CN113698388A

CN113698388A - 6-oxo-1, 6-dihydropyridine derivatives, preparation method and application thereof in medicines

Info

Publication number: CN113698388A
Application number: CN202110544668.2A
Authority: CN
Inventors: 杨方龙; 郑亮亮; 韩吉慧; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd; Chengdu Suncadia Pharmaceuticals Co Ltd
Priority date: 2020-05-20
Filing date: 2021-05-19
Publication date: 2021-11-26
Anticipated expiration: 2041-05-19
Also published as: CN113698388B

Abstract

The present disclosure relates to 6-oxo-1, 6-dihydropyridine derivatives, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a 6-oxo-1, 6-dihydropyridine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, especially in preparation of drugs for treating and/or preventing diseases modulated by thyroid hormone receptors. Wherein each substituent group in the general formula (I) is defined as the specification.

Description

6-oxo-1, 6-dihydropyridine derivatives, preparation method and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicine, and relates to a 6-oxo-1, 6-dihydropyridine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular to application of the derivative in preparing medicines for treating and/or preventing diseases such as obesity, diabetes, hyperlipidemia, thyroid diseases, nonalcoholic steatohepatitis, nonalcoholic fatty liver diseases and the like.

Background

Thyroid hormones are very important for the normal development of the human body and for maintaining metabolic homeostasis. Thyroid hormone has three major functions: (1) the thyroid hormone has the most obvious effect of promoting growth and development, the effect of promoting growth and development is the largest in the first five months after birth in the period of infants, the thyroid hormone mainly promotes the growth and development of bones, brain and reproductive organs, and the GH of pituitary cannot play a role without the thyroid hormone. (2) Affecting metabolism, thermogenic effect thyroid hormone increases oxygen consumption rate of most tissues and increases thermogenic effect, which may be due to thyroid hormone increasing Na on cell membrane⁺－K⁺The pump is synthesized and can increase its activity, which is an energy consuming process. (3) Thyroid hormone has important function for the activity of some organs, for example, it has important meaning for maintaining excitability of nervous system, and thyroid hormone can directly act on cardiac muscle to promote release of Ca from sarcoplasmic reticulum²⁺The heart muscle contraction force is enhanced, and the heart rate is accelerated.

The native thyroid hormone T3 exerts its physiological effects by binding to the Thyroid Hormone Receptor (THR). Thyroid hormone receptors have two distinct subtypes, THR a and THR β. THR β is distributed mainly in liver, and THR α is distributed mainly in brain and heart tissues. The natural thyroid hormone can act on THR alpha and THR beta at the same time without any selectivity. The native thyroid hormone T3 is capable of significantly reducing cholesterol, Low Density Lipoprotein (LDL), in animal models and humans. However, T3 has a cardiac side effect that is not useful for the treatment of obesity, hypercholesterolemia, and non-alcoholic fatty liver disease.

Studies have shown that the effect of thyroid hormone T3 on the heart, particularly on heart rate, is mediated by THR a. The action of thyroid hormone T3 on the liver, muscle and other tissues is mediated primarily by THR β. Therefore, selective THR β agonists should be useful for the treatment of obesity, hyperlipidemia, thyroid disease, non-alcoholic steatohepatitis without having an effect on heart rate and heart rhythm.

Thyroid hormone analogs that selectively and/or tissue selectively act on the thyroid hormone receptor beta (THR β) have been synthesized which provide adequate reduction in body weight, lipids, cholesterol and lipoproteins, with minimal effect on the normal function of the cardiovascular and hypothalamic/pituitary/thyroid axes. (Johan Malm, J.Med.chem.2003,46, 1580-.

Patents that have disclosed compounds as agonists of THR β include WO2006128055, WO2005051298, WO2007009913, and WO2009037172, among others.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

l is selected from the group consisting of alkylene, O atom, S (O) and S (O)₂(ii) a Wherein said alkylene is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, and heteroarylAmino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R²selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, carboxyl groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R³selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R⁴selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and is

n is 0, 1,2,3 or 4.

wherein:

R¹the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, halogens, alkyls, alkenyls, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R³selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radicalAryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁴selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; and is

n is 0, 1,2,3 or 4.

In some embodiments of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹～R⁴And L is as defined in formula (I).

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is selected from CH₂An O atom and an S atom.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is¹Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogenElement, C_1-6Alkyl radical, C_1-6Alkoxy and C_3-8A cycloalkyl group; preferably, R¹Are identical or different and are each independently halogen or C_1-6An alkyl group.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is²Selected from hydrogen, halogen, cyano, C_1-6Alkyl and C_3-8Cycloalkyl, preferably R²Is cyano.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is³Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_3-8Cycloalkyl and C_6-10An aryl group; preferably, R³Is a hydrogen atom or C_1-6An alkyl group; more preferably, R³Is C_1-6An alkyl group.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is⁴Selected from hydrogen atoms, C_1-6Alkyl and C_6-10An aryl group; wherein said C_1-6Alkyl and C_6-10Aryl is independently selected from halogen and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, cyano, amino, nitro, hydroxy, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl and 3 to 6 membered heterocyclyl; preferably, R⁴Is a hydrogen atom or a phenyl group; wherein said phenyl is optionally selected from halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, cyano, amino, nitro, hydroxy, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl and 3-to 6-membered heterocyclyl.

In some embodiments of the disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is⁴Is a hydrogen atom or C_1-6An alkyl group; preferably, R⁴Is a hydrogen atom.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

R^mis C_1-6An alkyl group;

l is selected from the group consisting of alkylene, O atom, S (O) and S (O)₂(ii) a Wherein said alkylene is optionally substituted with one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted by one substituent;

R⁴selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, arylAnd heteroaryl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and is

n is 0, 1,2,3 or 4.

wherein:

R^mis C_1-6An alkyl group;

R²selected from the group consisting of hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, carboxyl group, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group,Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R³the same or different, each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, halogens, alkyls, alkenyls, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1,2,3 or 4. Another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, of formula (IIA),

wherein

R^m、R¹～R⁴And L is as defined in formula (IA).

Table B typical compounds of general formula (IA) of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a process for preparing a compound of formula (I) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

intramolecular reaction of the compound of the general formula (IA) or a salt thereof to give a compound of the general formula (I),

wherein:

R^mis C_1-6An alkyl group;

L、R¹～R⁴and n is as defined in formula (I).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIA) or a salt thereof undergoes an intramolecular reaction to obtain a compound of the general formula (II),

wherein:

R^mis C_1-6An alkyl group;

l and R¹～R⁴As defined in formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II) and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a compound according to the present disclosure of formula (I), formula (II) and table a or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a THR β agonist.

The present disclosure further relates to the use of a compound of formula (I), formula (II) and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment and/or prevention of a disease modulated by thyroid hormone; preferably for the manufacture of a medicament for the treatment and/or prevention of metabolic disorders modulated by thyroid hormones.

The present disclosure further relates to the use of a compound of formula (I), formula (II) and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of thyroid hormone-mediated obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

The present disclosure also relates to a method of agonizing THR β comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method for treating and/or preventing diseases modulated by thyroid hormones, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II) and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method for treating and/or preventing obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular diseases, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) modulated by thyroid hormone, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), and shown in table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to compounds of general formula (I), general formula (II) and table a according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to compounds of formula (I), formula (II) and table a according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as THR β agonists.

The present disclosure further relates to a compound of general formula (I), general formula (II) and table a according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of diseases modulated by thyroid hormone; preferably as a medicament for the treatment and/or prevention of metabolic disorders modulated by thyroid hormones.

The present disclosure further relates to compounds of general formula (I), general formula (II) and table a according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for the treatment and/or prevention of thyroid hormone-mediated obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickening agent. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3,4,5, 6, 7, and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; indanyl and tetrahydronaphthyl are preferred.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy groups. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂But does not include the ring moiety of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4,5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3,4,5, 6, 7 and 8), of which 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2,3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)_1-10Alkyl or aryl)₃Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylSilicon group, t-butyldiphenylsilicon group, etc.; may be C_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C)_1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" or "oxo" means "═ O".

The term "carbonyl" refers to C ═ O.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, deuterated lithium aluminum hydrides, deuterated iodoethanes, and deuterated iodomethanes, among others. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The present disclosure relates to a method for preparing a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IA) or the salt thereof generates intramolecular reaction under the alkaline condition to obtain the compound of the general formula (I),

wherein:

R^mis C_1-6An alkyl group;

L、R¹～R⁴and n is as defined in formula (I).

Scheme two

The present disclosure relates to a method for preparing a compound represented by the general formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIA) or the salt thereof generates intramolecular reaction under the alkaline condition to obtain the compound of the general formula (II),

wherein:

R^mis C_1-6An alkyl group;

l and R¹～R⁴As defined in formula (II).

In the above schemes one and two, the reagent providing basic conditions comprises organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium acetate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium N-butoxide, and inorganic bases including but not limited to sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide and hydrates thereof; preferably sodium acetate;

the reactions of scheme one and scheme two above are preferably carried out in solvents including, but not limited to: acetic acid, glacial acetic acid, methanol, ethanol, N-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, ethylene glycol dimethyl ether, water or N, N-dimethylformamide and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS).NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).

Waters ACQuity UPLC-QD/SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector)

THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO QOxctive)

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260 DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

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

First step of

3- (prop-1-en-2-yl) pyridin-2 (1H) -one 1c

3-bromopyridin-2 (1H) -one 1a (1.40g, 8.04mmol, Shaoshima chemical technology (Shanghai) Co., Ltd.), isopropenylboronic acid pinacol ester 1b (1.62g, 9.64mmol, Shaoshima chemical technology (Shanghai) Co., Ltd.) were dissolved in N, N-dimethylformamide (20mL) and water (5mL), potassium phosphate (3.42g, 16.11mmol), tetratriphenylphosphine palladium (465mg, 0.40mmol) were added, and stirring was carried out at 95 ℃ for 3 hours. Filtration and concentration under reduced pressure were carried out to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (530mg, yield: 48.7%).

MS m/z(ESI):136.1[M+1]。

¹H NMR(400MHz,CDCl₃):7.58(dd,1H),7.53(dd,1H),6.49(t,1H),5.66(s,1H),5.29(s,1H),2.13(s,3H)。

Second step of

3-isopropylpyridin-2 (1H) -one 1d

Compound 1c (520mg, 3.84mmol) was dissolved in methanol (20mL), 10% palladium on carbon hydrogenation catalyst (dry) (41mg, 0.39mmol) was added, hydrogen was replaced twice, and the reaction was stirred for 2 hours. Filtration and concentration under reduced pressure gave the title compound 1d (520mg, yield: 98.5%).

MS m/z(ESI):138.2[M+1]。

The third step

5-hydroxy-3-isopropylpyridin-2 (1H) -one 1e

Compound 1d (250mg, 1.82mmol) was dissolved in water (7mL), cooled in an ice bath to 0-5 deg.C, and sodium hydroxide (364mg, 9.10mmol), ferrous sulfate heptahydrate (10mg, 0.04mmol), potassium persulfate (616mg, 2.28mmol) were added, the reaction warmed to room temperature, and stirred for 18 hours. The filtrate was filtered, acidified with concentrated sulfuric acid to pH 1-2, the filtrate was heated at 95 ℃ and stirred for 0.5 hour. pH was adjusted to 5-6 with 2N NaOH, concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain the title compound 1e (200mg, yield: 71.6%). MS M/z (ESI) 154.3[ M +1 ].

The fourth step

5- (2, 6-dichloro-4-nitrophenoxy) -3-isopropylpyridin-2 (1H) -one 1g

Compound 1e (125mg, 0.82mmol) was dissolved in N, N-dimethylformamide (10mL), and 1, 3-dichloro-2-fluoro-5-nitrobenzene 1f (206mg, 0.98mmol) and potassium carbonate (338mg, 2.45mmol) were added in this order and the reaction was stirred for 18 hours. Water was added to dilute (20mL), the pH was adjusted to 4-5 with 1N HCl, concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain 1g of the title compound (82mg, yield: 29.3%). MS M/z (ESI) 343.1[ M +1 ].

The fifth step

5- (4-amino-2, 6-dichlorophenoxy) -3-isopropylpyridin-2 (1H) -one 1H

After dispersing 1g (82mg, 0.24mmol) of the compound in a mixed solvent of ethanol (10mL) and water (5mL), iron powder (66mg, 1.18mmol) and ammonium chloride (64mg, 1.20mmol) were added to the reaction system, and the reaction system was stirred for 2 hours while being heated to 78 ℃ in an oil bath. Filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title compound 1h (55mg, yield: 73.5%).

MS m/z(ESI):313.0[M+1]。

The sixth step

(Z) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) hydrazone group) acetyl) carbamic acid ethyl ester 1j

Compound 1h (55mg, 0.18mmol) was suspended in water (4mL), concentrated hydrochloric acid (2mL) was added, cooled to 0 deg.C, and 1mL aqueous solution of sodium nitrite (16mg, 0.23mmol) was added, after which it was stirred at 0 deg.C for 1 hour to give yellow solution A. In another flask was added (2-cyanoacetyl) urethane 1i (30mg, 0.19mmol), water (4mL), pyridine (2mL) and cooled to 0 deg.C to give solution B. Solution A was slowly added to solution B at 0 deg.C, and the reaction was stirred at 0-5 deg.C for 1 hour. Filtration and collection of a filter cake were carried out, and vacuum drying was carried out to obtain the title compound 1j (60mg, yield: 71.1%).

MS m/z(ESI):480.1[M+1]。

Seventh step

Compound 1j (55mg, 0.11mmol) was dissolved in acetic acid (5mL), and sodium acetate (47mg, 0.57mmol) was added, and the reaction was stirred at 135 ℃ for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid preparation (Waters 2767-SQ Detector 2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 1(7mg, yield: 14.0%).

MS m/z(ESI):434.1[M+1]。

¹H NMR(400MHz,CD₃OD):7.72(s,2H),7.33(d,1H),7.23(d,1H),3.34-3.44(m,1H),1.37(d,6H)。

Example 2

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

First step of

2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carboxylic acid 2a

Compound 1(86mg, 0.20mmol) was dissolved in acetic acid (6mL), concentrated hydrochloric acid (1mL) and stirred at 120 ℃ for 2 hours. The starting material did not react, acetic acid (5mL) and concentrated hydrochloric acid (1mL) were added and stirring was continued for 2 hours to complete the reaction. Concentration and the resulting residue were purified to give the title compound 2a (90mg, yield: 100%).

MS m/z(ESI):451.0[M-1]。

Second step of

Compound 2a (90mg, 0.20mmol) was dissolved in mercaptoacetic acid (2mL, Shanghai chemical Co., Ltd., China pharmaceutical group) and stirred at 170 ℃ for 1 hour. After cooling, purification by high performance liquid chromatography (Waters 2767-SQ Detector 2, eluent: trifluoroacetic acid, water, acetonitrile) gave the title compound 2(30mg, yield: 36.9%).

MS m/z(ESI):409.0[M+1]。

¹H NMR(500MHz,DMSO-d₆):12.25-12.96(brs,1H),9.36-9.83(brs,1H),7.74(s,2H),7.66(s,1H),7.39(d,1H),7.21(d,1H),3.21-3.28(m,1H),1.30(d,6H)。

Example 3

2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 3

First step of

5- (2, 6-dibromo-4-nitrophenoxy) -3-isopropylpyridin-2 (1H) -one 3b

Compound 1e (100mg, 0.65mmol) was dissolved in N, N-dimethylformamide (8mL), and 1, 3-dibromo-2-fluoro-5-nitrobenzene 3a (205mg, 0.69mmol) and potassium carbonate (722mg, 5.22mmol) were added in this order and stirred at 55 ℃ for 18 hours. The mixture was filtered, and the filter cake was washed with a mixed solvent (20mL × 2) of dichloromethane and methanol (V/V ═ 5/1), and acetic acid was slowly added dropwise to the filtrate until the pH was 5 to 6. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 3b (150mg, yield: 53.1%).

MS m/z(ESI):432.9[M+1]。

Second step of

5- (4-amino-2, 6-dibromophenoxy) -3-isopropylpyridin-2 (1H) -one 3c

Compound 3b (140mg, 0.32mmol) was dispersed in a mixed solvent of ethanol (10mL) and water (5mL), and iron powder (91mg, 1.63mmol) and ammonium chloride (86mg, 1.61mmol) were added to the above reaction system, and the reaction was stirred for 2 hours with heating in an oil bath to 78 ℃. Filtration, concentration under reduced pressure, and purification of the resulting residue by silica gel column chromatography with eluent system A gave the title compound 3c (125mg, yield: 95.9%).

MS m/z(ESI):403.0[M+1]。

The third step

(Z) - (2-cyano-2- (2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) hydrazone) acetyl) carbamic acid ethyl ester 3d

Compound 3c (125mg, 0.31mmol) was suspended in water (4mL), concentrated hydrochloric acid (2mL) was added, cooled to 0 deg.C, and 1mL of an aqueous solution of sodium nitrite (28mg, 0.41mmol) was added, and after the addition, the mixture was stirred at 0 deg.C for 1 hour to give yellow solution A. In another vial was added compound 1i (54mg, 0.35mmol), water (4mL), pyridine (2mL) and cooled to 0 deg.C to give solution B. The solution A was slowly added to the solution B at 0 ℃ and stirred for 1 hour at 0-5 ℃. Filtration and collection of a filter cake were carried out, and vacuum drying was carried out to obtain the title compound 3d (115mg, yield: 65.0%).

MS m/z(ESI):570.0[M+1]。

The fourth step

Compound 3d (110mg, 0.19mmol) was dissolved in acetic acid (8mL), and sodium acetate (79mg, 0.96mmol) was added, and the reaction was stirred at 135 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid preparation (Waters 2767-SQ Detector 2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 3(22mg, yield: 21.8%).

MS m/z(ESI):523.8[M+1]。

¹H NMR(400MHz,CD₃OD):7.90(s,2H),7.32(d,1H),7.23(d,1H),3.34-3.40(m,1H),1.38(d,6H)。

Example 4

2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) -1,2, 4-triazine-3, 5(2H,4H) -dione 4

The title compound 4 was obtained by the method of example 2, substituting compound 3 for compound 1.

MS m/z(ESI):498.9[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ12.48-12.42(d,1H),9.59-9.47(s,1H),7.91-7.86(s,2H),7.71-7.68(d,1H),7.42-7.38(d,1H),7.23-7.21(d,1H),3.28-3.24(d,1H),1.35-1.30(d,6H)。

Example 5

2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) thio) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 5

First step of

3-bromo-2-methoxypyridine 5b

3-bromo-2-chloropyridine 5a (4.76g, 24.73mmol, Shaoyuan chemical technology (Shanghai) Co., Ltd.) was dissolved in N, N-dimethylformamide (30mL), 50% sodium methoxide (4.56g, 42.20mmol) was added, and the mixture was stirred at 80 ℃ for 0.5 hour. Quenched with water, extracted with ethyl acetate (80 mL. times.2), washed with saturated sodium chloride solution (50 mL. times.2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound 5b (4.7g, yield: 100.0%).

¹H NMR(400MHz,CDCl₃):8.05(d,1H),7.76(d,1H),6.68-7.79(m,1H),3.97(s,3H)。

Second step of

2-methoxy-3- (prop-1-en-2-yl) pyridine 5c

Compound 5b (3.0g,15.96mmol), compound 1b (3.2g, 19.04mmol) were dissolved in N, N-dimethylformamide (40mL) and water (8mL), palladium tetratriphenylphosphine (800mg,0.69mmol), potassium phosphate (6.9g, 32.51mmol) were added, and the mixture was stirred at 100 ℃ for 18 hours. Filtration, temperature reduction, dilution with water (50mL), extraction with ethyl acetate (30 mL. times.3), washing with saturated sodium chloride solution (30 mL. times.2), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove the solvent, and purification of the resulting residue by silica gel column chromatography with eluent system B to give the title compound 5c (1.6g, yield: 67.2%).

MS m/z(ESI):150.0[M+1]。

The third step

3-isopropyl-2-methoxypyridine 5d

Compound 5c (1.6g, 10.72mmol) was dissolved in methanol (20mL), 10% palladium on carbon hydrogenation catalyst (dry) (300mg, 0.25mmol) was added, hydrogen was replaced twice, and the reaction was stirred for 18 hours. Filtration and concentration under reduced pressure gave the title compound 5d (1.4g, yield: 86.3%).

MS m/z(ESI):152.1[M+1]。

¹H NMR(400MHz,CDCl₃):7.99(dd,1H),7.43(dd,1H),6.72-7.88(m,1H),3.94(s,3H),3.06-3.23(m,1H),1.20(d,6H)。

The fourth step

5-bromo-3-isopropyl-2-methoxypyridine 5e

Compound 5d (1.4g, 9.26mmol) was dissolved in acetic acid (20mL), sodium acetate (1.52g, 18.53mmol) was added, and liquid bromine (2.22g, 13.89mmol) was added dropwise at room temperature, and the reaction was stirred for 15 hours after completion of the dropwise addition. Water (20mL) was added, pH was adjusted to 7-8 with 2N NaOH, ethyl acetate was extracted (30mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5e (1.2g, yield: 56.3%).

MS m/z(ESI):230.0[M+1]。

The fifth step

2-ethylhexyl 3- ((5-isopropyl-6-methoxypyridin-3-yl) thio) propionate 5g

Compound 5e (500mg, 2.17mmol), 2-ethylhexyl 3-mercaptopropionate 5f (569mg, 2.61mmol, Shaosheng chemical technology (Shanghai) Co., Ltd.) were dissolved in 1, 4-dioxane (20mL) and tris (dibenzylideneacetone) dipalladium (199mg, 0.22mmol, Bailingwei technology Co., Ltd.), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (251mg, 0.43mmol, Shaosheng chemical technology (Shanghai) Co., Ltd.), N, N-diisopropylethylamine (561mg, 4.34mmol) were added, argon was substituted twice, and stirring was carried out at 105 ℃ for 48 hours. Filtration and concentration under reduced pressure were carried out to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5g (730mg, yield: 91.4%).

MS m/z(ESI):368.2[M+1]。

The sixth step

5-isopropyl-6-methoxypyridine-3-potassium mercaptide for 5h

5g (365mg, 0.99mmol) of the compound was dissolved in anhydrous tetrahydrofuran (5mL), replaced with argon twice, potassium tert-butoxide (390mg, 3.48mmol) was added, the reaction turned from colorless to yellow, and the reaction was stirred for 1 hour to give the title compound 5h (5mL, 0.20M tetrahydrofuran solution, yield: 100.0%) which was used in the next step as it was.

Seventh step

5- ((2, 6-dichloro-4-nitrophenyl) thio) -3-isopropyl-2-methoxypyridine 5i

Compound 1f (208mg, 0.99mmol) was dissolved in methanol (25mL), replaced with argon twice, and compound was added dropwise over ice for 5h (5mL, 0.20M in tetrahydrofuran, 1.00mmol), followed by addition of potassium carbonate (52mg, 0.38mmol) and stirring at 0 ℃ for 0.5 h. Diluting with water (30mL), adjusting pH 2-3 with 1N HCl, concentrating under reduced pressure, diluting with ethyl acetate (50mL), washing with saturated sodium chloride solution (30mL × 2), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove the solvent, and purifying the resulting residue with silica gel column chromatography using eluent system B to obtain the title compound 5i (243mg, yield: 65.8%).

MS m/z(ESI):373.0[M+1]。

¹H NMR(400MHz,DMSO-d₆):8.40(s,2H),7.95(s,1H),7.57(s,1H),3.86(s,3H),2.93-3.12(m,1H),1.12(d,6H)。

Eighth step

3, 5-dichloro-4- ((5-isopropyl-6-methoxypyridin-3-yl) thio) aniline 5j

Compound 5i (228mg, 0.61mmol) was dispersed in a mixed solvent of ethanol (10mL) and water (5mL), and iron powder (171mg, 3.07mmol) and ammonium chloride (164mg, 3.07mmol) were added to the above reaction system, heated to 80 ℃ in an oil bath, and reacted with stirring for 3 to 4 hours. Filtration, concentration, extraction with ethyl acetate (50 mL. times.2), washing with a saturated sodium chloride solution (30mL), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove the solvent, and purification of the resulting residue by silica gel column chromatography with eluent system B to give the title compound 5j (161mg, yield: 76.8%).

MS m/z(ESI):343.1[M+1]。

The ninth step

5- ((4-amino-2, 6-dichlorophenyl) thio) -3-isopropylpyridin-2 (1H) -one 5k

Compound 5j (155mg, 0.45mmol) was dissolved in N, N-dimethylformamide (8mL), pyridine hydrogen bromide (347mg, 2.25mmol, Hadamard reagent Co., Ltd.) was added, and the mixture was stirred at 95 ℃ for 18 hours. After cooling, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 5k (100mg, yield: 67.2%).

MS m/z(ESI):329.0[M+1]。

The tenth step

(Z) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) thio) phenyl) hydrazone group) acetyl) carbamic acid ethyl ester 5l

Compound 5k (100mg, 0.30mmol) was suspended in water (6mL), concentrated hydrochloric acid (3mL) was added, cooled to 0 deg.C, and 2mL of an aqueous solution of sodium nitrite (31mg,0.45mmol) was added, and after the addition, the mixture was stirred at 0 deg.C for 1 hour to give a reddish brown suspension A. In another vial was added compound 1i (52mg, 0.33mmol), water (6mL) was added, pyridine (3mL) was added, and cooled to 0 deg.C to give solution B. The solution A was slowly added to the solution B at 0 ℃ and stirred for 1 hour at 0-5 ℃. Filtration was carried out, and the filter cake was washed with water (30 mL. times.2) and n-hexane (30 mL. times.2) in this order and dried in vacuo to obtain 5l (100mg, yield: 66.3%) of the title compound.

MS m/z(ESI):496.0[M+1]。

The eleventh step

Compound 5l (100mg, 0.20mmol) was dissolved in acetic acid (8mL), and sodium acetate (132mg, 1.61mmol) was added, and the reaction was stirred at 135 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid preparation (Waters 2767-SQ Detector 2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 5(45mg, yield: 49.6%).

MS m/z(ESI):450.1[M+1]。

¹H NMR(400MHz,DMSO-d₆):13.05-13.47(brs,1H),11.82(s,1H),7.75(s,2H),7.48(d,1H),7.24(d,1H),2.80-2.96(m,1H),1.04(d,6H)。

Example 6

2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) thio) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 6

First step of

5- ((2, 6-dibromo-4-nitrophenyl) thio) -3-isopropyl-2-methoxypyridine 6a

Compound 3a (625mg, 2.09mmol) was dissolved in methanol (25mL), replaced with argon twice, and compound was added dropwise over an ice bath for 5h (10.5mL, 0.2M in tetrahydrofuran, 2.10mmol), followed by addition of potassium carbonate (87mg, 0.63mmol) and stirring at 0 deg.C for 0.5 h. Water was added to dilute (30mL), the pH was adjusted to 2-3 with 1N HCl, and the resulting residue was concentrated to obtain the title compound 6a (550mg, yield: 56.9%).

MS m/z(ESI):463.0[M+1]。

Second step of

3, 5-dibromo-4- ((5-isopropyl-6-methoxypyridin-3-yl) thio) aniline 6b

Compound 6a (540mg, 1.17mmol) was dispersed in a mixed solvent of ethanol (20mL) and water (10mL), and iron powder (326mg, 5.83mmol) and ammonium chloride (312mg, 5.83mmol) were added to the above reaction system, heated to 80 ℃ in an oil bath, and reacted with stirring for 3 to 4 hours. Filtration, concentration, extraction with ethyl acetate (50 mL. times.2), washing with saturated sodium chloride solution (30mL), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove the solvent, and purification of the resulting residue by silica gel column chromatography with eluent system B to give the title compound 6B (380mg, yield: 75.2%).

MS m/z(ESI):433.0[M+1]。

The third step

5- ((4-amino-2, 6-dibromophenyl) thio) -3-isopropylpyridin-2 (1H) -one 6c

Compound 6b (170mg, 0.39mmol) was dissolved in N, N-dimethylformamide (8mL), pyridine hydrogen bromide (315mg, 1.97mmol) was added, and the mixture was stirred at 80 ℃ for 3-4 hours. After cooling, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 6c (108mg, yield: 65.7%).

MS m/z(ESI):418.9[M+1]。

The fourth step

(Z) - (2-cyano-2- (2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) thio) phenyl) hydrazone) acetyl) ethyl carbamate 6d

Compound 6c (100mg, 0.24mmol) was suspended in water (6mL), concentrated hydrochloric acid (3mL) was added, the mixture was cooled to 0 ℃ and 2mL of an aqueous solution of sodium nitrite (25mg,0.36mmol) was added, and the mixture was stirred at 0 ℃ for 1 hour to obtain a reddish brown suspension A. In another vial was added compound 1i (41mg, 0.26mmol), water (6mL) was added, pyridine (3mL) was added, and cooled to 0 deg.C to give solution B. The solution A was slowly added to the solution B at 0 ℃ and stirred for 1 hour at 0-5 ℃. Filtration was carried out, and the filter cake was washed with water (30 mL. times.2) and n-hexane (30 mL. times.2) in this order, and the resulting solid was dried under vacuum to give the title compound 6d (100mg, yield: 71.4%).

MS m/z(ESI):586.0[M+1]。

The fifth step

Compound 6d (100mg, 0.17mmol) was dissolved in acetic acid (8mL), and sodium acetate (113mg, 1.38mmol) was added, and the reaction was stirred at 130 ℃ for 2 hours. Cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid preparation (Waters 2767-SQ Detector 2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 6(45mg, yield: 48.8%).

MS m/z(ESI):539.9[M+1]。

¹H NMR(400MHz,DMSO-d₆):13.98-13.61(brs,1H),11.83(s,1H),7.94(s,2H),7.47(d,1H),7.31(d,1H),2.82-2.94(m,1H),1.05(d,6H)。

Example 7

2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) methyl) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 7

First step of

Tert-butyl (3, 5-dichlorophenoxy) dimethylsilane 7a

The compound 3, 5-dichlorophenol (5.79g, 35.5mmol, san En Chemicals (Shanghai) Co., Ltd.) was dissolved in dichloromethane (30mL), N-diisopropylethylamine (69g, 53.3mmol, 4-dimethylaminopyridine (400mg, 3.24mmol, Shao Yuan Chemicals (Shanghai) Co., Ltd.) and tert-butyldimethylchlorosilane (6.5g, 43.1mmol, Shao Yuan Chemicals (Shanghai) Co., Ltd.) were added, and the mixture was stirred at room temperature for 16 hours. Extraction with ethyl acetate (100 mL. times.3), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to remove the solvent, and purification of the resulting residue by silica gel column chromatography with developer system B gave the title compound 7a (8.95g, yield: 90.8%).

Second step of

5-bromo-6-methoxy nicotinaldehyde 7b

6-Methoxynicotinaldehyde (12g, 87mmol) was dissolved in acetic acid (80mL), sodium acetate (14g, 170mmol) was added, heat was released, and a solution of liquid bromine (20g, 125mmol) in acetic acid (20mL) was added dropwise at room temperature, and the reaction was carried out at 90 ℃ for 5 hours. After cooling, concentration was performed, basification was performed with a 2N aqueous sodium hydroxide solution, extraction was performed with ethyl acetate (100 mL. times.3), drying was performed with anhydrous sodium sulfate, filtration was performed, concentration was performed under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developer system B to obtain the title compound 7B (6.0g, yield: 31.7%).

The third step

6-methoxy-5- (prop-1-en-2-yl) nicotinaldehyde 7c

Compound 7B (2.0g, 9.25mmol) was dissolved in N, N-dimethylacetamide (40mL), isopropenylboronic acid pinacol ester (3.5g, 20.8mmol), palladium tetrakistriphenylphosphine (1g, 0.86mmol), potassium phosphate (4g, 18.8mmol), water (4mL) was added, the mixture was reacted at an external temperature of 80 ℃ for 4 hours, water (40mL) was added after cooling, ethyl acetate was extracted (30 mL. times.3), dried over anhydrous sodium sulfate, filtered, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 7c (1.46g, yield: 89%).

The fourth step

(5-isopropyl-6-methoxypyridin-3-yl) methanol 7d

Compound 7c (1.46g, 8.23mmol) was dissolved in methanol (50mL), 10% palladium on charcoal (200mg, 0.16mmol) was added, and the mixture was replaced with hydrogen balloon 3 times and reacted at room temperature for 16 hours. Filtration and concentration under reduced pressure removed the solvent to give the title compound 7d (1.49g, yield: 99.7%).

The fifth step

5-isopropyl-6-methoxy nicotinaldehyde 7e

Compound 7d (1.49g, 8.22mmol) was dissolved in chloroform (100mL), manganese dioxide (14g, 161mmol) was added, and the reaction was carried out at room temperature for 72 hours. Filtration and concentration under reduced pressure were carried out to remove the solvent, and the resulting residue was purified by silica gel column chromatography with the developer system B to give the title compound 7e (880mg, yield: 59.7%).

MS m/z(ESI):180.2[M+1]。

The sixth step

3, 5-dichloro-4- (hydroxy (5-isopropyl-6-methoxypyridin-3-yl) methyl) phenol 7f

Compound 7a (680mg, 2.45mmol) was dissolved in tetrahydrofuran (12mL), cooled in a dry ice acetone bath to-78 deg.C, lithium diisopropylamide (2M, 1.34mL) was added dropwise, stirred at-78 deg.C for 0.5 h, compound 7e (400mg, 2.23mmol) in tetrahydrofuran (8mL) was added, stirred at-78 deg.C for 2h, slowly warmed to room temperature, and stirred for 16 h. The reaction was quenched by the addition of saturated ammonium chloride (5mL), acidified with 1N diluted aqueous hydrochloric acid, extracted with ethyl acetate (40 mL. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to give the title compound 7f (650mg, yield: 85.0%).

MS m/z(ESI):342.0[M+1]。

Seventh step

7g of 3, 5-dichloro-4- ((5-isopropyl-6-methoxypyridin-3-yl) methyl) phenol

Compound 7f (650mg, 1.89mmol) was dissolved in methylene chloride (12mL), and trifluoroacetic acid (1.1mL), triethylsilane (1.1mL) and boron trifluoride etherate (1.1mL) were added at room temperature, followed by stirring for 1 hour. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate (40 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 7g (350mg, yield: 56.4%).

MS m/z(ESI):326.1[M+1]。

Eighth step

3, 5-dichloro-4- ((5-isopropyl-6-methoxypyridin-3-yl) methyl) phenyl trifluoromethanesulfonate 7h

The compound (7 g, 190mg, 0.58mmol) was dissolved in dichloromethane (20mL), and 4-dimethylaminopyridine (11mg, 0.09mmol), triethylamine (118mg, 1.16mmol), N-phenylbis (trifluoromethanesulfonyl) imide (312mg, 0.87mmol, Shaoshima chemical technology, Ltd.) was added at 0 ℃ and stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 7h (260mg, yield: 97.4%).

MS m/z(ESI):458.0[M+1]。

The ninth step

N- (3, 5-dichloro-4- ((5-isopropyl-6-methoxypyridin-3-yl) methyl) phenyl) -1, 1-diphenylmethanimine 7i

The compound (7 h, 260mg, 0.57mmol) was dissolved in 1, 4-dioxane (15mL), benzophenone imine (260mg, 0.57mmol, Chemicals group, Inc., national drugs), cesium carbonate (369mg, 1.13mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (65mg, 0.113mmol), tris (dibenzylideneacetone) dipalladium (52mg, 0.06mmol) were added, and argon was substituted three times, followed by stirring at 80 ℃ for 2 hours. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 7i (240mg, yield: 86.4%).

MS m/z(ESI):489.1[M+1]。

The tenth step

5- (4-amino-2, 6-dichlorobenzyl) -3-isopropylpyridin-2 (1H) -one 7j

Compound 7i (120mg, 0.24mmol) was dissolved in N, N-dimethylformamide (10mL), pyridine hydrogen bromide (189mg, 1.22mmol) was added, and the mixture was stirred at 100 ℃ for 1 hour. Cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system A to give the title compound 7j (65mg, yield: 85.1%).

MS m/z(ESI):311.0[M+1]。

The eleventh step

(Z) - (2-cyano-2- (2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) methyl) phenyl) hydrazone) acetyl) carbamic acid methyl ester 7k

Using the sixth route in example 1, starting material 1h was replaced with starting material 7j to give the title compound 7k (120mg), yield: 65.0 percent.

MS m/z(ESI):478.1[M+1]。

The twelfth step

2- (3, 5-chloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) methyl) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 7

Using the seventh route of example 1, starting material 1j was replaced with starting material 7k to give the title compound 7(120mg), yield: 65.0 percent.

MS m/z(ESI):432.0[M+1]。

¹H NMR(400MHz,DMSO-d6)δ13.23(brs,1H),11.32(s,1H),7.65(s,2H),7.21(d,1H),6.75(s,1H),5.73(s,2H),2.90-2.91(m,1H),1.04(d,6H)。

Example 8

2- (3, 5-dibromo-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) methyl) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 8

Using the synthetic route of example 7, the starting material 2, 6-dichlorophenol of the first step was replaced with the starting material 2, 6-dibromophenol to afford the title compound 8(4mg), yield: 25.6 percent.

MS m/z(ESI):522.0[M+1]。

¹H NMR(400MHz,DMSO-d₆)δ13.22(brs,1H),11.32(s,1H),7.87(s,2H),7.25(s,1H),6.66(s,1H),4.08(s,2H),2.98～2.91(t,1H),1.08(d,6H)。

Example 9

2- (3, 5-dichloro-4- ((1- (3-chlorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 9

First step of

5- (2, 6-dichloro-4-nitrophenoxy) pyridin-2 (1H) -one 9b

5-hydroxypyridine-2 (1H) -one 9a (2.0g, 18.00mmol, Shanghai Biao pharmaceutical science Co., Ltd.) was dissolved in N, N-dimethylformamide (50mL), and then compound 1f (4.16g,19.81mmol, Shanghai Biao pharmaceutical science Co., Ltd.) and potassium carbonate (7.46g, 53.98mmol) were added in this order and stirred to react for 18 hours. Water (80mL) was added for dilution, extraction was performed with dichloromethane (80 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and the resulting residue was further purified to give the title compound 9b (2.7g, yield: 49.8%).

MS m/z(ESI):301.0[M+1]。

Second step of

1- (3-chlorophenyl) -5- (2, 6-dichloro-4-nitrophenoxy) pyridin-2 (1H) -one 9d

Compound 9b (250mg, 0.83mmol), 3-chlorobenzeneboronic acid 9c (196mg, 1.25mmol, Shaoyuan chemical technology (Shanghai) Co., Ltd.) was dissolved in dichloromethane (20mL), and triethylamine (168mg, 1.66mmol), pyridine (131mg, 1.66mmol), 4A molecular sieve powder (289mg, 1.66mmol, Afaha chemical Co., Ltd.) and copper acetate monohydrate (331mg, 1.66mmol, national pharmaceutical group chemical Co., Ltd.) were added in this order and stirred open for 4 hours. After the mixture was filtered through Celite, the filter cake was washed with methylene chloride (20 mL. times.2), and aqueous ammonia (10mL) was added to the filtrate and the mixture was stirred for 0.5 hour. The organic phase was collected by standing for separation, concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 9d (156mg, yield: 45.6%).

MS m/z(ESI):412.9[M+1]

¹H NMR(400MHz,CDCl₃):8.30(s,2H),7.30-7.45(m,4H),7.20-7.25(m,1H),6.82(d,1H),6.74(d,1H)。

The third step

5- (4-amino-2, 6-dichlorophenoxy) -1- (3-chlorophenyl) pyridin-2 (1H) -one 9e

Compound 9d (150mg, 0.36mmol) was dispersed in 22.5mL of a mixed solvent of ethanol and water (V/V ═ 2/1), and iron powder (102mg, 1.83mmol) and ammonium chloride (98mg, 1.83mmol) were added to the above reaction system, and the reaction system was heated in an oil bath to 78 ℃ and stirred for 2 hours. Filtration, the filter cake washed with ethanol (30ml) and water (30ml), concentrated under reduced pressure to remove ethanol, filtered, the filter cake collected and dried in vacuo to give the title compound 9e (135mg, yield: 97.1%).

MS m/z(ESI):381.0[M+1]。

The fourth step

(Z) - (2-cyano-2- (2- (3, 5-dichloro-4- ((1- (3-chlorophenyl) -6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) hydrazone) acetyl) carbamic acid ethyl ester 9f

Compound 9e (130mg, 0.34mmol) was suspended in water (6mL), concentrated hydrochloric acid (3mL) was added, the reaction was cooled to 0 ℃ and an aqueous solution (1mL) of sodium nitrite (31mg,0.45mmol) was added, and after the addition, stirring was carried out at 0 ℃ for 1 hour to give yellow solution A. In another flask was added (2-cyanoacetyl) urethane 1i (59mg, 0.38mmol, Shaosheng chemical technology (Shanghai), Inc.), water (6mL) and pyridine (3mL), and the reaction was cooled to 0 ℃ to obtain solution B. Solution A was slowly added to solution B at 0 deg.C, and the reaction was stirred at 0-5 deg.C for 1 hour. Filtration and collection of a filter cake were carried out, and vacuum drying was carried out to obtain the title compound 9f (120mg, yield: 64.2%).

The fifth step

Compound 9f (120mg, 0.22mmol) was dissolved in acetic acid (6mL), and sodium acetate (144mg, 1.76mmol) was added, and the reaction was stirred at 130 ℃ for 3 hours. The reaction was cooled, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 9(60mg, yield: 54.6%).

MS m/z(ESI):501.9[M+1]。

¹H NMR(400MHz,DMSO-d₆):13.09-13.42(brs,1H)，7.75(s,2H)，7.48-7.58(m,5H)，7.30-7.37(m,1H)，6.50-6.59(m,1H)。

Example 10

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-carbonitrile 10

First step of

5- (2, 6-dichloro-4-nitrophenoxy) -1-isopropylpyridin-2 (1H) -one 10b

Dissolving the compound 9b (3.5g, 11.62mmol) in ethylene glycol dimethyl ether (40mL), adding potassium tert-butoxide (1.26g, 11.23mmol, Hadamard reagent Co., Ltd.) to the reaction system, and stirring at room temperature for 40 minutes; bromoisopropane 10a (2.80g, 22.76mmol, Hadamard reagent Co., Ltd.) was then added and the mixture was oil-bathed to 86 ℃ and stirred for 22 hours. The solvent was removed by concentration under reduced pressure, and purified by silica gel column chromatography with eluent system B (n-hexane: ethyl acetate ═ 1:1) to give the title compound 10B (1.8g, yield: 45.1%).

MS m/z(ESI):342.9[M+1]。

Second step of

5- (4-amino-2, 6-dichlorophenoxy) -1-isopropylpyridin-2 (1H) -one 10c

Compound 10b (1.8g, 5.25mmol) was dispersed in 150mL of a mixed solvent of ethanol and water (V/V ═ 2/1), iron powder (1.8g, 32.23mmol) and ammonium chloride (1.90g, 35.67mmol) were added in this order, and the reaction was stirred for 1.5 hours while heating in an oil bath to 86 ℃. Celite was hot-filtered, the filter cake was washed with ethanol (30mL × 2), the filtrate was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography with eluent system B (n-hexane: ethyl acetate ═ 1:1) to give the title compound 10c (0.85g, yield: 51.74%).

MS m/z(ESI):312.9[M+1]。

The third step

(Z) - (2-cyano-2- (2- (3, 5-dichloro-4- ((1-isopropyl-6-oxo-1, 6-dihydropyridin-3-yl) oxy) phenyl) hydrazone) acetyl) carbamic acid ethyl ester 10d

Compound 10c (850mg, 2.71mmol) was suspended in water (20mL), concentrated hydrochloric acid (10mL) was added, the mixture was cooled to 0 ℃ and 5mL of an aqueous solution of sodium nitrite (281mg, 4.07mmol) was added, and the mixture was stirred at 0 ℃ for 1 hour to give yellow solution A. In another flask, compound 1i (423mg, 2.71mmol), water (10mL), pyridine (10mL) was added and cooled to 0 ℃ to give solution B. Solution A was slowly added to solution B at 0 deg.C, the reaction was stirred at 0-15 deg.C for 1 hour, water (200mL) was added to the reaction solution, and stirring vigorously was carried out for 15 minutes. Filtration and collection of a filter cake were carried out, and vacuum drying was carried out to obtain the title compound 10d (950mg, yield: 72.88%).

MS m/z(ESI):480.0[M+1]。

The fourth step

Compound 10d (950mg, 1.98mmol) was dissolved in dimethylacetamide (15mL), potassium acetate (233mg, 2.37mmol, Hadamard reagent Co., Ltd.) was added, and the reaction was stirred for 3 hours with heating in an oil bath to 120 ℃. Cooled to room temperature, and the reaction solution was purified by preparative chromatography (Waters 2767-SQ Detecor2, eluent: 0.1% aqueous trifluoroacetic acid/acetonitrile 35% -95% acetonitrile) to give the title compound 10(610mg, yield: 71.02%).

MS m/z(ESI):433.9[M+1]。

¹H NMR(400MHz,DMSO-d₆):13.27(s,1H)，7.78(s,2H)，7.58-7.57(d,1H)，7.25-7.22(dd,1H)，3.40-6.38(d,1H)，5.04-4.99(m,1H)，1.28-1.27(d,6H)。

Test example:

biological evaluation

Test example 1 agonism of Compounds of the present disclosure on THR α and THR β

1. Purpose of the experiment:

the aim of this experiment was to test the agonism of compounds on THR α (thyroid hormone receptor α) and THR β (thyroid hormone receptor β) stable reporter cell lines (reporter cell lines), according to EC₅₀And Emax size the selectivity of the compounds for THR α and THR β was evaluated.

2. The experimental method comprises the following steps:

compounds were formulated in dimethylsulfoxide (Sigma, # D2650) at an initial concentration of 10mM, 10-fold dilution of T3(Sigma, T2877), 9 dose points, 3-fold dilution of test compound, 9 dose points. The compound was further diluted 20-fold using DMEM/F12(GE, # SH30023.01) medium containing 0.5% FBS (corning, # 35-076-CV);

the constructed CHO-K1 cells simultaneously expressing the DR4 reaction element and THR alpha or THR beta were plated in a 96-well plate (Corning, #3903) at 37 ℃ with 5% CO at 5000 cells/well, respectively₂Cultured in an incubator (thermo scientific, # HERAcell 240i) for 24 hours.

The medium was removed from the cell plates, 95ul of DMEM/F12 medium containing 0.5% FBS and 5ul of diluted compound solution were added, respectively, and the mixture was placed at 37 ℃ and 5% CO₂Incubating for 24 hours in an incubator; after 24 hours, 100. mu.l of the prepared luciferase substrate (Promega, # E2610) was added to each well, left at room temperature in the dark for 5min, and then detected for chemiluminescence on a microplate reader (Perkinelmer, # Vector 3). EC of agonism of compounds of the disclosure on THR alpha and THR beta₅₀The values are shown in Table 1.

TABLE 1 EC for agonism of compounds of this disclosure on THR α and THR β₅₀Value of

And (4) conclusion: the disclosed compounds have highly selective agonistic effects on THR beta.

Claims

1. A compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl；

n is 0, 1,2,3 or 4.

2. The compound of formula (I) according to claim 1, wherein R is selected from the group consisting of tautomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof, or a pharmaceutically acceptable salt thereof⁴Selected from the group consisting of hydrogen atoms,Alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

3. The compound of the general formula (I) according to claim 1 or2, which is a compound of the general formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹～R⁴And L is as defined in claim 1.

4. A compound of general formula (I) according to any one of claims 1 to 3, wherein L is selected from CH, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof₂An O atom and an S atom.

5. The compound of general formula (I) according to any one of claims 1 to 4, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof¹Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy and C_3-8A cycloalkyl group; preferably, R¹Are identical or different and are each independently halogen or C_1-6An alkyl group.

6. The compound of the general formula (I) according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereofAn enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R²Selected from hydrogen, halogen, cyano, C_1-6Alkyl and C_3-8Cycloalkyl, preferably R²Is cyano.

7. The compound of general formula (I) according to any one of claims 1 to 6, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof³Selected from hydrogen atoms, halogens, C_1-6Alkyl radical, C_3-8Cycloalkyl and C_6-10An aryl group; preferably, R³Is a hydrogen atom or C_1-6An alkyl group.

8. The compound of general formula (I) according to any one of claims 1,3 to 7, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof⁴Selected from hydrogen atoms, C_1-6Alkyl and C_6-10An aryl group; wherein said C_1-6Alkyl and C_6-10Aryl is independently selected from halogen and C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, cyano, amino, nitro, hydroxy, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl and 3 to 6 membered heterocyclyl; preferably, R⁴Is a hydrogen atom or a phenyl group; wherein said phenyl is optionally selected from halogen, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, cyano, amino, nitro, hydroxy, C_1-6Hydroxyalkyl radical, C_3-6Cycloalkyl and 3-to 6-membered heterocyclyl.

9. A compound of general formula (I) according to any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

10. a compound of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein:

R^mis C_1-6An alkyl group;

R²selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, carboxyl, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aromatic radicalAnd heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1,2,3 or 4.

11. The compound of the general formula (IA) according to claim 10, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a salt thereof, selected from any one of the following compounds:

12. a process for the preparation of a compound of formula (I) according to claim 1 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein:

R^mis C_1-6An alkyl group;

L、R¹～R⁴and n is as defined in claim 1.

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

14. Use of a compound of general formula (I) according to any one of claims 1 to 9 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a THR β agonist.

15. Use of a compound of general formula (I) according to any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the treatment and/or prevention of a disease modulated by thyroid hormone; preferably for the manufacture of a medicament for the treatment and/or prevention of metabolic disorders modulated by thyroid hormones.

16. Use of a compound of general formula (I) according to any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment and/or prevention of thyroid hormone-mediated obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD).