CN113698388B

CN113698388B - 6-oxo-1, 6-dihydropyridine derivative, preparation method and application thereof in medicine

Info

Publication number: CN113698388B
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: 2022-11-22
Anticipated expiration: 2041-05-19
Also published as: CN113698388A

Abstract

The present disclosure relates to 6-oxo-1, 6-dihydropyridine derivatives, processes for their preparation and their use in medicine. In particular 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, 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 derivative, preparation method and application thereof in medicine

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) Influence generationMetabolic, thermogenic effect thyroid hormones increase oxygen consumption in most tissues and increase the thermogenic effect, which may be due to the thyroid hormone increasing Na on the 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 reticulum ²⁺ 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, which cannot be used 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 through THR a. The action of the 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 have been synthesized which act selectively and/or tissue selectively at the thyroid hormone receptor beta (THR β), and these compounds provide adequate reductions 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.2003,46,1580-1588, martha J.Kelly, J.Med.chem.2014,57, 3912-3923).

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

Disclosure of Invention

The present disclosure is directed to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a 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;

R ¹ the 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;

R ² selected 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 selected from one or more 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 groupsSubstituted with a plurality of substituents;

R ³ selected 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;

R ⁴ selected 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.

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:

R ¹ are the same or different, andeach independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyanos, amino, nitro, hydroxyls, hydroxyalkyls, cycloalkyls, heterocyclyls, aryls and heteroaryls, wherein said alkyls, alkenyls, alkynyls, alkoxys, hydroxyalkyls, cycloalkyls, heterocyclyls, aryls and heteroaryls are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, cyanos, aminos, nitro, hydroxyls, hydroxyalkyls, cycloalkyls, heterocyclyls, aryls and heteroaryls;

R ² selected 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;

R ⁴ selected 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, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R ¹ ～R ⁴ And 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 CH ₂ An O atom and an S atom.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy and C _3-8 A cycloalkyl group; preferably, R ¹ Are identical or different and are each independently halogen or C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ² Selected from hydrogen, halogen, cyano, C _1-6 Alkyl and C _3-8 Cycloalkyl, preferably, R ² Is cyano.

In some embodiments of the disclosure, a kit according to the disclosureA compound of the general formula (I) or (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ³ Selected from hydrogen, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl and C _6-10 An aryl group; preferably, R ³ Is a hydrogen atom or C _1-6 An alkyl group; more preferably, R ³ Is C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compounds of formula (I) and formula (II) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Selected from hydrogen atoms, C _1-6 Alkyl and C _6-10 An aryl group; wherein said C _1-6 Alkyl and C _6-10 Aryl is independently selected from halogen and C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkyl, halo C _1-6 Alkoxy, cyano, amino, nitro, hydroxy, C _1-6 Hydroxyalkyl radical, C _3-6 Cycloalkyl and 3 to 6 membered heterocyclyl; preferably, R ⁴ Is a hydrogen atom or a phenyl group; wherein said phenyl is optionally selected from halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkyl, halo C _1-6 Alkoxy, cyano, amino, nitro, hydroxy, C _1-6 Hydroxyalkyl, C _3-6 Cycloalkyl 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 is ⁴ Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁴ Is 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, or diastereomer thereof, or a mixture thereof, or a salt thereof:

wherein:

R ^m is C _1-6 An alkyl group;

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

wherein:

R ^m is C _1-6 An alkyl group;

R ³ the same or different, each 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, heteroaryl, and heteroaryl are substituted with one or more halogen atoms,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. 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 、R ¹ ～R ⁴ And 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 ^m is C _1-6 An alkyl group;

L、R ¹ ～R ⁴ and n is as defined in formula (I).

Another aspect of the present disclosure relates to a method for 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:

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

wherein:

R ^m is C _1-6 An alkyl group;

l and R ¹ ～R ⁴ As 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 manufacture of a medicament for the treatment and/or prevention of a disease modulated by thyroid hormone; preferably for the production of a medicament for the treatment and/or prevention of metabolic disorders regulated 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 of treating and/or preventing obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, 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 table a as described herein 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 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 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 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 the compositions of the disclosure by conventional means. 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 from 0.1 to 1000mg.

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 or 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 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 coloring agent 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 the oil phase, the injection or microemulsion being injectable in the bloodstream of the patient by local bolus 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 the drug administered depends on a variety of factors, including but not limited to the following: 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, 2, 3-dimethylhexyl 4, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and 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 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-ethylene (-CO-), and their useCH(CH ₃ ) -), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) -), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) -), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ -) 1, 4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. Alkylene groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any available point of attachment, preferably the substituents are independently optionally one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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 the group consisting 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 from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms (e.g., 3,4,5, 6, 7, and 8), more preferably from 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 ring 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:

such cycloalkyl rings include those wherein a cycloalkyl (including monocyclic, spiro, fused, and bridged rings) as described above is fused to an aryl, heteroaryl, or heterocycloalkyl ring, 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) ₂ But does not include the ring part of-O-O-, -O-S-or-S-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 5 to 20 membered polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between monocyclic rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ The 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 single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. 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 heterocyclyl 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) ₂ The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-to 4-or 3-to 5-membered3-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) ₂ The 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 so on.

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 that is attached to 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) _1-10 Alkyl or aryl) ₃ Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy-substituted C _1-6 Alkyl or phenyl substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy-substituted C _1-4 Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), etc.; may be (C) _1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; or (C) _1-6 Alkoxy or C _6-10 Aryloxy) 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 the alkyl group 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 the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

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 junctionA compound structurally different 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, or ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enrichment carbon (C) of (C) ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-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 hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the 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, and other chemical components, as well as other components such as physiological/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 compounds, 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 a case may be determined by a person skilled in the art in the light of routine tests.

The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and/or dosage forms 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 ^m is C _1-6 An alkyl group;

L、R ¹ ～R ⁴ and 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 ^m is C _1-6 An alkyl group;

l and R ¹ ～R ⁴ As 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, t-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.) at 10 ^-6 The 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) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatograph-Mass spectrometer (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 preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP, and Gilson GX-281.

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

CombiFlash flash 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 Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The 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 Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

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, shaoyuan chemical technology (Shanghai) Co., ltd.), isopropenylboronic acid pinacol ester 1b (1.62g, 9.64mmol, shaoyuan chemical technology (Shanghai) Co., ltd.) were dissolved in N, N-dimethylformamide (20 mL) and water (5 mL), potassium phosphate (3.42g, 16.11mmol), palladium tetratriphenylphosphine (465mg, 0.40mmol) were added, and stirred 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 (530 mg, yield: 48.7%).

MS m/z(ESI):136.1[M+1]。

¹ H NMR(400MHz,CDCl ₃ ):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 (20 mL), 10% palladium on carbon hydrogenation catalyst (dry) (41mg, 0.39mmol) was added, hydrogen replaced twice, and the reaction was stirred for 2 hours. Filtration and concentration under reduced pressure gave the title compound 1d (520 mg, 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 (7 mL), cooled to 0-5 ℃ in an ice bath, and then sodium hydroxide (364mg, 9.10mmol), ferrous sulfate heptahydrate (10mg, 0.04mmol) and potassium persulfate (616mg, 2.28mmol) were added to raise the temperature to room temperature, followed by stirring for 18 hours. Filtering, acidifying the filtrate with concentrated sulfuric acid to pH =1-2, heating the filtrate, 95 ℃, and stirring for 0.5 hours. pH =5-6 was adjusted 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 (200 mg, yield: 71.6%). MS m/z (ESI) 154.3[ 2 ], [ 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 (10 mL), 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 for dilution (20 mL), pH =4-5 was adjusted with 1N HCl, concentration was performed, and the resulting residue was purified by silica gel column chromatography with eluent system a to obtain 1g of the title compound (82 mg, yield: 29.3%). MS m/z (ESI) 343.1[ 2 ], [ M +1].

The fifth step

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

Compound 1g (82mg, 0.24mmol) was dispersed in a mixed solvent of ethanol (10 mL) and water (5 mL), and iron powder (66mg, 1.18mmol) and ammonium chloride (64mg, 1.20mmol) were added to the above reaction system, and the mixture was heated in an oil bath to 78 ℃ and stirred for reaction for 2 hours. 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 (55 mg, 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) acetyl) carbamic acid ethyl ester 1j

Compound 1h (55mg, 0.18mmol) was suspended in water (4 mL), concentrated hydrochloric acid (2 mL) was added, the mixture was cooled to 0 ℃ and 1mL of an aqueous solution of sodium nitrite (16mg, 0.23mmol) was added, and the mixture was stirred at 0 ℃ for 1 hour to give yellow solution A. In another flask was added (2-cyanoacetyl) urethane 1i (30mg, 0.19mmol), water (4 mL), pyridine (2 mL) 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, and vacuum drying gave the title compound 1j (60 mg, yield: 71.1%).

MS m/z(ESI):480.1[M+1]。

Seventh step

Compound 1j (55mg, 0.11mmol) was dissolved in acetic acid (5 mL), and sodium acetate (47mg, 0.57mmol) was added and the reaction 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 (7 mg, yield: 14.0%).

MS m/z(ESI):434.1[M+1]。

¹ H NMR(400MHz,CD ₃ OD):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 (6 mL) and concentrated hydrochloric acid (1 mL), and stirred at 120 ℃ for 2 hours. The starting material did not react, acetic acid (5 mL) and concentrated hydrochloric acid (1 mL) 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 (90 mg, yield: 100%).

MS m/z(ESI):451.0[M-1]。

Second step of

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

MS m/z(ESI):409.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):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 (8 mL), 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 (20 mL × 2) of dichloromethane and methanol (V/V = 5/1), and acetic acid was slowly added dropwise to a filtrate pH of 5 to 6. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3b (150 mg, 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 (10 mL) and water (5 mL), 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 while 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 (125 mg, 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) group) acetyl) urethane 3d

Compound 3c (125mg, 0.31mmol) was suspended in water (4 mL), concentrated hydrochloric acid (2 mL) was added, cooled to 0 deg.C, and 1mL 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 (4 mL) was added, pyridine (2 mL) 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 and collection of a filter cake were carried out, and vacuum drying was carried out to obtain the title compound 3d (115 mg, yield: 65.0%).

MS m/z(ESI):570.0[M+1]。

The fourth step

Compound 3d (110mg, 0.19mmol) was dissolved in acetic acid (8 mL), 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 Detecor2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 3 (22 mg, yield: 21.8%).

MS m/z(ESI):523.8[M+1]。

¹ H NMR(400MHz,CD ₃ OD):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]。

¹ H NMR(500MHz,DMSO-d ₆ )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) Ltd.) was dissolved in N, N-dimethylformamide (30 mL), 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 (4.7 g, yield: 100.0%).

¹ H NMR(400MHz,CDCl ₃ ):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 (40 mL) and water (8 mL), palladium tetratriphenylphosphine (800mg, 0.69mmol), potassium phosphate (6.9g, 32.51mmol) were added, and stirring was carried out at 100 ℃ for 18 hours. Filtration, temperature reduction, dilution with water (50 mL), 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 (1.6 g, yield: 67.2%).

MS m/z(ESI):150.0[M+1]。

The third step

3-isopropyl-2-methoxypyridine 5d

Compound 5c (1.6 g, 10.72mmol) was dissolved in methanol (20 mL), 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 (1.4 g, yield: 86.3%).

MS m/z(ESI):152.1[M+1]。

¹ H NMR(400MHz,CDCl ₃ ):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 (1.4 g, 9.26 mmol) was dissolved in acetic acid (20 mL), sodium acetate (1.52g, 18.53mmol) was added, bromine (2.22g, 13.89mmol) was added dropwise at room temperature, and the reaction was stirred for 15 hours after completion of addition. Water (20 mL) was added, pH was adjusted with 2N NaOH =7-8, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5e (1.2 g, 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 Chemicals (Shanghai) Co., ltd.) were dissolved in 1, 4-dioxane (20 mL) and tris (dibenzylideneacetone) dipalladium (199mg, 0.22mmol, bailingwei science Co., ltd.), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (251mg, 0.43mmol, shaosheng Chemicals (Shanghai) Co., ltd.), N, N-diisopropylethylamine (561mg, 4.34mmol) were added, and the mixture was replaced with argon twice, and stirred 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 (730 mg, 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 (5 mL), 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 in tetrahydrofuran, 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 (25 mL), replaced with argon twice, and compound was added dropwise over an ice bath for 5h (5mL, 0.20M in tetrahydrofuran, 1.00 mmol), followed by addition of potassium carbonate (52mg, 0.38mmol), and the reaction was stirred at 0 ℃ for 0.5 h. Diluting with water (30 mL), adjusting pH =2-3 with 1N HCl, concentrating under reduced pressure, diluting with ethyl acetate (50 mL), washing with saturated sodium chloride solution (30 mL × 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 with eluent system B to obtain the title compound 5i (243 mg, yield: 65.8%).

MS m/z(ESI):373.0[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):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 (10 mL) and water (5 mL), and iron powder (171mg, 3.07mmol) and ammonium chloride (164mg, 3.07mmol) were added to the above reaction system, and the reaction system was heated to 80 ℃ in an oil bath and stirred for 3 to 4 hours. Filtration, concentration, extraction with ethyl acetate (50 mL. Times.2), washing with a saturated sodium chloride solution (30 mL), 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 (161 mg, 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 (8 mL), pyridine hydrogen bromide (347mg, 2.25mmol, hadamard reagent, inc.) 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 obtain the title compound 5k (100 mg, 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) urethane 5l

Compound 5k (100mg, 0.30mmol) was suspended in water (6 mL), concentrated hydrochloric acid (3 mL) was added, cooled to 0 deg.C, and 2mL of an aqueous solution of sodium nitrite (31mg, 0.45mmol) was added, and after completion, the mixture was stirred at 0 deg.C for 1 hour to give a red-brown suspension A. In another flask, compound 1i (52mg, 0.33mmol) was added, water (6 mL) was added, pyridine (3 mL) was added, and cooling to 0 ℃ gave 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 (100 mg, yield: 66.3%) of the title compound.

MS m/z(ESI):496.0[M+1]。

The eleventh step

5l (100mg, 0.20mmol) of the compound was dissolved in acetic acid (8 mL), and sodium acetate (132mg, 1.61mmol) was added thereto, 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 (45 mg, yield: 49.6%).

MS m/z(ESI):450.1[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):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 (25 mL), replaced with argon twice, and added dropwise to the mixture under ice-cooling for 5 hours (10.5mL, 0.2M in tetrahydrofuran, 2.10 mmol), followed by addition of potassium carbonate (87mg, 0.63mmol), and the reaction was stirred at 0 ℃ for 0.5 hour. Water was added to dilute (30 mL), pH =2-3 was adjusted with 1N HCl, and concentrated, and the resulting residue was purified to obtain the title compound 6a (550 mg, 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 (20 mL) and water (10 mL), and iron powder (326mg, 5.83mmol) and ammonium chloride (312mg, 5.83mmol) were added to the above reaction system, and the mixture was heated in an oil bath to 80 ℃ and stirred to react for 3 to 4 hours. Filtration, concentration, extraction with ethyl acetate (50 mL. Times.2), washing with saturated sodium chloride solution (30 mL), 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 (380 mg, 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 (8 mL), pyridinium 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 (108 mg, 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) carbamic acid ethyl ester 6d

Compound 6c (100mg, 0.24mmol) was suspended in water (6 mL), concentrated hydrochloric acid (3 mL) 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 flask, compound 1i (41mg, 0.26mmol) was added, water (6 mL) was added, pyridine (3 mL) was added, and cooled to 0 ℃ 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 successively with water (30 mL. Times.2) and n-hexane (30 mL. Times.2), and the resulting solid was dried in vacuo to give the title compound 6d (100 mg, yield: 71.4%).

MS m/z(ESI):586.0[M+1]。

The fifth step

Compound 6d (100mg, 0.17mmol) was dissolved in acetic acid (8 mL), 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 Detecor2, eluent: trifluoroacetic acid, water, acetonitrile) to give the title compound 6 (45 mg, yield: 48.8%).

MS m/z(ESI):539.9[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):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 (30 mL), and N, N-diisopropylethylamine (69g, 53.3mmol, 4-dimethylaminopyridine (400mg, 3.24mmol, shao Yuan Chemicals (Shanghai) Co., ltd.) and tert-butyldimethylchlorosilane (6.5 g,43.1mmol, shao Yuan Chemicals (Shanghai) Co., ltd.) were added thereto, 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 (8.95 g, yield: 90.8%).

Second step of

5-bromo-6-methoxy nicotinaldehyde 7b

6-Methoxynicotinaldehyde (12g, 87mmol) was dissolved in acetic acid (80 mL), sodium acetate (14g, 170mmol) was added, heat was released, and a solution of liquid bromine (20g, 125mmol) in acetic acid (20 mL) 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 (6.0 g, 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 (40 mL), isopropenylboronic acid pinacol ester (3.5g, 20.8mmol), tetratriphenylphosphine palladium (1g, 0.86mmol), potassium phosphate (4g, 18.8mmol), water (4 mL) was added, the reaction was carried out at an external temperature of 80 ℃ for 4 hours, water (40 mL) was added after the temperature was decreased, ethyl acetate extraction (30 mL. Times.3), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography with developing agent system B to give the title compound 7c (1.46 g, yield: 89%).

The fourth step

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

Compound 7c (1.46g, 8.23mmol) was dissolved in methanol (50 mL), 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 (1.49 g, yield: 99.7%).

The fifth step

5-isopropyl-6-methoxy nicotinaldehyde 7e

Compound 7d (1.49g, 8.22mmol) was dissolved in chloroform (100 mL), 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 (880 mg, 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 (12 mL), and dry ice was cooled in an acetone bath to-78 ℃, lithium diisopropylamide (2M, 1.34ml) was added dropwise thereto, and the mixture was stirred at-78 ℃ for 0.5 hour, and a solution of compound 7e (400mg, 2.23mmol) in tetrahydrofuran (8 mL) was added, and the mixture was stirred at-78 ℃ for 2 hours, slowly warmed to room temperature, and stirred for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride (5 mL), 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 (650 mg, yield: 85.0%).

MS m/z(ESI):342.0[M+1]。

Step seven

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

Compound 7f (650mg, 1.89mmol) was dissolved in methylene chloride (12 mL), and trifluoroacetic acid (1.1 mL), triethylsilane (1.1 mL) and boron trifluoride ether (1.1 mL) were added at room temperature, and the mixture was stirred 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 (350 mg, yield: 56.4%).

MS m/z(ESI):326.1[M+1]。

The 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 methylene chloride (20 mL), and 4-dimethylaminopyridine (11mg, 0.09mmol), triethylamine (118mg, 1.16mmol), N-phenylbis (trifluoromethanesulfonyl) imide (312mg, 0.87mmol, shaoyuan chemical technology, shanghai, ltd.) were added at 0 ℃ and stirred at room temperature for 16 hours. The solvent was removed by concentration under the reduced pressure, and the resulting residue was purified by silica gel column chromatography with developer system B to give the title compound 7h (260 mg, 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

Compound 7h (260mg, 0.57mmol) was dissolved in 1, 4-dioxane (15 mL), benzophenone imine (260mg, 0.57mmol, national chemical group, ltd.), cesium carbonate (369mg, 1.13mmol), 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (65mg, 0.113mmol), tris (dibenzylideneacetone) dipalladium (52mg, 0.06mmol) were added, replaced with argon three times, and stirred 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 (240 mg, 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 (10 mL), 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 (65 mg, 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) methyl carbamate 7k

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

MS m/z(ESI):432.0[M+1]。

¹ H 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 was replaced with the starting material 2, 6-dibromophenol in the first step to afford the title compound 8 (4 mg), yield: 25.6 percent.

MS m/z(ESI):522.0[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ )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) -ketone 9a (2.0g, 18.00mmol, shanghai Biao medicine science and technology Co., ltd.) was dissolved in N, N-dimethylformamide (50 mL), and then compound 1f (4.16g, 19.81mmol, shanghai Biao medicine science and technology Co., ltd.) and potassium carbonate (7.46g, 53.98mmol) were sequentially added thereto, and the mixture was stirred and reacted for 18 hours. Water (80 mL) 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 (2.7 g, 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.) were dissolved in dichloromethane (20 mL), and triethylamine (168mg, 1.66mmol), pyridine (131mg, 1.66mmol), 4A molecular sieve powder (289mg, 1.66mmol, alfaesa (China) chemical Co., ltd.) and copper acetate monohydrate (331mg, 1.66mmol, national institute of chemical technology 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 (10 mL) 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 (156 mg, yield: 45.6%).

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

¹ H NMR(400MHz,CDCl ₃ ):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, heated to 78 deg.C in an oil bath, and reacted with stirring for 2 hours. Filtration, the filter cake washed with ethanol (30 ml) and water (30 ml), concentrated under reduced pressure to remove ethanol, filtered, the filter cake collected and dried in vacuo to give the title compound 9e (135 mg, 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 (6 mL), concentrated hydrochloric acid (3 mL) was added, the reaction was cooled to 0 ℃ and an aqueous solution (1 mL) of sodium nitrite (31mg, 0.45mmol) was added, and after the addition, stirring was carried out at 0 ℃ for 1 hour to give a yellow solution A. In another flask was added (2-cyanoacetyl) urethane 1i (59mg, 0.38mmol, shaoyuan chemical technology (Shanghai), inc.), water (6 mL) and pyridine (3 mL), 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 the filter cake, and vacuum drying gave the title compound 9f (120 mg, yield: 64.2%).

The fifth step

Compound 9f (120mg, 0.22mmol) was dissolved in acetic acid (6 mL), 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 (60 mg, yield: 54.6%).

MS m/z(ESI):501.9[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):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 (40 mL), 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) to obtain the title compound 10B (1.8 g, 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 a mixed solvent of 150mL of ethanol and water (V/V = 2/1), and 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 (30 mL × 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) to obtain the title compound 10c (0.85 g, 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) group) acetyl) urethane 10d

Compound 10c (850mg, 2.71mmol) was suspended in water (20 mL), concentrated hydrochloric acid (10 mL) was added thereto, the mixture was cooled to 0 ℃ and 5mL of an aqueous solution of sodium nitrite (281mg, 4.07mmol) was added thereto, and the mixture was stirred at 0 ℃ for 1 hour to obtain yellow solution A. In another flask, compound 1i (423mg, 2.71mmol), water (10 mL), pyridine (10 mL) 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 (200 mL) 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 (950 mg, yield: 72.88%).

MS m/z(ESI):480.0[M+1]。

The fourth step

Compound 10d (950mg, 1.98mmol) was dissolved in dimethylacetamide (15 mL), and potassium acetate (233mg, 2.37mmol, hadamard's reagent, ltd.) was added, and the reaction was stirred for 3 hours while heating in an oil bath to 120 ℃. Cooled to room temperature, the reaction liquid was purified by preparative chromatography (Waters 2767-SQ detector 2, eluent: 0.1% aqueous trifluoroacetic acid/acetonitrile =35% -95% acetonitrile) to obtain the title compound 10 (610 mg, yield: 71.02%).

MS m/z(ESI):433.9[M+1]。

¹ H NMR(400MHz,DMSO-d ₆ ):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 EC ₅₀ And 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 prepared 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. Further diluting the compound 20-fold using DMEM/F12 (GE, # SH 30023.01) medium containing 0.5-vol FBS (corning, # 35-076-CV);

the constructed CHO-K1 cells expressing both the DR4 response element and THR α or THR β were plated in 96-well plates (Corning, # 3903) at 5000 cells/well, 37 ℃ and 5% ₂ The cells were cultured in a incubator (thermo scientific, # HERACell 240 i) for 24 hours.

Removing the medium from the cell plate, adding 95ul of DMEM/F12 medium containing 0.5% FBS and 5. Mu.l of the diluted compound solution, placing at 37 ℃ and 5% CO ₂ Incubating 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 beta ₅₀ The values are shown in Table 1.

TABLE 1 EC for agonism of compounds of this disclosure on THR α and THR β ₅₀ Value 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 thereof, or a pharmaceutically acceptable salt thereof:

wherein:

l is selected from CH ₂ An O atom and an S atom;

R ¹ are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group;

R ² selected from the group consisting of hydrogen atoms, cyano groups and carboxyl groups;

R ³ is a hydrogen atom or C _1-6 An alkyl group;

R ⁴ selected from hydrogen atom, C _1-6 Alkyl and phenyl; said phenyl group being optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents of haloalkyl; and is

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

with the proviso that it is not a compound of the following formula:

2. a compound represented by the general formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein, the first and the second end of the pipe are connected with each other,

R ¹ ～R ⁴ and L is as defined in claim 1.

3. The compound of the general formula (I) or its tautomer or its pharmaceutically acceptable salt according to claim 1 or2Salts thereof, wherein R ⁴ Is phenyl, optionally substituted by halogen or C _1-6 One or more substituents in the alkyl group.

4. The compound of the general formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ¹ Is halogen.

5. The compound of the general formula (I) according to claim 1 or2, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, R ¹ Is chlorine or bromine.

6. The compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R is ² Is a hydrogen atom.

7. The compound of the general formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ² Is cyano.

8. The compound of the general formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R ³ Is a hydrogen atom.

9. The compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, R ³ Is C _1-6 An alkyl group.

10. The compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein R is ⁴ Is a hydrogen atom.

11. The compound of the general formula (I) according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

12. a compound represented by the general formula (IA):

wherein:

R ^m is C _1-6 An alkyl group;

l is selected from CH ₂ An O atom and an S atom;

R ³ is a hydrogen atom or C _1-6 An alkyl group;

R ⁴ selected from hydrogen atom, C _1-6 Alkyl and phenyl; wherein said phenyl is optionally selected from halogen, C _1-6 Alkyl and C _1-6 Substituted by one or more substituents in the haloalkyl group; and is

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

13. The compound represented by the general formula (IA) according to claim 12, or a tautomer thereof, or a salt thereof, which is selected from any one of the following compounds:

14. a process for producing a compound represented by the general formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:

wherein:

R ^m is C _1-6 An alkyl group;

L、R ¹ ～R ⁴ and n is as defined in claim 1.

15. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

16. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the preparation of a THR β agonist.

17. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment and/or prevention of diseases which are modulated by thyroid hormone.

18. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment and/or prevention of metabolic diseases which are modulated by thyroid hormone.

19. Use of a compound of general formula (I) according to any one of claims 1 to 11 or a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the preparation of a medicament for the treatment and/or prophylaxis of obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular diseases, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) modulated by thyroid hormone.