents; preferably, the solvent is selected from N,N-dimethylformamide; the reaction temperature is 100°C to 140°C; preferably, the reaction temperature is 130°C.

[0105] Reaction Scheme IV

[0106] When X 1 Stands for S, X 2 、X 3 、X 4 and X 5 Represents CH, R 1 and R 2 Forming a cyclopropane with the carbon atom to which it is attached

[0107] Ji, R 3 and R 4 represents H, Q represents CO, and the synthetic route of formula ID is:

[0108] wherein Y, Z, A and B are as defined herein.

[0109] Compound ID is prepared by reacting compound c with a demethylation reagent, wherein the demethylation reagent is selected from lithium chloride, aluminum chloride, boron tribromide, hydrobromic acid or hydroiodic acid; preferably, the demethylation reagent is selected from lithium chloride; the solvent is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, isopropanol, ethanol or a mixed solvent of the above solvents; preferably, the solvent is selected from N,N-dimethylformamide; the reaction temperature is 100°C to 140°C; preferably, the reaction temperature is 130°C.

[0110] Reaction Scheme V

[0111] When X 1 Represents O, X 2 Represents CH or N, X 3 、X4 and X 5 Represents CH, R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cyclopropyl group, R 3 and R 4 represents H, Q represents CO, and the synthetic route of formula IE is:

[0112] Among them, Y, Z, X 2 , A and B are as defined in the text.

[0113] Specifically, compound b first reacts with a chlorinating agent to form an acyl chloride compound, which is then reacted with compound i to prepare j, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or thionyl chloride; preferably, the chlorinating agent is selected from thionyl chloride; the solvent used is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone, tetrahydrofuran or a mixed solvent composed of the above solvents; preferably, the solvent used is selected from tetrahydrofuran; the reaction temperature is -5°C to 25°C; preferably, the reaction temperature is 0°C.

[0114] Compound IE is prepared by reacting compound j with a demethylation agent, wherein the demethylation agent is selected from lithium chloride, aluminum chloride, boron tribromide, hydrobromic acid or hydroiodic acid; preferably, the demethylation agent is selected from lithium chloride; the solvent is selected from N,N-dimethylformamide, N,N-diethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, isopropanol, ethanol or a mixed solvent of the above solvents; preferably, the solvent is selected from N,N-dimethylformamide; the reaction temperature is 100°C to 140°C; preferably, the reaction temperature is 130°C.

[0115] Compounds IA, IB, IC, ID and IE prepared by the above method are salified with corresponding acids to obtain pharmaceutically acceptable salts of the above URAT1 inhibitors.

[0116] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0117] Example 1: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A1)

[0118] Synthesis of (3,5-difluoro-4-methoxyphenyl)(spiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (IV-1)

[0119] To a 100 mL three-necked flask, 3,5-difluoro-4-methoxybenzoic acid (III-2, 500 mg, 2.37 mmol) and thionyl chloride (25 mL) were added. The mixture was heated to 70°C and stirred for 3 hours. The solvent was evaporated under reduced pressure. The crude product was dissolved in anhydrous THF (20 mL) and cooled to 0°C. Under nitrogen protection, a mixed solution of 3,4-dihydrospiro[benzo[b][1,4]thiazine-2,1'-cyclopropane] (II-1, 467 mg, 2.48 mmol) dissolved in anhydrous THF (15 mL) was slowly added dropwise. After the addition was completed, the mixture was reacted at 0°C for 1 hour and then moved to room temperature for 6 hours. TLC monitoring (petroleum ether:ethyl acetate = 20:1) showed that the reaction was almost complete. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:1 to 30:1) to obtain 600 mg of white solid IV-1 in a yield of 61.2%. MS (ESI (+) 70V) m / z [M+H] + :348.08.

[0120] Synthesis of (3,5-difluoro-4-methoxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (V-1)

[0121] IV-1 (150 mg, 0.43 mmol) and dichloromethane (10 mL) were added to a 50 mL three-necked flask, stirred and dissolved, cooled to 0 ° C, and a solution of m-chloroperbenzoic acid (74.2 mg, 0.43 mmol) in dichloromethane (5 mL) was slowly added dropwise. The dropwise addition was completed in about 0.5 hours. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed that the reaction was basically complete. Saturated aqueous sodium sulfite solution (50 mL) was added to quench the reaction, and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (15 mL × 3), and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 1:2) to obtain 130 mg of off-white solid V-1, with a yield of 82.9%. MS (ESI (+) 70V) m / z [M+H] + :364.38.

[0122] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A1)

[0123] Intermediate V-1 (110 mg, 0.30 mmol) and DMF (6 mL) were added to a 25 mL eggplant-shaped flask. After sufficient dissolution, lithium chloride (103 mg, 2.42 mmol) was added. The mixture was heated to 130°C under nitrogen for 8 hours. TLC monitoring (petroleum ether:ethyl acetate = 1:2) showed that the reaction was essentially complete. The mixture was cooled to room temperature and poured into ice water (5 mL). 2 mol / L hydrochloric acid was added to adjust the pH to 3-5. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1 to 1:1) to obtain 52 mg of I-A1 as a white solid in a yield of 49.2%. 1 H NMR(400MHz, DMSO-d6)δ(ppm):10.93(s,1H),7.71(dd,J=8.0,4.0Hz,1H),7.39–7.31(m,2H),7.05(d,J=1.6Hz,1H),7.04(d,J=1.7Hz,1H),7.01(dd, J=8.0,4.0Hz,1H),4.16(d,J=16.0Hz,1H),3.93(d,J=16.0Hz,1H),1.30-1 .24(m,1H),1.19-1.13(m,1H),1.02-0.91(m,2H).MS(ESI(+)70V)m / z[M+H] + :350.35.

[0124] Example 2: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A2)

[0125] Synthesis of (3,5-dichloro-4-methoxyphenyl)(spiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (IV-2)

[0126] Using intermediate II-1 (400 mg, 2.26 mmol) and 3,5-dichloro-4-methoxybenzoic acid (III-3, 499 mg, 2.26 mmol) as starting materials, following the preparation method of intermediate IV-1, 670 mg of off-white solid IV-2 was obtained in a yield of 78.1%. MS (ESI (+) 70V) m / z [M+H] + :380.02.

[0127] Synthesis of (3,5-dichloro-4-methoxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (V-2)

[0128] Using intermediate IV-2 (118 mg, 0.31 mmol) as starting material, following the preparation method of intermediate V-1, 100 mg of off-white solid V-2 was obtained with a yield of 81.3%. MS (ESI (+) 70V) m / z [M+H] + :396.01.

[0129] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A2)

[0130] Using intermediate V-2 (82 mg, 0.21 mmol) as raw material and referring to the preparation method of compound I-A1, 50 mg of off-white solid I-A2 was obtained with a yield of 63.2%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.72 (d, J = 6.1Hz, 1H), 7.40-7.32 (m, 4H), 7.04 (d, J = 7.3Hz, 1H), 4.18 (d, J = 13.6Hz, 1H),3.92(d,J=13.7Hz,1H),1.32-1.24(m,1H),1.17-1.13(m,1H),0.99-0.93(m,2H).MS(ESI(+)70V)m / z[M+H] + :381.99.

[0131] Example 3: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A3)

[0132] Synthesis of (3,5-dibromo-4-methoxyphenyl)(spiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (IV-3)

[0133] Using intermediate II-1 (400 mg, 2.26 mmol) and 3,5-dibromo-4-methoxybenzoic acid (III-5, 769 mg, 2.48 mmol) as starting materials, following the preparation method of intermediate IV-1, 450 mg of light yellow oil IV-3 was obtained in a yield of 42.5%. MS (ESI (+) 70 V) m / z [M+H] + :467.92.

[0134] Synthesis of (3,5-dibromo-4-methoxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (V-3)

[0135] Intermediate IV-3 (100 mg, 0.21 mmol) was used as the starting material and the preparation method of intermediate V-1 was followed to obtain 100 mg of off-white solid V-3 with a yield of 96.7%. MS (ESI (+) 70V) m / z [M+H] + :483.91.

[0136] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(1-oxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-A3)

[0137] Using intermediate V-3 (100 mg, 0.21 mmol) as raw material and referring to the preparation method of compound I-A1, 90 mg of off-white solid I-A3 was obtained with a yield of 92.7%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.73 (dd, J=7.3, 1.9Hz, 1H), 7.46 (s, 2H), 7.42–7.31 (m, 2H), 7.05 (dd, J=7.8, 1.5Hz, 1H), 4.17 (d,J=13.6Hz,1H),3.94(d,J=13.6Hz,1H),1.35–1.24(m,1H),1.23–1.12(m,1H),1.07–0.89(m,2H).MS(ESI(+)70V)m / z[M+H] + :469.90.

[0138] Example 4: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-B1)

[0139] Synthesis of (3,5-dichloro-4-methoxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (VI-1)

[0140] IV-2 (124 mg, 0.33 mmol) and dichloromethane (10 mL) were added to a 50 mL three-necked flask, stirred and dissolved, cooled to 0 ° C, and a solution of m-chloroperbenzoic acid (142.4 mg, 0.83 mmol) in dichloromethane (5 mL) was slowly added dropwise. The reaction was completed in about 0.5 hours. TLC monitoring (petroleum ether: ethyl acetate = 2:1) showed that the reaction was basically complete. Saturated aqueous sodium sulfite solution (25 mL) was added to quench the reaction. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (15 mL × 3), and dried over anhydrous sodium sulfate; filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 3:1) to obtain 110 mg of off-white solid VI-1, with a yield of 81.8%. MS (ESI (+) 70V) m / z [M+H] + :412.01.

[0141] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-B1)

[0142] Using intermediate VI-1 (80 mg, 0.19 mmol) as raw material and referring to the preparation method of compound I-A1, 50 mg of off-white solid I-B1 was obtained with a yield of 64.7%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 11.00 (s, 1H), 7.85 (dd, J = 7.7, 1.8Hz, 1H), 7.54–7.36 (m, 2H), 7.33 (s, 2 H),7.16(d,J=8.0Hz,1H),4.29(s,2H),1.41-1.37(m,2H),1.29–1.20(m,2H).MS(ESI(+)70V)m / z[M+H] + :397.99.

[0143] Example 5: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-B2)

[0144] Synthesis of (3,5-dibromo-4-methoxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (VI-2)

[0145] Using intermediate IV-3 (120 mg, 0.26 mmol) as starting material, following the preparation method of intermediate VI-1, 120 mg of off-white solid VI-2 was obtained with a yield of 93.6%. MS (ESI (+) 70 V) m / z [M+H] + :499.91.

[0146] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(1,1-dioxospiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-B2)

[0147] Using intermediate VI-2 (120 mg, 0.24 mmol) as raw material and referring to the preparation method of compound I-A1, 110 mg of off-white solid I-B2 was obtained with a yield of 94.3%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.80 (dd, J=7.8, 1.4Hz, 1H), 7.49–7.41 (m, 1H), 7.39 (s, 2H), 7.36–7.29 (m,1H),7.13–7.04(m,1H),4.25(s,2H),1.42–1.30(m,2H),1.30–1.19(m,2H).MS(ESI(+)70V)m / z[M+H] + :485.89.

[0148] Example 6: (3,5-dichloro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C1)

[0149] Synthesis of (3,5-dichloro-4-methoxyphenyl)(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-1)

[0150] Using 3,4-dihydro-2H-benzo[b][1,4]thiazine (VII-1, 2.0 g, 0.01 mol) and intermediate III-3 (3.51 g, 0.02 mol) as starting materials, following the preparation method of intermediate IV-1, 3.19 g of off-white solid VIII-1 was obtained in a yield of 68.1%. MS (ESI(+)70V) m / z [M+H] + :354.00

[0151] (3,5-dichloro-4-methoxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-1)

[0152] To a 15 mL pressure bottle, intermediate VIII-1 (1.0 g, 2.83 mmol) and methanol (5 mL) were added. After complete dissolution, iodobenzenediacetic acid (2.73 g, 8.5 mmol) and ammonium carbamate (1.1 g, 14.2 mmol) were added. The mixture was sealed and reacted at 25°C for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) indicated that the reaction was nearly complete. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 0.93 g of an off-white solid IX-1 in 85.5% yield. MS (ESI(+) 70 V) m / z [M+H] + :385.01.

[0153] (3,5-dichloro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C1)

[0154] Using intermediate IX-1 (50.0 mg, 0.13 mmol) as starting material and referring to the preparation method of compound I-A1, 30.8 mg of off-white solid I-C1 was obtained with a yield of 63.9%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):8.32(s,1H),7.94–7.82(m,1H),7.40–7.29(m,4H),7.05– 6.90(m,1H),4.90(s,1H),4.36-4.18(m,2H),3.78-3.62(m,2H).MS(ESI(+)70V)m / z[M+H] + :370.99.

[0155] Example 7: (3,5-dibromo-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C2)

[0156] Synthesis of (3,5-dibromo-4-methoxyphenyl)(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-2)

[0157] Using intermediate VII-1 (500 mg, 3.31 mmol) and III-5 (1.23 g, 3.39 mmol) as starting materials, following the preparation method of intermediate IV-1, 850 mg of off-white solid VIII-2 was obtained in a yield of 58.0%. MS (ESI (+) 70 V) m / z [M+H] + :441.90

[0158] (3,5-dibromo-4-methoxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-2)

[0159] Using intermediate VIII-2 (300 mg, 0.68 mmol) as starting material, following the preparation method of compound IX-1, 250 mg of off-white solid IX-2 was obtained with a yield of 77.9%. MS (ESI (+) 70V) m / z [M+H] + :472.91.

[0160] (3,5-dibromo-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C2)

[0161] Using intermediate IX-2 (200 mg, 0.42 mmol) as starting material and referring to the preparation method of compound I-A1, 126 mg of off-white solid I-C2 was obtained with a yield of 64.9%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.59(s,1H),7.93–7.83(m,1H),7.51(s,2H),7.38-7.30(m,2H),7. 06–6.91(m,1H),4.97(s,1H),4.26(q,J=6.3Hz,2H),3.70(q,J=6.0Hz,2H).MS(ESI(+)70V)m / z[M+H] + :458.89.

[0162] Example 8: (3,5-difluoro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C3)

[0163] Synthesis of (3,5-difluoro-4-methoxyphenyl)(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-3)

[0164] Using intermediates VII-1 (1.0 g, 6.6 mmol) and III-2 (1.5 g, 8.0 mmol) as starting materials, following the preparation method of intermediate IV-1, 1.86 g of off-white solid VIII-3 was obtained with a yield of 87.5%. MS (ESI (+) 70 V) m / z [M+H] + :322.06.

[0165] (3,5-difluoro-4-methoxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-3)

[0166] Using intermediate VIII-3 (500 mg, 1.6 mmol) as starting material, following the preparation method of compound IX-1, 347.7 mg of off-white solid IX-3 was obtained with a yield of 63.4%. MS (ESI (+) 70V) m / z [M+H] + :353.07.

[0167] (3,5-difluoro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C3)

[0168] Using intermediate IX-3 (246 mg, 0.70 mmol) as starting material and referring to the preparation method of compound I-A1, 97 mg of off-white solid I-C3 was obtained with a yield of 41.1%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.91 (s, 1H), 7.86 (dd, J=7.5, 2.7Hz, 1H), 7.35-7.31 (m, 2H), 7.05 (dd, J=6.9, 1.8Hz, 2H), 6.93 (dd, J =6.9,2.7Hz,1H),4.97(s,1H),4.37-4.28(m,1H),4.22-4.13(m,1H),3.76-3.70(m,1H),3.68-3.61(m,1H).MS(ESI(+)70V)m / z[M+H] + :339.05.

[0169] Example 9: (3-Fluoro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C4)

[0170] Synthesis of (2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)(3-fluoro-4-methoxyphenyl)methanone (VIII-4)

[0171] Using intermediate VII-1 (1.48 g, 0.01 mol) and 3-fluoro-4-methoxybenzoic acid (III-1, 1.9 g, 0.01 mol) as starting materials, following the preparation method of intermediate IV-1, 3.15 g of off-white solid VIII-4 was obtained in a yield of 87.3%. MS (ESI (+) 70 V) m / z [M+H] + :304.07.

[0172] (3-Fluoro-4-methoxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-4)

[0173] Using intermediate VIII-4 (500 mg, 1.66 mmol) as starting material, following the preparation method of compound IX-1, 472.8 mg of off-white solid IX-4 was obtained with a yield of 85.8%. MS (ESI (+) 70V) m / z [M+H] + :335.08.

[0174] (3-Fluoro-4-hydroxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 -benzo[b][1,4]thiazin-4(1H)-yl)

[0175] Synthesis of Ketone (I-C4)

[0176] Using intermediate IX-4 (200 mg, 0.60 mmol) as starting material and referring to the preparation method of compound I-A1, 89.4 mg of off-white solid I-C4 was obtained with a yield of 46.7%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.52 (s, 1H), 7.91-7.81 (m, 1H), 7.35-7.25 (m, 2H), 7.18-7.14 (m, 1H), 7.03 (dd, J=8.3, 2.0 Hz,1H),6.88-6.82(m,2H),4.93(s,1H),4.38-4.27(m,1H),4.23-4.14(m,1H),3.72-3.58(m,2H).MS(ESI(+)70V)m / z[M+H] + :321.06.

[0177] Example 10: (3,5-dichloro-4-hydroxyphenyl)(7-bromo-1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C5)

[0178] Synthesis of (3,5-dichloro-4-methoxyphenyl)(7-bromo-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-5)

[0179] Using 7-bromo-3,4-dihydro-2H-benzo[b][1,4]thiazine (VII-2, 500 mg, 2.17 mmol) and intermediate III-3 (576 mg, 2.61 mmol) as starting materials, following the preparation method of intermediate IV-1, 720 mg of off-white solid VIII-5 was obtained in a yield of 76.5%. MS (ESI(+)70V) m / z [M+H] + :431.91.

[0180] (3,5-dichloro-4-methoxyphenyl)(7-bromo-1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-Benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-5)

[0181] Using intermediate VIII-5 (300 mg, 0.69 mmol) as starting material, following the preparation method of compound IX-1, 210 mg of off-white solid IX-5 was obtained with a yield of 65.3%. MS (ESI (+) 70V) m / z [M+H] + :462.92.

[0182] (3,5-dichloro-4-hydroxyphenyl)(7-bromo-1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C5)

[0183] Using intermediate IX-5 (200 mg, 0.43 mmol) as starting material and referring to the preparation method of compound I-A1, 160 mg of off-white solid I-C5 was obtained with a yield of 82.5%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):8.02(d,J=2.3Hz,1H),7.54(dd,J=8.7,2.4Hz,1H),7.39(s,2H),7 .00(d,J=8.7Hz,1H),5.18(s,1H),4.39–4.14(m,2H),3.82–3.61(m,2H).MS(ESI(+)70V)m / z[M+H] + :448.91.

[0184] Example 11: (4-Hydroxy-3,5-diiodophenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4Synthesis of benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C6)

[0185] Synthesis of (3,5-diiodo-4-methoxyphenyl)(2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-6)

[0186] Using intermediate VII-1 (200 mg, 1.32 mmol) and 3,5-diiodo-4-methoxybenzoic acid (III-6, 589.7 mg, 1.46 mmol) as starting materials, following the preparation method of intermediate IV-1, 327.8 mg of off-white solid VIII-6 was obtained in a yield of 46.1%. MS (ESI (+) 70 V) m / z [M+H] + :537.88.

[0187] (3,5-diiodo-4-methoxyphenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-6)

[0188] Using intermediate VIII-6 (200 mg, 0.37 mmol) as starting material, following the preparation method of compound IX-1, 192.3 mg of off-white solid IX-6 was obtained with a yield of 90.9%. MS (ESI (+) 70V) m / z [M+H] + :568.88.

[0189] (4-Hydroxy-3,5-diiodophenyl)(1-imino-1-oxo-2,3-dihydro-1λ 4 Synthesis of benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C6)

[0190] Using intermediate IX-6 (92.0 mg, 0.17 mmol) as starting material and referring to the preparation method of compound I-A1, 56.2 mg of off-white solid I-C6 was obtained with a yield of 62.6%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):7.91-7.84(m,1H),7.70(s,2H),7.38-7.29(m,2H),6.97-6.9 3(m,1H),4.90(s,1H),4.25(t,J=6.3Hz,2H),3.68(t,J=6.1Hz,2H).MS(ESI(+)70V)m / z[M+H] + :554.87.

[0191] Example 12: 5-(7-Bromo-1-imino-1-oxo-1,2,3,4-tetrahydro-1λ4 Synthesis of 4-benzo[b][1,4]thiazine-4-carbonyl)-2-hydroxy-3-iodobenzonitrile (I-C7)

[0192] Synthesis of 4-(7-bromo-3,4-dihydro-2H-benzo[b][1,4]thiazine-4-carbonyl)-3-iodo-2-methoxybenzonitrile (VIII-7)

[0193] Using intermediate VII-2 (300 mg, 1.30 mmol) and 3-cyano-5-iodo-4-methoxybenzoic acid (III-9, 434.6 mg, 1.43 mmol) as starting materials, following the preparation method of intermediate IV-1, 500 mg of off-white solid VIII-7 was obtained in a yield of 74.5%. MS (ESI (+) 70 V) m / z [M+H] + :514.88.

[0194] 5-(7-Bromo-1-imino-1-oxo-1,2,3,4-tetrahydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazine-4-carbonyl)-3-iodo-2-methoxybenzonitrile (IX-7)

[0195] Using intermediate VIII-7 (500 mg, 0.97 mmol) as starting material, following the preparation method of compound IX-1, 100 mg of off-white solid IX-7 was obtained with a yield of 18.9%. MS (ESI (+) 70V) m / z [M+H] + :545.89.

[0196] 5-(7-Bromo-1-imino-1-oxo-1,2,3,4-tetrahydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazine-4-carbonyl)-2-hydroxy-3-iodobenzonitrile (I-C7)

[0197] Using intermediate IX-7 (90 mg, 0.17 mmol) as starting material and referring to the preparation method of compound I-A1, 78.2 mg of off-white solid I-C7 was obtained with a yield of 89.2%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 8.00 (d, J = 2.4Hz, 1H), 7.77 (d, J = 2.5Hz, 1H), 7.51 (dd, J = 8.9, 2.4Hz, 1H), 7 .28(d,J=2.5Hz,1H),6.93(d,J=8.9Hz,1H),4.39–4.11(m,2H),3.72-3.57(m,2H).MS(ESI(+)70V)m / z[M+H] + :531.87.

[0198] Example 13: (3,5-dichloro-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C8)

[0199] Synthesis of (3,5-dichloro-4-methoxyphenyl)(7-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-8)

[0200] Using 7-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (VII-3, 200 mg, 1.2 mmol) and intermediate III-3 (294 mg, 1.33 mmol) as starting materials, following the preparation method of intermediate IV-1, 300 mg of off-white solid VIII-8 was obtained in a yield of 67.1%. MS (ESI(+)70V) m / z [M+H] + :368.02.

[0201] (3,5-dichloro-4-methoxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-8)

[0202] Using intermediate VIII-8 (200 mg, 0.54 mmol) as starting material, following the preparation method of compound IX-1, 175 mg of off-white solid IX-8 was obtained with a yield of 80.7%. MS (ESI (+) 70V) m / z [M+H] + :399.03.

[0203] (3,5-dichloro-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C8)

[0204] Using intermediate IX-8 (140 mg, 0.35 mmol) as starting material and referring to the preparation method of compound I-A1, 66 mg of off-white solid I-C8 was obtained with a yield of 48.9%. 1H NMR (300MHz, DMSO-d6) δ (ppm): 10.84 (s, 1H), 7.68 (s, 1H), 7.34 (s, 2H), 7.14 (dd, J = 8.4, 2.1Hz, 1H), 6.85 (d, J = 8.1Hz, 1H),4.91(s,1H),4.32-4.14(m,2H),3.75-3.59(m,2H),2.31(s,3H).MS(ESI(+)70V)m / z[M+H] + :385.01.

[0205] Example 14: (3,5-dibromo-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C9)

[0206] Synthesis of (3,5-dibromo-4-methoxyphenyl)(7-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-9)

[0207] Using intermediate VII-3 (120 mg, 0.73 mmol) and intermediate III-5 (248 mg, 0.80 mmol) as starting materials, following the preparation method of intermediate IV-1, 200 mg of off-white solid VIII-9 was obtained in a yield of 60.2%. MS (ESI (+) 70 V) m / z [M+H] + :455.92.

[0208] (3,5-dibromo-4-methoxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-9)

[0209] Using intermediate VIII-9 (180 mg, 0.39 mmol) as starting material, following the preparation method of compound IX-1, 140 mg of off-white solid IX-9 was obtained with a yield of 72.8%. MS (ESI (+) 70V) m / z [M+H] + :486.92.

[0210] (3,5-dibromo-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C9)

[0211] Using intermediate IX-9 (120 mg, 0.25 mmol) as starting material and referring to the preparation method of compound I-A1, 64 mg of off-white solid I-C9 was obtained with a yield of 54.9%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 7.68 (s, 1H), 7.50 (s, 2H), 7.15 (dd, J = 8.4, 2.1Hz, 1H), 6.85 ( d,J=8.1Hz,1H),4.86(s,1H),4.31-4.14(m,2H),3.69-3.63(m,2H),2.31(s,3H).MS(ESI(+)70V)m / z[M+H] + :472.91.

[0212] Example 15: (3,5-difluoro-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C10)

[0213] Synthesis of (3,5-difluoro-4-methoxyphenyl)(7-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazin-4-yl)methanone (VIII-10)

[0214] Using intermediate VII-3 (150 mg, 0.91 mmol) and intermediate III-2 (188 mg, 1.0 mmol) as starting materials, following the preparation method of intermediate IV-1, 242 mg of yellow solid VIII-10 was obtained with a yield of 79.5%. MS (ESI (+) 70V) m / z [M+H] + :336.08.

[0215] (3,5-difluoro-4-methoxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4 Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (IX-10)

[0216] Using intermediate VIII-10 (220 mg, 0.66 mmol) as starting material, following the preparation method of compound IX-1, 190 mg of off-white solid IX-10 was obtained with a yield of 79.1%. MS (ESI (+) 70V) m / z [M+H] + :367.08.

[0217] (3,5-difluoro-4-hydroxyphenyl)(1-imino-7-methyl-1-oxo-2,3-dihydro-1λ 4Synthesis of 4-benzo[b][1,4]thiazin-4(1H)-yl)methanone (I-C10)

[0218] Using intermediate IX-10 (170 mg, 0.46 mmol) as starting material and referring to the preparation method of compound I-A1, 77 mg of off-white solid I-C10 was obtained with a yield of 50.0%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.86 (s, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.13 (dd, J = 8.4, 2.0Hz, 1H), 7.04 (dd, J = 6.8, 1.6Hz, 2H), 6.80 (d, J = 8 .4Hz,1H),4.88(s,1H),4.34-4.27(m,1H),4.18-4.11(m,1H),3.74-3.68(m,1H),3.64-3.57(m,1H),2.31(s,3H).MS(ESI(+)70V)m / z[M+H] + :353.07.

[0219] Example 16: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-D1)

[0220] Using intermediate IV-2 (100 mg, 0.26 mmol) as starting material and referring to the preparation method of compound I-A1, 87 mg of off-white solid I-D1 was obtained with a yield of 90.3%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.85(s,1H),7.43–7.05(m,4H),7.02–6.70(m,2 H),3.93(s,2H),1.10-1.06(m,2H),0.98-0.82(m,2H).MS(ESI(+)70V)m / z[M+H] + :366.00.

[0221] Example 17: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[benzo[b][1,4]thiazin-2,1'-cyclopropane]-4(3H)-yl)methanone (I-D2)

[0222] Using intermediate IV-3 (100 mg, 0.21 mmol) as starting material and referring to the preparation method of compound I-A1, 55 mg of off-white solid I-D2 was obtained with a yield of 56.7%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 7.35-7.27 (m, 2H), 7.26-7.16 (m, 1H), 7.08 (td, J = 7.6, 1.6Hz, 1H), 6.93 (td, J = 7. 7,1.5Hz,1H),6.82(d,J=8.1Hz,1H),3.89(s,2H),1.08-0.96(m,2H),0.91-0.84(m,2H).MS(ESI(+)70V)m / z[M+H] + :453.90.

[0223] Example 18: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E1)

[0224] Synthesis of (3,5-difluoro-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-1)

[0225] Starting from 3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (X-1, 150.0 mg, 0.93 mmol) and intermediate III-2 (210.0 mg, 1.12 mmol), following the preparation method of intermediate IV-1, 266.91 mg of an off-white solid XI-1 was obtained in a yield of 86.6%. MS (ESI(+)70V) m / z [M+H] + :332.10.

[0226] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E1)

[0227] Using intermediate XI-1 (130.0 mg, 0.39 mmol) as starting material and referring to the preparation method of compound I-A1, 96.8 mg of off-white solid I-E1 was obtained with a yield of 77.8%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.89 (s, 1H), 7.35 (s, 1H), 7.29–7.17 (m, 2H), 7.08–6.98 (m, 1H), 6. 95–6.75(m,2H),3.85(s,2H),0.97(t,J=6.4Hz,2H),0.72(t,J=6.4Hz,2H).MS(ESI(+)70V)m / z[M+H] + :318.09.

[0228] Example 19: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E2)

[0229] Synthesis of (3,5-dichloro-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-2)

[0230] Using intermediate X-1 (100.0 mg, 0.62 mmol) and III-3 (150.8 mg, 0.68 mmol) as starting materials, following the preparation method of intermediate IV-1, 126.4 mg of off-white solid XI-2 was obtained in a yield of 55.9%. MS (ESI (+) 70 V) m / z [M+H] + :364.04.

[0231] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E2)

[0232] Using intermediate XI-2 (85.0 mg, 0.23 mmol) as starting material and referring to the preparation method of compound I-A1, 58.9 mg of off-white solid I-E2 was obtained with a yield of 72.1%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 7.51 (s, 2H), 7.35 (d, J = 6.7Hz, 1H), 7.04 (t, J = 7.3Hz, 1H) ,6.97–6.71(m,2H),3.86(s,2H),0.96(t,J=6.2Hz,2H),0.75(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :350.03.

[0233] Example 20: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E3)

[0234] Synthesis of (3,5-dibromo-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-3)

[0235] Using intermediate X-1 (150.0 mg, 0.93 mmol) and intermediate III-5 (346.1 mg, 1.12 mmol) as starting materials, following the preparation method of intermediate IV-1, 287.9 ​​mg of off-white solid XI-3 was obtained in a yield of 68.3%. MS (ESI (+) 70 V) m / z [M+H] + :451.94.

[0236] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E3)

[0237] Using intermediate XI-3 (170.0 mg, 0.38 mmol) as starting material and referring to the preparation method of compound I-A1, 108.3 mg of off-white solid I-E3 was obtained with a yield of 65.7%. 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.61 (s, 2H), 7.06-7.00 (m, 1H), 6.88 (dd, J = 8.3, 1.5Hz, 1H), 6.81–6. 68(m,1H),6.28(s,1H),3.91(s,2H),1.14(t,J=6.6Hz,2H),0.76(t,J=6.6Hz,2H).MS(ESI(+)70V)m / z[M+H] + :437.93.

[0238] Example 21: Synthesis of 5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxy-3-iodobenzonitrile (I-E4)

[0239] Synthesis of 5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-3-iodo-2-methoxybenzonitrile (XI-4)

[0240] Using intermediate X-1 (150 mg, 0.93 mmol) and intermediate III-9 (338.4 mg, 1.12 mmol) as starting materials, following the preparation method of intermediate IV-1, 240.7 mg of off-white solid XI-4 was obtained in a yield of 58.0%. MS (ESI (+) 70 V) m / z [M+H] + :447.01.

[0241] Synthesis of 5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxy-3-iodobenzonitrile (I-E4)

[0242] Using intermediate XI-4 (118.0 mg, 0.93 mmol) as starting material and referring to the preparation method of compound I-A1, 106.5 mg of off-white solid I-E4 was obtained with a yield of 61.1%. 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.01(d,J=2.2Hz,1H),7.65(d,J=2.2Hz,1H),7.30(d,J=8.2Hz,1H),7.07–6.95 (m,1H),6.92–6.76(m,2H),3.84(s,2H),0.95(t,J=6.4Hz,2H),0.73(t,J=6.4Hz,2H).MS(ESI(+)70V)m / z[M+H] + :433.00.

[0243] Example 22: Synthesis of (4-hydroxy-3,5-diiodophenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E5)

[0244] Synthesis of (3,5-diiodo-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-5)

[0245] Using intermediate X-1 (150.0 mg, 0.93 mmol) and intermediate III-6 (451.0 mg, 1.12 mmol) as starting materials, following the preparation method of intermediate IV-1, 286.8 mg of off-white solid XI-5 was obtained in a yield of 56.3%. MS (ESI (+) 70 V) m / z [M+H] + :547.91.

[0246] Synthesis of (4-hydroxy-3,5-diiodophenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E5)

[0247] Using intermediate XI-5 (177.0 mg, 0.32 mmol) as starting material and referring to the preparation method of compound I-A1, 109.2 mg of off-white solid I-E5 was obtained with a yield of 65.9%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H), 7.84 (s, 2H), 7.39–7.21 (m, 1H), 7.09–6.96 (m, 1H), 6. 89-6.82(m,2H),3.85(s,2H),0.96(t,J=6.2Hz,2H),0.75(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H]+ :533.90.

[0248] Example 23: Synthesis of (3-fluoro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E6)

[0249] Synthesis of (3-fluoro-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-6)

[0250] Using intermediate X-1 (100 mg, 0.62 mmol) and intermediate III-1 (106 mg, 0.62 mmol) as starting materials, following the preparation method of intermediate IV-1, 170 mg of off-white solid XI-6 was obtained in a yield of 87.5%. MS (ESI (+) 70 V) m / z [M+H] + :314.11.

[0251] Synthesis of (3-fluoro-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E6)

[0252] Using intermediate XI-6 (130 mg, 0.41 mmol) as raw material and referring to the preparation method of compound I-A1, 40 mg of off-white solid I-E6 was obtained with a yield of 32.2%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 7.32 (d, J = 11.6Hz, 1H), 7.28–7.12 (m, 2H), 7.05–6.93 (m, 2H) ),6.90–6.76(m,2H),3.84(s,2H),0.96(t,J=6.2Hz,2H),0.72(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :300.10.

[0253] Example 24: Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E7)

[0254] Synthesis of (3-chloro-4-methoxy-5-nitrophenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-7)

[0255] Using intermediate X-1 (486 mg, 3.59 mmol) and 3-chloro-4-methoxy-5-nitrobenzoic acid (III-7, 1.0 g, 4.32 mmol) as starting materials, following the preparation method of intermediate IV-1, 299.3 mg of yellow solid XI-7 was obtained in a yield of 26.5%. MS (ESI (+) 70 V) m / z [M+H] + :375.07.

[0256] Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E7)

[0257] Using intermediate XI-7 (0.9 g, 2.6 mmol) as starting material and referring to the preparation method of compound I-A1, 786.5 mg of off-white solid I-E7 was obtained with a yield of 90.8%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.74-7.67 (m, 4H), 7.21 (dd, J = 8.8, 2.4Hz, 1H), 6.85 (d, J = 8. 7Hz,1H),3.83(s,2H),0.93(t,J=6.2Hz,2H),0.73(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :361.05.

[0258] Example 25: Synthesis of (3-bromo-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E8)

[0259] Synthesis of (3-bromo-4-methoxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-8)

[0260] Using intermediate X-1 (150 mg, 0.93 mmol) and 3-bromo-4-methoxybenzoic acid (III-4, 258 mg, 1.12 mmol) as starting materials, following the preparation method of intermediate IV-1, 120 mg of light yellow oil XI-8 was obtained in a yield of 34.5%. MS (ESI (+) 70 V) m / z [M+H] + :374.03.

[0261] Synthesis of (3-bromo-4-hydroxyphenyl)(spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E8)

[0262] Using intermediate XI-8 (120 mg, 0.32 mmol) as starting material and referring to the preparation method of compound I-A1, 40 mg of off-white solid I-E8 was obtained with a yield of 34.6%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.94 (s, 1H), 7.64 (s, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.29–7.14 (m, 1H), 7.07–6 .92(m,2H),6.92–6.73(m,2H),3.85(s,2H),0.98–0.93(m,2H),0.74–0.68(m,2H).MS(ESI(+)70V)m / z[M+H] + :360.02.

[0263] Example 26: Synthesis of 3-bromo-5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxybenzonitrile (I-E9)

[0264] Synthesis of 1-bromo-5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-methoxybenzonitrile (XI-9)

[0265] Using intermediate X-1 (150 mg, 0.93 mmol) and 3-bromo-4-methoxy-5-cyanobenzoic acid (III-8, 238 mg, 0.93 mmol) as starting materials, following the preparation method of intermediate IV-1, 236 mg of off-white solid XI-9 was obtained in a yield of 63.5%. MS (ESI (+) 70 V) m / z [M+H] + :399.03.

[0266] Synthesis of 3-bromo-5-(3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxybenzonitrile (I-E9)

[0267] Using intermediate XI-9 (150 mg, 0.38 mmol) as starting material and referring to the preparation method of compound I-A1, 111 mg of off-white solid I-E9 was obtained with a yield of 76.7%. 1H NMR (300MHz, DMSO-d6) δ (ppm): 7.97 (d, J = 2.1Hz, 1H), 7.84 (d, J = 2.0Hz, 1H), 7.42 (s, 1H), 7.06 (td, J = 8.4, 7.0, 1 .6Hz,1H),6.94–6.81(m,2H),3.86(s,2H),0.96(t,J=6.2Hz,2H),0.74(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :385.01.

[0268] Example 27: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E10)

[0269] Synthesis of (3,5-dichloro-4-methoxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-10)

[0270] Starting from 7-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (X-2, 180 mg, 0.75 mmol) and intermediate III-3 (166 mg, 0.75 mmol), following the preparation method of intermediate IV-1, 217.3 mg of off-white solid XI-10 was obtained in a yield of 65.3%. MS (ESI(+)70V) m / z [M+H] + :441.95.

[0271] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E10)

[0272] Using intermediate XI-10 (150 mg, 0.34 mmol) as starting material and referring to the preparation method of compound I-A1, 110 mg of off-white solid was obtained with a yield of 75.7%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.80–7.73 (m, 1H), 7.57 (s, 2H), 7.22 (dd, J = 8.8, 2.4Hz, 1H), 6.87 (d ,J=8.7Hz,1H),3.84(s,2H),0.94(t,J=6.2Hz,2H),0.73(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :427.94.

[0273] Example 28: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E11)

[0274] Synthesis of (3,5-difluoro-4-methoxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-11)

[0275] Using intermediate X-2 (150 mg, 0.62 mmol) and intermediate III-2 (118 mg, 0.62 mmol) as starting materials, following the preparation method of intermediate IV-1, 187 mg of off-white solid XI-11 was obtained in a yield of 73.0%. MS (ESI (+) 70V) m / z [M+H] + :410.01.

[0276] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E11)

[0277] Using intermediate XI-11 (150 mg, 0.37 mmol) as raw material and referring to the preparation method of compound I-A1, 120 mg of off-white solid I-E10 was obtained with a yield of 82.8%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 7.89 (s, 2H), 7.72 (s, 1H), 7.22 (dd, J = 8.8, 2.4Hz, 1H), 6.87 (s, 1H) ,6.85(s,1H),3.83(s,2H),0.94(t,J=6.0Hz,2H),0.74(t,J=6.0Hz,2H).MS(ESI(+)70V)m / z[M+H] + :396.00.

[0278] Example 29: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E12)

[0279] Synthesis of (3,5-difluoro-4-methoxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-12)

[0280] Starting from 3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine] (X-3, 150 mg, 0.93 mmol) and intermediate III-2 (208 mg, 0.85 mmol), following the preparation method of intermediate IV-1, 109.48 mg of off-white solid XI-12 was obtained in a yield of 35.6%. MS (ESI(+)70V) m / z [M+H] + :333.31.

[0281] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E12)

[0282] Using intermediate XI-12 (70 mg, 0.21 mmol) as starting material and referring to the preparation method of compound I-A1, 39.45 mg of off-white solid I-E12 was obtained with a yield of 58.8%. 1 H NMR(400MHz,Chloroform-d)δ(ppm):8.68-8.57(m,1H),8.16-7.97(m,1H),8.07(s,1H),7.26(s,2H), 7.20-6.90(m,1H),3.91(s,2H),1.01(t,J=6.3Hz,2H),0.71(t,J=6.3Hz,2H).MS(ESI(+)70V)m / z[M+H] + :319.28.

[0283] Example 30: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E13)

[0284] Synthesis of (3,5-dichloro-4-methoxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-13)

[0285] Using intermediate X-3 (300 mg, 0.92 mmol) and intermediate III-3 (490 mg, 1.1 mmol) as starting materials, following the preparation method of intermediate IV-1, 278.19 mg of off-white solid XI-13 was obtained in a yield of 41.2%. MS (ESI (+) 70V) m / z [M+H] + :366.21.

[0286] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E13)

[0287] Using intermediate XI-13 (150 mg, 0.41 mmol) as starting material and referring to the preparation method of compound I-A1, 79.63 mg of off-white solid I-E13 was obtained with a yield of 55.2%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 8.68 (s, 1H), 8.16 (d, J = 5.6Hz, 1H), 7.58 (s, 2H), 7.01 (d, J = 5. 5Hz,1H),3.93(s,2H),1.01(t,J=6.2Hz,2H),0.80(t,J=6.2Hz,2H).MS(ESI(+)70V)m / z[M+H] + :352.18.

[0288] Example 31: Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E14)

[0289] Synthesis of (3-chloro-4-methoxy-5-nitrophenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-14)

[0290] Using intermediate X-2 (100 mg, 0.45 mmol) and intermediate III-7 (130 mg, 0.56 mmol) as starting materials, following the preparation method of intermediate IV-1, 96.6 mg of light yellow solid XI-14 was obtained, with a yield of 51.1%. MS (ESI (+) 70 V) m / z [M+H] + :454.67.

[0291] Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E14)

[0292] Using intermediate XI-14 (140 mg, 0.33 mmol) as starting material, and referring to the preparation method of compound I-A1, 119.7 mg of yellow solid I-E14 was obtained, with a yield of 88.2%. MS (ESI (+) 70V) m / z [M+H] + :440.65. 1HNMR(300MHz,DMSO-d6)δ(ppm):8.04(d,J=2.3Hz,1H),7.83(d,J=2.3Hz,1H),7.76(d,J=2.4Hz,1H),7.21 (dd,J=8.7,2.4Hz,1H),6.86(d,J=8.8Hz,1H),3.86(s,2H),0.94(t,J=5.2Hz,2H),0.72(t,J=5.2Hz,2H).

[0293] Example 32: Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E15)

[0294] Synthesis of (3-chloro-4-methoxy-5-nitrophenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-15)

[0295] Using intermediate X-3 (150 mg, 0.93 mmol) and intermediate III-7 (257 mg, 1.11 mmol) as starting materials, following the preparation method of intermediate IV-1, 166.5 mg of off-white solid XI-15 was obtained in a yield of 47.9%. MS (ESI (+) 70 V) m / z [M+H] + :376.77.

[0296] Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E15)

[0297] Using intermediate XI-15 (170 mg, 0.45 mmol) as starting material, and referring to the preparation method of compound I-A1, 146.2 mg of yellow solid I-E15 was obtained, with a yield of 89.3%. MS (ESI (+) 70V) m / z [M+H] + :362.74. 1 HNMR (300MHz, DMSO-d6) δ (ppm): 8.44 (s, 1H), 8.08 (d, J=5.6Hz, 1H), 7.97 (d, J= 2.6Hz,1H),7.51(d,J=2.5Hz,1H),6.94(d,J=5.6Hz,1H),3.95(s,2H),1.00(t,J =6.1Hz,2H),0.80(t,J=6.2Hz,2H).

[0298] Example 33: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E16)

[0299] Synthesis of (3,5-difluoro-4-methoxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-16)

[0300] Starting from 6-fluoro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (X-4, 150 mg, 0.84 mmol) and intermediate III-2 (189 mg, 1.0 mmol), following the preparation method of intermediate IV-1, 100 mg of off-white solid XI-16 was obtained in a yield of 31.2%. MS (ESI(+)70V) m / z [M+H] + :350.31.

[0301] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E16)

[0302] Using intermediate XI-16 (160 mg, 0.49 mmol) as starting material, and referring to the preparation method of compound I-A1, 56 mg of off-white solid I-E16 was obtained, with a yield of 36.5%. MS (ESI (+) 70V) m / z [M+H] + :336.28. 1 H NMR (300 MHz, DMSO-d 6 )δ(ppm):7.23(dd,J=12.0,3.0Hz,1H),7.08(dd,J=9.0,3.0Hz,2H),6.87(d,J=9.0Hz,2H),3.84(s,2H),0.92(t,J=6.0Hz,2H),0.70(t,J=6.0Hz,2H).

[0303] Example 34: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E17)

[0304] Synthesis of (3,5-dichloro-4-methoxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-17)

[0305] Using intermediate X-4 (150 mg, 0.84 mmol) and intermediate III-3 (222 mg, 1.0 mmol) as starting materials, following the preparation method of intermediate IV-1, 159.2 mg of off-white solid XI-17 was obtained in a yield of 49.8%. MS (ESI (+) 70 V) m / z [M+H] + :383.21.

[0306] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E17)

[0307] Using intermediate XI-17 (85 mg, 0.22 mmol) as starting material and referring to the preparation method of compound I-A1, 30 mg of off-white solid I-E17 was obtained with a yield of 36.6%. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 7.46 (s, 2H), 7.30 (d, J = 10.6Hz, 1H), 6.89 (d, J = 1.7Hz, 1H), 6.87 (d ,J=1.7Hz,1H),3.84(s,2H),0.93(t,J=5.6Hz,2H),0.72(t,J=5.6Hz,2H).MS(ESI(+)70V)m / z[M+H] + :368.02.

[0308] Example 35: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E18)

[0309] Synthesis of (3,5-dibromo-4-methoxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-18)

[0310] Using intermediate X-4 (160 mg, 0.89 mmol) and intermediate III-5 (360 mg, 1.16 mmol) as starting materials, following the preparation method of intermediate IV-1, 180 mg of off-white solid XI-18 was obtained in a yield of 42.8%. MS (ESI (+) 70V) m / z [M+H] + :472.12.

[0311] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E18)

[0312] Using intermediate XI-18 (160 mg, 0.34 mmol) as starting material and referring to the preparation method of compound I-A1, 34 mg of off-white solid I-E18 was obtained with a yield of 19.5%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.53(s,2H),7.14(dd,J=11.0,2.8Hz,1H),6.90–6.78(m, 2H),3.83(s,2H),0.92(t,J=5.7Hz,2H),0.72(t,J=5.7Hz,2H).MS(ESI(+)70V)m / z[M+H] + :458.09.

[0313] Example 36: Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E19)

[0314] Synthesis of (3-chloro-4-methoxy-5-nitrophenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-19)

[0315] Using intermediate X-4 (100 mg, 0.56 mmol) and intermediate III-7 (155 mg, 0.67 mmol) as starting materials, following the preparation method of intermediate IV-1, 168.9 mg of off-white solid XI-19 was obtained in a yield of 77.1%. MS (ESI (+) 70 V) m / z [M+H] + :393.77.

[0316] Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E19)

[0317] Using intermediate XI-19 (100 mg, 0.26 mmol) as starting material and referring to the preparation method of compound I-A1, 88.2 mg of yellow solid I-E19 was obtained with a yield of 91.5%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):8.07(d,J=2.2Hz,1H),7.94(d,J=2.2Hz,1H),7.50(d,J=11.0Hz,1H),6 .98–6.87(m,2H),3.86(s,2H),0.93(t,J=5.7Hz,2H),0.73(t,J=5.7Hz,2H).MS(ESI(+)70V)m / z[M+H] + :379.74.

[0318] Example 37: Synthesis of 5-(6-fluoro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxybenzonitrile (I-E20)

[0319] Synthesis of 5-(6-fluoro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-methoxybenzonitrile (XI-20)

[0320] Using intermediate X-4 (160 mg, 0.89 mmol) and intermediate 3-cyano-4-methoxybenzoic acid (III-10, 190 mg, 1.07 mmol) as starting materials, following the preparation method of intermediate IV-1, 210 mg of off-white solid XI-20 was obtained in a yield of 69.5%. MS (ESI (+) 70V) m / z [M+H] + :339.34.

[0321] Synthesis of 5-(6-fluoro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4-carbonyl)-2-hydroxybenzonitrile (I-E20)

[0322] Using intermediate XI-20 (184 mg, 0.54 mmol) as starting material, and referring to the preparation method of compound I-A1, 50 mg of off-white solid I-E20 was obtained in a yield of 15.1%. MS (ESI (+) 70V) m / z [M+H] + :325.31. 1 HNMR (300MHz, DMSO-d6) δ (ppm): 11.80 (s, 1H), 7.85 (d, J = 2.2Hz, 1H), 7.73–7.62 (m, 1H), 7.35 (d, J = 10.6Hz ,1H),7.07(d,J=8.7Hz,1H),6.96–6.85(m,2H),3.83(s,2H),0.94(t,J=5.2Hz,2H),0.72(t,J=5.2Hz,2H).

[0323] Example 38: Synthesis of (3-chloro-5-fluoro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E21)

[0324] Synthesis of (3-chloro-5-fluoro-4-methoxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-21)

[0325] Using intermediate X-4 (150 mg, 0.84 mmol) and 3-chloro-5-fluoro-4-methoxybenzoic acid (III-11, 206 mg, 1.0 mmol) as starting materials, following the preparation method of intermediate IV-1, 175 mg of off-white solid XI-21 was obtained in a yield of 57.2%. MS (ESI (+) 70 V) m / z [M+H] + :366.76.

[0326] Synthesis of (3-chloro-5-fluoro-4-hydroxyphenyl)(6-fluorospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E21)

[0327] Using intermediate XI-21 (145 mg, 0.40 mmol) as starting material and referring to the preparation method of compound I-A1, 93 mg of off-white solid I-E21 was obtained with a yield of 66.7%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):11.11(s,1H),7.45–7.38(m,3H),6.97–6.83(m,2H), 3.84(s,2H),0.93(t,J=5.7Hz,2H),0.72(t,J=5.7Hz,2H).MS(ESI(+)70V)m / z[M+H] + :352.73.

[0328] Example 39: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E22)

[0329] Synthesis of (3,5-dichloro-4-methoxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-22)

[0330] Starting from 6-(trifluoromethyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (X-5, 100 mg, 0.44 mmol) and intermediate III-3 (116 mg, 0.52 mmol), following the preparation method of intermediate IV-1, 136.6 mg of off-white solid XI-22 was obtained in a yield of 72.4%. MS (ESI(+)70V) m / z [M+H] + :433.22.

[0331] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E22)

[0332] Using intermediate XI-22 (80 mg, 0.19 mmol) as starting material, and referring to the preparation method of compound I-A1, 56.5 mg of white solid I-E22 was obtained, with a yield of 73.0%. MS (ESI (+) 70V) m / z [M+H] + :419.19. 1 HNMR(300MHz,DMSO-d6)δ(ppm):10.92(s,1H),7.96(s,1H),7.59(s,2H),7.41(dd, J=8.6,2.4Hz,1H),7.10(d,J=8.4Hz,1H),3.91(s,2H),1.00(t,J=6.3Hz,2H),0.79(t,J=6.3Hz,2H).

[0333] Example 40: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E23)

[0334] Synthesis of (3,5-dibromo-4-methoxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (XI-23)

[0335] Using intermediate X-5 (150 mg, 0.65 mmol) and intermediate III-5 (243 mg, 0.79 mmol) as starting materials, following the preparation method of intermediate IV-1, 170.4 mg of off-white solid XI-23 was obtained in a yield of 50.0%. MS (ESI (+) 70V) m / z [M+H] + :522.13.

[0336] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(6-(trifluoromethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-4(3H)-yl)methanone (I-E23)

[0337] Using intermediate XI-23 (170 mg, 0.33 mmol) as starting material, and referring to the preparation method of compound I-A1, 109.8 mg of off-white solid I-E23 was obtained, with a yield of 66.4%. MS (ESI (+) 70V) m / z [M+H] + :508.10. 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.69 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.71-7.62 (m, 1H), 7.41 (dd, J=8.7,2.3Hz,1H),7.09(d,J=8.6Hz,1H),3.91(s,2H),1.00(t,J=5.1Hz,2H),0.78(t,J=5.1Hz,2H).

[0338] Example 41: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E24)

[0339] Synthesis of (3,5-dibromo-4-methoxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-24)

[0340] Using intermediate X-3 (150 mg, 0.93 mmol) and intermediate III-5 (343.97 mg, 1.11 mmol) as starting materials, following the preparation method of intermediate IV-1, 169.98 mg of off-white solid XI-24 was obtained in a yield of 40.47%. MS (ESI (+) 70V) m / z [M+H] + :455.12.

[0341] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E24)

[0342] Using intermediate XI-24 (65 mg, 0.14 mmol) as starting material, and referring to the preparation method of compound I-A1, 42.99 mg of off-white solid I-E24 was obtained, with a yield of 68.25%. MS (ESI (+) 70V) m / z [M+H] + :441.09. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.61 (s, 1H), 8.12 (d, J = 5.5Hz, 1H), 7.73 (s, 2H), 6.95(d,J=5.5Hz,1H),3.92(s,2H),1.01(t,J=6.6Hz,2H),0.79(t,J=6.6Hz,2H).

[0343] Example 42: Synthesis of (3-chloro-5-fluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E25)

[0344] Synthesis of (3-chloro-5-fluoro-4-methoxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-25)

[0345] Using intermediate X-3 (150 mg, 0.93 mmol) and intermediate III-11 (227.08 mg, 1.11 mmol) as starting materials, following the preparation method of intermediate IV-1, 162.54 mg of off-white solid XI-25 was obtained in a yield of 50.39%. MS (ESI (+) 70V) m / z [M+H] + :349.76.

[0346] Synthesis of (3-chloro-5-fluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E25)

[0347] Using intermediate XI-25 (80 mg, 0.23 mmol) as starting material, and referring to the preparation method of compound I-A1, 83 mg of off-white solid I-E25 was obtained, with a yield of 69.03%. MS (ESI (+) 70V) m / z [M+H] + :335.73. 1 HNMR (400MHz, DMSO-d6) δ (ppm): 11.30 (s, 1H), 8.65 (s, 1H), 8.15 (s, 1H), 7.44 (d, J = 2.52Hz, 1H), 7.4 1(d,J=1.96Hz,1H),6.99(d,J=5.4Hz,1H),3.93(s,2H),1.02(t,J=6.5Hz,2H),0.78(t,J=6.5Hz,2H).

[0348] Example 43: Synthesis of (3-bromo-5-chloro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E26)

[0349] Synthesis of (3-bromo-5-chloro-4-methoxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (XI-26)

[0350] Using intermediate X-3 (150 mg, 0.93 mmol) and 3-bromo-5-chloro-4-methoxybenzoic acid (III-12, 295 mg, 1.11 mmol) as starting materials, following the preparation method of intermediate IV-1, 63 mg of off-white solid XI-26 was obtained in a yield of 16.63%. MS (ESI (+) 70 V) m / z [M+H] + :410.66.

[0351] Synthesis of (3-bromo-5-chloro-4-hydroxyphenyl)(spiro[cyclopropane-1,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-yl)methanone (I-E26)

[0352] Using intermediate XI-26 (50 mg, 0.12 mmol) as starting material, and referring to the preparation method of compound I-A1, 48 mg of off-white solid I-E26 was obtained in a yield of 99.4%. MS (ESI (+) 70V) m / z [M+H] + :395.64. 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.59 (s, 1H), 8.12 (d, J = 5.6Hz, 1H), 7.66 (d, J = 2.2Hz, 1H), 7.56 ( d,J=2.1Hz,1H),6.95(d,J=5.6Hz,1H),3.92(s,2H),1.01(t,J=6.5Hz,2H),0.79(t,J=6.6Hz,2H).

[0353] Example 44: Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E27)

[0354] Synthesis of (3,5-difluoro-4-methoxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (XI-27)

[0355] Starting from 1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine] (Intermediate X-6, 100 mg, 0.62 mmol) and Intermediate III-2 (127.6 mg, 0.68 mmol), following the preparation method of Intermediate IV-1, 115.7 mg of off-white solid XI-27 was obtained in a yield of 56.5%. MS (ESI(+)70V) m / z [M+ H] + :333.31.

[0356] Synthesis of (3,5-difluoro-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E27)

[0357] Using intermediate XI-27 (163 mg, 0.49 mmol) as starting material, and referring to the preparation method of compound I-A1, 122.4 mg of off-white solid I-E27 was obtained, with a yield of 78.4%. MS (ESI (+) 70V) m / z [M+H] + :319.28. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 7.96 (d, J = 5.6Hz, 2H), 7.30 (dd, J = 6.9, 1.8Hz, 2H),7.03(dd,J=7.8,4.9Hz,1H),3.88(s,2H),1.01(t,J=5.2Hz,2H),0.76(t,J=5.2Hz,2H).

[0358] Example 45: Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E28)

[0359] Synthesis of (3,5-dichloro-4-methoxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (XI-28)

[0360] Using intermediate X-6 (100 mg, 0.62 mmol) and intermediate III-3 (149.9 mg, 0.68 mmol) as starting materials, following the preparation method of intermediate IV-1, 177.5 mg of light yellow oily liquid XI-28 was obtained in a yield of 78.8%. MS (ESI (+) 70V) m / z [M+H] + :366.21.

[0361] Synthesis of (3,5-dichloro-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E28)

[0362] Using intermediate XI-28 (140 mg, 0.38 mmol) as starting material, and referring to the preparation method of compound I-A1, 99.8 mg of off-white solid I-E28 was obtained, with a yield of 74.2%. MS (ESI (+) 70V) m / z [M+H] + :352.18. 1H NMR(300MHz,DMSO-d6)δ(ppm):10.88(s,1H),7.99-7.95(m,2H),7.58(s,2H),7.03 (dd,J=7.9,4.8Hz,1H),3.89(s,2H),1.01(t,J=5.2Hz,2H),0.77(t,J=5.2Hz,2H).

[0363] Example 46: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E29)

[0364] Synthesis of (3,5-dibromo-4-methoxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (XI-29)

[0365] Using intermediate X-6 (100 mg, 0.62 mmol) and intermediate III-5 (210.14 mg, 0.68 mmol) as starting materials, following the preparation method of intermediate IV-1, 105.92 mg of light yellow oily liquid XI-29 was obtained in a yield of 37.8%. MS (ESI (+) 70V) m / z [M+H] + :455.12.

[0366] Synthesis of (3,5-dibromo-4-hydroxyphenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E29)

[0367] Using intermediate XI-29 (160 mg, 0.35 mmol) as starting material, and referring to the preparation method of compound I-A1, 107.3 mg of off-white solid I-E29 was obtained, with a yield of 69.2%. MS (ESI (+) 70V) m / z [M+H] + :441.09. 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.65(s,1H),8.04–7.89(m,2H),7.73(s,2H),7.03 (dd,J=7.8,4.9Hz,1H),3.89(s,2H),1.01(t,J=5.1Hz,2H),0.78(t,J=5.1Hz,2H).

[0368] Example 47: Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E30)

[0369] Synthesis of (3-chloro-4-methoxy-5-nitrophenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (XI-30)

[0370] Using intermediate X-6 (200 mg, 1.23 mmol) and intermediate III-7 (342.75 mg, 1.48 mmol) as starting materials, following the preparation method of intermediate IV-1, 199.7 mg of off-white solid XI-30 was obtained in a yield of 43.1%. MS (ESI (+) 70V) m / z [M+H] + :376.06.

[0371] Synthesis of (3-chloro-4-hydroxy-5-nitrophenyl)(spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)methanone (I-E30)

[0372] Using intermediate XI-30 (170 mg, 0.45 mmol) as starting material, and referring to the preparation method of compound I-A1, 92.4 mg of yellow solid I-E30 was obtained, with a yield of 56.5%. MS (ESI (+) 70V) m / z [M+H] + :362.74. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 8.03-7.96 (m, 3H), 7.87 (s, 1H), 7.05 (dd, J = 7.8, 4.7Hz, 1H), 3.91 (s, 2H), 1.01 (t, J = 6.1Hz, 2H), 0.78 (t, J = 6.1Hz, 2H).

[0373] Example 48: In vitro inhibitory activity test of the compounds of the present invention on hURAT1

[0374] 1. Cell Culture and Inoculation

[0375] HEK-293T cells stably expressing hURAT1 (from Wise Chemical Research) were cultured in a medium consisting of DMEM + 10% fetal bovine serum + 500 μg / mL G418 + 1% P / S. When the cells reached 80% growth, the medium was discarded and the cells were washed once with PBS. Trypsin was then added for digestion. Once the cells detached from the cell wall, the medium was added and pipetted to release the cells. The cells were collected by centrifugation and then pipetted to form a cell suspension. The cell density was adjusted to 7 × 10 5 / mL, and then inoculated into 96-well cell culture plates at a volume of 100 μL / well and cultured for 12 to 24 hours.

[0376] 2. Compound Preparation

[0377] The quality control compound benzbromarone was prepared by using DMSO to prepare a 20 mM stock solution, and then DMSO and Cl - The stock solution was diluted to a concentration of 2 μM in free HBSS buffer (including: 125 mM sodium D-gluconate, 4.8 mM potassium D-gluconate, 1.3 mM calcium D-gluconate, 1.2 mM KH2PO4, 1.2 mM MgSO4, 5.6 mM glucose, 25 mM HEPES (pH 7.4)) (volume ratio 1:49). Then, 25 μL / well of 0.1 μCi / mL dapoxetine was added. 14 C-uric acid buffer and 25 μL / well of 2 μM compound were prepared to 1 μM compound for use.

[0378] 3. 14 C-uric acid absorption in cells stably expressing hURAT1

[0379] After the cells in the 96-well plate have attached to the wall, the absorption test can be performed. - Wash the cells once with free HBSS buffer. Aspirate each well and immediately add 50 μL / well containing the corresponding compound and 0.1 μCi / mL 14 C-uric acid solution. Incubate the plate with the compound added in a 37°C incubator for 5 minutes.

[0380] Immediately add 150 μL of ice-cold Cl - Free HBSS buffer was added to terminate the absorption. Each well was washed three times with buffer. During the washing process, try to avoid cell shedding. 50 μL of 100 mM NaOH lysis solution was added to each well and placed on an oscillator at a speed of 900 rpm for 5 minutes. 150 μL of scintillation fluid Microsint40 was added to each well and oscillated at a speed of 900 rpm for 5 minutes. Finally, the microplate was sent to the MicroBeta2 (manufactured by PerkinElmer) instrument to measure the radioactivity. The radioactivity was measured at compound dilution concentrations of 3 μmol / L, 1 μmol / L, 0.33 μmol / L, 0.11 μmol / L, 0.037 μmol / L, 0.012 μmol / L, 0.004 μmol / L, and 0.0014 μmol / L, respectively, and the data were analyzed and the IC of each compound was calculated using GraphPad Prism 5 software. 50 .

[0381] 4. Test Results

[0382] Table 1 In vitro inhibitory activity of the compounds of the present invention against hURAT1 Note: At 100 nM, the inhibition rates of A, B, and C are as follows: A ≥ 75%, 50% ≤ B < 75%, C < 50%.

[0383] The results in Table 1 show that at a concentration of 100 nM, the compounds of the present invention have strong inhibitory activity against hURAT1, especially compounds I-E2, I-E3, I-E5, I-E7, I-E9, I-E17, I-E18, I-E19, I-E24 and I-E26, whose inhibition rates against hURAT1 at a concentration of 100 nM exceed 75%.

[0384] Some compounds with higher inhibition rates were selected and their IC values ​​for hURAT1 were determined. 50 The results are shown in Table 2.

[0385] Table 2 IC values ​​of some compounds of the present invention for hURAT1 50 Determination Note: The ranges of A, B, and C are as follows: A ≤ 30 nM, 30 nM < B ≤ 200 nM, 200 nM < C ≤ 1000 nM.

[0386] The results in Table 2 show that the IC values ​​of most of the tested compounds were 50 No more than 200 nM, among which compounds I-E3, I-E5, I-E7, I-E17 to I-E19, I-E21 and I-E24 had IC 50 Not exceeding 30nM.

[0387] Example 49: Selective inhibitory activity of compound I-E24 of the present invention on uric acid transporter

[0388] 1. Breast Cancer Resistance Protein (BCRP / ABCG2) Inhibitory Activity Experiment

[0389] Test system: expressing human BCRP vesicles (purchased from GenoMembrane, Japan)

[0390] Incubation conditions: incubation time: 10 min; temperature: 37°C; test concentrations: 100, 50, 10, 3, and 0.1 μM;

[0391] Experimental and control group settings: Experimental group: Different concentrations of I-E24 were pre-incubated with human BCRP vesicles at 37°C for 5 minutes, and then incubated with the fluorescent yellow probe substrate at 37°C for 5 minutes under the condition of adding ATP or AMP respectively; Positive control group: Human BCRP vesicles were pre-incubated with Dotinurad at 37°C for 5 minutes, and then incubated with the probe substrate at 37°C for 5 minutes under the condition of adding ATP or AMP respectively;

[0392] Assay steps: 1) Preincubate the test substance with vesicles expressing human BCRP at 37°C for 5 minutes, followed by incubation with the probe substrate at 37°C for 5 minutes in the presence of either ATP or AMP. 2) Terminate the assay with pre-chilled stop and wash buffer (400 mM MOPS-Tris / 700 mM KCl) (BCRP). Transfer the test sample to a 96-well filter plate and vacuum filter. Wash the plate five times with 0.2 mL of pre-chilled Buffer B2 (BCRP). Solubilize the vesicles on the filter plate with 50 μL of 10% SDS and collect the collected solution. Centrifuge the solution at 2000 rpm for 2 minutes, collect the supernatant, and repeat the above steps. 3) Combine the two supernatants and mix to obtain approximately 100 μL of a solution, to which an equal volume of DMSO is added. Quantify the fluorescence intensity of Lucifer Yellow (LFY) using a fluorescence microplate reader (excitation: 428 nm, emission: 536 nm).

[0393] 2. Organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) inhibitory activity test

[0394] Test system: HEK293 cells expressing human OAT1 and OAT3 transporters (purchased from GenoMembrane, Japan)

[0395] Incubation conditions: incubation time: 10 min; temperature: 37°C; test concentrations: 100, 50, 10, 3, and 0.1 μM;

[0396] Experimental and control group settings: Experimental group: A mixed solution of different concentrations of I-E24 and the probe substrate p-aminohippuric acid (OAT1 probe substrate) / estrone 3-sulfate (OAT3 probe substrate) was incubated with different transporter cells at 37°C for 10 minutes; Positive control group: A mixed solution of Dotinurad and the probe substrate was incubated with different transporter cells at 37°C for 10 minutes.

[0397] Experimental steps: 1) HEK293 cells expressing human OAT1 and OAT3 transporters were cultured in DMEM medium (purchased from Gibco, catalog number 11885-084) at 37°C and 5% CO2. 510 cells / well were seeded in a 96-well plate. 2) Prior to the assay, the culture medium was aspirated from the plate and the cells were washed twice with 37°C pre-warmed transport buffer (pH 7.4, containing 125 mM NaCl / 4.8 mM KCl / 5.6 mM D-(+)-glucose / 1.2 mM CaCl2 / 1.2 mM KH2PO4 / 1.2 mM MgSO4 / 25 mM HEPES), 0.1 mL / well each wash. The second wash buffer was left in the plate and equilibrated at 37°C for 5 minutes. 3) Aspirate the buffer solution, add 0.05mL of preheated substrate p-aminohippuric acid (OAT1 probe substrate) / estrone 3-sulfate (OAT3 probe substrate) and a mixed solution of different concentrations of I-E24 or Dotinurad, and incubate at 37°C for 10 minutes; after the incubation, immediately aspirate the incubation solution and wash 3 times with pre-cooled transport buffer, 0.1mL / well each time. 4) After washing, add 0.1mL of distilled water to each well, and freeze and thaw repeatedly with liquid nitrogen 3 times (-196°C to -37°C) to completely lyse the cells. 5) Take part of the lysate and mix it with methanol containing the internal standard (tolbutamide) at a ratio of 1:4. After the precipitate is precipitated, transfer it to a new 1.5mL centrifuge tube, centrifuge at 12000rpm and 4°C for 5 minutes, collect the supernatant, and use LC-MS / MS method to quantitatively detect the content of the probe substrate in each sample. 6) Take a certain amount of lysate and use The BCA protein assay kit was used to determine the cellular protein concentration in the sample.

[0398] 3. Test results

[0399] Table 3 IC of the compounds of the present invention on uric acid transporters 50 Determination

[0400] The results in Table 3 show that compound I-E24 inhibited the uptake of uric acid by transporters other than URAT1 (BRCP (ABCG2), OAT1, OAT3) in a concentration-dependent manner. 50 The IC values ​​of Dotinurad for (BRCP (ABCG2), OAT1, OAT3) were 37.1μM, 6.16μM and 6.62μM respectively; while the IC values ​​of Dotinurad for (BRCP (ABCG2), OAT1, OAT3) 50 The inhibitory activity of dotinurad against URAT1 was 12.3 μM, 2.7 μM, and 6.07 μM, respectively. Dotinurad showed 311-fold, 68-fold, and 153-fold selectivity for URAT1 inhibition relative to the inhibitory transporters BRCP (ABCG2), OAT1, and OAT3, respectively. Compound I-E24 showed 7894-fold, 1311-fold, and 1408-fold selectivity for URAT1 inhibition, respectively. In summary, compound I-E24 can highly selectively inhibit URAT1 activity.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: or its stereoisomers, solvates, prodrugs, isotope-labeled substances, and pharmaceutically acceptable salts, in, X 1 Selected from O, S, Se, NR 5 、CHR 5 , SO, SO2 or S(O)=NR 5 , where R 5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl or C1-C6 alkanoyl; X 2 、X 3 、X 4 、X 5 Each independently selected from N or CR 6 , where R 6 is independently selected at each occurrence from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy; A, B, Y, and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, nitro, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl-substituted C1-C6 alkoxy, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-substituted C1-C6 alkyl; 9 C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-substituted C1-C6 alkyl; R 1 、R 2 、R 3 or R 4 Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-membered or 6-membered heteroaryl, optionally substituted 3-membered to 6-membered heterocyclic group, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-membered or 6-membered heteroaryl, 3-membered to 6-membered heterocyclyl are optionally substituted by a group selected from the group consisting of H, halogen, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted C1~C6 alkyl, CO2R 8 or CONR 8 R 8’ ;or R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 carbocyclic ring or an optionally substituted 3- to 6-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by a group selected from the group consisting of H, halogen, C1-C6 alkyl, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted C1~C6 alkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 Not forming a carbocyclic ring or a heterocyclic ring at the same time; Q is selected from CH2, CO, SO or SO2.

2. The compound according to claim 1 or its stereoisomer, solvate, prodrug, isotope-labeled substance, and pharmaceutically acceptable salt, wherein: X 1 Selected from O, S, SO, SO2 or S(O)=NR 5 , where R 5 Selected from H, C1~C3 alkyl, C3~C6 cycloalkyl. X 2 、X 3 、X 4 、X 5 Each independently selected from N or CR 6 , where R 6 is independently selected at each occurrence from H, F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,-difluoroethoxy; A, B, Y, and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, COR 8 、CO2R 8 、CONR 8 R 8’ NR 8 R 8’ 、SOR 9 or SO2R 9 , R 8 or R 8’ R is independently selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-; 9 Selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, or cyclohexyl-CH2-.

3. The compound according to claim 1 or its stereoisomer, solvate, prodrug, isotope-labeled substance, and pharmaceutically acceptable salt, wherein: X 2 、X 3 、X 4 、X 5 are each independently selected from N or CH; A, B, Y, and Z are each independently selected from N or CR 7 , where R 7 Each occurrence is independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, nitro, cyclopropyl, cyclopropyl-CH2-, cyclopropyloxy, cyclopropyl-CH2O-, CO2CH3, CO2C2H5, CONH2 or CONHCH3.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof, wherein: R 1 、R 2 、R 3 or R 4 Each is independently selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 3- to 6-membered heterocyclyl, wherein the C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 3- to 6-membered heterocyclyl is optionally substituted by a group selected from the following: H, halogen, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C3~C6 cycloalkyl substituted 1～ C3 alkyl, CO2R 8 or CONR 8 R 8’ ;or R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted C3-C6 carbocyclic ring or an optionally substituted 3- to 6-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring or the 3- to 6-membered heterocyclic ring is optionally substituted by a group selected from the group consisting of H, halogen, C1-C6 alkyl, OR 5 NR 8 R 8’ , C3~C6 cycloalkyl, C1~C3 alkyl substituted by C3~C6 cycloalkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 A carbocyclic ring or a heterocyclic ring cannot be formed at the same time.

5. The compound according to claim 4 or its stereoisomer, solvate, prodrug, isotope-labeled substance, and pharmaceutically acceptable salt, wherein: R 1 、R 2 、R 3 or R 4 each independently selected from H, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, dioxanyl, morpholinyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, thienyl, thiazolyl, optionally substituted with a group selected from H, halogen, OR 5 NR 8 R 8’ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3~C6 cycloalkyl-CH2-, CO2R 8 or CONR 8 R 8’ ;or R 1 and R 2 、R 2 and R 3 、R 3 and R 4 Together with the carbon atom to which it is attached, it forms an optionally substituted cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, oxetane ring, tetrahydropyrrole ring, piperidine ring, tetrahydrofuran ring, tetrahydropyran ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydrothiazole ring, dioxane ring, morpholine ring, which is optionally substituted by a group selected from the following: H, halogen, OR 5 、C1~C6 alkyl、NR 8 R 8’ , C3~C6 cycloalkyl, C1~C3 alkyl substituted by C3~C6 cycloalkyl, CO2R 8 or CONR 8 R 8’ , provided that R 1 、R 2 、R 3 and R 4 The above-mentioned carbocyclic ring or heterocyclic ring is not formed at the same time.

6. The compound according to any one of claims 1 to 5, which is a compound represented by formula (II) or formula (II') or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 、R 3 、R 4 , A, B, Y, Z, Q are as defined in any one of claims 1-5.

7. The compound according to any one of claims 1 to 5, which is a compound represented by formula (III) or formula (III') or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 , A, B, Y, Z, Q are as defined in any one of claims 1-5.

8. The compound according to any one of claims 1 to 5, which is a compound represented by formula (IV) or formula (IV') or its stereoisomers, solvates, prodrugs, isotope labels, and pharmaceutically acceptable salts, wherein X 1 、R 1 、R 2 , A, B, Y, Z are as defined in any one of claims 1-5.

9. The compound according to claim 1, which is selected from: or a stereoisomer, solvate, prodrug, isotope-labeled substance, or pharmaceutically acceptable salt thereof. 10 . A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomer, solvate, prodrug, isotope-labeled substance, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9 or its stereoisomer, solvate, prodrug, isotope-labeled substance and pharmaceutically acceptable salt in the preparation of URAT1 inhibitor drugs.

12. Use of the compound according to any one of claims 1 to 9 or its stereoisomers, solvates, prodrugs, isotope-labeled substances and pharmaceutically acceptable salts in the preparation of medicaments for treating diseases such as gout and hyperuricemia.

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