1,2,4-triazine-3,5-dione compounds and preparation method and application thereof

Abstract

The present invention provides a 1,2,4-triazine-3,5-dione compound and a preparation method and application thereof. The 2,4-triazine-3,5-dione compound having a structure shown in formula (I) provided by the present invention has a selective agonist effect on THRβ, has significant advantages in activity, selectivity and metabolic stability over the disclosed compounds, and can be used as a therapeutic and / or preventive drug for thyroid hormone receptor-related diseases. Thyroid hormone receptor-related diseases include but are not limited to obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, fatty liver disease, non-alcoholic fatty liver, non-alcoholic steatohepatitis, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and thyroid cancer.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a 1,2,4-triazine-3,5-dione compound and a preparation method and application thereof. Background Art

[0002] Thyroid hormone plays a key role in normal growth and development of the body and in maintaining metabolic balance (Physiological Reviews 2001, 81 (3), 1097-1126.). Thyroid hormone is produced by the thyroid gland and secreted into the circulatory system (hypothalamus / pituitary / thyroid system) in two different forms, T4 and T3, of which T4 is the main form secreted by the thyroid gland, while T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but mainly in liver and kidney tissues.

[0003] The physiological activity of thyroid hormone is mainly mediated by thyroid hormone receptor (THR) (Endocrine Reviews 1993, 14, 348-399.). THR belongs to the nuclear receptor superfamily, and it forms a heterodimer with the retinoid receptor, which acts as a ligand-induced transcription factor. THR has a ligand binding domain, a DNA binding domain and an amino terminal domain, and regulates gene expression by interacting with DNA response elements and various nuclear co-activators and co-repressors. THR is encoded by different genes expressed α and β on human chromosomes 17 and 3, and different protein subtypes are produced by selective shearing of primary transcripts. Each gene produces two subtypes, namely THRα1, THRα2, THRβ1, and THRβ2. THRβ1 and THRβ2 are obtained by differential expression of promoters, and the two subtypes differ only in the amino termini. THRα1 and THRα2 are derived from differential splicing of precursor mRNA, and the main differences are at the carboxyl termini. THRα1, THRβ1 and THRβ2 can bind thyroid hormones. Studies have shown that thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses. THRβ1 plays an important role in regulating thyroid stimulating hormone and thyroid hormone in the liver, while THRβ2 plays a major role in regulating thyroid stimulating hormone. Studies have shown that the two subtypes of THR, α and β, coexist in the liver, of which THRβ related to lipid metabolism accounts for 70-80%. In the heart, THRα is associated with increased heart rate and increased cardiac output (Endocrinology 2001, 142, 544; J.Biol.Chem. 1992, 267, 11794.).

[0004] Thyroid hormones are metabolized in target organs and excreted mainly in bile. Their physiological effects in mammals are mainly manifested in growth and differentiation and in maintaining life functions, such as the control and regulation of heart rate, cholesterol and triglyceride concentrations in the blood, and systemic metabolic rate and body weight. From a pathophysiological perspective, tachycardia, arrhythmia, heart failure, fatigue, shortness of breath, skeletal muscle reduction, and osteoporosis are observed in hyperthyroidism such as Graves' disease (Physiol. Rev. 2001, 81, 1097; J. Steroid. Biochem. Mol. Biol. 2001, 76, 31.).

[0005] The therapeutic use of thyroid hormone itself is limited by adverse side effects associated with hyperthyroidism, particularly cardiovascular toxicity. A thyroid hormone analog, if it can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormone, may be used in the treatment of responsive diseases, such as metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.

[0006] Thyroid hormone analogs with different structures from the compounds of the present invention have been disclosed (Agricultural and Biol. Chem. 1974, 38 (6), 1169; J. Med. Chem. 1989, 32, 320; J. Med. Chem. 2014, 57 (10), 3912; WO2007009913; WO2010122980). WO2007009913 discloses a pyridazinone derivative, especially Example 8 (Compound 31, i.e., MGL-3196), which is a thyroid hormone analog with THRβ selectivity and liver tissue selectivity, and has achieved good results and may be used to treat a variety of diseases. However, MGL-3196 still has problems such as insufficient activity and rapid metabolism in the body. Therefore, it is necessary to continue to discover and develop new compounds with high activity, high selectivity and high metabolic stability that have the beneficial effects of thyroid hormones and can avoid adverse effects, for the treatment of diseases related to thyroid hormone receptors. Summary of the invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a 1,2,4-triazine-3,5-dione compound and a preparation method and application thereof. The compound provided by the present invention has not only high activity and selectivity, but also good metabolic stability.

[0008] Compared with the prior art, the present invention provides a 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof. The compound having a structure shown in formula (I) provided by the present invention has a selective agonist effect on THRβ, and has significant advantages in activity, selectivity and metabolic stability over the disclosed compounds, and can be used as a therapeutic and / or preventive drug for thyroid hormone receptor-related diseases. Thyroid hormone receptor-related diseases include but are not limited to obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, fatty liver disease, non-alcoholic fatty liver, non-alcoholic steatohepatitis, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism, and thyroid cancer. DETAILED DESCRIPTION

[0009] The present invention provides a 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof, wherein the 1,2,4-triazine-3,5-dione compound has a structure as shown in formula (I):

[0010]

[0011] Wherein, A is substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C5-C20 heteroaryl, substituted or unsubstituted C3-C18 heterocyclyl, hydroxyl or halogen;

[0012] X is a substituted methylene, -O- or -S-,

[0013] Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR,

[0014] R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C2-C15 unsaturated hydrocarbon, halogen or cyano;

[0015] m and n are each an integer of 0-3.

[0016] According to the present invention, the substituents in the substituted C1-C15 alkyl, substituted C1-C15 alkoxy, substituted C3-C18 cycloalkyl, substituted C6-C20 aryl, substituted C5-C20 heteroaryl, substituted C3-C18 heterocyclic group and substituted C2-C15 unsaturated hydrocarbon group are hydroxyl, fluorine, chlorine, bromine, iodine or amino.

[0017] In the present invention, A is preferably a substituted or unsubstituted C3-C10 alkyl, a substituted or unsubstituted C3-C10 alkoxy, a substituted or unsubstituted C5-C12 cycloalkyl, a substituted or unsubstituted C10-C15 aryl, a substituted or unsubstituted C8-C15 heteroaryl, a substituted or unsubstituted C5-C10 heterocyclic group, a hydroxyl group or a halogen; more preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, , 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, pyridyl, pyrrolyl, furanyl, pyranyl, hydroxy, fluorine, chlorine, bromine or iodine.

[0018] According to the present invention, R is preferably hydrogen, substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkoxy, substituted or unsubstituted C5-C12 cycloalkyl, substituted or unsubstituted C5-C10 unsaturated hydrocarbon group, halogen or cyano, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2 ... -hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, , 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, pyridyl, pyrrolyl, furanyl, pyranyl, 1-methylvinyl, propenyl, butenyl, hydroxy, fluorine, chlorine, bromine or iodine.

[0019] According to the present invention, R1 is preferably hydrogen, substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkoxy, substituted or unsubstituted C5-C12 cycloalkyl, substituted or unsubstituted C5-C10 unsaturated hydrocarbon group, halogen or cyano, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl -hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, , 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, pyridyl, pyrrolyl, furanyl, pyranyl, 1-methylvinyl, propenyl, butenyl, hydroxy, fluorine, chlorine, bromine or iodine.

[0020] According to the present invention, R2 is preferably hydrogen, substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkoxy, substituted or unsubstituted C5-C12 cycloalkyl, substituted or unsubstituted C5-C10 unsaturated hydrocarbon group, halogen or cyano, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl -hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, , 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, pyridyl, pyrrolyl, furanyl, pyranyl, 1-methylvinyl, propenyl, butenyl, hydroxy, fluorine, chlorine, bromine or iodine.

[0021] According to the present invention, R3 is preferably hydrogen, substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkoxy, substituted or unsubstituted C5-C12 cycloalkyl, substituted or unsubstituted C5-C10 unsaturated hydrocarbon group, halogen or cyano, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl -hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, , 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, anthracenyl, pyridyl, pyrrolyl, furanyl, pyranyl, 1-methylvinyl, propenyl, butenyl, hydroxy, fluorine, chlorine, bromine or iodine.

[0022] More specifically, the structure shown in formula (I) is:

[0023]

[0024]

[0025] The present invention provides a method for preparing a 1,2,4-triazine-3,5-dione compound, comprising:

[0026] The compound of formula 1b is converted into a compound of formula 1c, and then the compound of formula 1c is converted into a 1,2,4-triazine-3,5-dione compound having a structure of formula (I),

[0027]

[0028] Wherein, A is substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C5-C20 heteroaryl, substituted or unsubstituted C3-C18 heterocyclyl, hydroxyl or halogen;

[0029] X is a substituted methylene, -O- or -S-,

[0030] Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR,

[0031] R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C2-C15 unsaturated hydrocarbon, halogen or cyano;

[0032] m and n are each an integer from 0 to 3;

[0033] R4 is a C1-C6 alkyl group.

[0034] According to the present invention, the compound of formula 1b is converted into the compound of formula 1c. Specifically, the compound 1b is obtained by esterification reaction with alcohol under acidic conditions; wherein the acid providing the acidic conditions is one or more of hydrochloric acid, sulfuric acid, glacial acetic acid and trifluoroacetic acid; the alcohol includes but is not limited to methanol and ethanol.

[0035] In the present invention, there is no special requirement for the preparation method of compound 1b, which can be obtained by hydrolyzing 1a under acidic conditions. Specifically, in the acidic conditions of the hydrolysis, the acid is one or more of hydrochloric acid, sulfuric acid, glacial acetic acid and trifluoroacetic acid, and the reaction solvent is N,N-diformylamide.

[0036]

[0037] According to the present invention, the present invention also converts the compound of formula 1c into a 1,2,4-triazine-3,5-dione compound having a structure of formula (I). Specifically, the present invention reacts compound 1c with a reducing agent to obtain a compound of formula (I), wherein the reducing agent includes but is not limited to lithium aluminum hydride, sodium borohydride, lithium borohydride, DIBAL-H, red aluminum, etc. The reaction is carried out in an organic solvent, and the solvent includes but is not limited to methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc.

[0038] Specifically, the reaction process is as follows:

[0039]

[0040] The substitution of each group is the same as defined above.

[0041] Specifically, the present invention also prepares the compound of formula (Ib) by fluorination reaction of the compound of formula (Ia), wherein the reagents used in the fluorination reaction include but are not limited to DAST, HF, n-Bu4NF, SF4, NaF, KF, AgF, HgF2, SbF3, etc. The specific reaction formula is as follows:

[0042]

[0043] Each of R, R1, R2, R3, X, Y1, Y2, Y3, Y4, Z1, Z2, m and n has the meaning as described in the present invention.

[0044] Specifically, the present invention further oxidizes compound (Ia) and then fluorinates to obtain a compound of formula (Ic), wherein the oxidizing agent includes but is not limited to PCC, MnO2, KMnO4, IBX, PhI(OAc)2, Dess-Martin reagent, etc.; the oxidation reaction is carried out in an organic solvent, and the organic solvent includes but is not limited to dichloromethane, chloroform, carbon tetrachloride, DMF, tetrahydrofuran, etc.

[0045] The specific reaction process is as follows:

[0046]

[0047] Each of R, R1, R2, R3, X, Y1, Y2, Y3, Y4, Z1, Z2, m and n has the meaning as described in the present invention.

[0048] m and n are each an integer of 0-3.

[0049] The present invention also provides a method for preparing a 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof, comprising:

[0050] Compound 4d and compound 4e are reacted to obtain a 1,2,4-triazine-3,5-dione compound having a structure of formula (I).

[0051]

[0052] Wherein, A is substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C5-C20 heteroaryl, substituted or unsubstituted C3-C18 heterocyclyl, hydroxyl or halogen;

[0053] X is a substituted methylene, -O- or -S-,

[0054] Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR,

[0055] R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C2-C15 unsaturated hydrocarbon, halogen or cyano;

[0056] m and n are each an integer of 0-3.

[0057] According to the present invention, the compound of the 4d structure is prepared according to the following method:

[0058] The compound of formula 4c is converted into the compound of formula 4d,

[0059]

[0060] Wherein: X is a substituted methylene, -O- or -S-,

[0061] Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR,

[0062] R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C2-C15 unsaturated hydrocarbon, halogen or cyano;

[0063] m and n are each an integer of 0-3.

[0064] In the present invention, 4c is obtained by condensing 4b with acetone under acidic conditions, and 4b is obtained by reacting 4a with sodium nitrite under acidic conditions.

[0065] Specifically, the reaction process is as follows:

[0066]

[0067] Among them, compound 4a can be prepared by the method in the literature. Compound 4b can be prepared by reacting compound 4a with sodium nitrite under acidic conditions to obtain the corresponding diazo compound, and then under the action of stannous chloride under acidic conditions. Compound 4c is obtained by condensing compound 4b with acetone under acidic conditions. Compound 4d is prepared by reacting compound 4c with potassium cyanate under acidic conditions. Compound formula (I) is obtained by condensing compound 4d with compound 4e under acidic conditions. The acidic conditions include but are not limited to hydrochloric acid, sulfuric acid, formic acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.

[0068] The present invention also provides an application of the 1,2,4-triazine-3,5-dione compounds and pharmaceutically acceptable salts thereof in the preparation of THR agonists. Preferably, the THR agonist is a THRβ agonist. The compounds provided by the present invention can also be applied to diseases affected by thyroid hormone receptors, including but not limited to obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, fatty liver disease, non-alcoholic fatty liver, non-alcoholic steatohepatitis, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism, and thyroid cancer.

[0069] The groups represented by each term and each symbol in the present specification are explained below.

[0070] "alkyl

[0071] " " when used as a group or a part of a group refers to a C1-C20 aliphatic hydrocarbon group including a straight chain or branched chain, preferably a C1-C10 alkyl group, more preferably a C1-C6 alkyl group, and particularly preferably a C1-C4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted.

[0072] "Alkylene" is a divalent alkyl group. Preferably it is C1-C10 alkylene, more preferably C1-C6 alkylene, and particularly preferably C1-C4 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, etc. The alkylene group may be substituted or unsubstituted.

[0073] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Preferably C2-C4 alkylene. Alkenyl can be optionally substituted or unsubstituted.

[0074] "Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. Preferably, C2-C10 alkynyl, more preferably C2-C6 alkynyl, most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl may be substituted or unsubstituted.

[0075] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, condensed, bridged or spirocyclic carbocyclic ring. Preferably, it is a C3-C12 cycloalkyl, more preferably a C3-C8 cycloalkyl, and most preferably a C3-C6 cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl.

[0076] "Cycloalkylene" is a divalent cycloalkylene. Preferably it is C3-C12 cycloalkylene, more preferably C3-C8 cycloalkylene, and most preferably C3-C6 cycloalkylene. Examples of alkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. Cycloalkylene may be substituted or unsubstituted.

[0077] "Cyclopropylene" means

[0078] "Cyclobutylene" means

[0079] "Spirocycloalkyl" refers to a 5 to 18-membered polycyclic group containing two or more cyclic structures and in which the monocyclic rings share one carbon atom (called a spiro atom), and the ring may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into a single spiro, a double spiro or a multi-spirocycloalkyl, preferably a single spiro and a double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0080] "Fused cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron aromatic system, preferably 6-12 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthrenyl.

[0081] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron aromatic system. It is preferably 6-14 members, and more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or pyridone, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

[0082] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted.

[0083] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged and spirocyclic rings. Preferably, there are 5 to 7-membered monocyclic or 7 to 10-membered bi- or tricyclic rings, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl group may be substituted or unsubstituted.

[0084] "Spiro heterocyclic group" refers to a 5 to 18-membered polycyclic group containing two or more cyclic structures and one atom shared between monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)q (wherein q is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, spiro alkyl is divided into single spiral heterocyclic group, double spiral heterocyclic group or multi-spiro heterocyclic group, preferably single spiral heterocyclic group and double spiral heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to, 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0085] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)q (where q is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, pyridone or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

[0086] "Bridged heterocyclic group" refers to a 5-18 membered, preferably 5-14 membered, polycyclic group containing two or more cyclic structures and sharing two atoms that are not directly connected to each other, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)q (wherein q is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or pyridone, and more preferably a bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl. The heterocyclyl may be optionally substituted or unsubstituted.

[0087] "Heterocyclylene" refers to a divalent heterocyclic group. Preferably, it has a 5- to 7-membered monocyclic heterocyclic group or a 7- to 10-membered bicyclic heterocyclic group or a tricyclic heterocyclic group, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. The heterocyclic group may be substituted or unsubstituted.

[0088] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, the aryl is a C6-C10 aryl, more preferably phenyl and naphthyl, and most preferably phenyl. The aryl may be substituted or unsubstituted. The "aryl" may be fused with a heteroaryl, a heterocyclic group, or a cycloalkyl group, wherein the aryl ring is linked to the parent structure, and non-limiting examples include, but are not limited to:

[0089]

[0090] "Heteroaryl" refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. The embodiment of "heteroaryl" includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

[0091]

[0092] "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl is as defined herein. C1-C6 alkoxy is preferred, and C1-C4 alkoxy is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0093] "Hydroxy" refers to an -OH group.

[0094] "Halogen" refers to fluorine, chlorine, bromine and iodine, with chlorine, bromine and iodine being preferred.

[0095] "Amino" refers to -NH2.

[0096] "Cyano" refers to -CN.

[0097] "Nitro" refers to -NO2.

[0098] "Benzyl" refers to -CH2-phenyl.

[0099] "Carboxy" refers to -C(O)OH.

[0100] "Carboxylate" refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0101] "DMSO" refers to dimethyl sulfoxide.

[0102] "Mercapto" refers to -SH.

[0103] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefinic bond).

[0104] "Substitution" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR11, -SR11, -NR9R10, -C(O)NR9R10, -C(O)R11, -OC(O)R11, -S(O)nNR9R10, -C(O)OR11 or -NR9C(O)R10, wherein n is 0, 1 or 2;

[0105] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. The pharmaceutically acceptable salts of the compound of formula (I) can be metal salts, amine salts formed with suitable acids, preferably alkali metals and alkaline earth metal salts, and suitable acids include inorganic acids and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is hydrochloride.

[0106] "Pharmaceutical composition" means a mixture containing one or more compounds described herein (including pharmaceutically acceptable salts or stereoisomers, tautomers or prodrugs thereof) and other optional pharmaceutically active ingredients, which may contain other optional components such as pharmaceutically acceptable carriers and / or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0107] Herein, the term "plurality" includes two or more, for example, two, three, four, etc.

[0108] 1H NMR spectra were obtained using a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). 1H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplet. Coupling constants, when provided, are in Hz.

[0109] The mass spectrometry analysis was performed using a Shimadzu LCMS-2020 liquid spectrometer, and the ionization mode could be ESI or APCI.

[0110] The purification was performed using Shimadzu LC-20AP preparative high performance liquid chromatography.

[0111] Flash column chromatography was performed using a Biotage Isolera™ Prime flash preparative chromatograph.

[0112] Microwave reactions were performed using an Anton Paar Monowave 400 microwave reactor.

[0113] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0114] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0115] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0116] D3OD: Deuterated methanol

[0117] CDCl3: deuterated chloroform

[0118] DMSO-d6: deuterated dimethyl sulfoxide

[0119] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.

[0120] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0121] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0122] The compound is purified by silica gel column chromatography and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added for adjustment.

[0123] The following will be described clearly and completely in conjunction with the technical solutions of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0124] Example 1

[0125] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0126]

[0127] first step

[0128] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0129] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-cyano 1a (300 mg, 0.69 mmol, synthesis method see WO2014043706A1) was dissolved in 10 mL of glacial acetic acid, concentrated hydrochloric acid (2 mL) was added, and the mixture was heated to 120 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 20 mL of water was added to dilute, stir and filter, and then dried to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 1b (260 mg, light yellow solid), with a yield of 84%. 1H NMR (400MHz, DMSO-d6) δ12.71 (s, 1H), 12.21 (s, 1H), 7.82 (s, 2H), 7.45 (s, 1H), 3.21 (m, 1H), 1.19 (d, J = 6.4Hz, 6H). MS m / z(ESI): 453.8[M+1] + .

[0130] Step 2

[0131] Methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate

[0132] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 1b (200 mg, 0.44 mmol) was dissolved in 20 mL of methanol, thionyl chloride (2 mL) was slowly added under ice bath, and the reaction solution was heated to 100° C. for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residual solid was slurried and filtered with petroleum ether:ethyl acetate (10:1), and dried to obtain methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 1c (200 mg, light yellow solid), yield: 97%. MS m / z(ESI):466.2[M-1] - .

[0133] Step 3

[0134] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0135] Methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 1c (200 mg, 0.43 mmol) was dissolved in 20 mL of tetrahydrofuran, sodium borohydride (82 mg, 2.15 mmol) was added at room temperature, and then methanol was slowly added dropwise. After the reaction was completed, 20 mL of water was added and the pH was adjusted to 6 with 3 M dilute hydrochloric acid, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 0:1) to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 1 (150 mg, white solid), yield: 79%.

[0136] MS m / z(ESI):438.2[M-1] - . 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),12.25(s,1H),7.86(s,2H),7.45(s,1H),5 .33(t,J=6.4Hz,1H), 4.40(d,J=6.0Hz,2H), 3.21(m,1H), 1.19(d,J=6.4Hz,6H).

[0137] Example 2

[0138] 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0139]

[0140] first step

[0141] 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0142] Methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 1 (100 mg, 0.23 mmol) was dissolved in 20 mL of dichloromethane, DAST (5 drops) was added under ice bath, and the reaction solution was reacted at this temperature for 30 minutes. After the reaction was completed, the reaction solution was added to 20 mL of ice water, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 2 (45 mg, white solid), yield: 45%. MS m / z (ESI): 442.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),12.21(s,1H),7.81(s,2H),7.43(s,1H),5.29(d,J=48.0Hz,1H),3.21(m,1H),1.19(d,J=6.4Hz,6H). 19 FNMR (400MHz, DMSO-d6) δ-219.9ppm.

[0143] Example 3

[0144] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0145]

[0146] first step

[0147] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbaldehyde

[0148] Methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 1 (100 mg, 0.23 mmol) was dissolved in 20 mL of dichloromethane, 2-iodoacylbenzoic acid (129 mg, 0.46 mmol) was added at room temperature, and the reaction solution was heated to 50°C for 30 minutes. After the reaction was completed, the reaction solution was added to 20 mL of ice water and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbaldehyde 3a (65 mg, white solid), yield: 65%. MS m / z (ESI): 438.2 [M+1] + .

[0149] Step 2

[0150] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0151] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbaldehyde 3a (60 mg, 0.14 mmol) was dissolved in 20 mL of dichloromethane, DAST (1 mL) was added under ice bath, and the reaction solution was warmed to room temperature for 10 minutes. After the reaction was completed, the reaction solution was added to 20 mL of ice water and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to give 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 3 (40 mg, white solid), yield: 62%.

[0152] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),12.22(s,1H),7.81(s,2H),7.45(s,1H),6.90(t,J=5.2Hz,1H),3.21(m,1H),1.19(d,J=6.4Hz,6H).19 F NMR (400MHz, DMSO-d6) δ-122.1ppm. MS m / z(ESI): 459.9[M+1] + .

[0153] Example 4

[0154] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione

[0155]

[0156] first step

[0157] 6-(2,6-Dichloro-4-hydrazinophenoxy)-4-isopropylpyridazin-3(2H)-one

[0158] 6-(-4-Amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one 4a (1.0 g, 3.19 mmol, see WO2014043706A1 for the synthesis method) was dissolved in 20 mL of 6M dilute hydrochloric acid, and sodium nitrite (440 mg, 6.38 mmol) was added under ice bath. The reaction solution was reacted at this temperature for 1 hour, and then stannous chloride (1.21 g, 6.38 mmol) dissolved in 2 mL of hydrochloric acid solution was slowly added, and the reaction was continued for 3 hours. After the reaction was completed, the reaction solution was added to 50 mL of ice water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude compound 6-(2,6-dichloro-4-hydrazinophenoxy)-4-isopropylpyridazine-3(2H)-one 4b (800 mg, yellow solid), yield: 79%. MS m / z (ESI): 329.1 [M+1] + .

[0159] Step 2

[0160] 6-(2,6-dichloro-4-(2-(propyl-2-vinyl)hydrazine)phenoxy)-4-isopropylpyridazin-3(2H)-one

[0161] 6-(2,6-dichloro-4-hydrazinephenoxy)-4-isopropylpyridazine-3(2H)-one 4b (800 mg, 2.44 mmol) was dissolved in 50 mL of ethanol, and acetone (5 mL) and acetic acid (1 mL) were added in sequence. The reaction solution was heated to 100° C. and refluxed for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude compound 6-(2,6-dichloro-4-(2-(propyl-2-ethylenediyl)hydrazine)phenoxy)-4-isopropylpyridazine-3(2H)-one 4c (850 mg, brown oil) with a yield of 94%.

[0162] Step 3

[0163] 6-(2,6-dichloro-4-(3,3-dimethyl-5-oxo-1,2,4-triazolidin-1-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one

[0164] 6-(2,6-dichloro-4-(2-(propyl-2-ethylenediyl)hydrazine)phenoxy)-4-isopropylpyridazine-3(2H)-one 4c (850 mg, 2.3 mmol) was dissolved in 50 mL of acetic acid and water (5:1) solution, potassium cyanate was added, and the mixture was reacted at room temperature for three hours. After the reaction was completed, 50 mL of water was added to the reaction solution, stirred and filtered, and the filter cake was dried to obtain a crude compound 6-(2,6-dichloro-4-(3,3-dimethyl-5-oxo-1,2,4-triazolidin-1-yl)phenoxy)-4-isopropylpyridazine-3(2H)-one 4d (500 mg, yellow solid), with a yield of 53%.

[0165] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.92(s,1H),7.73(s,2H),7.35(s,1H),6.27(s,1H),3.18(m,1H),1.32(s,6H),1.19(d,J=6.4Hz,6H).

[0166] Step 4

[0167] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione

[0168] 6-(2,6-dichloro-4-(3,3-dimethyl-5-oxo-1,2,4-triazolidin-1-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one 4d (500 mg, 1.22 mmol) was dissolved in 10 mL of dioxane solution, and a catalytic amount of sulfuric acid (0.5 mL) and pyruvic acid 4e (215 mg, 2.44 mmol) were added, and the reaction solution was heated to 120 ° C for 5 hours. After the reaction was completed, 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain compound 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione 4 (40 mg, yellow solid), yield: 8%. MS m / z (ESI): 424.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.41(br s,1H),12.21(s,1H),7.79(s,2H),7.42(s,1H),3.04(m,1H),2.15(s,3H),1.19(d,J=6.4Hz,6H).

[0169] Example 5

[0170] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0171]

[0172] first step

[0173] 3,6-Dichloro-4-cyclopentylpyridazine

[0174] 3,6-dichloropyridazine 5a (2.5 g, 16.8 mmol) was dissolved in a mixture of 84 mL of water and 3.7 mL of concentrated sulfuric acid, and silver nitrate (0.575 g, 3.36 mmol) and cyclopentanoic acid 5b (3.25 g, 28.56 mmol) were added in sequence. 40 mL of an aqueous solution of ammonium persulfate (13 g, 56.97 mmol) was slowly added dropwise at room temperature within half an hour. After the addition was completed, the temperature was raised to 70°C for reaction for 0.5 hours, and the reaction was cooled to room temperature. The pH was adjusted to 7 with aqueous ammonia, and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,6-dichloro-4-cyclopentylpyridazine 5c (3.3 g, colorless oily liquid) with a yield of 91%. MS m / z (ESI): 217.0 [M+1] + .

[0175] Step 2

[0176] 3,5-Dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)aniline

[0177] 3,6-dichloro-4-cyclopentylpyridazine 5c (1 g, 4.6 mmol) and 4-amino-2,6-dichlorophenol 5d (0.819 g, 4.69 mmol) were dissolved in 10 mL N,N-dimethylacetamide, and cesium carbonate (1.73 g, 5.29 mmol) was added to heat the reaction to 110°C and stir for 3 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)aniline 5e (1.3 g, white solid), with a yield of 78%. MS m / z (ESI): 358.0 [M+1] + .

[0178] Step 3

[0179] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0180] Take 3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)aniline 5e (1.30 g, 3.64 mmol) and dissolve it in 8 mL of acetic acid and 2 mL of water. Cool it to zero degrees, add 1 mL of concentrated hydrochloric acid, slowly add 4 mL of sodium nitrite (256 mg, 3.65 mmol) aqueous solution, stir for 10 minutes after the addition is complete, add 5 mL of sodium acetate (830 mg, 10.8 mmol) aqueous solution, and then Ethyl (2-cyanoacetic acid) carbamate 5f (579 mg, 3.65 mmol) was added, the ice bath was removed and the temperature was raised to room temperature for reaction for 1 hour, 20 mL of water was added, the solid was filtered and dried to obtain solid (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 5g (1.20 g, white solid), yield: 63%. MS m / z (ESI): 525.1 [M+1] + .

[0181] Step 4

[0182] 2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0183] Take compound (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 5g (1.20g, 2.3mmol) and dissolve it in 10mL Potassium acetate (270 mg, 2.76 mmol) was added to N,N-dimethylacetamide, the reaction temperature was raised to 120°C and stirred for 3 hours, then cooled to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5h (1.0 g, white solid), yield: 91%. MS m / z (ESI): 479.1 [M+1] + .

[0184] Step 5

[0185] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0186] Take compound 2-(3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5h (1.00 g, 2.1 mmol) and dissolve it in 10 mL of acetic acid. Then add sodium acetate (344 mg, 4.2 mmol). Heat the reaction to 110 ° C and stir for 3 hours. Then cool to room temperature. Add 20 mL of water to the reaction solution and add 20 mL of water. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5i (823 mg, white solid), yield: 85%. MS m / z (ESI): 461.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.28(s,1H),12.21(s,1H),7.79(s,2H),7.46(s,1H) ,3.02-3.17(m,1H),1.97-1.99(m,2H),1.74-1.76(m,2H),1.59-1.66(m,4H).

[0187] Step 6

[0188] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0189] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5i (823 mg, 1.8 mmol) was dissolved in 10 mL of glacial acetic acid, 4 mL of concentrated hydrochloric acid was added, and the mixture was heated to 120°C for 5 hours. After the reaction was completed, the solution was cooled to room temperature, 20 mL of water was added to dilute and stir, and the mixture was filtered. The solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 5j (820 mg, light yellow solid), with a yield of 95%. MS m / z(ESI):480.0[M+1] + .

[0190] Step 7

[0191] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0192] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 5j (820 mg, 1.71 mmol) was dissolved in 10 mL of methanol, 2 mL of thionyl chloride was slowly added under ice bath, and the reaction solution was heated to 80 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residual solid was slurried and filtered with petroleum ether: ethyl acetate (20:1), and the solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 5k (819 mg, light yellow solid), yield: 97%. MS m / z (ESI): 494.0 [M+1] + .

[0193] Step 8

[0194] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0195] Take 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 5k (819 mg, 1.66 mmol) and dissolve it in 10 mL of tetrahydrofuran. Then add sodium borohydride (315 mg, 8.3 mmol). Heat to 60 ° C, slowly add methanol dropwise until no gas is generated, heat to react for 3 hours, after the reaction is completed, add 20 mL of water and 3M dilute hydrochloric acid was adjusted to pH=6, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 5 (688 mg, white solid), yield: 89%. MS m / z (ESI): 466.0 [M+1] + .

[0196] Example 6

[0197] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0198]

[0199] first step

[0200] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0201] 6-(2,6-dichloro-4-(3,3-dimethyl-5-oxo-1,2,4-triazolidin-1-yl)phenoxy)-4-isopropylpyridazin-3(2H)-one 4a (200 mg, 0.486 mmol) was dissolved in 4 mL of dioxane, and ethyl trifluoropyruvate (82 mg, 0.486 mmol) and 2 drops of concentrated sulfuric acid were added in sequence, and the mixture was heated to 100°C for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 6 (1.5 mg, white solid), yield: 1%. MS m / z (ESI): 478.0 [M+1] + .

[0202] 1 H NMR (400MHz, DMSO-d6) δ12.21 (s, 1H), 7.78 (s, 2H), 7.45 (s, 1H), 3.06-3.03 (m, 1H), 1.20 (d, J = 4.0Hz, 6H).

[0203] Example 7

[0204] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione

[0205]

[0206] first step

[0207] 4-((Benzyloxy)methyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione

[0208] 4-((Benzyloxy)methyl)-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione 7a (1 g, 3.21 mmol) (synthesis method see WO 2010006962) was added to 5 mL of methanol, and sodium methoxide (434 mg, 8.04 mmol) was added, and then microwaved at 100°C for 4 hours. The solvent was removed by concentration under reduced pressure, 10 mL of 1N dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, and washed with petroleum ether:ethyl acetate from 1:0 to 2:1 to obtain 4-((Benzyloxy)methyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7b (230 mg, white solid) with a yield of 27%. MS m / z (ESI): 262.0 [M-1] - .

[0209] Step 2

[0210] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropylpyridazin-3(2H)-one

[0211] 6-(4-Amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one 4a (950 mg, 3.02 mmol) (synthesis method see WO 2014043706) was dissolved in 20 mL of dilute sulfuric acid (20%). After the system was cooled to 0°C, 5 mL of sodium nitrite aqueous solution (0.25 g, 3.33 mmol) was slowly added dropwise. The system was kept between 0°C and 5°C. After reacting for 20 minutes, 15 mL of potassium iodide aqueous solution (0.55 g, 3.33 mmol) was added dropwise to the system. The system was then placed at room temperature for reaction. After 3 hours, the reaction was complete as detected by TLC. The system was extracted with ethyl acetate for 3 times, and the organic phase was concentrated and then slurried to obtain a suspension, which was filtered to obtain a filter cake, which was dried to obtain 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazin-3(2H)-one 7c (750 mg, light yellow solid). Yield: 58%. MS m / z (ESI): 425.0 [M+1] + .

[0212] Step 3

[0213] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropyl-2-(methoxymethyl)pyridazin-3(2H)-one

[0214] 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazin-3(2H)-one 7c (563 mg, 1.33 mmol) was added to 12 mL of anhydrous tetrahydrofuran. Under nitrogen protection, sodium hydride (64 mg, 60%, 1.59 mmol) was added at 0°C. After warming to room temperature for ten minutes, methoxymethyl bromide (332 mg, 2.66 mmol) was added. After ten minutes of reaction, 10 mL of saturated brine was added. The mixture was extracted with ethyl acetate (10 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with petroleum ether:ethyl acetate in a ratio of 1:0 to 5:1 to obtain 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-(methoxymethyl)pyridazin-3(2H)-one 7d (350 mg, white solid) with a yield of 56%. MS m / z(ESI): 469.0[M+1] + .

[0215] Step 4

[0216] 4-((Benzyloxy)methyl)-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione

[0217] 4-((Benzyloxy)methyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7b (90 mg, 0.34 mmol) was dissolved in 2 mL of dioxane, and 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-(methoxymethyl)pyridazin-3(2H)-one 7d (160 mg, 0.34 mmol) was added, followed by trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine (10 mg, 0.068 mmol) and potassium iodide (57 mg, 0.34 mmol), cuprous iodide (65 mg, 0.34 mmol), potassium carbonate (95 mg, 0.68 mmol), and then microwaved at 130°C for 2 hours. 10 mL of ethyl acetate and 10 mL of water were added to the reaction solution, and the liquid was separated. The aqueous phase was extracted once with 10 mL of ethyl acetate again. The organic phases were combined, washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, and petroleum ether:ethyl acetate was washed from 1:0 to 5:1 to obtain 4-((benzyloxy)methyl)-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7e (160 mg, colorless oil) with a yield of 77%. MS m / z (ESI): 604.0 [M+1]+ .

[0218] Step 5

[0219] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione

[0220] 4-((Benzyloxy)methyl)-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7e (80 mg, 0.13 mmol) was dissolved in 2 mL of dichloromethane. Under nitrogen protection, boron tribromide (0.40 mL, 1 mol / L) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was quenched by adding 1 mL of methanol, the solvent was removed by concentrating under reduced pressure, and then 1 mL of methanol and 1 mL of concentrated sulfuric acid were added. The reaction was allowed to proceed for 1 hour at 100°C. After the reaction was completed, the reaction solution was cooled to room temperature and added dropwise to ice water. The pH value was adjusted to 5-6 with saturated aqueous potassium carbonate solution. The solution was extracted twice with ethyl acetate (20 mL×2). The organic phases were combined and washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7 (10 mg, light yellow solid) with a yield of 17%. MS m / z(ESI): 440.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 12.50 (s, 1H), 12.20 (s, 1H), 7.85 (s, 2H), 7.43 (s, 1H), 3.84 (s, 3H), 3.01-3.07 (m, 1H), 1.19-1.20 (d, J = 4.0Hz, 6H).

[0221] Example 8

[0222] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0223]

[0224] first step

[0225] 3,6-Dichloro-4-cyclohexylpyridazine

[0226] Under nitrogen protection, 3,6-dichloropyridazine 8a (1.49 g, 10 mmol), cyclohexanecarboxylic acid (4.49 g, 35 mmol), silver nitrate (0.17 g, 1 mmol) and concentrated sulfuric acid (1.81 mL, 30 mmol) were added to 300 mL of water, heated to 70°C, ammonium persulfate (2.28 g, 10 mmol) was dissolved in 100 mL of water, and the solution was added dropwise to the above reaction solution within ten minutes, and reacted at 70°C for 24 hours. The reaction system was cooled to room temperature, adjusted to pH = 8 with ammonia water, extracted with dichloromethane (100 mL × 3), and the organic phases were combined and washed once with 1N sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified with a silica gel column, washed with petroleum ether: ethyl acetate from 1:0 to 5:1 to obtain 3,6-dichloro-4-cyclohexylpyridazine 8b (829 mg, colorless oil) with a yield of 36%. MS m / z(ESI):231[M+1] + .

[0227] Step 2

[0228] 3,5-Dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)aniline

[0229] 3,6-Dichloro-4-cyclohexylpyridazine 3b (829 mg, 3.6 mmol), 4-amino-2,6-dichlorophenol 8d (642 mg, 3.6 mmol), potassium carbonate (2.0 g, 14.4 mmol) and cuprous iodide (686 mg, 3.6 mmol) were added to 13 mL of dimethyl sulfoxide, replaced with nitrogen three times, and then the reaction solution was reacted at 120°C for 16 hours, 100 mL of water was added, and extracted with ethyl acetate (20 mL×3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified on a silica gel column, washed with petroleum ether: ethyl acetate from 1:0 to 3:1, to obtain 3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)aniline 8e (678 mg, white solid), with a yield of 50%. MS m / z (ESI): 373 [M+1] + .

[0230] Step 3

[0231] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0232] 3,5-Dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)aniline 8e (2 g, 5.376 mmol) was dissolved in a mixed solvent (64 mL of acetic acid, 16 mL of water and 8 mL of concentrated hydrochloric acid) and cooled to 0°C. Sodium nitrite (445 mg, 6.45 mmol) was added at this temperature and reacted for 10 minutes. Then sodium acetate (1.33 g, 16.1 mmol) was added and the reaction was continued at 0°C for 10 minutes. Add (2-cyanoacetic acid) ethyl carbamate 8f (1.0 g, 6.45 mmol), react at room temperature for 2 hours, add 50 mL of water, filter, rinse the filter cake once with water, and dry the filter cake in a vacuum oven to obtain (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 8g (1.8 g, light yellow solid), yield 62%. MS m / z (ESI): 540 [M+1] + .

[0233] Step 4

[0234] 2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0235] 8 g (1.8 g, 3.34 mmol) of (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate was dissolved in 36 mL of N,N-dimethylacetamide, and potassium acetate (492 mg, 5 mmol) was added. The reaction solution was reacted at 120° C. for 2 hours, then added to 100 mL of water and filtered. The obtained solid was dried in a vacuum drying oven to obtain 2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8h (1.65 g, light yellow solid) with a yield of 100%. MS m / z (ESI): 494 [M+1] + .

[0236] Step 5

[0237] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0238] 2-(3,5-dichloro-4-((6-chloro-5-cyclohexylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8h (1.66 g, 3.37 mmol) was added to 30 mL of glacial acetic acid, and sodium acetate (552 mg, 6.73 mmol) was added. The solution was heated to 120° C. and reacted for 24 hours. 100 mL of water was added and filtered. The filter cake was dried in a vacuum drying oven and slurried with 50 mL of ethyl acetate to obtain 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8i (1.09 g, light yellow solid) with a yield of 68%.

[0239] 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),12.23(s,1H),7.78(s,2H),7.39(s,1H),2.67-2.80(m,1H),1.65-1.90(m,5H),1.15-1.45(m,5H). MS m / z(ESI): 475[M+1] + .

[0240] Step 6

[0241] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0242] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8i (500 mg, 1.05 mmol) was added to a mixed solvent (4 mL of concentrated hydrochloric acid and 10 mL of glacial acetic acid), and the mixture was reacted at 120 ° C. for 5 hours in a sealed tube. After cooling to room temperature, 20 mL of water was added and the mixture was filtered. The filter cake was dried in a vacuum drying oven to obtain 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 8j (380 mg, light yellow solid) with a yield of 73%. MS m / z(ESI):494[M+1] + .

[0243] Step 7

[0244] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0245] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 8j (380 mg, 0.77 mmol) was suspended in 10 mL of methanol, 1 mL of dichlorothionyl was added dropwise under ice-water bath, refluxed for 3 hours, and concentrated under reduced pressure to give 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 8k (380 mg, light yellow solid), yield 97%. MS m / z (ESI): 508 [M+1] + .

[0246] Step 8

[0247] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0248] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 8k (380 mg, 0.749 mmol) was dissolved in 20 mL of tetrahydrofuran, sodium borohydride (57 mg, 1.5 mmol) was added, and 5 mL of methanol was slowly added dropwise under reflux. , the reaction was continued under reflux for 5 hours, saturated ammonium chloride solution was added to quench the reaction (50 ml), filtered, and the filter cake was dried in a vacuum oven to obtain 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 8 (258 mg, light yellow solid), with a yield of 72%. MS m / z (ESI): 480 [M+1] + .

[0249] Example 9

[0250] 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0251]

[0252]

[0253] In the first step, 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 8 (70 mg, 0.15 mmol) was suspended in 5 mL of dichloromethane, and diethylaminosulfur trifluoride (228 mg, 1.42 mmol) was slowly added dropwise under an ice-water bath. The mixture was heated to room temperature and reacted. After 15 minutes, ice water was added to quench the reaction, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-cyclohexyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 9 (10 mg, white solid) with a yield of 14%. MS m / z (ESI): 482 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.67(s,1H),12.20(s,1H),7.81(s,2H),7.40(s,1H),5.1 9-5.39(d,J=44.0Hz,2H), 1.93-2.05(m,1H), 1.67-1.88(m,5H), 1.31-1.40(m,5H).

[0254] Example 10

[0255] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0256]

[0257] first step

[0258] 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 5 (80 mg, 0.17 mmol) was dissolved in 5 mL of dichloromethane, and DAST (34 mg, 1.05 mmol) was added under ice bath, and the reaction solution was reacted at this temperature for 30 minutes. After the reaction was completed, the reaction solution was added to 10 mL of ice water, extracted with dichloromethane (5 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 10 (10 mg, white solid), yield: 12%. MS m / z (ESI): 468.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),12.21(s,1H),7.82(s,2H),7.48(s,1H),5.31(d,J=44.0H z,1H),5.25(s,1H),3.14-3.20(m,1H),1.98-2.00(m,2H),1.76-1.78(m,2H),1.62-1.68(m,4H).

[0259] Embodiment 11

[0260] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0261]

[0262] first step

[0263] 3,6-Dichloro-4-cyclopropylpyridazine

[0264] 3,6-dichloropyridazine 11a (5g, 33.5mmol) was dissolved in a mixture of 160mL water and 7.4mL concentrated sulfuric acid, and silver nitrate (1.14g, 6.7mmol) and cyclopropionic acid 11b (4.89g, 57.0mmol) were added in sequence. 60mL of ammonium persulfate (25.97g, 113.9mmol) aqueous solution was slowly added dropwise at room temperature within half an hour. After the addition was completed, the temperature was raised to 70°C for reaction for 0.5 hours, and the reaction was cooled to room temperature. The pH was adjusted to 7 with ammonia water, and extracted with ethyl acetate (100mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,6-dichloro-4-cyclopropylpyridazine 11c (2.02g, colorless oily liquid) with a yield of 33%. MS m / z (ESI): 189.0 [M+1] + .

[0265] Step 2

[0266] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline

[0267] 3,6-dichloro-4-cyclopentylpyridazine 11c (2.02 g, 10.7 mmol) and 4-amino-2,6-dichlorophenol 11d (2.09 g, 11.1 mmol) were dissolved in 20 mL N,N-dimethylacetamide, and cesium carbonate (4.17 g, 12.8 mmol) was added to heat the reaction to 110°C and stir for 3 hours. The reaction was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline 11e (1.7 g, white solid), with a yield of 56%. MS m / z (ESI): 329.9 [M+1] + .

[0268] Step 3

[0269] (E)-Ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0270] Take 3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline 11e (1.13 g, 3.64 mmol) and dissolve it in 8 mL of acetic acid and 2 mL of water. Cool it to zero degrees, add 1 mL of concentrated hydrochloric acid, slowly add 4 mL of sodium nitrite (241 mg, 3.71 mmol) aqueous solution, stir for 10 minutes after the addition is complete, add 5 mL of sodium acetate (781 mg, 10.1 mmol) aqueous solution, and then Ethyl (2-cyanoacetic acid) carbamate 11f (546 mg, 3.71 mmol) was added, the ice bath was removed and the temperature was raised to room temperature for reaction for 1 hour, 20 mL of water was added, the solid was filtered and dried to obtain solid (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 11g (1.33 g, white solid), yield: 73%. MSm / z (ESI): 496.9 [M+1] + .

[0271] Step 4

[0272] 2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0273] Take compound (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 11g (1.33g, 2.7mmol) and dissolve it in 10mL Potassium acetate (314 mg, 3.21 mmol) was added to N,N-dimethylacetamide, the reaction temperature was raised to 120°C and stirred for 3 hours, then cooled to room temperature, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 11h (1.0 g, white solid), yield: 82%. MS m / z (ESI): 450.9 [M+1] + .

[0274] Step 5

[0275] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0276] Take compound 2-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 11h (600 mg, 1.3 mmol) and dissolve it in 10 mL of acetic acid. Then add sodium acetate (120 mg, 1.47 mmol). Heat the reaction to 110 ° C and stir for 3 hours. Then cool to room temperature. Add 20 mL of water to the reaction solution and add 20 mL of water. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 11i (440 mg, white solid), yield: 75%. MS m / z (ESI): 433.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),7.77(s,2H),7.18(s,1H),2.08-2.17(m,1H),1.06-1.15(m,2H),0.95-1.03(m,2H).

[0277] Step 6

[0278] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0279] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl 11i (440 mg, 1.0 mmol) was dissolved in 10 mL of glacial acetic acid, 4 mL of concentrated hydrochloric acid was added, and the mixture was heated to 120° C. for 5 hours. After the reaction was completed, the solution was cooled to room temperature, 20 mL of water was added to dilute and stir, and the mixture was filtered. The solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 11j (352 mg, light yellow solid), with a yield of 80%. MS m / z(ESI):451.9[M+1] + .

[0280] Step 7

[0281] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0282] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 11j (268 mg, 0.59 mmol) was dissolved in 10 mL of methanol, 2 mL of thionyl chloride was slowly added under ice bath, and the reaction solution was heated to 80° C. for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residual solid was slurried and filtered with petroleum ether: ethyl acetate (20:1), and the solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 11k (279 mg, light yellow solid), yield: 100%. MS m / z (ESI): 466.0 [M+1] + .

[0283] Step 8

[0284] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0285] Take 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 11k (279 mg, 0.6 mmol) and dissolve it in 50 mL of tetrahydrofuran. Then add sodium borohydride (68 mg, 1.8 mmol). Heat to 60 ° C, slowly add methanol dropwise until no gas is generated, heat to react for 3 hours. After the reaction is completed, add 10 mL of water and stir for 3 hours. The mixture was adjusted to pH=6 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11 (250 mg, white solid), yield: 95%. MS m / z (ESI): 437.95 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.20(s,1H),7.86(s,2H),7.18(s,1H),5.30(t,J=6.0Hz,1 H), 4.40 (d, J = 6.0Hz, 2H), 2.18-2.12 (m, 1H), 1.06-1.11 (m, 2H), 0.98-1.04 (m, 2H).

[0286] Example 12

[0287] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0288]

[0289] first step

[0290] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0291] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11 (100 mg, 0.22 mmol) was dissolved in 5 mL of dichloromethane, and DAST (34 mg, 1.05 mmol) was added under ice bath, and the reaction solution was reacted at this temperature for 30 minutes. After the reaction was completed, the reaction solution was added to 10 mL of ice water and extracted with dichloromethane (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 12 (26 mg, white solid), yield: 26%. MS m / z (ESI): 439.95 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.81(s,2H),7.18(s,1H),5.35-5.23 (d,J=48.0Hz,2H),2.13-2.15(m,1H),1.09-1.24(m,2H),1.01-1.07(m,2H).

[0292] Embodiment 13

[0293] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0294]

[0295]

[0296] first step

[0297] 3,6-Dichloro-4-cyclobutylpyridazine

[0298] 3,6-dichloropyridazine 13a (5.0 g, 33.6 mmol) was dissolved in a mixture of 168 mL of water and 7.4 mL of concentrated sulfuric acid, and silver nitrate (1.14 g, 6.72 mmol) and cyclobutyric acid 13b (3.5 ml, 36.9 mmol) were added in sequence. 65 mL of an aqueous solution of ammonium persulfate (23 g, 100.6 mmol) was slowly added dropwise at room temperature within half an hour. After the addition was completed, the temperature was raised to 70°C for reaction for 0.5 hours, and the reaction was cooled to room temperature. The pH was adjusted to 7 with aqueous ammonia, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,6-dichloro-4-cyclobutylpyridazine 13c (6.2 g, colorless oily liquid) with a yield of 91%. MS m / z (ESI): 204.0 [M+1] + .

[0299] Step 2

[0300] 3,5-Dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)aniline

[0301] 3,6-Dichloro-4-cyclobutylpyridazine 13c (5.23 g, 25.75 mmol) and 4-amino-2,6-dichlorophenol 5d (4.58 g, 25.75 mmol) were dissolved in 50 mL of dimethyl sulfoxide, and potassium carbonate (7.1 g, 51.50 mmol) and cuprous iodide (2.45 g, 12.88 mmol) were added. The reaction temperature was raised to 90 °C and stirred for 5 hours. The reaction temperature was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,5-dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)aniline 13e (6.5 g, white solid) with a yield of 73%. MS m / z(ESI):345.0[M+1]+ .

[0302] Step 3

[0303] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0304] Take 3,5-dichloro-4-((6-chloro-5-cyclopentylpyridazin-3-yl)oxy)aniline 13e (1.72 g, 5.0 mmol) and dissolve it in 16 mL of acetic acid and 4 mL of water. Cool it to zero degrees, add 2 mL of concentrated hydrochloric acid, slowly add 1 mL of sodium nitrite (414 mg, 6.00 mmol) aqueous solution, stir for 10 minutes after the addition is complete, add 5 mL of sodium acetate (1.23 g, 15.0 mmol) aqueous solution, and then Ethyl (2-cyanoacetic acid) carbamate 13f (936 mg, 6.00 mmol) was added, the ice bath was removed and the temperature was raised to room temperature for reaction for 1 hour, 30 mL of water was added, the solid was filtered and dried to obtain solid (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 13g (2.2 g, light yellow solid), yield: 85%. MSm / z(ESI): 512.1[M+1] + .

[0305] Step 4

[0306] 2-(3,5-dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0307] Take compound (E)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-cyclobutylpyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 13g (1.53g, 3.0mmol) and dissolve it in 30mL glacial acetic acid, then add sodium acetate (792mg, 6.0mmol), raise the temperature to 120℃ and stir for 3 hours, cool to room temperature, add 50mL water to the reaction solution, and use ethyl acetate to dry. (30mL×3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 13h (1.14 g, white solid), yield: 85%. MSm / z(ESI): 448.1[M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.28(brs,1H),12.19(s,1H),7.78(s,2H),7.49(d,J=1.2H z,1H),3.48-3.62(m,1H),2.23-2.33(m,2H),1.88-2.02(m,1H),1.75-1.86(m,1H).

[0308] Step 5

[0309] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0310] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 13h (1.34 g, 3.0 mmol) was dissolved in 25 mL of glacial acetic acid, 5 mL of concentrated hydrochloric acid was added, and the mixture was heated to 120°C for 5 hours. After the reaction was completed, the liquid was cooled to room temperature, 50 mL of water was added to dilute and stir, and the mixture was filtered. The solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 13i (1.3 g, light yellow solid), with a yield of 93%. MS m / z(ESI):467.0[M+1] + .

[0311] Step 6

[0312] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0313] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 13i (466 mg, 1.0 mmol) was dissolved in 10 mL of methanol, 2 mL of thionyl chloride was slowly added under ice bath, and the reaction solution was heated to 80 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residual solid was slurried and filtered with petroleum ether: ethyl acetate (20:1), and the solid was dried to obtain 2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 13j (450 mg, light yellow solid), yield: 93%. MS m / z (ESI): 481.1 [M+1] + .

[0314] Step 7

[0315] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0316] Take 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 13j (450 mg, 0.93 mmol) and dissolve it in 10 mL of tetrahydrofuran. Then add sodium borohydride (344 mg, 9.3 mmol). Heat to 60 ° C, slowly add methanol dropwise until no gas is generated, heat to react for 3 hours, and after the reaction is completed, add 20 mL of water and use 3M dilute hydrochloric acid was adjusted to pH=6, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 13 (300 mg, white solid), yield: 71%. MS m / z (ESI): 452.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.46(brs,1H),12.15(s,1H),7.86(s,2H),7.47(d,J=1.2Hz,1H),5.30(t,J=6.4Hz,1H),4. 40(d,J=6.4Hz,2H),3.48-3.61(m,1H),2.22-2.28(m,2H),2.07-2.16(m,2H),1.97-2.02(m,1H),1.76-1.85(m,1H).

[0317] Embodiment 14

[0318]

[0319] first step

[0320] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 14

[0321] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 13 (200 mg, 0.416 mmol) was dissolved in 5 mL of dichloromethane, and diethylaminosulfur trifluoride (0.55 ml, 4.16 mmol) was added at 0°C for 0.5 hour. The solvent was removed by concentration under reduced pressure and purified by preparative chromatography to give 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 14 (5.5 mg, white solid) with a yield of 2.8%. MS m / z(ESI):454.0[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.68(brs,1H),12.17(s,1H)7.81(s,2H),7.49(d,J=1.2Hz,1H),5.30 (d,J=48.0Hz,2H),3.52-3.62(m,1H),2.11-2.23(m,2H),1.96-2.05(m,1H),1.74-1.84(m,1H).

[0322] Embodiment 15

[0323] 2-(3,5-dichloro-4-((5-(2-fluoropropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0324]

[0325] first step

[0326] 3,6-Dichloro-4-(2-fluoropropan-2-yl)pyridazine

[0327] 3,6-dichloropyridazine 15a (5 g, 33.56 mmol) was dissolved in a mixture of 20 mL of water and 4.09 mL of concentrated sulfuric acid, and silver nitrate (0.57 g, 3.35 mmol) and fluoroisobutyric acid 15b (3.25 g, 28.56 mmol) were added in sequence. 10 mL of ammonium persulfate (15.31 g, 67.1 mmol) was slowly added dropwise at room temperature within half an hour. After the addition was completed, the temperature was raised to 80°C for reaction for 0.4 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 7 with aqueous ammonia. The mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,6-dichloro-4-(2-fluoropropane-2-yl)pyridazine 15b (3.3 g, white solid) with a yield of 47%. MS m / z (ESI): 209.0 [M+1] + .

[0328] Step 2

[0329] 3,5-Dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazin-3-yl)oxy)aniline

[0330] 3,6-Dichloro-4-(2-fluoropropane-2-yl)pyridazine 15b (3.3 g, 15.79 mmol) and 4-amino-2,6-dichlorophenol 15c (3.65 g, 20.52 mmol) were dissolved in 40 mL of dimethyl sulfoxide, and potassium carbonate (4.36 g, 31.57 mmol) and cuprous iodide (1.5 g, 7.89 mmol) were added to raise the temperature to 90 °C and stirred for 4 hours. The reaction was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3,5-dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazine-3-yl)oxy)aniline 15d (5.1 g, yellow solid) in a yield of 92%. MS m / z(ESI):351.2[M+1] + .

[0331] Step 3

[0332] (E) Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-(2-fluoropropan-2-yl)pyridazin-3-yl)oxy)phenyl)hydrazinyl)acetylcarbamate

[0333] Take 3,5-dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazin-3-yl)oxy)aniline 15d (2 g, 5.7 mmol) and dissolve it in 32 mL of acetic acid and 8 mL of water. Cool it to zero degrees, add 4 mL of concentrated hydrochloric acid, slowly add 1 mL of sodium nitrite (512 mg, 7.42 mmol) aqueous solution, stir at zero degrees for 10 minutes after the addition is complete, add 5 mL of sodium acetate (1.4 g, 17.11 mmol) aqueous solution, and then add acetic acid. The mixture was stirred for 1 h at room temperature, and the reaction mixture was stirred for 1 h. After the reaction mixture was cooled to room temperature, 30 mL of water was added. The solid was filtered and dried to give (E)ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-(2-fluoropropan-2-yl)pyridazin-3-yl)oxy)phenyl)hydrazinyl)acetylcarbamate 15f (3.1 g, light yellow solid). The yield was 94.8%. MS m / z (ESI): 517.0 [M+1] + .

[0334] Step 4

[0335] 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

[0336] Compound (E) ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-(2-fluoropropan-2-yl)pyridazin-3-yl)oxy)phenyl)hydrazinyl)acetylcarbamate 15f (2.75 g, 5.31 mmol) was dissolved in 30 mL of glacial acetic acid, and sodium acetate (871 mg, 10.6 mmol) was added. The temperature was raised to 120 ° C and stirred for 4 hours, then cooled to room temperature, and 50 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 15 g (1.8 g, yellow solid), yield: 71.8%. MS m / z (ESI): 452.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.52(brs,1H),7.81(s,2H),7.51(s,1H),1.72(d,J=24.0Hz,6H).

[0337] Step 5

[0338] 2-(3,5-dichloro-4-((5-(2-fluoropropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0339] 15 g (300 mg, 0.62 mmol) of 2-(3,5-dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile was dissolved in 4 mL of methanol, 2 mL of thionyl chloride was slowly added under ice bath, and the reaction solution was heated to 80° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 15 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 15h (300 mg, light yellow solid), yield: 93%. MS m / z (ESI): 485.9 [M+1] + .

[0340] Step 6

[0341] 2-(3,5-dichloro-4-((5-(2-fluoropropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0342] Take 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 15h (100 mg, 0.205 mmol) and dissolve it in 6 mL of tetrahydrofuran, then add sodium borohydride (40 mg, 1.03 mmol), raise the temperature to 60 ° C, slowly add methanol dropwise until no gas is generated, heat the reaction for 3 hours, and after the reaction is completed, add 20 mL of water and The pH value was adjusted to 6 with 3M dilute hydrochloric acid, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 15 (90 mg, white solid), yield: 95.5%. MS m / z (ESI): 457.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.50 (s, 1H), 12.46 (brs, 1H), 7.88 (s, 2H), 7.50 (s, 1H), 5.32 (t, J = 4.0Hz, 1H), 4.40 (d, J = 4.0Hz, 2H), 1.72 (d, J = 24.0Hz, 6H).

[0343] Example 16

[0344] 3-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0345]

[0346] first step

[0347] 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0348] 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 15 (90 mg, 0.20 mmol) was dissolved in 5 mL of dichloromethane, and diethylaminosulfur trifluoride (158 mg, 0.98 mmol) was added at 0°C. The mixture was reacted for 2 minutes, and the solvent was removed by concentration under reduced pressure. The mixture was purified by preparative chromatography to give 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 16 (16.0 mg, white solid), with a yield of 18%. MS m / z(ESI):459.9[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 12.68 (brs, 1H), 12.49 (s, 1H) 7.83 (s, 2H), 7.50 (s, 1H), 5.30 (d, J = 44.0Hz, 2H) 1.71 (d, J = 24Hz, 6H).

[0349] Embodiment 17

[0350] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0351]

[0352]

[0353] first step

[0354] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0355] 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 15a (1.5 g, 3.31 mmol) was dissolved in acetic acid (25 ml), and then hydrochloric acid (5 ml) was slowly added dropwise. The mixture was stirred at 120 °C for 4 hours, cooled to room temperature, and then washed with ethyl acetate (2 5mL×3) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 17a (1.0 g, yellow solid), yield: 67%. MS m / z (ESI): 451.9 [M+1] + .

[0356] Step 2

[0357] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0358] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 17a (300 mg, 0.663 mmol) was dissolved in 4 mL of methanol, 2 mL of thionyl chloride was slowly added under ice bath, and the reaction solution was heated to 70 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 15 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 17b (250 mg, light yellow solid), yield: 81%. MS m / z (ESI): 466.0 [M+1] + .

[0359] Step 3

[0360] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0361] Take 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 17b (100 mg, 0.214 mmol) and dissolve it in 6 mL of tetrahydrofuran. Then add sodium borohydride (41 mg, 1.7 mmol). Heat to 60 ° C, slowly add methanol dropwise until no gas is generated, heat to react for 4 hours, and after the reaction is completed, add 20 mL of water and 3M dilute hydrochloric acid was adjusted to pH=6, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 17 (90.0 mg, white solid), yield: 96%. MS m / z (ESI): 437.9 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),12.36(s,1H),7.86(s,2H),7.56(s,1H),6. 50(s,1H),5.56(s,1H),5.30(t,J=4.0Hz,1H),4.40(d,J=4.0Hz,2H),2.11(s,3H).

[0362] Embodiment 18

[0363] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0364]

[0365] first step

[0366] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0367] 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 17 (90 mg, 0.20 mmol) was dissolved in 5 mL of dichloromethane, and diethylaminosulfur trifluoride (158 mg, 0.98 mmol) was added at 0°C. The reaction was continued for 2 minutes, and the solvent was removed by concentration under reduced pressure. The product was purified by preparative chromatography to give 2-(3,5-dichloro-4-((6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 18 (4.0 mg, white solid) in a yield of 4.4%. MS m / z(ESI):439.9[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),12.36(s,1H)7.83(s,2H),7.56(s,1H),6.50(s,1H),5.56(s,1H),5.30(d,J=48.0Hz,2H),2.11(s,3H).

[0368] Embodiment 19

[0369] 6-Cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0370]

[0371]

[0372] first step

[0373] 4-((Benzyloxy)methyl)-6-cyclopropyl-1,2,4-triazine-3,5(2H,4H)-dione

[0374] 4-((Benzyloxy)methyl)-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione 7a (500 mg, 1.61 mmol) was added to 20 mL of dioxane, followed by cyclopropylboric acid (690 mg, 8.0 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (210 mg, 0.32 mmol) and 2 mol / L aqueous sodium carbonate solution (5 mL). The mixture was replaced with nitrogen three times, and then reacted at 80° C. for 7 hours. The solvent was removed by concentration under reduced pressure, and 1 mol / L hydrochloric acid solution (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL) and the mixture was stirred for 3 hours. x3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate, eluted from 1:0 to 3:1) to give 4-((benzyloxy)methyl)-6-cyclopropyl-1,2,4-triazine-3,5(2H,4H)-dione 19a (120 mg, white solid) with a yield of 27%. MS m / z (ESI): 274.0 [M+1] + .

[0375] Step 2

[0376] 4-((Benzyloxy)methyl)-6-cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0377] 4-((Benzyloxy)methyl)-6-cyclopropyl-1,2,4-triazine-3,5(2H,4H)-dione 19a (76 mg, 0.28 mmol) was dissolved in 2 mL of dioxane, and 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-(methoxymethyl)pyridazin-3(2H)-one 7d (130 mg, 0.28 mmol) was added, followed by trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine (8 mg, 0.055 mmol) and potassium iodide (46 mg, 0.28 mmol), cuprous iodide (53 mg, 0.28 mmol), and potassium carbonate (77 mg, 0.56 mmol), and then microwaved at 130°C for 2 hours. 10 mL of ethyl acetate and 10 mL of water were added to the reaction solution, and the liquid was separated. The aqueous phase was extracted once with 10 mL of ethyl acetate again. The organic phases were combined, washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate, washing from 1:0 to 5:1) to obtain 4-((benzyloxy)methyl)-6-cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 19b (150 mg, colorless oil) with a yield of 88%. MS m / z (ESI): 614.0 [M+1] + .

[0378] Step 3

[0379] 6-Cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0380] 4-((Benzyloxy)methyl)-6-cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-1-(methoxymethyl)-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 19b (75 mg, 0.12 mmol) was dissolved in 2 mL of dichloromethane. Under nitrogen protection, boron tribromide (0.36 mL, 1 mol / L) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was quenched by adding 1 mL of methanol, the solvent was removed by concentrating under reduced pressure, and then 1 mL of methanol and 1 mL of concentrated sulfuric acid were added. The reaction was allowed to proceed for 1 hour at 100°C. After the reaction was completed, the reaction solution was cooled to room temperature and added dropwise to ice water. The pH was adjusted to 5-6 with saturated aqueous potassium carbonate solution. The solution was extracted with ethyl acetate twice (20 mL×2). The organic phases were combined and washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography to obtain 6-cyclopropyl-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 19 (20.0 mg, white solid) with a yield of 36%. MS m / z(ESI): 450.0[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.39(brs,1H),12.20(s,1H),7.76(s,2H),7.44(s,1H) ,3.03-3.10(m,1H),2.15-2.23(m,1H),1.20(d,J=4.0Hz,6H),0.88-1.00(m,4H).

[0381] Embodiment 20

[0382] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione

[0383]

[0384] first step

[0385] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione

[0386] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 7 (25 mg, 0.057 mmol) was dissolved in 1 mL of hydrobromic acid and 1 mL of acetic acid, and the mixture was reacted at 100°C for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by preparative chromatography to give 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione 20 (0.5 mg, white solid) with a yield of 2%. MS m / z (ESI): 426.2 [M+1] + .

[0387] Example 21 THRβ binding assay

[0388] Experimental methods: In vitro analysis of the agonistic effect of compounds on THRβ was performed using a time-resolved fluorescence resonance energy transfer coactivator peptide recruitment assay. The assay used Eu-anti-GST antibody, biotin-SRC2-2 coactivator peptide, streptavidin-d2, RXRα, and GST-tagged THRβ-LBD. Eu-anti-GST antibody indirectly labeled THRβ-LBD by binding to the GST tag. Streptavidin-d2 indirectly labeled SRC2-2 coactivator peptide by binding to the biotin tag. In the presence of RXRα, THRβ-LBD can form a heterodimer THRβ-LBD / RXRα with it. Agonists bind to THRβ-LBD / RXRα and cause conformational changes in THRβ-LBD, thereby increasing the heterodimer's ability to recruit SRC2-2 coactivator peptide. At the same time, the resulting decrease in the distance between d2-labeled SRC2-2 coactivator peptide and Eu-anti-GST antibody increases the THR-FRET signal. The agonist ability of the compound can be evaluated based on the effect of different concentrations of the compound on THRβ activity.

[0389] The detailed procedures are as follows.

[0390] a. Prepare 100X reference compound or compound in DMSO and dilute 1:3 in equal proportions.

[0391] b. Dilute the reference compound or compound to 4X with 1X reaction buffer and add to the assay plate.

[0392] c. Prepare a mixed solution of 4X THRβ-LBD and 4X RXRα using 1X reaction buffer and add it to the experimental plate.

[0393] d. Prepare a mixed solution of 2X biotin-SRC2-2, 2X Eu-anti-GST, and 2X streptavidin-d2 using 1X reaction buffer and add it to the experimental plate.

[0394] e. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 4 hours in the dark.

[0395] f. Read the fluorescence signal values ​​at 665nm and 615nm on an EnVision 2104 plate reader and calculate the Ratio665nm / 615nm.

[0396] Experimental results: see Table 1

[0397] Table 1: THRβ binding assay test results

[0398] Example No. <![CDATA[EC 50 (nM)]]> Emax(%) 1 737 109.3 2 5 92.76 3 23 100.6 4 159 123.8 9 101 108.4 10 94 109.9 12 71 105.4 14 42 117.4 16 163.6 111.3 18 23.6 124.5 19 7249 77.7 20 >10000 / *Compound 1 0.6 97.3 *Compound 2 204 105.4

[0399] *Compound 1 is T3; Comparative compound 2 is Example 8 of WO2007009913 (Compound 31).

[0400] Example 22 THRα binding assay

[0401] Experimental Method: The in vitro analysis of the agonistic effect of the compound on THRα was carried out using a method similar to the THRβ binding assay in Example 11, except that THRα was used instead of THRβ.

[0402] Experimental results: see Table 2

[0403] Table 2: THRα binding assay test results

[0404]

[0405]

[0406] *Compound 1 is T3; Comparative compound 2 is Example 8 of WO2007009913 (Compound 31).

[0407] Example 23 In vitro liver microsome stability experiment

[0408] Experimental methods:

[0409] (I) Solution preparation

[0410] The test substance and the positive control verapamil were dissolved in DMSO to 10 mM as stock solutions, and the 10 mM stock solutions were diluted with 70% acetonitrile aqueous solution to a concentration of 0.25 mM.

[0411] The NADPH regeneration system was prepared to contain final concentrations of 6.5 mM NADP, 16.5 mM G-6-P, 3 U / mL G-6-PDH and 3.3 mM magnesium chloride.

[0412] The stop solution was an acetonitrile solution containing tolbutamide and propranolol (both internal standards).

[0413] Phosphate buffer was 100 mM K3PO4 (pH=7.4) buffer containing 3.3 mM MgCl2.

[0414] The liver microsome incubation system contains 0.2 mg / mL liver microsomal protein and 1 μM test substance / positive control in 100 mM phosphate buffer.

[0415] (II) Incubation process

[0416] Take 80 μL of the mixed solution from the incubation system, add 400 μL of the stop solution to precipitate the protein, vortex and add 20 μL of the NADPH regeneration system as the 0 min sample point.

[0417] Add 130 μL of NADPH regeneration system to the remaining 520 μL protein drug mixture, mix well, and start incubation. The final incubation system is 650 μL, containing 0.2 mg / mL liver microsomal protein, 1 μM test substance / positive control, 1.3 mM NADP, 3.3 mM G-6-P, and 0.6 U / mL G-6-PDH.

[0418] The mixed system was incubated in a 37°C water bath with slow shaking. At 5, 10, 30, and 60 min, 100 μL of the incubation solution was transferred to each well of a new 96-well plate containing 400 μL of stop solution. The mixture was mixed and the protein was precipitated (centrifuged at 4000 × g for 15 min at 4°C).

[0419] Take 100 μL of the supernatant, dilute it with water at a ratio of 1:2, and analyze the sample using the LC-MS / MS method.

[0420] Experimental results: See Table 3.

[0421] Table 3: In vitro liver microsome stability test results

[0422]

[0423]

[0424] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. 1,2,4-triazine-3,5-dione compounds and pharmaceutically acceptable salts thereof, characterized in that: The 1,2,4-triazine-3,5-dione compound has a structure shown in formula (I), wherein A is fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 1,1-difluorobutyl; X is -O-, Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR, R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, halogen or cyano; The substituents of R1, R2, R3 and R are independently selected from hydroxyl, fluorine, chlorine, bromine, iodine or amino; m and n are 0.

2. The 1,2,4-triazine-3,5-dione compound and its pharmaceutically acceptable salt according to claim 1, characterized in that: R1, R2, R3 and R are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 2-hydroxypentyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine or iodine. 3.1,2,4-triazine-3,5-dione compounds and pharmaceutically acceptable salts thereof, characterized in that: The specific structure is as follows:

4. A method for preparing a 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof, comprising: The compound of formula 1b is converted into a compound of formula 1c, and then the compound of formula 1c is converted into a 1,2,4-triazine-3,5-dione compound having a structure of formula (I), wherein A is fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 1,1-difluorobutyl; X is -O-, Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR, R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, halogen or cyano; The substituents of R1, R2, R3 and R are independently selected from hydroxyl, fluorine, chlorine, bromine, iodine or amino; m and n are 0; R4 is a C1-C6 alkyl group.

5. The preparation method according to claim 4, characterized in that: The formula 1b is prepared according to the following method: Hydrolyzing the compound of formula 1a under acidic conditions to obtain a compound of formula 1b; Wherein, X is -O-, Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR, R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, halogen or cyano; The substituents of R1, R2, R3 and R are independently selected from hydroxyl, fluorine, chlorine, bromine, iodine or amino; m and n are 0.

6. A method for preparing a 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof, comprising: Compound 4d and compound 4e are reacted to obtain a 1,2,4-triazine-3,5-dione compound having a structure of formula (I). wherein A is fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoropropyl, 1-fluoroisopropyl, 1-fluorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl or 1,1-difluorobutyl; X is -O-, Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR, R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, halogen or cyano; The substituents of R1, R2, R3 and R are independently selected from hydroxyl, fluorine, chlorine, bromine, iodine or amino; m and n are 0.

7. The preparation method according to claim 6, characterized in that: The compound of the 4d structure is prepared according to the following method: The compound of formula 4c is converted into the compound of formula 4d, Where: X is -O-, Y1, Y2, Y3, Y4, Z1 and Z2 are independently selected from N or CR, R1, R2, R3 and R are independently selected from hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted C3-C18 cycloalkyl, halogen or cyano; The substituents of R1, R2, R3 and R are independently selected from hydroxyl, fluorine, chlorine, bromine, iodine or amino; m and n are 0.

8. Use of the 1,2,4-triazine-3,5-dione compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a THR agonist.

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