2-pyridinone derivatives, processes for their preparation and their use in medicine

Abstract

The application provides a 2-pyridone derivative, which has a structure shown in formula I or a stereoisomer or a pharmaceutically acceptable salt thereof. The activity experiment results show that the 2-pyridone derivative provided by the application has high activity and selectivity, and can be used for treating diseases related to thyroid hormone receptors.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a compound that can serve as a novel agonist of the THRβ receptor, its preparation method and uses, specifically to a 2-pyridone derivative, its preparation method and its pharmaceutical applications. Background Technology

[0002] Thyroid hormones are essential for normal growth and development as well as maintaining metabolic homeostasis (Physiologi cal Reviews 2001, 81(3), 1097-1126). Thyroid hormones are produced by the thyroid gland and secreted into the circulatory system (hypothalamus / pituitary / thyroid system) in two different forms, T4 and T3. T4 is the main form secreted by the thyroid gland, while T3 is the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues but are mainly found in the liver and kidneys.

[0003]

[0004] The circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamic / pituitary / thyroid axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism has profound effects on the heart, weight, metabolism, metabolic rate, body temperature, cholesterol, bones, muscles, and behavior.

[0005] The biological activity of thyroid hormones is mediated by the thyroid hormone receptor (THR) (Endocrine Reviews (1993) 14 348-399). THRs belong to the nuclear receptor family and are encoded by different genes expressing α and β on human chromosomes 17 and 3. Different protein isoforms are produced through selective splicing of the primary transcript; each gene produces two isoforms: THRα1, THRα2, THRβ1, and THRβ2. THRβ1 and THRβ2 are derived from promoter differential expression, differing only at the N-terminus. THRα1 and THRα2 are derived from differential splicing of precursor mRNA, differing primarily at the C-terminus. THRα1, THRβ1, and THRβ2 can bind thyroid hormones. THRβ is mainly distributed in the liver, kidneys, pituitary gland, and brain tissues, playing an important role in regulating TRH and the behavior of thyroid hormones in the liver. THRα, on the other hand, is widely distributed throughout the body and is mainly associated with extrahepatic cardiovascular and skeletal / muscle adverse effects (Drugs (2017) 77 1613–1621). Therefore, if a thyroid hormone analog can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones, it may be applicable to the treatment of response diseases, such as metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other conditions such as hepatic steatosis and nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid diseases, etc.

[0006] The therapeutic use of thyroid hormones themselves is limited by adverse side effects associated with hyperthyroidism, particularly cardiovascular toxicity. A series of thyroid hormone agonists have been developed in the prior art, and these structural agonists are almost all designed and developed based on the structure of the natural ligand T3 of the THR receptor. For example, thyroid hormone analogs with structures different from the compounds of this 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). Among them, Example 8 (Compound 31) disclosed in WO2007009913 is MGL-3196, a first-in-class, orally administered small molecule selective agonist of the hepatic thyroid hormone receptor β subtype (THR-β). Preclinical toxicology and Phase 1 clinical data show that MGL-3196 can significantly reduce LDL cholesterol, triglycerides and lipoproteins as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemia, making it an ideal candidate for reducing cardiovascular risk in NASH patients and for dyslipidemia patients who are intolerant to moderate doses of statins. Phase 2 clinical data show that adverse reactions (AEs) were mainly mild (85%) and moderate (15%), with 3 cases of serious adverse reactions unrelated to treatment. Furthermore, MGL3196 was structurally modified in WO2009037172A1 and CN 110938094 A, respectively, by substituting the nitrogen atom of the pyridazine ring to form an inactive or very low-activity MGL3196 prodrug. This prodrug is then metabolized in vivo to form the original drug, thereby achieving technical effects such as improving the absorption, distribution, transport and metabolism of the drug in vivo, increasing bioavailability, improving the selectivity of the drug on the target site, reducing the toxic side effects of the drug, prolonging the duration of action, and reducing the influence of food.

[0007] Following this, numerous publications such as WO2020073974, CN 111320609 A, and WO2019240938 disclosed a series of structural modifications to the pyridazinone ring in different directions based on the MGL-3196 structure. However, the parent core always possessed a pyridazinone structure similar to the MGL-3196 structure. WO2020169069 disclosed similar structures to pyridine and pyridinone, but the THRβ biological activity and THRβ / THRα selectivity both decreased. In particular, the pharmacological activity was almost completely lost after the nitrogen atom on the pyridinone was substituted.

[0008]

[0009] The compounds and investigational drugs disclosed in these existing technologies still have problems in terms of efficacy, safety, or selectivity. Therefore, it is necessary to continue to discover and develop new compounds with high activity and high selectivity 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

[0010] In view of this, the technical problem to be solved by the present invention is to provide a 2-pyridone derivative, its preparation method and its application in medicine, which has high activity and selectivity.

[0011] To achieve the above objectives, the present invention provides a 2-pyridone derivative having the structure shown in Formula I or its stereoisomers, and a pharmaceutically acceptable salt:

[0012]

[0013] Among them, R1 is selected from C 1～6 alkyl, C 3～6 Saturated or unsaturated cycloalkyl groups, C 5～10 aryl or C 5～10 heteroaryl groups; the C 1～6 The alkyl group may optionally be converted by one or more halogens, deuterium, hydroxyl groups, alkoxy groups, oxo groups, amino groups, C groups. 3～6 Cycloalkyl, five- to ten-membered aryl, or five- to ten-membered heteroaryl substitutions; the C 3～6 The saturated or unsaturated cycloalkyl group may optionally be substituted with one or more halogens, deuterium, hydroxyl groups, alkoxy groups, oxo groups, or amino groups; the C 5～10 aryl, C 5～10 The heteroaryl, five- to ten-membered aryl, or five- to ten-membered heteroaryl group may optionally be replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkyl, cyano, hydroxyl, and amino substitutions;

[0014] R2 is selected from hydrogen or C. 1～6 Alkyl groups;

[0015] R3 is selected from hydrogen, halogens, and C. 1～6 alkyl or C 3～6 cycloalkyl;

[0016] R4 is independently selected from hydrogen, hydroxyl group, C 1～6 Alkyl, halogen, C 1～6 alkoxy, C 3～6 Cycloalkyl groups, or two adjacent R4 groups forming C 3～6 cycloalkyl, wherein the C 1～6alkyl, C 3～6 cycloalkyl or C 1～6 The alkoxy group may optionally be further replaced by one or more hydroxyl groups or halogens;

[0017] n is 1, 2, or 3;

[0018] R5 is selected from hydrogen, cyano, carboxyl, and C. 1～6 alkyl, C 3～6 cycloalkyl, the C 1～6 alkyl, C 3～6 The cycloalkyl group may optionally be converted by one or more halogens, hydroxyl groups, C-type compounds. l～6 Alkyl substitution;

[0019] R6 is selected from hydrogen, C 1～6 alkyl;

[0020] L is selected from -CH2-, -O-, -CF2-, or -S-;

[0021] X is selected from O or S;

[0022] Alternatively, R1 and R2, together with their attached atoms, form a 4- to 10-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group may further contain 0, 1, or 2 optional oxygen, sulfur, and nitrogen atoms in addition to the nitrogen atom originally attached to R1, and the heterocyclic alkyl group may optionally be further bonded by one or more C atoms. l -C6 alkyl, hydroxyl, halogen, cycloalkyl substitution;

[0023] When R3 is C 1～6 When R1 is an alkyl group and / or a C3-C6 cycloalkyl group, R1 is not a C1. 1～6 alkyl, C 3～6 Saturated or unsaturated cycloalkyl groups.

[0024] Preferably, in this invention, the C 5～10 aryl, C 5～10 The heteroaryl, five- to ten-membered aryl, or five- to ten-membered heteroaryl group may optionally be replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkyl or cyano substitution;

[0025] The C 1～6 Alkyl, C 3～6 cycloalkyl, C 1～6 The alkoxy group may optionally be substituted with one or more F atoms.

[0026] Preferably, the substituents of the substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkoxy groups are preferably 1, 2, or 3 fluorine atoms.

[0027] Preferably, in this invention, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, -CH(CH2CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, thiophene, and thiazolyl.

[0028] Preferably, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and -CH(CH2CH3)2 may optionally be converted by one or more halogens, deuterium, hydroxyl groups, or C. 1～6 alkoxy, oxo, amino, C 3～6 Cycloalkyl, phenyl, naphthyl, pyridyl or pyrroleyl substitution.

[0029] Preferably, the phenyl, naphthyl, pyridyl, or pyrrole group may optionally be further replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkoxy, cyano, hydroxy, and amino substitutions.

[0030] The above-mentioned alkoxy group is preferably C. 1～6 alkoxy groups.

[0031] The C of this invention 1～6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, or pentoxy.

[0032] The above C 3～6 The cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0033] Preferably, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl groups may optionally be converted by one or more halogens, deuterium, hydroxyl groups, or C. 1～6 The alkoxy, oxo, or amino groups are substituted.

[0034] The above C 1～6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, or pentoxy.

[0035] The phenyl, thiophene, or thiazolyl groups may optionally be replaced by one or more halogens, substituted or unsubstituted C groups. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6Alkoxy, cyano, hydroxy, and amino substitutions.

[0036] The above C 1～6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0037] The above C 1～6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, or pentoxy.

[0038] The above C 3～6 The cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0039] The above C 1～6 Alkyl, C 1～6 alkoxy, C 3～6 The cycloalkyl group may optionally be further substituted with 1 to 3 fluorine atoms.

[0040] Alternatively, R1 and R2 together with the atoms to which they are attached form a 4- to 10-membered heterocyclic alkyl group, preferably a five- or six-membered monocyclic heterocyclic group, more preferably a tetrahydropyrrole group.

[0041] In addition to the nitrogen atom originally attached to R1, the heterocyclic alkyl group may further contain 0, 1, or 2 optional oxygen, sulfur, and nitrogen atoms, and the heterocyclic alkyl group may optionally be further bonded by one or more C atoms. l -C6 alkyl, hydroxyl, halogen, cycloalkyl substitution.

[0042] More preferably by one or more C 1～3 Alkyl, halogen or C 3～6 Cycloalkyl substitution.

[0043] Further preferably, it is substituted with one or more fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0044] Preferably, R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or -CH(CH2CH3)2. More preferably, it is hydrogen.

[0045] Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, -CH(CH2CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, it is selected from hydrogen, fluorine, chlorine, methyl, or cyclopropyl.

[0046] Preferably, in this invention, R4 is fluorine, chlorine, bromine, or iodine.

[0047] More preferably, R4 is an L-position ortho-dihalogenated form. Specifically, it is an L-position ortho-difluoro, ortho-dichloro, or ortho-dibromo.

[0048] More preferably, R4 is chlorine, and the substitution position is adjacent to the L position, i.e., 2,6-disubstituted, as shown in the following structure (taking L as O as an example):

[0049]

[0050] Preferably, in this invention, R5 is selected from cyano or C. 1～6 Alkyl groups.

[0051] The C 1～6 The alkyl group may optionally be replaced by one or more halogens, hydroxyl groups, or amino groups.

[0052] More preferably, R5 is selected from hydrogen, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or -CH(CH2CH3)2.

[0053] Preferably, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or -CH(CH2CH3)2 may optionally be substituted with 1 to 3 fluorine atoms.

[0054] In some specific embodiments of the present invention, R5 is cyano, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0055] Preferably, R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or -CH(CH2CH3)2. More preferably, it is hydrogen.

[0056] The n is preferably 1, 2 or 3, and more preferably 2.

[0057] The L is preferably -CH2-, -O-, -CF2-, or -S-; more preferably -O-.

[0058] X is preferably O or S; more preferably O.

[0059] Preferably, the 2-pyridone derivative of the present invention has any one of the structures of formula IIa to IIc:

[0060]

[0061] Among them, R 1a Selected from C 1～6 alkyl, C 3～6 Saturated or unsaturated cycloalkyl groups; the C 1～6The alkyl group may optionally be further converted by one or more halogens, deuteriums, hydroxyl groups, alkoxy groups, oxo groups, amino groups, C- groups. 3～6 Cycloalkyl, five- to ten-membered aryl, or five- to ten-membered heteroaryl substitutions; the C 3～6 The saturated or unsaturated cycloalkyl group may optionally be further substituted with one or more halogens, deuteriums, hydroxyl groups, alkoxy groups, oxo groups or amino groups;

[0062] The 5- to 10-membered aryl or 5- to 10-membered heteroaryl group may optionally be replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkyl, cyano, hydroxyl, and amino substitutions;

[0063] R 1b Selected from C 5～10 Aryl or C 5～10 The heteroaryl group, the C 5～10 Aryl or C 5～10 The heteroaryl group may optionally be further reacted with one or more C groups selected from halogens, substituted or unsubstituted C groups. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkyl, cyano, hydroxyl, and amino substitutions;

[0064] In formula IIc, ring A is a 4- to 10-membered heterocyclic alkyl group containing the attached nitrogen atom. In addition to the originally attached nitrogen atom, the 4- to 10-membered heterocyclic alkyl group may further contain 0, 1, or 2 optional oxygen, sulfur, and nitrogen atoms. The heterocyclic alkyl group may optionally be further surrounded by one or more C atoms. l -C6 alkyl, hydroxyl, halogen, cycloalkyl substitution;

[0065] R5 is selected from hydrogen, cyano, carboxyl, and C. 1～6 alkyl, C 3～6 cycloalkyl, the C 1～6 alkyl, C 3～6 The cycloalkyl group may optionally be converted by one or more halogens, hydroxyl groups, C-type compounds. l～6 Alkyl-substituted.

[0066] The above-mentioned alkoxy group is preferably C. 1～6 alkoxy groups.

[0067] Preferably, in this invention, the R 1a Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, -CH(CH2CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.

[0068] The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and -CH(CH2CH3)2 groups may optionally be reacted with one or more halogens, deuterium, hydroxyl groups, or C. 1～6 alkoxy, oxo, amino, C 3～6 Cycloalkyl, phenyl, naphthyl, pyridyl, and pyrroleyl substitutions.

[0069] Preferably, in this invention, the phenyl, naphthyl, pyridyl, and pyrrole groups may optionally be replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkoxy, cyano, hydroxy, and amino substitutions.

[0070] Preferably, in this invention, the C 1～6 Alkyl, C 3～6 cycloalkyl, C 1～6 The alkoxy group may be further optionally substituted with one or more F atoms.

[0071] The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl groups may optionally be converted by one or more halogens, deuterium, hydroxyl groups, or C. 1～6 The alkoxy, oxo, or amino groups are substituted.

[0072] The R 1b C is preferred 5～10 Aryl or C 5～10 Mixed aromatic compounds.

[0073] Preferably, in this invention, the C 5～10 aryl, C 5～10 The heteroaryl group may optionally be replaced by one or more halogens, substituted or unsubstituted C. 1～6 Alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkyl or cyano substitution.

[0074] Preferably, in this invention, the C 1～6 Alkyl, C 3～6 cycloalkyl, C 1～6 The alkoxy group may be further optionally substituted with one or more F atoms.

[0075] More preferably, the R 1b Selected from substituted or unsubstituted phenyl, thiophene, or thiazolyl groups.

[0076] The phenyl, thiophene, or thiazolyl groups may optionally be replaced by one or more halogens, substituted or unsubstituted C groups. 1～6 Alkyl, substituted or unsubstituted C3～6 cycloalkyl, substituted or unsubstituted C 1～6 Alkoxy, cyano, hydroxy, and amino substitutions.

[0077] The above C 1～6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0078] The above C 1～6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, or pentoxy.

[0079] The above C 3～6 The cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0080] The above C 1～6 Alkyl, C 1～6 alkoxy, C 3～6 The cycloalkyl group may optionally be further substituted with 1 to 3 fluorine atoms.

[0081] Preferably, in the present invention, ring A in formula IIc is a 5-6 member monocyclic heterocyclic group or a 7-10 member spirocyclic heterocyclic group.

[0082] Preferably, in formula IIc, ring A and / or R1 and R2, together with the atoms originally attached to them, form a 4- to 10-membered ring, which is a 5-membered or 6-membered monocyclic ring.

[0083] Preferably, in the present invention, ring A in formula IIc is a five-membered or six-membered monocyclic heterocyclic group; more preferably, it is a tetrahydropyrrole ring.

[0084] The five- or six-membered monocyclic heterocyclic group may optionally be converted by one or more halogens, C 1～3 Alkyl, C 3～6 Cycloalkyl substitution.

[0085] Specifically, it can be optionally substituted by one or more fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0086] The selectable range of R5 in formulas IIa to IIc is the same as above, and will not be repeated here.

[0087] Preferably, in this invention, R2 is H;

[0088] R3 is H;

[0089] The R4 is fluorine, chlorine, bromine or iodine; further, it is an ortho-difluoro, ortho-dichloro or ortho-dibromo group at the L position;

[0090] R6 is H;

[0091] The L is -O-;

[0092] X is O.

[0093] Preferably, the 2-pyridone derivative of the present invention has any of the following structures:

[0094]

[0095]

[0096]

[0097] Some embodiments of the compounds of this invention can be implemented by the following reaction flow diagram:

[0098]

[0099] The present invention also provides the use of the above-mentioned 2-pyridone derivatives in the preparation of medicaments for the prevention, treatment and / or relief of diseases caused by thyroid hormone analogue regulation.

[0100] Preferably, the diseases induced by thyroid hormone analogues include one or more of the following: obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

[0101] The present invention also provides a pharmaceutical formulation comprising the above-mentioned 2-pyridone derivatives and pharmaceutically acceptable excipients.

[0102] In this invention, the dosage form of the pharmaceutical preparation can be tablets, hard capsules, soft capsules, dry suspensions, pellets, or micro-pellets.

[0103] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes examples in which the event or condition occurs, as well as examples in which the event or condition does not occur. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, such a group is not intended to introduce any sterically unrealizable, synthetically infeasible, and / or inherently unstable substitution or substituent form.

[0104] "Alkyl" includes straight-chain and branched alkyl groups having a specified number of carbon atoms (typically 1-20 carbon atoms, e.g., 1-8 carbon atoms, e.g., 1-6 carbon atoms). For example, C1-C6 alkyl groups include straight-chain and branched alkyl groups with 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc. Alkylenes are another subset of alkyl groups, referring to the same residues as alkyl groups but with two bonding sites. Alkylenes typically have 2-20 carbon atoms, e.g., 2-8 carbon atoms, e.g., 2-6 carbon atoms. When naming alkyl residues with a specific number of carbons, all geometric isomers having that number of carbons are intended to be included; for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having 1 to 4 carbons.

[0105] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (typically 1-8 carbon atoms, e.g., 2-4 carbon atoms) and at least 1-2 vinyl (>C=C<) unsaturated sites. Examples of such groups are, for example, vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers. "Lower alkenyl" refers to an alkenyl group having 1-4 carbon atoms, which can be represented by C2-C4 alkenyl groups.

[0106] “Cycloalkyl” refers to a non-aromatic, partially saturated or fully saturated carbon ring having a specified number of carbon ring atoms (e.g., 3-10, 3-8, or 3-6 ring carbon atoms). Cycloalkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl, as well as bridged and cage-like cyclic groups (e.g., bicyclic [2.2.2]octane). Lower cycloalkanes generally refer to 3-6 monocyclic rings.

[0107] "Aryl" refers to an aromatic carbon ring having a specified number of carbon atoms (e.g., 6-12 or 6-10 carbon atoms). Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group may include a non-aromatic ring fused to an aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl), provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Thus, 1,2,3,4-tetrahydronaphth-5-yl (wherein the portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while 1,2,3,4-tetrahydronaphth-1-yl (wherein the portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinoline-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinoline-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" as defined herein, regardless of the bonding point (e.g., quinoline-5-yl and quinoline-2-yl are both heteroaryl groups). In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Other examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.

[0108] "Carboxy" or "carboxyl" means -COOH or its salt.

[0109] "Heteroaryl" refers to an aromatic ring containing a specified number of ring atoms (e.g., 5-12 or 5-10 membered heteroaryls), said ring atoms being composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. A 5-membered heteroaryl is a heteroaryl having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl having 6 ring atoms. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 1. Unless otherwise stated, the heteroaryl can be bonded to the parent structure by carbon or nitrogen atoms, provided the valence allows. For example, "pyridinyl" includes 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, and "pyrroloyl" includes 1-pyrroloyl, 2-pyrroloyl, and 3-pyrroloyl. When nitrogen is present in a heteroaryl ring, it can exist in an oxidized state (i.e., N+-O-), provided that the properties of adjacent atoms and groups allow. Similarly, when sulfur is present in a heteroaryl ring, it can exist in an oxidized state (i.e., S+-O- or SO₂), provided that the properties of adjacent atoms and groups allow. Heteroaryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0110] In some cases, heteroaryl groups are monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazolium, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0111] In other cases, polycyclic heteroaryl groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the portion is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups composed of heteroaryl rings fused to non-aromatic rings are described below.

[0112] "Heterocyclic alkyl" refers to a non-aromatic, partially or fully saturated ring (e.g., 3-10 or 3-7 membered heterocyclic alkyl) having a specified number of ring atoms, wherein the ring atoms consist of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), and the remaining ring atoms are carbon. A 5-membered heterocyclic alkyl is a heterocyclic alkyl having 5 ring atoms. A 6-membered heterocyclic alkyl is a heterocyclic alkyl having 6 ring atoms. Heterocyclic alkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocyclic alkyl include oxopropyl, aziridinepropyl, aziridinebutyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. When nitrogen is present in the heterocyclic alkyl ring, it may be in an oxidized state (i.e., N+-O-) where the nature of adjacent atoms and groups allows. Examples include piperidinyl N-oxide and morpholinyl N-oxide. Furthermore, when sulfur is present in a heterocyclic alkyl ring, it can exist in an oxidized state (i.e., S+-O- or -SO 2-), provided that the properties of adjacent atoms and groups allow. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of a polycyclic heterocyclic alkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinoline-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkyl group, while 1,2,3,4-tetrahydroquinoline-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkyl group. Examples of polycyclic heterocyclic alkyl groups composed of heterocyclic alkyl groups fused with aromatic rings are described below.

[0113] "Alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy also includes cycloalkyl groups as defined above, which are also connected by oxygen bridges. Alkoxy groups typically have 1-6 carbon atoms connected by oxygen bridges. "Lower alkoxy" refers to an alkoxy group having 1-4 carbon atoms.

[0114] The term "halogenated" includes fluorinated, chlorinated, bromine, and iodinated compounds, while the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0115] As used herein, the term "substitution" means that any one or more hydrogen atoms on a specified atom or group are selectively replaced by a specified group, provided that the substitution does not exceed the normal valence of the specified atom. When the substituent is oxo (i.e., =O), then two hydrogen atoms on the stated atom are substituted. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures are intended to imply that the compound is robust enough to withstand separation from the reaction mixture and subsequent formulation as a reagent with at least practical utility. Unless otherwise indicated, substituents are named to the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of connection between the substituent and the core structure is in the alkyl moiety.

[0116] Pharmaceutically acceptable salts include, but are not limited to: salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobroms, sulfates, sulfinates, nitrates, and similar salts; and salts with organic acids, such as malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkylates such as acetates, HOOC-(CH2)n-COOH (where n is 0-4), and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to: sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0117] Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0118] The terms “group,” “residue,” or “fragment” used in this article are synonymous and are intended to refer to functional groups or molecular fragments that can be attached to bonds or other molecular fragments.

[0119] The term “therapeutic effective amount” or “effective amount” refers to an amount that, when administered to a human or non-human subject, effectively provides therapeutic benefits such as improvement of symptoms, delay of disease progression, or prevention of disease, or inhibits myofascitis activity in vitro or in vivo. For example, a therapeutic effective amount may be an amount sufficient to reduce the symptoms of disease in response to inhibition of myofascitis activity.

[0120] "Treatment" refers to any treatment of a patient's illness, including:

[0121] a) Disease prevention, that is, preventing the development of clinical symptoms of disease;

[0122] b) Inhibit disease progression;

[0123] c) Slowing or halting the development of clinical symptoms; and / or

[0124] d) Alleviate the disease, that is, cause the clinical symptoms to subside.

[0125] "Subject" or "patient" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful in both human therapeutic and veterinary applications. In some embodiments, the subject is a mammal; in other embodiments, the subject is a human.

[0126] The compounds described herein can be formulated into pharmaceutical compositions and administered to mammalian hosts (such as human patients) in a variety of forms suitable for a chosen route of administration, including oral or parenteral, intravenous, intramuscular, local, transdermal, intrathecal, ocular, intranasal, intraperitoneal, or subcutaneous routes.

[0127] The compounds described herein can be administered systemically, for example, orally or intravenously in combination with pharmaceutically acceptable media (such as inert diluents or assimilated, edible carriers). They can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly mixed with the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, rice paper capsules, etc.

[0128] The starting materials used in the following reactions are usually known compounds, or can be prepared by known operations or obvious modifications thereof.

[0129] Where appropriate, the various starting materials, intermediates, and compounds described herein can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and a variety of other spectroscopic analyses.

[0130] This disclosure is not intended to limit itself to the specific embodiments described herein, which are intended to be illustrative of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent compositions, devices, and methods within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the appended claims and the full scope of equivalents conferred by such claims. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which are of course subject to variation. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0131] Furthermore, when features or aspects of this disclosure are described in the manner of the Markush group, those skilled in the art will recognize that this disclosure is thereby also described in the manner of any individual member or subgroup of the Markush group.

[0132] Although certain embodiments have been illustrated and described by way of example, it should be understood that variations and modifications may be made therein in accordance with common art without departing from the art as defined in its broader sense in the following claims.

[0133] Compared with existing technologies, this invention provides a 2-pyridone derivative having the structure shown in Formula I or its stereoisomers, or a pharmaceutically acceptable salt. Activity assays show that the 2-pyridone derivative provided by this invention exhibits high activity and selectivity, and can be used to treat diseases related to thyroid hormone receptors. Detailed Implementation

[0134] To further illustrate the present invention, the following detailed description of the 2-pyridone derivatives provided by the present invention, their preparation methods, and their applications in medicine are provided in conjunction with the embodiments.

[0135] Example 1

[0136] 2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0137]

[0138] first step

[0139] 5-(2,6-Dichloro-4-nitrophenoxy)-2-methoxypyridine

[0140] 6-Methoxypyridine-3-ol 1a (6.3 g, 50.4 mmol) was dissolved in 80 mL of N,N-dimethylformamide, followed by the addition of 3,5-dichloro-4-fluoroaniline (13.8 g, 65.5 mmol) and potassium carbonate (20.8 g, 151.0 mmol). The reaction mixture was then reacted at 24 °C for 16 hours. 70 mL of water was added to the reaction solution until a large amount of white solid precipitated. The mixture was then filtered, and the filter cake was washed with water one to two times. The filter cake was then dissolved in isopropanol and concentrated. This process was repeated twice, and the solvent was removed under reduced pressure to obtain 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxypyridine 1b (15.0 g, pale yellow solid). Yield: 94.5%. MS m / z (ESI): 315.00 [M+1] + .

[0141] Step 2

[0142] 5-(2,6-Dichloro-4-nitrophenoxy)-2-carbonylpyridine

[0143] 15.0 g (47.60 mmol) of 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxypyridine 1b was dissolved in 30 mL of a 1:1 mixture of hydrobromic acid and acetic acid. The mixture was then heated to 100 °C and reacted under nitrogen protection for 4 hours. Part of the solvent was evaporated under reduced pressure until a large amount of solid precipitated. The solid was filtered, dissolved in isopropanol, and concentrated. This process was repeated 2-3 times to obtain 13.0 g (pale yellow solid) of 5-(2,6-dichloro-4-nitrophenoxy)-2-hydroxypyridine 1c, with a yield of 90.7%. MS m / z (ESI): 300.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 8.52 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H).

[0144] Step 3

[0145] 5-(2,6-Dichloro-4-nitrophenoxy)-1-isopropyl-2-hydroxypyridine

[0146] 5-(2,6-dichloro-4-nitrophenoxy)-2-hydroxypyridine 1c (2.5 g, 8.3 mmol) was dissolved in 30 mL of ethylene glycol dimethyl ether, followed by the addition of potassium tert-butoxide (932.0 mg, 8.3 mmol) and stirring at room temperature for 40 minutes. Then, potassium carbonate (803.0 mg, 5.81 mmol) and isopropane iodophosphate (2.5 mL, 24.91 mmol) were added. The temperature was raised to 100 °C, and the reaction was carried out at this temperature for 4 hours. A portion of the solvent was concentrated under reduced pressure, and 30 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL × 3), and 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 give 5-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-2-hydroxypyridine 1d (1.1 g, yellow solid), in 38.6% yield. MS m / z (ESI): 343.00 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.31 (s, 2H), 7.11 (dd, J = 8.0, 4.0Hz, 1H), 7.05 (d, J = 4.0Hz, 1H), 6.63 (d, J = 8.0Hz, 1H), 5.30-5.20 (m, 1H), 1.33 (d, J = 8.0Hz, 6H).

[0147] Step 4

[0148] 5-(4-Amino-2,6-dichlorophenoxy)-1-isopropyl-2-hydroxypyridine

[0149] 5-(2,6-dichloro-4-nitrophenoxy)-1-isopropyl-2-hydroxypyridine 1d (1.1 g, 3.2 mmol) was dissolved in 10 mL of methanol, then saturated ammonium chloride aqueous solution (1 mL) and iron powder (895.0 mg, 16 mmol) were added, and the reaction was carried out at 100 °C for 4 hours. The reaction solution was filtered, the filtrate was evaporated to dryness, and 30 mL of water was added. 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 give 5-(4-amino-2,6-dichlorophenoxy)-1-isopropyl-2-hydroxypyridine 1e (760.0 mg, gray solid), yield 75.7%. MS m / z (ESI): 313.05 [M+1] + .

[0150] Step 5

[0151] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate

[0152] 5-(4-amino-2,6-dichlorophenoxy)-1-isopropyl-2-hydroxypyridine 1e (760.0 mg, 2.43 mmol) was dissolved in 6N hydrochloric acid aqueous solution and cooled to 0 °C. Then, sodium nitrite aqueous solution (251.1 mg, 3.64 mmol, 1 mL) was added to the reaction and reacted at 0 °C for 30 minutes. Then, N-cyanoaceturane (568.3 mg, 3.64 mmol) was dissolved in 3 mL of water and cooled to 0 °C. Pyridine (5 mL) was added, and the previous reaction solution was slowly added dropwise to the subsequent reaction solution. The reaction was then carried out at 0 °C for 30 minutes. Adding 15 mL of water to the above reaction solution resulted in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dissolved in isopropanol and concentrated. This process was repeated 2 to 3 times to obtain crude ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate 1f (1.0 g, reddish-brown solid). MS m / z (ESI): 482.05 [M+1] + .

[0153] Step 6

[0154] 2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0155] Crude ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate 1f (1.0 g) was dissolved in N,N-dimethylacetamide (15 mL) and sodium acetate (512.3 mg, 2.08 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. 30 mL of water was added to the reaction solution, and ethyl acetate (30 mL) was used as the solvent. ×3) Extract, then wash twice with saturated sodium chloride aqueous solution, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to give (3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 1 (650.0 mg, red solid), two-step yield 61.6%. MS m / z (ESI): 434.00 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.78(s,2H),7.58(d,J=4.0Hz,1H),7.23(dd,J=8.0,4.0Hz,1H),6.38(d,J=8.0Hz,1H),5.10–4.93(m,1H),1.27(d,J=8.0Hz,8H).

[0156] Example 2

[0157] 2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1H-1,2,4-triazine-6-nitrile)

[0158]

[0159] first step

[0160] 5-(4-amino-2,6-dichlorophenoxy)-2-carbonylpyridine

[0161] 5-(4-nitro-2,6-dichlorophenoxy)-2-carbonylpyridine 1c (400.0 mg, 1.33 mmol) was dissolved in 6 mL of methanol, followed by the addition of iron powder (222.5 mg, 3.99 mmol) and 1 mL of saturated ammonium chloride aqueous solution. The mixture was then reacted at 85 °C for 6 hours. The iron powder was removed using a magnetic ploughing rod, and the reaction solution was evaporated to dryness. 20 mL of ethyl acetate and 15 mL of water were added to the reaction solution, and the mixture was extracted three times. The solution was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness. The solution was then purified by rapid column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-2-carbonylpyridine 2a (100.0 mg, brown solid), yield: 27.8%. MS m / z (ESI): 271.00 [M+1] + .

[0162] Step 2

[0163] (E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate

[0164] 5-(4-amino-2,6-dichlorophenoxy)-2-carbonylpyridine 2a (100.0 mg, 0.37 mmol) was dissolved in 4 mL of (6N) hydrochloric acid aqueous solution, cooled to 0 °C, and then sodium nitrite (38.1 mg, 0.55 mmol) dissolved in 0.5 mL of aqueous solution was slowly added dropwise. The reaction mixture was then stirred for 20 minutes. Next, N-cyanoaceturane (86.4 mg, 0.55 mmol) was dissolved in 3 mL of water, cooled to 0 °C, and then 2 mL of pyridine was added. The mixture was stirred at 0 °C for 10 minutes. The subsequent reaction mixture was then slowly added dropwise to the previous reaction mixture, and the reaction was carried out at 0 °C for 30 minutes. Adding 20 mL of water to the reaction solution resulted in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dissolved in anhydrous ethanol and then concentrated. This process was repeated 2-3 times to obtain (E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate 2b (100.0 mg, red solid), yield 61.8%. MS m / z (ESI): 437.95 [M+1] + .

[0165] Step 3

[0166] 2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0167] Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate 2b (100.0 mg, 0.23 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and then sodium acetate (74.9 mg, 0.91 mmol) was added. The temperature was then raised to 120 °C, and the reaction was carried out at this temperature for 4 hours. 20 mL of water was added to the reaction solution, 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. Prep-HPLC was used to prepare 2-(3,5-dichloro-4-((6-oxo-1,6-dihydropyridin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 2 (4.99 mg, white solid), yield 5.6%. MS m / z (ESI): 391.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),7.78(s,2H),7.38(dd,J=9.6Hz,3.2Hz,1H),7.21(s,1H),6.46(d,J=9.6Hz,1H).

[0168] Example 3

[0169] 2-(3,5-dichloro-4-[(1-cyclobutyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0170]

[0171] Using the method of Example 1, iodoisopropane was replaced with bromocyclobutane to prepare the title product 2-(3,5-dichloro-4-[(1-cyclobutyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 3 (35.0 mg, white solid). MS m / z (ESI): 446.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.79 (s, 2H), 7.62 (d, J = 3.2Hz, 1H), 7.25 (dd, J = 10.0, 3.2Hz, 1H), 6.36 (d, J = 10.0Hz, 1H), 5.07–4.95 (m, 1H), 2.30–2.21 (m, 4H), 1.79–1.67 (m, 2H).

[0172] Example 4

[0173] 2-(3,5-dichloro-4-[(1-cyclobutyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0174]

[0175] Using the method of Example 1, iodoisopropane was replaced with 2-chlorocyclopentanone to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(2-oxocyclopentyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 4 (20.0 mg, white solid, yield 23.03%). MS m / z (ESI): 471.95 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ13.28(br s,1H),7.78(s,2H),7.47(d,J=4.0Hz,1H),7.43(d,J=4.0Hz,1H),6.43(d ,J=10.0Hz,1H),4.59–4.54(m,1H),2.56-2.21(m,5H),1.81–1.69(m,1H).

[0176] Example 5

[0177] 2-(3,5-dichloro-4-((1-(cyclopentylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0178]

[0179] Using the method of Example 1, iodoisopropane was replaced with (bromomethyl)cyclopentane to prepare the title product 2-(3,5-dichloro-4-((1-(cyclopentylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 5 (16.0 mg, white solid, yield 41.29%). MS m / z (ESI): 471.95 [M⁻¹] - . 1 H NMR(400MHz,DMSO-d6)δ13.27(br s,1H),7.78(s,2H),7.43-7.37(m,2H),6.42(d,J=8.0Hz,1H),3.78(d,J=8.0Hz,2H),2.33-2.20(m,1H),1.76–1.30(m,6H),1.19-1.10(m,2H).

[0180] Example 6

[0181] 2-(3,5-Dichloro-4-[(1-(2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0182]

[0183] Using the method of Example 1, iodoisopropane was replaced with 1-iodo-2-methylpropane to prepare the title product 2-(3,5-dichloro-4-[(1-(2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 6 (70.0 mg, white solid), in 77.8% yield. MS m / z (ESI): 448.00 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ13.28(s,1H),7.78(s,2H),7.43(dd,J=10.0,3.6Hz,1H),7.38(d,J=3.2 Hz,1H),6.44(d,J=10.0Hz,1H),3.66(d,J=7.2Hz,2H),2.08–1.94(m,1H),0.81(d,J=6.8Hz,6H).

[0184] Example 7

[0185] 2-(3,5-dichloro-4-((6-oxo-1-(pentan-3-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0186]

[0187] Using the method of Example 1, iodoisopropane was replaced with 3-bromopentane to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(pentan-3-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 7 (70 mg, pale yellow solid, yield 29.76%). MS m / z (ESI): 460.00 [M-1] - . 1 HNMR(400MHz,DMSO-d6)δ13.29(s,1H),7.77(s,2H),7.39(s,1H),7.26(dd,J=10.0,3.6 Hz,1H),6.41(d,J=10.0Hz,1H),4.69(m,1H),1.71-1.62(m,4H),0.70(t,J=8.0Hz,6H).

[0188] Example 8

[0189] 2-(3,5-dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0190]

[0191] Using the method of Example 1, iodoisopropane was replaced with 1-bromo-2-methoxyethane to prepare the title product 2-(3,5-dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 8 (257.0 mg, white solid, yield 15.24%). MS m / z (ESI): 449.95 [M+1] + .

[0192] Example 9

[0193] 2-(3,5-dichloro-4-((1-cyclohexyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0194]

[0195] Using the method of Example 1, iodopropane was replaced with p-cyclohexyl toluenesulfonate to prepare the title product 2-(3,5-dichloro-4-((1-cyclohexyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 9 (12.0 mg, white solid), yield: 83.8%. MS m / z (ESI): 475.30 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),7.79(s,2H),7.55(d,J=4.0Hz,1H),7.24(dd,J=8.0,4.0Hz,1H),6.40(d ,J=8.0Hz,1H),4.71-4.56(m,1H),1.86-1.76(m,2H),1.73-1.54(m,5H),1.44-1.28(m,2H),1.27-1.14(m,1H).

[0196] Example 10

[0197] 2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0198]

[0199] first step

[0200] 1-Cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)pyridine-2(1H)-one

[0201] 5-(2,6-dichloro-4-nitrophenoxy)-2-hydroxypyridine 1c (0.6 g, 1.99 mmol) was dissolved in 10 mL of toluene, followed by the addition of cyclopropylboronic acid (342.0 mg, 3.99 mmol), copper acetate (361.9 mg, 1.99 mmol), pyridine (0.8 mL, 9.96 mmol), and sodium di(trimethylsilyl)amino (365.0 mg, 1.99 mmol). The reaction was then carried out at 100 °C for 4 hours. The reaction was quenched with water, concentrated, and then 30 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3), and 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 give 1-cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)pyridine-2(1H)-one 10a (265.0 mg, yellow solid), with a yield of 31.2%. MS m / z (ESI): 341.00 [M+1] + .

[0202] Step 2

[0203] 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropylpyridine-2(1H)-one

[0204] 1-Cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)pyridine-2(1H)-one 10a (265.0 mg, 0.78 mmol) was dissolved in 4 mL of methanol, followed by the addition of 0.5 mL of saturated ammonium chloride aqueous solution and iron powder (173.5 mg, 3.11 mmol). The mixture was then reacted at 100 °C for 4 hours. The mixture was filtered, and the filtrate was evaporated to dryness. 15 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 give 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropylpyridine-2(1H)-one 10b (150.0 mg, brown solid), yield: 77.6%. MS m / z (ESI): 311.00 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.20 (dd, J=12.0Hz, 4.0Hz, 1H), 6.99 (d, J=4.0Hz, 1H), 6.68 (s, 2H), 6 .36(d,J=12.0Hz,1H),5.69(s,2H),3.31–3.21(m,1H),0.97-0.94(m,2H),0.75-0.72(m,2H).

[0205] Step 3

[0206] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate

[0207] 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropylpyridine-2(1H)-one 10b (150.0 mg, 0.482 mmol) was dissolved in 4 mL of (6N) hydrochloric acid aqueous solution, cooled to 0 °C, and then sodium nitrite (49.8 mg, 0.723 mmol) dissolved in 0.5 mL of water was added to the reaction mixture, which was then reacted at 0 °C for 30 minutes. N-cyanoaceturane (112.9 mg, 0.723 mmol) was dissolved in 3 mL of water, cooled to 0 °C, and pyridine (2 mL) was added to it. The previous reaction solution was then slowly added dropwise to the subsequent reaction solution, and the mixture was reacted at 0 °C for 30 minutes. Adding 15 mL of water to the reaction solution resulted in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dissolved in isopropanol and concentrated. This process was repeated 2 to 3 times to obtain crude ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamate 10c (140.0 mg, reddish-brown solid). MS m / z (ESI): 478.05 [M+1] + .

[0208] Step 4

[0209] 2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0210] Crude (ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazone)acetyl)carbamic acid 10c (140.0 mg, 0.29 mmol)) was dissolved in N,N-dimethylacetamide (5 mL) and potassium acetate (86.1 mg, 0.87 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. 20 mL of water was added to the reaction solution, and the solution was diluted with ethyl acetate. Extracted by (30 mL × 3), washed twice with saturated sodium chloride aqueous solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative HPLC to give 10 (37.7 mg, white solid) of 2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, yield 30.0%. MS m / z (ESI): 432.00 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),7.78(s,2H),7.31-7.28(m,2H),6.38 (d,J=12.0Hz,1H),3.33-3.24(m,1H),0.99-0.93(m,2H),0.83-0.80(m,2H).

[0211] Example 11

[0212]

[0213] first step

[0214] 1-(cyclopentyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one

[0215] 5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 1c (2.00 g, 6.60 mmol) was dissolved in 20 mL of toluene, followed by the sequential addition of pyridine (2.61 g, 33.00 mmol), copper acetate (1.20 g, 6.60 mmol), cyclopentyl-1-en-1-ylboronic acid (2.96 g, 26.40 mmol), and sodium di(trimethylsilyl)amino (1.22 g, 6.60 mmol). The reaction was carried out at 100 °C for 8 hours. After removing the solvent, the solution was purified by rapid silica gel column chromatography to give 1-(cyclopentyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 11a (0.70 g, white solid), yield 28.1%. MS m / z (ESI): 367.00 [M+1] + .

[0216] Step 2

[0217] 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclopentyl-1-en-1-yl)pyridin-2(1H)-one

[0218] 1-(cyclopentyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 11a (200.0 mg, 0.54 mmol) and iron powder (152.0 mg, 2.73 mmol) were dissolved in 10.0 mL of ethanol, and then 2.0 mL of saturated ammonium chloride aqueous solution was added. The mixture was heated to 100 °C and reacted for 4 hours. After removing the solvent, the mixture was purified by rapid silica gel column chromatography to obtain 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclopentyl-1-en-1-yl)pyridin-2(1H)-one 11b (180.0 mg, white solid), yield 98.1%. MS m / z (ESI): 337.05 [M+1] + .

[0219] Step 3

[0220] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclopentyl-1-en-1-yl)-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate

[0221] Dissolve 11b (180.0 mg, 0.53 mmol) of 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclopentyl-1-en-1-yl)pyridin-2(1H)-one in 8.0 mL of acetic acid and 2.0 mL of water. Cool to 0 °C, then add 1.0 mL of concentrated hydrochloric acid. Slowly add 2.0 mL of sodium nitrite (44.0 mg, 0.63 mmol) aqueous solution. After the addition is complete, stir for ten minutes. Then add sodium acetate (23.5 mg, 0.34 mmol) and N2O. -Cyanoacetylurane (165.3 mg, 1.06 mmol) was reacted at room temperature for 12 hours after removing the ice bath. 15 mL of water was added, and a solid was formed. The solid was filtered and dried to give (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclopentyl-1-en-1-yl)-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate 11c (179.0 mg, yellow solid), yield: 67.3%. The crude product was used directly in the next step. MS m / z (ESI): 504.05 [M+1] + .

[0222] Step 4

[0223] 2-(3,5-dichloro-4-((1-(cyclopentyl-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0224] Crude (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclopentyl-1-en-1-yl)-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazyl)acetyl)carbamate 11c (179.0 mg, 0.35 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL) and potassium acetate (104.0 mg, 1.06 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. After solvent removal, HPLC purification yielded 2-(3,5-dichloro-4-[(5-cyclopropyl-6-oxo-1-(prop-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 11 (22.0 mg, white solid), in 13.1% yield. MS m / z (ESI): 458.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),7.78(s,2H),7.41(dd,J=10.0,3.2Hz,1H),7.27(d,J=3.2Hz,1H ), 6.44 (d, J = 10.0Hz, 1H), 6.00-5.96 (s, 1H), 2.70-2.59 (m, 2H), 2.43-2.38 (m, 2H), 2.01-1.89 (m, 2H).

[0225] Example 12

[0226]

[0227] first step

[0228] 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentylpyridine-2(1H)-one

[0229] 1-(cyclopentyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 11a (500.0 mg, 0.54 mmol) was dissolved in ethyl acetate (10.0 mL), and then 10% wetted palladium on carbon (50.0 mg) was added. The reaction was carried out at room temperature for 12 hours under a hydrogen atmosphere (15 psi). After filtration to remove the solvent, the solution was purified by rapid silica gel column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentylpyridin-2(1H)-one 12a (301.0 mg, white solid), yield 60.1%. MS m / z (ESI): 339.05 [M+1] + .

[0230] Step 2

[0231] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)hydrazone)acetyl)carbamate

[0232] Dissolve 180.0 mg (0.53 mmol) of 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentylpyridin-2(1H)-one 12a in 8.0 mL of acetic acid and 2.0 mL of water. Cool to zero degrees Celsius, then add 1.0 mL of concentrated hydrochloric acid. Slowly add 2.0 mL of sodium nitrite (44.0 mg, 0.63 mmol) aqueous solution. After the addition is complete, stir for ten minutes. Then add sodium acetate (23.53 mg, 0.34 mmol) and N2O. -Cyanoacetylurane (165.3 mg, 1.06 mmol) was reacted at room temperature for 12 hours after removing the ice bath. 15 mL of water was added, and a solid was formed. The solid was filtered and dried to give (ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)hydrazone)acetyl)carbamate 12b (189.0 mg, yellow solid), yield: 24.0%. MS m / z (ESI): 506.10 [M+1] + .

[0233] Step 3

[0234] 2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0235] Crude ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)hydrazone)acetyl)carbamate 12b (189.0 mg, 0.37 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL) and potassium acetate (109.0 mg, 1.12 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. After removing the solvent, the product was purified by HPLC to give 2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 12 (120.0 mg, white solid), yield 70.1%. MS m / z (ESI): 460.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),7.79(s,2H),7.44(d,J=3.2Hz,1H),7.27(dd,J=10.0, 3.2Hz, 1H), 6.39 (d, J = 10.0Hz, 1H), 5.04-4.98 (m, 1H), 2.00-1.90 (m, 2H), 1.81-1.53 ​​(m, 6H).

[0236] Example 13

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

[0238]

[0239] first step

[0240] 1-(cyclohexyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one

[0241] 5-(2,6-dichloro-4-nitrophenoxy)-2-hydroxypyridine 1c (2.00 g, 6.6 mmol) was dissolved in 40 mL of toluene, followed by the addition of cyclohexenylboronic acid (3.60 g, 26.6 mmol), copper acetate (1.20 g, 6.6 mmol), sodium bis(trimethylsilyl)amino (1.20 g, 6.6 mmol), and pyridine (2.68 mL, 33.0 mmol). The mixture was then reacted at 80 °C for 4 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by rapid column chromatography to give 1-(cyclohexyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridine-2(1H)-one 13a (720.0 m, yellow solid), yield: 28.5%. MS m / z (ESI): 381.00 [M+1] + .

[0242] Step 2

[0243] 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclohex-1-en-1-yl)pyridin-2(1H)-one

[0244] 1-(cyclohexyl-1-en-1-yl)-5-(2,6-dichloro-4-nitrophenoxy)pyridin-2(1H)-one 13a (200.0 mg, 0.53 mmol) and reduced iron powder (147.0 mg) were dissolved in a mixture of 1 mL ethanol and 1 mL saturated ammonium chloride. The mixture was refluxed for 2 hours, the ethanol was removed by concentration under reduced pressure, and the mixture was extracted with dichloromethane (2 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclohexyl-1-en-1-yl)pyridin-2(1H)-one 13b (126.0 mg, yellow oil), yield: 68.4%. MS m / z (ESI): 351.00 [M+1] + .

[0245] Step 3

[0246] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclohex-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0247] 5-(4-amino-2,6-dichlorophenoxy)-1-(cyclohex-1-en-1-yl)pyridin-2(1H)-one 13b (126.0 mg, 0.36 mmol) was dissolved in a mixed solvent consisting of 3.2 mL acetic acid, 0.8 mL water, and 0.4 mL concentrated hydrochloric acid. Sodium nitrite (31.0 mg, 0.44 mmol) was added at 0 °C, and after reacting for 10 minutes, sodium acetate (90.0 mg, 1.10 mmol) was added. After reacting for 10 minutes, N-cyanoaceturane (69.0 mg, 0.44 mmol) was added, and the reaction was carried out at room temperature for 72 hours. After adding 5 mL of water, the mixture was filtered and dried to give crude (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclohex-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 13c (70.0 mg, yellow solid), yield: 37.0%. MS m / z (ESI): 518.09 [M+1] + .

[0248] Step 4

[0249] 2-(3,5-dichloro-4-((1-(cyclohexyl-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0250] (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-(cyclohex-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 13c (55.0 mg, 0.11 mmol) was dissolved in 2.0 mL of N,N-dimethylacetamide, and potassium acetate (21.0 mg, 0.22 mmol) was added. The mixture was reacted at 120 °C for 2 hours, and the solvent was removed by concentration under reduced pressure. The solution was then purified by preparative chromatography to obtain 2-(3,5-dichloro-4-((1-(cyclohex-1-en-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 13 (15.0 mg, white solid), yield: 30.0%. MS m / z (ESI): 472.05 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.77(s,2H),7.43(d,J=4.0Hz,1H),7.21(dd,J=8.0,4.0Hz,1H),6.41(d,J=8.0 Hz,1H),5.72-5.62(m,1H),2.24-2.18(m,2H),2.15-2.08(m,2H),1.72-1.64(m,2H),1.60-1.52(m,2H).

[0251] Example 14

[0252] 2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbazene)

[0253]

[0254] first step

[0255] Deuterated cyclopentanol

[0256] Cyclopentanone 14a (5.00 g, 59.44 mmol) was dissolved in 100.0 mL of methanol, and sodium borodeuteride (6.20 g, 148.60 mmol) was added. The reaction was carried out at room temperature for 2 hours, and the reaction was quenched with 2.0 mL of 1N hydrochloric acid. The solvent was removed by concentration under reduced pressure, and 100 mL of dichloromethane was added. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give deuterated cyclopentanol 14b (4.86 g, colorless oil), yield: 93.9%.

[0257] Step 2

[0258] Deuterated cyclopentyl 4-toluene-1-sulfonate

[0259] Deuterated cyclopentanol 14b (4.86 g, 55.8 mmol) was dissolved in 100.0 mL of dichloromethane, followed by the addition of p-toluenesulfonyl chloride (10.64 g, 55.8 mmol), 4-dimethylaminopyridine (0.68 g, 5.58 mmol), and triethylamine (16.94 g, 167.4 mmol). The mixture was stirred at room temperature for 12 hours. After solvent removal, column chromatography was performed to obtain deuterated cyclopentyl 4-toluene-1-sulfonate 14c (3.20 g, colorless oil), in 23.5% yield. MS m / z (ESI): 240.31 [M+1] + .

[0260] Step 3

[0261] Deuterated 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-1,2-dihydropyridine-2-one

[0262] 5-(2,6-dichloro-4-nitrophenoxy)-2-hydroxypyridine 1c (1.50 g, 4.98 mmol) was dissolved in 30.0 mL of 1,4-dioxane, and deuterated cyclopentyl 4-toluene-1-sulfonate 14c (2.4 g, 9.96 mmol) and cesium carbonate (4.87 g, 14.94 mmol) were added. The reaction was carried out at 100 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography to give deuterated 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-1,2-dihydropyridin-2-one 14d (1.0 g, yellow solid), yield: 52.4%. MS m / z (ESI): 370.21 [M+1] + .

[0263] Step 4

[0264] Deuterated 1-cyclopentyl-5-(2,6-dichloro-4-aminophenoxy)-1,2-dihydropyridin-2-one

[0265] Deuterated 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-1,2-dihydropyridin-2-one 14d (985.0 mg, 2.67 mmol) was dissolved in a mixed solvent of 10.0 mL saturated ammonium chloride and 10.0 mL ethanol. Reduced iron powder (750.0 mg, 13.4 mmol) was added, and the reaction was carried out at 100 °C for 2 hours. The ethanol was removed by concentration under reduced pressure, and the mixture was extracted with dichloromethane (20.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated. The crude product was purified by rapid silica gel column chromatography to obtain deuterated 1-cyclopentyl-5-(2,6-dichloro-4-aminophenoxy)-1,2-dihydropyridin-2-one 14e (720.0 mg, pale yellow oil), yield: 73.0%. MS m / z (ESI): 340.07 [M+1] + .

[0266] Step 5

[0267] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate

[0268] Deuterated 1-cyclopentyl-5-(2,6-dichloro-4-aminophenoxy)-1,2-dihydropyridin-2-one 14e (360.0 mg, 0.98 mmol) was dissolved in a mixed solvent consisting of 4.8 mL acetic acid, 1.2 mL water, and 0.6 mL concentrated hydrochloric acid. Sodium nitrite (81.1 mg, 1.18 mmol) was added at 0 °C, and after reacting for 10 minutes, sodium acetate (241.2 mg, 2.94 mmol) was added, followed by further reaction. After 10 minutes, N-cyanoaceturane (183.6 mg, 1.18 mmol) was added, and the reaction was carried out at room temperature for 72 hours. After adding 10.0 mL of water, the mixture was filtered and dried to give crude (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 14f (620.0 mg, yellow solid), yield: 92.0%. The crude product was used directly in the next step. MS m / z (ESI): 507.10 [M+1] + .

[0269] Step 6

[0270] 2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbazene)

[0271] (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 14f (570.0 mg, 0.90 mmol) was dissolved in 10.0 mL of N,N-dimethylacetamide, and potassium acetate (176.7 mg, 1.80 mmol) was added. The mixture was reacted at 120 °C for 2 hours. The solvent was removed by concentration under reduced pressure. The crude product was purified by preparative HPLC to obtain 2-(3,5-dichloro-4-((deuterated 1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 14 (70.0 mg, white solid), yield: 17.0%. MS m / z (ESI): 461.06 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.79(s,2H),7.43(d,J=4.0Hz,1H),7.24(dd,J=4.0,8.0Hz,1H),6.40(d,J=8.0Hz,1H),1.97-1.95(m,2H),1.76-1.59(m,6H).

[0272] Example 15

[0273]

[0274] first step

[0275] 2-(3,5-dichloro-4-[(5-chloro-1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0276] 2-(3,5-dichloro-4-((1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 12 (30.0 mg, 0.06 mmol) was dissolved in 3.0 mL of N,N-dimethylformamide, and then N-chlorosuccinimide (12.0 mg, 0.09 mmol) was added. The mixture was heated to 70 °C. The reaction was carried out at ℃ for 1 hour, the solvent was removed, and the product was purified by preparative HPLC to give 2-(3,5-dichloro-4-[(5-chloro-1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 15 (13.0 mg, white solid), yield 43.1%. MS m / z (ESI): 493.95 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),7.82–7.76(m,3H),7.52(d,J=2.8Hz,1H ),5.09–5.00(m,1H),2.00-1.94(m,2H),1.80–1.68(m,4H),1.64–1.57(m,2H).

[0277] Example 16

[0278] 2-(3,5-dichloro-4-((1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0279]

[0280] first step

[0281] 5-Fluoro-6-methoxypyridine-3-ol

[0282] 5-Bromo-3-fluoro-2-methoxypyridine 16a (2.00 g, 9.71 mmol) and trimethyl borate (2.20 g, 21.17 mmol) were dissolved in 60.0 mL of anhydrous tetrahydrofuran. The solution was purged three times with nitrogen. Butyllithium (8.74 mL, 2.5 N, 21.86 mmol) was added dropwise at -78 °C. After reacting for 2 hours at -78 °C, 20% peracetic acid (8.10 g, 21.30 mmol) was added. The reaction was continued for 10 minutes, then the temperature was raised to 0 °C and stirred for one hour. A saturated sodium sulfite solution was added dropwise at 0 °C until the temperature no longer increased. 50 mL of ethyl acetate was added, and the solution was dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and purified by column chromatography to obtain 5-fluoro-6-methoxypyridine-3-ol 16b (755.0 mg, colorless oil). Yield: 46.5%. MS m / z (ESI): 144.11 [M+1] + .

[0283] Step 2

[0284] 5-(2,6-Dichloro-4-nitrophenoxy)-3-fluoro-2-methoxypyridine

[0285] 5-Fluoro-6-methoxypyridin-3-ol 16b (755.0 mg, 4.52 mmol) was dissolved in 10.0 mL of N,N-dimethylformamide, and 1,3-dichloro-2-fluoro-5-nitrobenzene (949.2 mg, 4.52 mmol) and potassium carbonate (1874.1 mg, 13.56 mmol) were added. The mixture was reacted at room temperature for 3 hours, then 80 mL of water was added. The mixture was filtered, concentrated under reduced pressure, and evaporated to dryness to give 5-(2,6-dichloro-4-nitrophenoxy)-3-fluoro-2-methoxypyridinium 16c (1.48 g, yellow solid), yield: 94.96%. MS m / z (ESI): 334.10 [M+1] + .

[0286] Step 3

[0287] 5-(2,6-Dichloro-4-nitrophenoxy)-3-fluoropyridine-2-ol

[0288] 1.43 g (4.15 mmol) of 5-(2,6-dichloro-4-nitrophenoxy)-3-fluoro-2-methoxypyridine 16c was dissolved in a mixed solvent of 15.0 mL acetic acid and 15.0 mL hydrobromic acid. The reaction was carried out at 100 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the mixture was cooled to room temperature, filtered, and dried under reduced pressure to give 1.30 g (yellow solid) of 5-(2,6-dichloro-4-nitrophenoxy)-3-fluoropyridine-2-ol 16d, yield: 97.0%. MS m / z (ESI): 320.07 [M+1] + .

[0289] Step 4

[0290] 1-Cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-fluoro-1,2-dihydropyridin-2-one

[0291] 1.25 g (3.85 mmol) of 5-(2,6-dichloro-4-nitrophenoxy)-3-fluoropyridin-2-ol 16d was dissolved in 25.0 mL of 1,4-dioxane. Cyclopentyl 4-toluene-1-sulfonate (2.78 g, 11.55 mmol) and cesium carbonate (3.76 g, 11.55 mmol) were added. The reaction was carried out at 100 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography to give 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-fluoro-1,2-dihydropyridin-2-one 16e (520.0 mg, yellow solid), yield: 34.3%. MS m / z (ESI): 388.19 [M+1] + .

[0292] Step 5

[0293] 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentyl-3-fluoro-1,2-dihydropyridin-2-one

[0294] 1-Cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-fluoro-1,2-dihydropyridin-2-one 16e (470.0 mg, 1.19 mmol) was dissolved in a mixture of 10.0 mL saturated ammonium chloride and 10.0 mL ethanol. Reduced iron powder (332.3 mg, 5.95 mmol) was added, and the mixture was reacted at 100 °C for 2 hours. The ethanol was removed by concentration under reduced pressure, and the mixture was extracted with dichloromethane (20.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentyl-3-fluoro-1,2-dihydropyridin-2-one 16f (288.0 mg, pale yellow oil), yield: 53.3%. MS m / z (ESI): 357.21 [M+1] + .

[0295] Step 6

[0296] N-[(E)-cyanoethyl(2-(3,5-dichloro-4-[(1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)hydrazine-1-imide)carbonyl]carbamate]

[0297] 16f of 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentyl-3-fluoro-1,2-dihydropyridin-2-one (144.0 mg, 0.32 mmol) was dissolved in a mixed solvent consisting of 3.2 mL acetic acid, 0.8 mL water, and 0.4 mL concentrated hydrochloric acid. Sodium nitrite (26.5 mg, 0.38 mmol) was added at 0 °C, and after reacting for 10 minutes, sodium acetate (78.8 mg, 0.96 mmol) was added. After reacting for 10 minutes, N-cyanoaceturane (59.9 mg, 0.38 mmol) was added, and the reaction was carried out at room temperature for 72 hours. After adding 5.0 mL of water, the mixture was filtered and dried to give 16 g (183.0 mg, yellow solid) of crude N-[(E)-cyanoethyl(2-(3,5-dichloro-4-[(1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)hydrazine-1-imide)carbonyl]carbamate, yield: 79.0%. MS m / z (ESI): 524.33 [M+1] + .

[0298] Step 7

[0299] 2-(3,5-dichloro-4-[(1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxo]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0300] 16 g (183.0 mg, 0.25 mmol) of (N-[(E)-cyanoethyl(2-(3,5-dichloro-4-[(1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)hydrazine-1-imide)carbonyl]carbamate was dissolved in 3.0 mL of N,N-dimethylacetamide, and potassium acetate (73.61 mg, 0.75 mmol) was added. The mixture was reacted at 120 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by preparative chromatography to obtain 16 g (70.0 mg, white solid) of 2-(3,5-dichloro-4-[(1-cyclopentyl-5-fluoro-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate, yield: 31.2%. MS m / z (ESI): 478.26 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.78 (s, 2H), 7.56 (d, J = 4.0Hz, 1H), 7.30 (d, J = 4.0Hz, 1H), 5.08-5.04 (m, 2H), 1.97-1.95 (m, 2H), 1.74-1.60 (m, 6H).

[0301] Example 17

[0302] 2-(3,5-dichloro-4-[(1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0303]

[0304] first step

[0305] Cyclopentyl 4-toluene-1-sulfonate

[0306] Cyclopentanol 17a (10.00 g, 116.10 mmol) was dissolved in 100 mL of dichloromethane, followed by the addition of p-toluenesulfonyl chloride (22.13 g, 116.10 mmol), 4-dimethylaminopyridine (1.42 g, 11.61 mmol), and triethylamine (29.37 g, 290.25 mmol). The mixture was stirred at room temperature for 12 hours. After removing the solvent, rapid silica gel column chromatography was performed to give cyclopentyl 4-toluene-1-sulfonate 17b (13.12 g, colorless oil), in 42.8% yield.

[0307] Step 2

[0308] 5-Bromo-1-cyclopentyl-3-methyl-1,2-dihydropyridin-2-one

[0309] Cyclopentyl 4-toluene-1-sulfonate 17b (3.77 g, 15.96 mmol) was dissolved in 10 mL of 1,2-dimethoxyethane, followed by the addition of 5-bromo-3-methylpyridin-2-one (1.00 g, 5.32 mmol) and potassium carbonate (2.21 g, 15.96 mmol). The mixture was heated to 80 °C and reacted for 12 hours. After removing the solvent, the solution was purified by rapid silica gel column chromatography to give 5-bromo-1-cyclopentyl-3-methyl-1,2-dihydropyridin-2-one 17c (0.92 g, white solid), in 62.1% yield. MS m / z (ESI): 256.05 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.31(d,J=2.4Hz,1H),7.22(d,J=1.2Hz,1H),5.32-5.24(m, 1H),2.23–2.11(m,5H),1.88-1.84(m,2H),1.78–1.71(m,2H),1.65-1.60(m,2H).

[0310] Step 3

[0311] 1-Cyclopentyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one

[0312] 5-Bromo-1-cyclopentyl-3-methyl-1,2-dihydropyridin-2-one 17c (300.0 mg, 1.08 mmol), pinacol diborate (411.3 mg, 1.62 mmol), potassium acetate (317.9 mg, 3.24 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (79.0 mg, 0.11 mmol) were dissolved in 10 mL of 1,4-dioxane, purged with nitrogen, heated to 100 °C, and reacted for 6 hours. After removing the solvent, the solution was purified by rapid silica gel column chromatography to obtain 1-cyclopentyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one 17d (343.0 mg, colorless oil), yield 71.2%. MS m / z (ESI): 304.15 [M+1] + .

[0313] Step 4

[0314] 1-Cyclopentyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one

[0315] 1-Cyclopentyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one 17d (100.0 mg, 0.22 mmol) was dissolved in 5.0 mL of N,N-dimethylformamide, cooled to 0 °C, and peracetic acid (167.3 mg, 0.44 mmol) was added dropwise. After the addition was complete, the reaction was carried out at 0 °C for 1 hour. Then, 1.0 mL of saturated sodium sulfite aqueous solution was added. The unpurified 1-cyclopentyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one 17e reaction solution was used directly in the next step. MS m / z (ESI): 194.15 [M+1] + .

[0316] Step 5

[0317] 1-Cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one

[0318] 1,3-Dichloro-2-fluoro-5-nitrobenzene (46.2 mg, 0.22 mmol) and potassium carbonate (304.0 mg, 2.20 mmol) were dissolved in 1-cyclopentyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one 17e reaction solution. The reaction was carried out at room temperature for 3 hours. After removing the solvent, 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one 17f (0.07 g, yellow oil) was purified by rapid silica gel column chromatography, with a yield of 59.8%. MS m / z (ESI): 383.00 [M+1]+ .

[0319] Step 6

[0320] 17 f (70.0 mg, 0.13 mmol) of 1-cyclopentyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one was dissolved in 5.0 mL of ethanol, and then 117.3 mg (0.52 mmol) of stannous dichloride dihydrate was added. The mixture was heated to 80 °C and reacted for 2 hours. The pH was adjusted to greater than 7 with aqueous sodium hydroxide solution, the solvent was removed, and the solution was purified by rapid silica gel column chromatography to obtain 17 g (70.0 mg, white solid) of 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentyl-3-methyl-1,2-dihydropyridin-2-one, in 98.0% yield. MS m / z (ESI): 353.10 [M+1] + .

[0321] Step 7

[0322] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridine-3-l)oxy)phenyl)hydrazine)acetyl)carbamate

[0323] Dissolve 17 g (70.0 mg, 0.18 mmol) of 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopentyl-3-methyl-1,2-dihydropyridin-2-one in 3 mL of acetic acid and 1 mL of water. Cool to 0 °C, then add 0.5 mL of concentrated hydrochloric acid. Slowly add 1 mL of sodium nitrite (13.6 mg, 0.20 mmol) aqueous solution. After the addition is complete, stir for ten minutes, then add sodium acetate (44.3 mg, 0.54 mmol). N-cyanoacetylurane (28.1 mg, 0.18 mmol) was reacted at room temperature for 12 hours after removing the ice bath. 10 mL of water was added, the solid was filtered, and dried to give ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridine-3-l)oxy)phenyl)hydrazine)acetyl)carbamate (100.0 mg, yellow solid) for 17 hours, yield: 51.0%. The crude product was used directly in the next step. MS m / z (ESI): 520.00 [M+1] + .

[0324] Step 8

[0325] 2-(3,5-dichloro-4-[(1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0326] Crude ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridin-3-l)oxy)phenyl)hydrazine)acetyl)carbamate 17h (100.0 mg, 0.09 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL) and potassium acetate (26.5 mg, 0.27 mmol) was added. The mixture was then reacted at 120 °C for 3 h. After removing the solvent, the product was purified by preparative HPLC to give 2-(3,5-dichloro-4-[(1-cyclopentyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 17 (8.0 mg, white solid), yield 17.6%. MS m / z (ESI): 474.00 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),7.78(s,2H),7.22(s,2H),5.05–5.15( m,1H),2.01(s,3H),1.98-1.94(m,2H),1.78-1.70(s,2H),1.68-1.60(m,2H).

[0327] Example 18

[0328] 2-(3,5-dichloro-4-((1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0329]

[0330] first step

[0331] 5-Bromo-1-cyclopropyl-3-methylpyridin-2(1H)-one

[0332] 5-Bromo-3-methylpyridin-2-one 18a (2.00 g, 10.6 mmol) was dissolved in 20 mL of 1,2-dichloroethane, followed by the addition of 2,2'-bipyridine (8.31 g, 53.2 mmol), copper acetate (1.58 g, 12.7 mmol), cyclopropylboronic acid (1.37 g, 15.9 mmol), and sodium carbonate (2.26 g, 21.2 mmol). The reaction was carried out at 70 °C for 6 hours. After removing the solvent, the solution was purified by rapid silica gel column chromatography to give 5-bromo-1-cyclopropyl-3-methyl-1,2-dihydropyridin-2-one 18b (2.10 g, white solid), in 84.9% yield. MS m / z (ESI): 228.05 [M+1] + .

[0333] Step 2

[0334] 1-Cyclopropyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one

[0335] Dissolve 5-bromo-1-cyclopropyl-3-methyl-1,2-dihydropyridin-2-one 18b (1.50 g, 6.5 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxane-2-yl)-1,3,2-dioxane (1.64 g, 6.5 mmol), potassium acetate (0.63 g, 6.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (4.73 g, 6.5 mmol) in 20 mL In 1,4-dioxane, nitrogen was purged, and the mixture was heated to 100°C for 6 hours. After solvent removal, the solution was purified by rapid silica gel column chromatography to give 1-cyclopropyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one 18c (1.78 g, colorless oil), yield 82.4%. MS m / z (ESI): 276.15 [M+1] + .

[0336] Step 3

[0337] 1-Cyclopropyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one

[0338] 1-Cyclopropyl-3-methyl-5-(tetramethyl-1,3,2-dioxin-2-yl)-1,2-dihydropyridin-2-one 18c (0.30 g, 0.90 mmol) was dissolved in 5.0 mL of N,N-dimethylformamide, cooled to 0 °C, and hydrogen peroxide (0.09 g, 0.79 mmol) was added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 12 hours. No purification was required. The resulting 1-cyclopropyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one 18d reaction solution was used directly in the next step. MS m / z (ESI): 166.20 [M+1] + .

[0339] Step 4

[0340] 1-Cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one

[0341] 1,3-Dichloro-2-fluoro-5-nitrobenzene (0.20 g, 0.98 mmol) and potassium carbonate (0.27 g, 1.95 mmol) were dissolved in 1-cyclopropyl-5-hydroxy-3-methyl-1,2-dihydropyridin-2-one 18d reaction solution and reacted at room temperature for 3 hours. After removing the solvent, the solution was purified by rapid silica gel column chromatography to give 1-cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one 18e (0.24 g, colorless oil), yield 88.0%. MS m / z (ESI): 355.00 [M+1] + .

[0342] Step 5

[0343] 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropyl-3-methyl-1,2-dihydropyridin-2-one

[0344] 1-Cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1,2-dihydropyridin-2-one 18e (0.24 g, 0.57 mmol) and stannous chloride dihydrate (0.64 g, 2.85 mmol) were dissolved in 5.0 mL of ethanol. The mixture was heated to 80 °C and reacted for 3 hours. The pH was adjusted to greater than 7 with sodium hydroxide aqueous solution to remove the solvent. The solution was purified by rapid silica gel column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropyl-3-methyl-1,2-dihydropyridin-2-one 18f (0.13 g, yellow solid), yield 69.9%. MS m / z (ESI): 325.05 [M+1] + .

[0345] Step 6

[0346] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridine-3-l)oxy)phenyl)hydrazone)acetyl)carbamate

[0347] Dissolve 0.13 g (0.40 mmol) of 5-(4-amino-2,6-dichlorophenoxy)-1-cyclopropyl-3-methyl-1,2-dihydropyridin-2-one 18f in 4 mL of acetic acid and 1.0 mL of water. Cool to 0 °C, then add 0.5 mL of concentrated hydrochloric acid. Slowly add 1 mL of sodium nitrite (0.03 g, 0.48 mmol) aqueous solution. After the addition is complete, stir for ten minutes, then add sodium acetate (0.03 g, 0.40 mmol). ), N-cyanoacetylurane (0.06 g, 0.40 mmol), were reacted at room temperature for 12 hours after removing the ice bath. 10 mL of water was added, the solid was filtered, and dried to give 18 g (0.06 g, yellow solid) of ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridine-3-l)oxy)phenyl)hydrazone)acetyl)carbamate, yield: 22.6%. The crude product was used directly in the next step. MS m / z (ESI): 492.00 [M+1] + .

[0348] Step 7

[0349] 2-(3,5-dichloro-4-[(1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0350] 18 g (0.06 g, 0.09 mmol) of crude ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridin-3-l)oxy)phenyl)hydrazone)acetyl)carbamate was dissolved in N,N-dimethylacetamide (5.0 mL) and potassium acetate (0.01 g, 0.12 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. After removing the solvent, the product was purified by preparative HPLC to give 18 g (30.0 mg, white solid) of 2-(3,5-dichloro-4-[(1-cyclopropyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate, in 74.3% yield. MS m / z (ESI): 446.00 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.28(s,1H),7.78(s,2H),7.24(d,J=2.0Hz,1H),7.09(d,J =3.2Hz,1H),3.34–3.28(m,1H),2.01(s,3H),0.99-0.94(m,2H),0.80-0.75(m,2H).

[0351] Example 19

[0352] 2-(3,5-dichloro-4-((5-cyclopropyl-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0353]

[0354] first step

[0355] 3-Cyclopropyl-5-(2,6-Dichloro-4-nitrophenoxy)-1-ethyl-1,2-dihydropyridin-2-one

[0356] 5-(2,6-dichloro-4-nitrophenoxy)-3-iodo-1-(propyl-2-yl)-1,2-dihydropyridin-2-one 19a (200.0 mg, 0.39 mmol) was dissolved in 5.0 mL of 1,4-dioxane, followed by the addition of cyclopropylboronic acid (100.5 mg, 1.17 mmol), tripotassium phosphate (248.3 mg, 1.17 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (28.5 mg, 0.04 mmol). The mixture was heated to 100 °C for 8 hours under nitrogen protection. After removing the solvent, the mixture was purified by rapid silica gel column chromatography to give 3-cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)-1-ethyl-1,2-dihydropyridin-2-one 19b (150.0 mg, yellow solid), with a yield of 93.7%. MS m / z (ESI): 383.00 [M+1] + .

[0357] Step 2

[0358] 5-(4-amino-2,6-dichlorophenoxy)-3-cyclopropyl-1-(propyl-2-yl)-1,2-dihydropyridin-2-one

[0359] 3-Cyclopropyl-5-(2,6-dichloro-4-nitrophenoxy)-1-ethyl-1,2-dihydropyridin-2-one 19b (150.0 mg, 0.35 mmol) and stannous dichloride dihydrate (394.8 mg, 1.75 mmol) were dissolved in 10.0 mL of ethanol. The mixture was heated to 80 °C and reacted for 3 hours. The pH was adjusted to greater than 7 with aqueous sodium hydroxide solution to remove the solvent. The solution was purified by rapid silica gel column chromatography to give 5-(4-amino-2,6-dichlorophenoxy)-3-cyclopropyl-1-(propyl-2-yl)-1,2-dihydropyridin-2-one 19c (122.0 mg, yellow solid), yield 89.8%. MS m / z (ESI): 353.10 [M+1] + .

[0360] Step 3

[0361] N-[(Z)-cyano(2-(3,5-dichloro-4-[(5-cyclopropyl-6-oxo-1-(propyl-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)hydrazine-1-ylide)carbonyl]carbamate]ethyl carbamate

[0362] Dissolve 19c (122.0 mg, 0.31 mmol) of 5-(4-amino-2,6-dichlorophenoxy)-3-cyclopropyl-1-(propyl-2-yl)-1,2-dihydropyridin-2-one in 4.0 mL of acetic acid and 1.0 mL of water. Cool to 0°C, then add 0.5 mL of concentrated hydrochloric acid. Slowly add 4.0 mL of sodium nitrite (0.03 g, 0.48 mmol) aqueous solution. After the addition is complete, stir for ten minutes. Then add sodium acetate (23.5 mg, 0.34 mmol). l) N-cyanoacetylurane (96.8 mg, 0.62 mmol), removed from the ice bath and reacted at room temperature for 12 hours. 10 mL of water was added, the solid was filtered, and dried to give N-[(Z)-cyano(2-(3,5-dichloro-4-[(5-cyclopropyl-6-oxo-1-(propyl-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)hydrazine-1-ylidene)carbonyl]carbamate 19d (300.0 mg, yellow solid). The crude product was used directly in the next step. MS m / z (ESI): 520.05 [M+1] + .

[0363] Step 4

[0364] 2-(3,5-Dichloro-4-[(5-cyclopropyl-6-oxo-1-(prop-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0365] Crude N-[(Z)-cyano(2-(3,5-dichloro-4-[(5-cyclopropyl-6-oxo-1-(prop-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)hydrazine-1-yl)carbonyl]carbamate 19d (140.0 mg, 0.25 mmol) was dissolved in N,N-dimethylacetamide (5.0 mL) and potassium acetate (73.6 mg, 0.75 mmol) was added. The mixture was then reacted at 120 °C for 3 hours. After solvent removal, HPLC purification yielded 2-(3,5-dichloro-4-[(5-cyclopropyl-6-oxo-1-(prop-2-yl)-1,6-dihydropyridin-3-yl)oxy]phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 19 (19.0 mg, white solid), in 15.8% yield. MS m / z (ESI): 474.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),7.85(s,2H),7.21(d,J=3.2Hz,1H),6.93(d,J=2.8Hz,1H),5 .18-5.11(m,1H),2.18-2.10(m,1H),1.31(d,J=6.8Hz,6H),0.97-0.92(m,2H),0.77-0.73(m,2H).

[0366] Example 20

[0367] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0368]

[0369] first step

[0370] 5-(2,6-Dichloro-4-nitrophenoxy)-1-phenylpyridine-2(1H)-one

[0371] 5-(4-nitro-2,6-dichlorophenoxy)-2-carbonylpyridine 1c (2.00 g, 6.22 mmol) was dissolved in 200 mL of anhydrous dichloromethane, followed by the sequential addition of phenylboronic acid (2.28 g, 18.66 mmol), triethylamine (3.46 mL, 34.88 mmol), and copper acetate (0.77 g, 6.22 mmol). The reaction mixture was then reacted at 20 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified by rapid column chromatography (PE:EA = 1:2) to give 5-(2,6-dichloro-4-nitrophenoxy)-1-phenylpyridine-2(1H)-one 20a (2.30 g, yellow solid), yield: 83.6%. MS m / z (ESI): 377.00 [M+1] + .

[0372] Step 2

[0373] 5-(2,6-Dichloro-4-aminophenoxy)-1-phenylpyridine-2(1H)-one

[0374] 5-(2,6-dichloro-4-nitrophenoxy)-1-phenylpyridin-2(1H)-one 20a (2.30 g, 5.20 mmol) was dissolved in 30 mL of methanol, followed by the addition of iron powder (1.16 g, 20.80 mmol) and ammonium chloride (0.56 g, 10.40 mmol) dissolved in 1.5 mL of aqueous solution. The mixture was then reacted at 85 °C for 4 hours. The reaction solution was concentrated, and then 20 mL of water and 35 mL of ethyl acetate were added. The mixture was extracted three times, dried over anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness to give 5-(2,6-dichloro-4-aminophenoxy)-1-phenylpyridin-2(1H)-one 20b (2.10 g, brown solid), yield 95.7%. MS m / z (ESI): 347.00 [M+1] + .

[0375] Step 3

[0376] Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate

[0377] Compound 5-(2,6-dichloro-4-aminophenoxy)-1-phenylpyridin-2(1H)-one 20b (2.00 g, 4.74 mmol) was dissolved in 30 mL of (6N) hydrochloric acid aqueous solution, cooled to 0 °C, and then sodium nitrite (0.49 g, 7.11 mmol) dissolved in 1 mL of aqueous solution was slowly added dropwise. The reaction mixture was then stirred for 15 minutes. Next, N-cyanoaceturane (1.11 g, 7.11 mmol) was dissolved in 20 mL of water, cooled to 0 °C, and then 32 mL of pyridine was added. The mixture was stirred at 0 °C for 10 minutes. The subsequent reaction mixture was then slowly added dropwise to the previous reaction mixture, and the reaction was carried out at 0 °C for 30 minutes. Adding 20 mL of water to the reaction solution resulted in the precipitation of a large amount of solid. The mixture was then filtered, and the filter cake was dissolved in anhydrous ethanol and concentrated. This process was repeated 2-3 times to obtain crude ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate 20c (2.65 g, red solid). This crude product was used directly in the next step. MS m / z (ESI): 514.05 [M+1] + .

[0378] Step 4

[0379] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0380] Dissolve 20c (2.65g, 4.59mmol) of (ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)hydrazine)acetylcarbamate in 30mL In N,N-dimethylacetamide, sodium acetate (1.13 g, 13.77 mmol) was added, followed by raising the temperature to 120 °C and reacting at this temperature for 4 hours. 20 mL of water was added to the reaction mixture, 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 and purified by rapid silica gel column chromatography to obtain the crude product. 450 mg of the crude product was subjected to Prep-HPLC to prepare 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 20 (290.0 mg, white solid), yield 66.4%. MS m / z (ESI): 467.95 [M+1] + . 1HNMR (400MHz, DMSO-d6) δ7.76(s,2H),7.58–7.47(m,3H),7.46–7.41(m,2H),7.37-7.33(m,2H),6.55(d,J=10.0Hz,1H).

[0381] Example 21

[0382] 2-(3,5-dichloro-4-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0383]

[0384] Using the method of Example 20, but replacing phenylboronic acid with p-fluorophenylboronic acid, the title product 2-(3,5-dichloro-4-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 21 (273.0 mg, white solid) was prepared in 64.8% yield. MS m / z (ESI): 485.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 7.75 (s, 2H), 7.53 (dd, J = 10.0Hz, 3.2Hz, 1H), 7.47(d,J=2.8Hz,1H),7.44–7.38(m,2H),7.36–7.27(m,2H),6.54(d,J=10.0Hz,1H).

[0385] Example 22

[0386] 2-(3,5-dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0387]

[0388] Using the method of Example 20, phenylboronic acid was replaced with m-fluorophenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 22 (30 mg, pale yellow solid, yield 34.18%). MS m / z (ESI): 485.95 [M+1] +. 1 HNMR (400MHz, DMSO-d6) δ7.75(s,2H),7.62-7.58(m,1H),7.47(d,J=2.8Hz,3H),7.35–7.20(m,3H),6.55(d,J=8.0Hz,1H).

[0389] Example 23

[0390] 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0391]

[0392] Using the method of Example 20, phenylboronic acid was replaced with m-trifluoromethylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 23 (17.0 mg, white solid, yield: 99.8%). MS m / z (ESI): 536.01 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),7.81(s,2H),7.78-7.72(m,3H),7.70-7.65( m,1H),7.62(d,J=4.0Hz,1H),7.55(dd,J=4.0,4.0Hz,1H),6.57(d,J=12.0Hz,1H).

[0393] Example 24

[0394] 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethoxy)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0395]

[0396] Using the method of Example 20, phenylboronic acid was replaced with m-trifluoromethoxyphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethoxy)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 24 (40.0 mg, white solid, yield: 90.1%). MS m / z (ESI): 551.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),7.76(s,2H),7.63(t,J=8.0Hz,1H),7.56-7.40(m,5H),6.56(d,J=8.0Hz,1H).

[0397] Example 25

[0398] 2-(3,5-dichloro-4-((6-oxo-1-(4-methylphenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0399]

[0400] Using the method of Example 20, phenylboronic acid was replaced with p-methylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(4-methylphenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 25 (50.0 mg, pale yellow solid, yield 38.02%). MS m / z (ESI): 482.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),7.75(s,2H),7.50(dd,J=10.0,3.2Hz,1H) ,7.36(d,J=3.2Hz,1H),7.30-7.19(m,4H),6.52(d,J=10.0Hz,1H),2.33(s,3H).

[0401] Example 26

[0402] 2-(3,5-dichloro-4-((6-oxo-1-(3-methylphenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0403]

[0404] Using the method of Example 20, phenylboronic acid was replaced with m-methylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(3-methylphenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 26 (280.00 mg, white solid, yield: 22.86%). MS m / z (ESI): 482.28 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.76(s,2H),7.51(dd,J=10.0,3.2Hz,1H),7.40(d,J=3.2Hz,1H),7.36(d,J=8.0 Hz,1H),7.24(d,J=8.0Hz,1H),7.18(s,1H),7.13(d,J=8.0Hz,1H),6.53(d,J=10.0Hz,1H),2.34(s,3H).

[0405] Example 27

[0406] 2-(3,5-dichloro-4-((6-oxo-1-(o-tolyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-1,2,3,4-4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0407]

[0408] Using the method of Example 20, phenylboronic acid was replaced with o-methylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(o-tolyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-1,2,3,4-4,5-tetrahydro-1,2,4-triazine-6-onitrile 27 (61.1 mg, white solid, yield: 40.45%). MS m / z (ESI): 482.28 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),7.74(s,2H),7.58(dd,J=10.0,4.0Hz,1H),7.35(d,J =4.0Hz,2H),7.33–7.26(m,2H),7.19(d,J=8.0Hz,1H),6.56(d,J=10.0Hz,1H),2.03(s,3H).

[0409] Example 28

[0410] 2-(3,5-dichloro-4-((1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-1,2,3,4-4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0411]

[0412] Using the method of Example 20, phenylboronic acid was replaced with m-cyanobenonic acid to prepare the title product 2-(3,5-dichloro-4-((1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-1,2,3,4-4,5-tetrahydro-1,2,4-triazine-6-onitrile 28 (125.1 mg, white solid, yield: 78.61%). MS m / z (ESI): 493.26 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),7.96(s,1H),7.91(d,J=7.2Hz,1H),7.76(s,2H),7.74–7.66(m,2H),7.62–7.51(m,2H),6.58(d,J=10.0Hz,1H).

[0413] Example 29

[0414] 2-(3,5-dichloro-4-((1-(3,5-difluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0415]

[0416] Using the method of Example 20, phenylboronic acid was replaced with 3,5-difluorophenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((1-(3,5-difluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 29 (50.0 mg, white solid, yield: 98.84%). MS m / z (ESI): 504.23 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),7.76(s,2H),7.58-7.50(m,2H),7.41-7.33(m,1H),7.30-7.23(m,2H),6.60-6.51(m,1H).

[0417] Example 30

[0418] 2-(3,5-dichloro-4-((1-(3,5-dimethylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2-,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0419]

[0420] Using the method of Example 20, phenylboronic acid was replaced with 3,5-dimethylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((1-(3,5-dimethylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2-,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 30 (262.1 mg, white solid, yield: 24.68%). MS m / z (ESI): 496.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.25 (s, 1H), 7.76 (s, 2H), 7.49 (dd, J = 10.0, 4.0Hz, 1H), 7. 36(d,J=4.0Hz,1H),7.06(s,1H),6.95(s,2H),6.51(d,J=10.0Hz,1H),2.30(s,6H).

[0421] Example 31

[0422] 2-(3,5-dichloro-4-((1-(3-cyclopropylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0423]

[0424] Using the method of Example 20, phenylboronic acid was replaced with 3-cyclopropylphenylboronic acid to prepare the title product 2-(3,5-dichloro-4-((1-(3-cyclopropylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 31 (50.0 mg, white solid, yield: 97.47%). MS m / z (ESI): 508.05 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.24(s,1H),7.75(s,2H),7.52-7.47(m,1H),7.45-7.40(m,1H),7.38-7.31( m,1H),7.19-7.02(m,3H),6.61-6.47(m,1H),2.02-1.91(m,1H),1.01-0.93(m,2H),0.75-0.67(m,2H).

[0425] Example 32

[0426] 2-(3,5-dichloro-4-((6-oxo-1-(thiophen-3-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0427]

[0428] Using the method of Example 20, phenylboronic acid was replaced with 3-thiopheneboronic acid to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(thiophen-3-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate KPC00134 (50.0 mg, white solid, yield: 97.83%). MS m / z (ESI): 473.98 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.23 (s, 1H), 7.85-7.70 (m, 3H), 7.65-7.57 (m, 1H), 7.54-7.43 (m, 2H), 7.27 (d, J = 4.0Hz, 2H), 6.54 (d, J = 12.0Hz 1H).

[0429] Example 33

[0430] 2-(3,5-dichloro-4-((6-oxo-1-(thiophen-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0431]

[0432] Using the method of Example 1, iodoisopropane was replaced with 2-bromothiophene to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(thien-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 33 (130.0 mg, white solid, yield 19.71%). MS m / z (ESI): 473.90 [M+1] + .

[0433] Example 34

[0434] 2-(3,5-dichloro-4-((6-oxo-1-(thiazo-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate)

[0435]

[0436] Using the method of Example 1, iodoisopropane was replaced with 2-bromothiazole to prepare the title product 2-(3,5-dichloro-4-((6-oxo-1-(thiazol-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 34 (13.0 mg, white solid, yield 22.48%). MS m / z (ESI): 474.90 [M+1] + . 1 HNMR(400MHz,DMSO-d6),8.13(d,J=3.2Hz,1H),7.88(s,2H),7.84(dd,J=10.0,4 .0Hz,1H),7.74(d,J=4.0Hz,1H),7.62(d,J=4.0Hz,1H),6.91(d,J=10.0Hz,1H).

[0437] Examples 35 / 36

[0438] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0439] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione

[0440]

[0441] first step

[0442] Methyl 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridinyl-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester

[0443] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile 20 (1.50 g, 1.60 mmol) was dissolved in 15 mL of anhydrous methanol, and then thionyl chloride (2.50 mL, 34.46 mmol) was slowly added dropwise at room temperature, and the reaction was carried out at 100 °C for 4 hours. After cooling to room temperature and concentrating the solvent, the reaction solution was extracted three times with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE:EA = 0-100%) with silica gel as a stirrer to give methyl 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridinyl-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 35a (1.45 g, red solid). Yield: 66.62%. MS m / z (ESI): 501.00 [M+1] + .

[0444] Step 2

[0445] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0446] Methyl 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridinyl-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester 35a (1.45 g, 1.93 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran. Triethylamine (0.20 g, 1.93 mmol) was then added at 20 °C and stirred for 10 minutes. Sodium borohydride (0.07 g, 1.93 mmol) was then added, followed by the slow addition of 5.0 mL of anhydrous methanol. After the addition was complete, the reaction was carried out at 20 °C for 20 minutes. The reaction was quenched with water, the solvent was evaporated, and the reaction mixture was extracted three times with water and ethyl acetate. The solution was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE:EA = 0-100%) with silica gel as a binder to give 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 35b (0.83 g, red solid). Yield: 74.83%. MS m / z (ESI): 472.95 [M+1]+.

[0447] Step 3

[0448] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0449] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione

[0450] 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione 35b (680 mg, 1.18 mmol) was added to 10 mL of dichloromethane, followed by slow dropwise addition of DAST (380.4 mg, 2.36 mmol). After the addition was complete, the mixture was reacted at 20°C for 10 minutes. The reaction was quenched with water, followed by three extractions. The product was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness before being subjected to Prep-HPLC (column type: Welch Ultimate XB-C18, 21.2*250mm, 10µm; mobile phase: A: 0.05% TFA aqueous solution, B: acetonitrile) to prepare 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione (142.4 mg, white solid) 35 (142.4 mg, white solid, yield: 25.19%). MS m / z (ESI): 474.95 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.66(s,1H),7.81(s,2H),7.55–7.46(m,3H),7.45–7 .40(m,1H),7.39–7.33(m,3H),6.54(d,J=10.0Hz,1H),5.28(d,J=46.8Hz,2H).

[0451] We also obtained 2-(3,5-dichloro-4-((6-oxo-1-phenyl-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione 36 (26.8 mg, white solid). MS m / z (ESI): 457.27 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ7.80 (s, 2H), 7.62–7.23 (m, 7H), 6.54 (d, J = 10.0Hz, 1H), 2.15 (s, 3H).

[0452] Example 37

[0453] 2-(3,5-Dichloro-4-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0454]

[0455] Using the method of Example 35, starting with 21, the title product 2-(3,5-dichloro-4-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 37 (164.0 mg, white solid, yield: 34.82%) was prepared. MS m / z (ESI): 493.25 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),7.80(s,2H),7.51(dd,J=10.0,4.0Hz,1H),7. 46–7.38(m,3H),7.36–7.26(m,2H),6.54(d,J=10.0Hz,1H),5.28(d,J=46.8Hz,2H).

[0456] Example 38

[0457] 2-(3,5-Dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0458]

[0459] Using the method of Example 35, starting with 22, the title product 2-(3,5-dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 38 (20.0 mg, white solid, yield 26.6%) was prepared. MS m / z (ESI): 493.05 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.67(s,1H),7.80(s,2H),7.68-7.45(m,3H),7.36-7 .28(m,2H),7.25-7.19(m,1H),6.55(d,J=8.0Hz,1H),5.26(d,J=48.0Hz,2H).

[0460] Example 39

[0461] 2-(3,5-Dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0462]

[0463] Using the method of Example 35, starting with 23, the title product 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 39 (4.0 mg, white solid, yield: 96.6%) was prepared. MS m / z (ESI): 543.02 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.72(s,1H),7.89-7.79(m,4H),7.77-7.71(m,1H),7.70-7.66(m,1H),7 .59(d,J=4.0Hz,1H), 7.52(dd,J=4.0,4.0Hz,1H), 6.56(d,J=12.0Hz,1H), 5.28(d,J=48.0Hz,2H).

[0464] Example 40

[0465] 2-(3,5-Dichloro-4-((6-oxo-1-(3-(trifluoromethoxy)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0466]

[0467] Using the method of Example 35, starting with 24, the title product 2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethoxy)phenyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 40 (8.0 mg, white solid, yield: 50.6%) was obtained. MS m / z (ESI): 559.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 2H), 7.52-7.47 (m, 1H), 7.45-7.36 (m, 5H), 6.55 (d, J = 8.8Hz, 1H), 5.27 (d, J = 48.0Hz, 2H).

[0468] Example 41

[0469] 2-(3,5-Dichloro-4-((6-oxo-1-(p-tolyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0470]

[0471] Using the method of Example 35, starting with 25, the title product 2-(3,5-dichloro-4-((6-oxo-1-(p-tolyl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 41 (8.5 mg, pale yellow solid, yield 3.0%) was prepared. MS m / z (ESI): 489.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 2H), 7.51-7.45 (m, 1H), 7.41-7.17 (m, 5H), 6.53 (d, J = 8.0Hz, 1H), 5.27 (d, J = 48.0Hz, 2H), 2.34 (s, 3H).

[0472] Example 42

[0473] 2-(3,5-Dichloro-4-((1-(3,5-dimethylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0474]

[0475] Using the method of Example 35, starting with 30, the title product 2-(3,5-dichloro-4-((1-(3,5-dimethylphenyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 42 (280.00 mg, white solid, yield: 44.9%) was prepared. MS m / z (ESI): 503.31 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),7.81(s,2H),7.47(dd,J=10.0,3.6Hz,1H),7.32(d,J=3.6 Hz,1H),7.06(s,1H),6.95(s,2H),6.52(d,J=10.0Hz,1H),5.29(d,J=46.8Hz,2H),2.30(s,6H).

[0476] Example 43

[0477] 2-(3,5-Dichloro-4-((6-oxo-1-(thiophen-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0478]

[0479] Using the method of Example 35, starting with 33, the title product 2-(3,5-dichloro-4-((6-oxo-1-(thiophen-2-yl)-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 43 (1.98 mg, white solid, yield 3.9%) was prepared. MS m / z (ESI): 480.95 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.69 (s, 1H), 7.93 (d, J = 4.0Hz, 1H), 7.83 (s, 2H), 7. 49-7.35(m,3H),7.03(s,1H),6.64(d,J=12.0Hz,1H),5.29(d,J=36.0Hz,2H).

[0480] Example 44

[0481] 2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0482]

[0483] Using the method of Example 35, starting from product 1, the title product 2-(3,5-dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 44 (150.0 mg, white solid, yield 35.0%) was prepared. MS m / z (ESI): 441.00 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.68 (s, 1H), 8.10 (s, 2H), 7.51 (d, J = 4.0Hz, 1H), 7.24-7.17 (m, 1H), 6.41-6.32 (m, 1H), 5.99 (d, J = 40.0Hz, 2H), 5.04-4.98 (m, 1H), 1.25 (d, J = 4.0Hz, 6H).

[0484] Example 45

[0485] 2-(3,5-Dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0486]

[0487] Using the method of Example 35, starting with 8, the title product 2-(3,5-dichloro-4-((1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione 45 (114.0 mg, white solid, yield 46.0%) was prepared. MS m / z (ESI): 467.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),7.82(s,2H),7.42-7.40(m,1H),7.30(s,1H),6.43(d,J= 8.0Hz, 1H), 5.29 (d, J = 44.0Hz, 2H), 4.00 (t, J = 8.0Hz, 2H), 3.49 (t, J = 8.0Hz, 2H), 3.19 (s, 3H).

[0488] Example 46

[0489] 2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0490]

[0491] first step

[0492] 3-Bromo-2-(3-Buten-1-yl)-6-methoxypyridine

[0493] 3-Bromo-6-methoxy-2-methylpyridine 46a (5.0 g, 24.75 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) under nitrogen protection. Diisopropylaminolithium (27.23 mL, 54.45 mmol) was added dropwise at -78 °C. After reacting at -50 °C for 40 min, 3-bromopropene (6.587 g, 54.45 mmol) was added. The reaction was continued at -50 °C for 30 min, then allowed to rise naturally to room temperature for 16 h. The reaction was quenched with 3 mL of saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 3-bromo-2-(3-buten-1-yl)-6-methoxypyridine 46b (3.79 g, colorless oil), yield: 53.43%. MS m / z (ESI): 242.01 [M+1] + .

[0494] Step 2

[0495] 5-Bromo-6-(3-iodobutyl)pyridine-2(1H)-one

[0496] 3-Bromo-2-(3-buten-1-yl)-6-methoxypyridine 46b (2.38 g, 9.83 mmol) was dissolved in hydroiodic acid (20.0 mL) and reacted at 65 °C for 2 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The extract was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-bromo-6-(3-iodobutyl)pyridine-2(1H)-one 46c (3.33 g, black oil). Yield: 95.14%. MS m / z (ESI): 355.91 [M+1] + .

[0497] Step 3

[0498] 8-Bromo-3-methyl-2,3-dihydroindole-5(1H)-one

[0499] 5-Bromo-6-(3-iodobutyl)pyridin-2(1H)-one 46c (3.33 g, 9.35 mmol) was dissolved in 60.0 mL of ethanol, and potassium hydroxide (1.57 g, 28.05 mmol) was added. The mixture was reacted at 25 °C for 30 min, the solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography to give 8-bromo-3-methyl-2,3-dihydroindole-5(1H)-one 46d (1.40 g, white solid), yield: 65.65%. MS m / z (ESI): 227.99 [M+1] + .

[0500] Step 4

[0501] 3-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)-2,3-dihydroindole-5(1H)-one

[0502] Dihydroindole-5(1H)-one 46d (1.18 g, 5.17 mmol) was dissolved in 1,4-dioxane (24.0 mL), and pinacol borate (2.63 g, 10.34 mmol), potassium acetate (1.01 g, 10.34 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (378.0 mg, 0.52 mmol) were added. The mixture was purged with nitrogen three times and refluxed for 16 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography to give 3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)-2,3-dihydroindole-5(1H)-one 46e (550.0 mg, white solid). Yield: 38.6%. MS m / z (ESI): 276.17 [M+1] + .

[0503] Step 5

[0504] 8-Hydroxy-3-methyl-2,3-dihydroindole-5(1H)-one

[0505] 3-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)-2,3-dihydroindole-5(1H)-one 46e (550.0 mg, 2.0 mmol) was dissolved in a mixture of 12.0 mL tetrahydrofuran and 2.0 mL water. 30% hydrogen peroxide (680.0 mg, 6.0 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. Ethyl acetate (30 mL) was added, and the mixture was dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and purified by column chromatography to give 8-hydroxy-3-methyl-2,3-dihydroindole-5(1H)-one 46f (280.0 mg, white solid). Yield: 84.75%. MS m / z (ESI): 166.08 [M+1] + .

[0506] Step 6

[0507] 8-(2,6-Dichloro-4-nitrophenoxy)-3-methyl-2,3-dihydroindole-5(1H)-one

[0508] 46 f (92.5 mg, 0.56 mmol) of 8-hydroxy-3-methyl-2,3-dihydroindole-5(1H)-one was dissolved in 2.0 mL of N,N-dimethylformamide, and 1,3-dichloro-2-fluoro-5-nitrobenzene (117.6 mg, 0.56 mmol) and potassium carbonate (232.2 mg, 1.68 mmol) were added. The mixture was reacted at 25 °C for 2 hours. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography to give 46 g (100.0 mg, white solid) of 8-(2,6-dichloro-4-nitrophenoxy)-3-methyl-2,3-dihydroindole-5(1H)-one. Yield: 50.28%. MS m / z (ESI): 355.02 [M+1] + .

[0509] Step 7

[0510] 46 g (480 mg, 1.35 mmol) of 8-(2,6-dichloro-4-nitrophenoxy)-3-methyl-2,3-dihydroindole-5(1H)-one was dissolved in a mixture of 10 mL ethanol and 10 mL saturated ammonium chloride. Reduced iron powder (377 mg, 6.75 mmol) was added, and the mixture was refluxed for 2 hours. The mixture was filtered, concentrated to remove ethanol, extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 46 h (220.0 mg, colorless oil) of 8-(4-amino-2,6-dichlorophenoxy)-3-methyl-2,3-dihydroindole-5(1H)-one (yield: 50.0%). MS m / z (ESI): 325.04 [M+1] + .

[0511] Step 8

[0512] (E)-Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)hydrazone)acetyl)carbamate

[0513] 8-(4-amino-2,6-dichlorophenoxy)-3-methyl-2,3-dihydroindole-5(1H)-one (150.0 mg, 0.46 mmol) was dissolved in a mixed solvent consisting of 3.2 mL acetic acid, 0.8 mL water, and 0.4 mL concentrated hydrochloric acid. Sodium nitrite (33.3 mg, 0.48 mmol) was added at 0 °C, and after reacting for 10 minutes, sodium acetate (113.2 mg, 1.38 mmol) was added. After reacting for another 10 minutes, N-cyanoaceturane (143.6 mg, 0.92 mmol) was added, and the mixture was reacted at room temperature for 72 hours. After adding 5 mL of water, the mixture was filtered and dried to obtain crude (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)hydrazone)acetyl)carbamate 46i (180.0 mg, yellow solid). Yield: 79.5%. MS m / z (ESI): 492.08 [M+1] + .

[0514] Step 9

[0515] 2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate

[0516] (E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)hydrazone)acetyl)carbamate 46i (180.0 mg, 0.37 mmol) was dissolved in 3.0 mL of N,N-dimethylacetamide, and potassium acetate (108.9 mg, 1.11 mmol) was added. The mixture was reacted at 120 °C for 2 hours, and the solvent was removed by concentration under reduced pressure. Preparative chromatographic purification yielded 2-(3,5-dichloro-4-((3-methyl-5-oxo-1,2,3,5-tetrahydroindole-8-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbamate 46 (60.0 mg, white solid). Yield: 35.3%. MSm / z (ESI): 446.03 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 7.77 (s, 2H), 7.02 (d, J = 12.0Hz, 1H), 6.13 (d, J = 8.0Hz, 1H), 4.72-4.68(m,1H),3.26-3.11(m,2H),2.37-2.32(m,1H),1.91-1.88(m,1H),1.32(d,J=8.0Hz,2H).

[0517] Example 47: THRβ Binding Experiment

[0518] Experimental Methods: In vitro analysis of the agonistic effect of the compounds on THRβ was performed using a time-resolved fluorescence resonance energy transfer (FRET) coactivator recruitment assay. This assay employed a biotin-SRC2-2 coactivator, streptavidin-d2, RXRα, and a GST-tagged THRβ-LBD Eu-anti-GST antibody. The Eu-anti-GST antibody indirectly labeled THRβ-LBD by binding to a GST tag. Streptavidin-d2 indirectly labeled the SRC2-2 coactivator by binding to a biotin tag. In the presence of RXRα, THRβ-LBD could form a heterodimer, THRβ-LBD / RXRα. The agonist bound to THRβ-LBD / RXRα, causing a conformational change in THRβ-LBD, thereby increasing the recruitment capacity of the heterodimer for the SRC2-2 coactivator. Simultaneously, the resulting decrease in the distance between the d2-labeled SRC2-2 coactivator and the Eu-anti-GST antibody increased the THR-FRET signal. The agonistic ability of compounds can be evaluated by considering the effect of different concentrations of the compound on THRβ activity.

[0519] The detailed procedure is as follows:

[0520] a. Prepare a 100X reference compound or compound using DMSO and dilute it 1:3.

[0521] b. Dilute the reference compound or compound to 4X using 1X reaction buffer at a gradient of 100X and add to the experimental plate.

[0522] c. Prepare a mixed solution of 4X THRβ-LBD and 4X RXRα using 1X reaction buffer and add it to the experimental plate.

[0523] 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.

[0524] Centrifuge at 1000 rpm for 1 min and incubate at room temperature and in the dark for 4 hours.

[0525] f. Read the fluorescence signal values ​​at 665nm and 615nm on the EnVision 2104 board reader and calculate the Ratio. 665nm / 615nm .

[0526] Experimental results: See Table 1

[0527] Table 1: Experimental Results of THRβ Binding

[0528]

[0529]

[0530] *Control compound 1 is T3; control compound 2 is WO2007009913 Example 8 (compound 31), NA is not detected.

[0531] Example 48: THRα Binding Experiment

[0532] Experimental method: The in vitro analysis of the agonistic effect of the compound on THRα was performed using a similar method to the THRβ binding experiment in Example 49, except that THRα was used instead of THRβ.

[0533] Experimental results: See Table 2

[0534] Table 2: Experimental Results of THRα Binding

[0535]

[0536]

[0537] *Control compound 1 is T3; control compound 2 is WO2007009913. Example 8 (compound 31).

[0538] Conclusion: Compared with the disclosed control compound 2, some compounds of the present invention unexpectedly showed high THRβ activity, and some compounds showed higher selectivity for THRβ than control compound 2.

[0539] Example 49 In vitro liver microsomal stability experiment

[0540] Experimental methods:

[0541] (I) Solution Preparation

[0542] The test substance and the positive control verapamil were dissolved in DMSO to a concentration of 10 mM to prepare stock solutions. The 10 mM stock solutions were then diluted with 70% acetonitrile aqueous solution to a concentration of 0.25 mM.

[0543] An NADPH regeneration system was prepared containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U / mL G-6-PDH, and 3.3 mM magnesium chloride.

[0544] The stop solution was an acetonitrile solution containing tolbutamide and propranolol (both internal standards).

[0545] The phosphate buffer is a 100mM K3PO4 (pH=7.4) buffer containing 3.3mM MgCl2.

[0546] The liver microsome incubation system contained 0.2 mg / mL liver microsome protein and 1 μM test substance / positive control in 100 mM phosphate buffer.

[0547] (II) Incubation Process

[0548] Take 80 μL of the mixture from the incubation system, add 400 μL of stop solution to precipitate the protein, vortex, and then add 20 μL of NADPH regeneration system as the 0 min sample point.

[0549] Add 130 μL of NADPH regeneration system to the remaining 520 μL of protein drug mixture, mix well, and begin incubation. The final incubation volume is 650 μL, containing 0.2 mg / mL liver microsomal protein, 1 μM test substance / positive control, 1.3 mM NADP, 3.3 mM MG-6-P, and 0.6 U / mL G-6-PDH.

[0550] The mixture was incubated with gentle shaking in a 37°C water bath. At 5, 10, 30, and 60 min, 100 μL of the incubation solution was added to each well of a new 96-well plate containing 400 μL of stop solution. The mixture was then mixed and the protein was precipitated (4000 × g, centrifuged at 4°C for 15 min).

[0551] Take 100 μL of the supernatant, dilute it with water at a ratio of 1:2, and then analyze the sample using LC-MS / MS.

[0552] Experimental results: See Table 3.

[0553] Table 3: Results of in vitro liver microsomal stability test

[0554] Example number Liver microsomal stability (species: human): T1 / 2, min 3 62.8 4 110.4 5 2.1 9 7.0 10 >120 11 41.6 12 4.4 14 4.6 15 11.5 16 5.1 17 3.2 20 >120 22 >120 35 >120

[0555] The above experimental results show that most aromatic-substituted pyridone compounds have better liver microsomal stability.

[0556] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A 2-pyridone derivative having the structure shown in Formula I or a pharmaceutically acceptable salt thereof: wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, -CH(CH2CH3)2, phenyl or thiophene; The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and -CH(CH2CH3)2 may optionally be substituted by one or more halogens, deuterium, hydroxyl, oxo or amino groups. said phenyl, thienyl group is optionally substituted by one or more halogen, C 1~6 alkyl, C 1~6 alkoxy, cyano, hydroxy, amino; the above C 1~6 alkyl, C 1~6 alkoxy group is optionally further substituted by 1 to 3 fluorine atoms; R2 is selected from hydrogen; R3 is selected from hydrogen; R4 is independently selected from hydrogen, hydroxyl, or halogen; n is 1, 2, or 3; R5 is selected from methyl or monofluoromethyl; R6 is selected from hydrogen; L is selected from -O-; X is selected from O.

2. The 2-pyridone derivative according to claim 1, characterized in that, R4 is an L-position ortho-difluoro, ortho-dichloro, or ortho-dibromo.

3. 2-pyridinone derivatives characterized in that, It has the structure shown in Equation IIc: Among them, ring A is a tetrahydropyrrole group; The tetrahydropyrrolyl group can optionally be substituted with one or more halogen, C 1~3 alkyl; R5 is selected from cyano.

4. 2-pyridinone derivatives characterized in that, It has the structure shown in Equation IIb: wherein R 1b is selected from phenyl, thienyl or thiazolyl; said phenyl, thienyl, thiazolyl groups are optionally substituted by one or more halogen, C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 alkoxy, cyano, hydroxy, amino; said C 1~6 alkyl, C 1~6 alkoxy, C 3~6 Cycloalkyl groups can optionally be further substituted by 1 to 3 fluorine atoms; R5 is selected from cyano.

5. 2-pyridinone derivatives characterized in that, It has any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The use of the 2-pyridone derivatives according to any one of claims 1 to 5 in the preparation of medicaments for the prevention, treatment and / or relief of diseases caused by thyroid hormone analogue regulation.

7. Use according to claim 6, characterized in that, The diseases regulated by thyroid hormone analogs include one or more of the following: obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, and thyroid cancer.

8. A pharmaceutical preparation comprising a 2-pyridone derivative as described in any one of claims 1 to 5, and a pharmaceutically acceptable excipient.

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