TW202220977A - 6-oxo-1,6-dihydropyridazine derivative, preparation method therefor and application thereof in medicine - Google Patents

Abstract

The present application provides a 6-oxo-1,6-dihydropyridazine derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present application provides a 6-oxo-1,6- dihydropyridazine derivative as represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, and an application of the derivative as a therapeutic agent, particularly the use of same in the preparation of a drug for treating or preventing diseases regulated by thyroid hormones, wherein substituents in the formula have the same definitions as those in the description.

Description

6-Oxygen-1,6-dihydropyridazine derivatives, preparation method and medical application thereof

The present disclosure belongs to the field of medicine, and relates to a 6-oxo-1,6-dihydropyridazine derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent , especially for the preparation of medicines for the treatment and/or prevention of obesity, diabetes, hyperlipidemia, thyroid disease, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

Thyroid hormones are very important for the normal development of the body and for maintaining metabolic homeostasis. Three major functions of thyroid hormone: (1) Promote growth and development. Thyroid hormone has the most obvious role in promoting growth and development in infancy, and has the greatest impact in the first five months after birth. It mainly promotes the growth and development of bones, brain and reproductive organs. Without thyroid hormone, GH from the pituitary gland cannot function. (2) Affect metabolism, thermogenesis effect, thyroid hormone can increase the oxygen consumption rate of most tissues, increase thermogenesis effect, this thermogenesis effect may be due to thyroid hormone can increase the synthesis of Na ⁺ -K ⁺ pump on the cell membrane, and can increase its Vitality, the latter is an energy-consuming process. (3) Thyroid hormone plays an important role in the activities of some organs. For example, it is of great significance to maintain the excitability of the nervous system. Thyroid hormone can directly act on the myocardium, promote the release of Ca ²⁺ from the sarcoplasmic reticulum, and increase the contractility of the myocardium. Enhanced, heart rate increases.

The natural thyroid hormone T3 exerts physiological effects by binding to the thyroid hormone receptor (THR). Thyroid hormone receptors have two distinct subtypes, THRα and THRβ. THRβ is mainly distributed in the liver, while THRα is mainly distributed in the brain and heart tissue. Natural thyroid hormones act on both THRα and THRβ without any selectivity. The natural thyroid hormone T3 significantly reduces cholesterol, low-density lipoprotein (LDL) in animal models and humans. However, T3 has side effects on the heart and it cannot be used for obesity, hypercholesterolemia and non-alcoholic fatty liver treatment.

Studies have shown that the effects of thyroid hormone T3 on the heart, especially heart rate, are mediated by THRα. The effect of thyroid hormone T3 on liver, muscle and other tissues is mainly mediated by THRβ. Therefore, selective THRβ agonists should be able to treat obesity, hyperlipidemia, thyroid disease, and nonalcoholic steatohepatitis without affecting heart rate and rhythm.

Thyroid hormone receptor β (THRβ)-selective and/or tissue-selective acting thyroid hormone analogs have been synthesized that provide modest reductions in body weight, lipids, cholesterol, and lipoproteins, whereas cardiovascular and hypothalamic Has little effect on normal function of the pituitary/thyroid axis (Johan Malm, J. Med. Chem. 2003, 46, 1580-1588; Martha J. Kelly, J. Med. Chem. 2014, 57, 3912-3923) .

Patents that have disclosed compounds that are agonists of THRβ include WO2006128055A2, WO2005051298A2, WO2007009913A1, and WO2009037172A1, among others.

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

in,

R ^1a and R ^{1b are} the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl , cycloalkyl and heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl , substituted by one or more substituents in alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl;

R ² is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, carboxyl, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkane base and heterocyclyl;

^R is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl, alkenyl, alkynyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane substituted with one or more substituents of oxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and R ^a ; and

^Ra is selected from alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkyne , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, Substituted with one or more substituents of haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In some embodiments of the present disclosure, the compound represented by the general formula (I) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^{1b are} the same or different, and are each independently halogen or C _1-6 alkyl.

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

in,

R ² and R ³ are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, asymmetric Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from C _1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered Aryl and 5- to 10-membered heteroaryl; wherein the C _1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl Each independently optionally selected from pendant oxygen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino , nitro, hydroxyl, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl and one of R ^a or multiple substituents; R ^a is a 6- to 10-membered aryl group, wherein the 6- to 10-membered aryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C ₁ -Substituted with one or more substituents among _-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, nitro, hydroxyl and C _1-6 hydroxyalkyl.

、 正丙基和乙基；環A為3至8員環烷基或6至10員芳基；R⁴相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基、氰基和C_1-6羥烷基；n為0或1。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, asymmetric an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from

, n-propyl and ethyl; Ring A is a 3- to 8-membered cycloalkyl group or a 6- to 10-membered aryl group; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

、 正丙基和乙基；環A選自環丙基、環丁基和苯基；R⁴相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基、氰基和C_1-6羥烷基；n為0或1。 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, asymmetric an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from

, n-propyl and ethyl; Ring A is selected from cyclopropyl, cyclobutyl and phenyl; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, it is the compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or its In the form of a mixture or a pharmaceutically acceptable salt thereof:

in,

Ring A is selected from the group consisting of 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl;

R ⁴ are the same or different, each independently selected from hydrogen atom, pendant oxygen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy , cyano, amino, nitro, hydroxyl, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl , wherein the 6- to 10-membered aryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano , substituted with one or more substituents in amine, nitro, hydroxyl and C _1-6 hydroxyalkyl;

n is 0, 1, 2, 3, 4 or 5;

R ² is as defined in general formula (I).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II) and general formula (III) according to the present disclosure or their tautomers, racemates, enantiomers Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R is selected from ^hydrogen atoms, cyano groups, C _1-6 alkyl groups, and 3- to 8-membered cycloalkyl groups, Preferably, R ² is cyano.

In some embodiments of the present disclosure, the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 3- to 8-membered cycloalkyl group or a 6- to 10-membered aryl group; preferably, Ring A is selected from cyclopropyl, cyclobutyl and phenyl.

In some embodiments of the present disclosure, the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or In the form of mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _{1- 6} hydroxyalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

、正丙基和乙基；環A為3至8員環烷基或6至10員 芳基；R⁴相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基、氰基和C_1-6羥烷基；n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein R ^1a and R ^{1b are} the same or different, and each independently is halogen or C _1-6 alkyl; R ² is selected from hydrogen atom, cyano group, C _1-6 Alkyl and 3- to 8-membered cycloalkyl; ^R is selected from

, n-propyl and ethyl; Ring A is a 3- to 8-membered cycloalkyl group or a 6- to 10-membered aryl group; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

、正丙基和乙基；環A為3至8員環 烷基或6至10員芳基；R⁴相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基、氰基和C_1-6羥烷基；n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein R ² is selected from hydrogen atom, cyano group, C _1-6 alkyl and 3- to 8-membered cycloalkyl; R ³ is selected from

, n-propyl and ethyl; Ring A is a 3- to 8-membered cycloalkyl group or a 6- to 10-membered aryl group; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a hydrogen atom, a cyano group, a C _1-6 alkyl group, and a 3- to 8-membered cycloalkyl group; Ring A is a 3- to 8-membered cycloalkyl group or a 6-membered cycloalkyl group to 10-membered aryl; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein R ² is cyano; Ring A is selected from cyclopropyl, cyclobutyl and phenyl; R ⁴ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl; n is 0 or 1.

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, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof Medicinal salts:

in,

R ^m is C _1-6 alkyl;

R ^1a , R ^1b , R ² and R ³ are as defined in general formula (I).

Another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A pharmaceutically acceptable salt of general formula (IIA),

in,

R ^m is C _1-6 alkyl;

R ² and R ³ are as defined in general formula (II).

Another aspect of the present disclosure relates to a compound of formula (IA) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A pharmaceutically acceptable salt of general formula (IIIA),

in,

R ^m is C _1-6 alkyl;

Ring A, R ² , R ⁴ and n are as defined in general formula (III).

Typical compounds of formula (IA) of the present disclosure include, but are not limited to:

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

The compound of general formula (IA) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction to obtain the compound of general formula (I),

in,

R ^m is C _1-6 alkyl;

R ^1a , R ^1b , R ² and R ³ are as defined in general formula (I).

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

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

in,

R ^m is C _1-6 alkyl;

R ² and R ³ are as defined in general formula (II).

Another aspect of the present disclosure relates to a method for preparing the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound of general formula (IIIA) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction to obtain the compound of general formula (III),

in,

R ^m is C _1-6 alkyl;

Ring A, R ² , R ⁴ and n are as defined in general formula (III).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the compounds of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or their tautomers isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients .

The present disclosure further relates to the compounds of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or tautomers, racemates, enantiomers thereof Use of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a THRβ agonist.

The present disclosure further relates to the compounds of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or tautomers, racemates, enantiomers thereof Use of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the manufacture of a medicament for the treatment and/or prevention of a disease regulated by thyroid hormones ; preferably in the preparation of a medicament for the treatment and/or prevention of metabolic diseases regulated by thyroid hormones.

The present disclosure further relates to the compounds of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or tautomers, racemates, enantiomers thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation for the treatment and/or prevention of obesity, hypothyroidism, thyroid cancer regulated by thyroid hormones , diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) use in medicine.

The present disclosure also relates to a method of agonizing THRβ, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table A according to the present disclosure The compounds shown, or tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

The present disclosure also relates to a method of treating and/or preventing a disease regulated by thyroid hormone, preferably a method of treating and/or preventing a metabolic disease regulated by thyroid hormone, comprising administering to a patient in need thereof a therapeutically effective amount of a treatment according to the present disclosure The compounds of the general formula (I), general formula (II), general formula (III) and Table A or their tautomers, racemates, enantiomers, and diastereomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a treatment and/or prevention of obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis modulated by thyroid hormones (NASH) and a method for nonalcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) and formula (III) according to the present disclosure. The compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them thing.

The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a 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 a compound of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a THRβ agonist.

The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or a tautomer, racemate, enantiomer thereof Isomers, 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 diseases regulated by thyroid hormones; Preferably as a drug for the treatment and/or prevention of metabolic diseases regulated by thyroid hormones.

The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure or a tautomer, racemate, enantiomer thereof A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of obesity, hypothyroidism, Drugs for thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure can also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

As a general guide, the active compounds are preferably presented in unit doses or in such a manner that the patient can self-administer in a single dose. Unit doses of a compound or composition of the present disclosure can be expressed as tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstituted powders, or liquids. A suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: filler (diluent), binder, wetting agent, disintegrant or excipient Formulations, etc. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The 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.

Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifying agents 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 sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous Continuous intravenous drug delivery device. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This 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 non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

The compounds of the present disclosure can 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 that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the medical condition of the patient, the behavior, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment modality such as mode of treatment, daily dose of compound or pharmaceutically acceptable The type of salt can be verified according to traditional treatment protocols.

Glossary

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 1 to 12 (eg 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, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyhexyl Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, th Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl pentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituent Preferably independently optionally selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, One or more substituents of nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "(or) alkylene group" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, It is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 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 (or alkylene) alkylene include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3 -Propylidene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The (or extended) alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkenyl, alkynyl, Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, One or more substituents of aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Preferably alkenyl groups containing 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkenyl groups containing 2 to 6 carbon atoms . Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cyclic Alkyloxy, One or more substituents of heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably alkynyl groups contain 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkynyl groups contain 2 to 6 carbon atoms . Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more substituents of alkyloxy, 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 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 20 carbon atoms. 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spirocycloalkyl or poly-spirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl . More preferably 3-member/5-member, 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Multiple double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3/4, 3/5, 3/6 Member, 4 Member/4 Member, 4 Member/5 Member, 4 Member/6 Member, 5 Member/4 Member, 5 Member/5 Member, 5 Member/6 Member, 6 Member/3 Member, 6 Member/4 Member, 6-membered/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

)、四氫萘基(

)、 苯并環庚烷基(

)等；較佳茚滿基(

)和四氫萘基 (

)。 The cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached at Rings taken together are cycloalkyl, non-limiting examples include indanyl (

), tetrahydronaphthyl (

), benzocycloheptyl (

) etc.; preferably indanyl (

) and tetrahydronaphthyl (

).

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

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. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, Haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, sulfur, S(O ) or S(O) ₂ heteroatoms, but not including ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are Heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , Homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, and one atom (called a spiro atom) is shared between the single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, S (O) or S(O) ₂ heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably 3-member/5-member, 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl 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 other rings in the system, and one or more rings may contain one or more Double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) ₂ and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3/4, 3/5, 3/6 Member, 4 Member/4 Member, 4 Member/5 Member, 4 Member/6 Member, 5 Member/4 Member, 5 Member/5 Member, 5 Member/6 Member, 6 Member/3 Member, 6 Member/4 Member, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O) ₂ , and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure The rings linked together are heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

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

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

Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkane among the radicals, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (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 members (eg 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as 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 linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

The aforementioned cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived by removing one hydrogen atom from the parent carbon atom (ie, a monovalent group), or from the same parent carbon atom or two different A residue derived from the removal of two hydrogen atoms from a carbon atom (ie, a divalent group).

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 alkyl-S-, wherein alkyl is as defined above.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy 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 hydroxy 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 "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "pendant oxy" or "pendant oxygen" refers to "=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, cycloalkyl are as defined above.

”或“

”，或者同時包含“

”和“

”兩種構型。本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即可以為Z構型或E構型，或者同時包含兩種構型。 In the chemical structures of the compounds described in the present disclosure, the bond "/" represents an unspecified configuration, that is, if a chiral isomer exists in the chemical structure, the bond "/" can be "/"

"or"

", or both "

"and"

"Two configurations. In the chemical structure of the compound described in this disclosure, the bond"

” does not specify a configuration, i.e. it can be either the Z configuration or the E configuration, or both.

The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structures of the present disclosure, hydrogen is replaced with "deuterium" or "tritium," or fluorine is replaced ^with18F -fluorine labeling ( ^18F isotope), ^or11C- , ^13C- , ^or14C -enriched Compounds in which carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in 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 by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

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

"Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5 (eg 1, 2, 3, 4 or 5), more preferably 1 to 3 hydrogen atoms are independently of each other number of substituents substituted. Those of ordinary skill in the art can determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other chemical components, together with other components such as a physiologically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals, and have the desired biological activity. They can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, Also depending on the specific active substance, the appropriate effective amount in a case can be determined by one of ordinary skill in the art based on routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are 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 indicated that the parameter can vary by ±10%, and sometimes preferably within ±5%. As will be understood by one of ordinary skill in the art, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

Synthetic methods of compounds of the present disclosure

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

Option One

The present disclosure is the synthesis method of the compound represented by the general formula (I) or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt , which includes the following steps:

The compound of general formula (IA) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction under basic conditions to obtain the compound of general formula (I),

in,

R ^m is C _1-6 alkyl;

R ^1a , R ^1b , R ² and R ³ are as defined in general formula (I).

Option II

The present disclosure is the synthesis method of the compound represented by the general formula (II) or its tautomer, racemate, enantiomer, diastereomer, or its mixture or its pharmaceutically acceptable salt , which includes the following steps:

The compound of general formula (IIA) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction under basic conditions to obtain the compound of general formula (II),

in,

R ^m is C _1-6 alkyl;

R ² and R ³ are as defined in general formula (II).

third solution

Another aspect of the present disclosure relates to a method for preparing the compound represented by the general formula (III) according to the present disclosure or a tautomer, racemate, enantiomer, diastereomer, or tautomer, racemate, enantiomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Under basic conditions, the compound of general formula (IIIA) or its pharmaceutically acceptable salt undergoes an intramolecular cyclization reaction to obtain the compound of general formula (III),

in,

R ^m is C _1-6 alkyl;

Ring A, R ² , R ⁴ and n are as defined in general formula (III).

In the above scheme, the reagents providing alkaline conditions include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropyl Lithium propylamide, lithium bistrimethylsilylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, the inorganic bases include but are not limited to sodium bicarbonate, Potassium bicarbonate, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide and their hydrates; preferably potassium acetate;

The reaction of the above scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, glacial acetic acid, methanol, ethanol, n-butanol, 3-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate , n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N , N -dimethylformamide, N , N -dimethylacetamide and its mixture.

Figure 1 shows the effect of the compound of Example 3 on the serum total cholesterol of SD rats with hypercholesterolemia.

Figure 2 shows the effect of the compound of Example 3 on serum non-high-density lipoprotein cholesterol in hypercholesterolemic SD rats.

Figure 3 shows the effect of the compound of Example 3 on serum low-density lipoprotein cholesterol in hypercholesterolemic SD rats.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

The determination of MS was performed with an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS); waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

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

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

HPLC preparations were performed using Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for TLC separation and purification products is 0.4mm ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Accela ChemBio Inc. Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.

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

Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

Pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction used a CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography include: A : dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

2-(3,5-Dichloro-4-((1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)- 3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1

first step

2-(4-Amino-2,6-dichlorophenyl)-2-(6-chloropyridazin-3-yl)acetonitrile 1c

3,6-Dichloropyridazine 1a (7.4g, 49.7mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and 2-(4-amino-2,6-dichlorophenyl)acetonitrile 1b (10g, 49.7 mmol, prepared by the method disclosed in the intermediate 7c on page 44 of the specification in the patent application US2020115362A1) was dissolved in tetrahydrofuran (120mL), 0 ℃, added potassium third butoxide (16.7g, 148.8mmol), the reaction was stirred for 5 minutes . Under ice bath, water (250 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1c (15 g), This product was used directly in the next step without purification.

MS m/z (ESI): 312.9 [M+1].

second step

6-(4-Amino-2,6-dichlorobenzyl)pyridazin-3( 2H )-one 1d

Compound 1c (15 g, 47.8 mmol) was added to water (25 mL), 12M concentrated hydrochloric acid (100 mL) and glacial acetic acid (50 mL) were added, and the reaction was heated to 120° C. and stirred for 48 hours. 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 1d (8.2 g, yield: 63.5%).

MS m/z (ESI): 269.9 [M+1].

third step

3-(3-(4-Amino-2,6-dichlorobenzyl)-6-oxopyridazin-1( 6H )-yl)benzonitrile 1e

Compound 1d (500mg, 1.85mmol) was dissolved in dichloromethane (100mL), 3-cyanophenylboronic acid (400mg, 2.72mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, copper acetate monohydrate (740mg, 3.71 mmol), triethylamine (375mg, 3.71mmol, 515μL), pyridine (300mg, 3.79mmol, 305μ) and 4Å molecular sieve (815mg, 1.85mmol), the reaction was stirred openly for 18 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (370 mg, yield: 53.8%).

MS m/z (ESI): 370.9 [M+1].

the fourth step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridine) Azin-3-yl) methyl) phenyl) hydrazone) acetyl) ethyl carbamate 1g

Compound 1e (360 mg, 0.97 mmol) was suspended in water (6 mL), 12 M concentrated hydrochloric acid (3 mL) was added under an ice bath, the reaction was cooled to -5~0 °C, and an aqueous solution of sodium nitrite (270 mg, 3.9 mmol) was added dropwise (0.5 mL), the reaction was stirred at -5~0 °C for 1 hour to obtain suspension A; at -5~0 °C, (2-cyanoacetyl) ethyl carbamate 1f (170 mg, 1.1 mmol, complete medicine) was suspended in water (6 mL), pyridine (3 mL) was added, and the reaction was stirred for 10 minutes to obtain a clear solution B. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred at -5~0°C for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give 1 g (522 mg) of the crude title compound, which was used in the next step without purification.

MS m/z (ESI): 537.8 [M+1].

the fifth step

2-(3,5-Dichloro-4-((1-(3-cyanophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)- 3,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1

Compound 1 g (522 mg, 0.97 mmol) was dissolved in N , N -dimethylacetamide (10 mL), potassium acetate (115 mg, 1.17 mmol) was added, the reaction was heated to 120 ° C, stirred for 4 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: ammonium bicarbonate = 58%: 42%: 0.1%) to give the title compound 1 (102 mg, Yield: 21.4%).

MS m/z (ESI): 490.0 [M-1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 8.04(s,1H), 7.85(d,1H), 7.81(d,1H), 7.70(s,2H), 7.68(t,1H), 7.48(d , 1H), 7.10 (d, 1H), 6.45 (brs, 1H), 4.34 (s, 2H).

Example 2

2-(3,5-Dichloro-4-((6-oxo-1-propyl-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-bilateral Oxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-propylpyridazin-3( 2H )-one 2a

Compound 1d (250 mg, 0.93 mmol) was dissolved in ethylene glycol dimethyl ether (20 mL), n-propane bromide (140 mg, 1.14 mmol, 0.1 mL) and cesium carbonate (450 mg, 1.38 mmol) were added, and the reaction was heated to 100 ° C and stirred. 16 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 2a (180 mg, yield: 62.3%).

MS m/z (ESI): 311.9 [M+1].

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-propyl-1,6-dihydropyridazin-3-yl)) Methyl)phenyl)hydrazone)acetyl)carbamate 2b

Compound 2a (180mg, 0.58mmol) was suspended in water (4mL), 12M concentrated hydrochloric acid (2mL) was added under ice bath, the reaction was cooled to -5~0°C, and an aqueous solution (0.5%) of sodium nitrite (160mg, 2.32mmol) was added dropwise. mL), the reaction was stirred at -5~0 °C for 1 hour to obtain suspension A; at -5~0 °C, compound 1f (100 mg, 0.64 mmol) was suspended in water (4 mL), pyridine (2 mL) was added, and the reaction was stirred After 10 minutes, a clear solution B was obtained. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. After filtration, the filter cake was washed with water and dried in vacuo to give crude title compound 2b (276 mg), which was used in the next step without purification.

MS m/z (ESI): 478.9 [M+1].

third step

2-(3,5-Dichloro-4-((6-oxo-1-propyl-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-bilateral Oxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2

Compound 2b (276 mg, 0.58 mmol) was dissolved in N , N -dimethylacetamide (5 mL), potassium acetate (70 mg, 0.71 mmol) was added, the reaction was heated to 120°C, stirred for 4 hours, and the reaction was cooled to room temperature . Concentrated under reduced pressure, the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 47%: 53%: 0.1%) to give the title compound 2 (168 mg, yield rate: 67.3%).

MS m/z (ESI): 432.9 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.23 (brs, 1H), 7.67 (s, 2H), 7.40 (d, 1H), 6.92 (d, 1H), 4.29 (s, 2H), 3.85 (t , 2H), 1.61-1.54 (m, 2H), 0.74 (t, 3H).

Example 3

2-(3,5-Dichloro-4-((6-oxo-1-ethyl-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-bilateral Oxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-ethylpyridazin-3( 2H )-one 3a

Compound 1d (300 mg, 1.11 mmol) was dissolved in N , N -dimethylformamide (6 mL), iodoethane (138 mg, 0.88 mmol) and cesium carbonate (1.08 g, 3.33 mmol) were added, and the reaction was heated to 40 °C , stirring for 5 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 3a (120 mg, yield: 36.2%).

MS m/z (ESI): 297.9 [M+1].

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-ethyl-1,6-dihydropyridazin-3-yl)) Methyl)phenyl)hydrazone)acetyl)carbamate 3b

Compound 3a (120mg, 0.40mmol) was suspended in water (8mL), 12M concentrated hydrochloric acid (4mL) was added under ice bath, the reaction was cooled to -5~0°C, and an aqueous solution of sodium nitrite (55.5mg, 0.80mmol) was added dropwise ( 1.5mL), the reaction was stirred at -5~0°C for 1 hour to obtain suspension A; at -5~0°C, compound 1f (62.8mg, 0.40mmol) was suspended in water (4mL), pyridine (4mL) was added, The reaction was stirred for 10 minutes to obtain clear solution B. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give crude title compound 3b (140 mg), which was used in the next step without purification.

MS m/z (ESI): 465.0 [M+1].

third step

2-(3,5-Dichloro-4-((6-oxo-1-ethyl-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-bilateral Oxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3

Compound 3b (140 mg, 0.30 mmol) was dissolved in N , N -dimethylacetamide (10 mL), potassium acetate (35 mg, 0.36 mmol) was added, the reaction was heated to 120°C, stirred for 4 hours, and the reaction was cooled to room temperature . It was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 47%: 53%: 0.1%) to give the title compound 3 (100 mg, yield rate: 79.2%).

MS m/z (ESI): 417.0 [M-1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.25(brs,1H), 7.69(s,2H), 7.40(d,1H), 6.93(d,1H), 4.30(s,2H), 3.91-3.96 (m, 2H), 1.13 (t, 3H).

Example 4

2-(3,5-Dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 4

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-(3-fluorophenyl)pyridazin-3( 2H )-one 4a

Compound 1d (600mg, 2.22mmol) was dissolved in dichloromethane (50mL), 3-fluorophenylboronic acid (466mg, 3.33mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, copper acetate monohydrate (887mg, 4.44mmol) ), triethylamine (450mg, 4.44mmol, 618μL), pyridine (351mg, 4mmol, 357μL), 4Å molecular sieve (773mg, 4.44mmol), the reaction was stirred openly for 18 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 4a (328 mg, yield: 40.8%).

MS m/z (ESI): 364.1 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 7.52 (q, 1H), 7.42 (d, 2H), 7.32 (d, 1H), 7.25 (m, 1H), 7.04 (d, 1H), 6.65 (s , 2H), 5.68 (s, 2H), 4.10 (s, 2H).

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridazine) -3-yl)methyl)phenyl)hydrazone)acetyl)carbamate 4b

Compound 4a (247mg, 0.68mmol) was suspended in water (6mL), 12M concentrated hydrochloric acid (3mL) was added under ice bath, cooled to -5~0°C, and an aqueous solution (0.5mL) of sodium nitrite (140mg, 2.02mmol) was added dropwise ), the reaction was stirred at -5~0 °C for 1 hour to obtain suspension A; at -5~0 °C, compound 1f (117 mg, 0.75 mmol) was suspended in water (6 mL), pyridine (3 mL) was added, and stirred for 10 minutes, A clear solution B was obtained. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give crude title compound 4b (270 mg), which was used in the next step without purification.

MS m/z (ESI): 530.9 [M+1].

third step

2-(3,5-Dichloro-4-((1-(3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 4

Compound 4b (216 mg, 0.41 mmol) was dissolved in N , N -dimethylacetamide (3 mL), potassium acetate (60 mg, 0.61 mmol) was added, the reaction was heated to 120°C, stirred for 4 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 50%: 50%: 0.1%) to give the title compound 4 (170 mg, Yield: 86.2%).

MS m/z (ESI): 485.0 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.23 (brs, 1H), 7.69 (s, 2H), 7.54 (d, 1H), 7.48 (m, 1H), 7.35 (m, 2H), 7.22 (td , 1H), 7.11 (d, 1H), 4.39 (s, 2H).

Example 5

2-(3,5-Dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-cyclopropylpyridazin-3( 2H )-one 5a

Compound 1d (346mg, 1.28mmol) was dissolved in dichloromethane (50mL), cyclopropylboronic acid (165mg, 1.92mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added at room temperature, copper acetate monohydrate (512mg, 2.56 mmol), triethylamine (260 mg, 2.56 mmol, 357 μL), pyridine (203 mg, 2.56 mmol, 206 μL), 4Å molecular sieve (446 mg, 2.56 mmol), and stirred openly at 40°C for 18 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5a (300 mg, yield: 75.5%).

MS m/z (ESI): 310.1 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 7.27(s,2H), 7.23(d,1H), 6.86(d,1H), 6.64(s,2H), 6.56(brs,2H), 4.07-4.01 (m, 1H), 0.86-0.83 (m, 2H), 0.81-0.78 (m, 2H).

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl) ) methyl) phenyl) hydrazone) acetyl) ethyl carbamate 5b

Compound 5a (224 mg, 0.72 mmol) was suspended in water (6 mL), 12 M concentrated hydrochloric acid (3 mL) was added under an ice bath, the reaction was cooled to -5~0 °C, and an aqueous solution (0.5 mL), the reaction was stirred at -5~0 °C for 1 hour to obtain a clear solution A; at -5~0 °C, 2 compound 1f (135 mg, 0.86 mmol) was suspended in water (6 mL), pyridine (3 mL) was added, and stirred for 10 minutes, a clear solution B was obtained. At -5~0°C, the clear solution A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give crude title compound 5b (115 mg), which was used in the next step without purification.

MS m/z (ESI): 476.9 [M+1].

third step

2-(3,5-Dichloro-4-((1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5

Compound 5b (110 mg, 0.23 mmol) was dissolved in N , N -dimethylacetamide (3 mL), potassium acetate (34 mg, 0.35 mmol) was added, the reaction was heated to 120°C, stirred for 6 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 66%: 34%: 0.1%) to obtain the title compound 5 (60 mg, Yield: 60.4%).

MS m/z (ESI): 431.0 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.24(brs,1H), 7.69(s,2H), 7.45(d,1H), 6.93(d,1H), 4.27(s,2H), 4.04-4.00 (m, 1H), 0.82-0.78 (m, 2H), 0.68-0.64 (m, 2H).

Example 6

2-(3,5-Dichloro-4-((1-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 6

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-cyclobutylpyridazin-3( 2H )-one 6a

Compound 1d (500 mg, 1.85 mmol) was dissolved in dimethyl ether (20 mL), bromocyclobutane (500 mg, 3.70 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added at room temperature, cesium carbonate (905 mg, 2.77 mmol), tetrabutylammonium iodide (62 mg, 0.19 mmol), potassium iodide (31 mg, 0.19 mmol), and the reaction was stirred at 110° C. for 18 hours. It was cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 6a (270 mg, yield: 45.0%).

MS m/z (ESI): 323.9 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 7.21(d,1H), 6.82(d,1H), 6.66(s,2H), 5.64(brs,2H), 5.27(m,1H), 4.06(s , 2H), 2.28-2.21 (m, 2H), 2.20-2.15 (m, 2H), 1.77-1.64 (m, 2H).

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl) ) methyl) phenyl) hydrazone) acetyl) ethyl carbamate 6b

Compound 6a (220mg, 0.68mmol) was suspended in water (6mL), 12M concentrated hydrochloric acid (3mL) was added under ice bath, the reaction was cooled to -5~0°C, and an aqueous solution (0.5%) of sodium nitrite (140mg, 2.03mmol) was added dropwise. mL), the reaction was stirred at -5~0 °C for 1 hour to obtain a clear solution A; at -5~0 °C, compound 1f (127 mg, 0.81 mmol, Bidder Pharmaceuticals) was suspended in water (6 mL), and pyridine (3 mL) was added. , the reaction was stirred for 10 minutes to obtain a clear solution B. At -5~0°C, the clear solution A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give crude title compound 6b (322 mg), which was used in the next step without purification.

MS m/z (ESI): 491.1 [M+1].

third step

2-(3,5-Dichloro-4-((1-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 6

Compound 6b (297 mg, 0.60 mmol) was dissolved in N , N -dimethylacetamide (3 mL), potassium acetate (90 mg, 0.92 mmol) was added, the reaction was heated to 120 °C, stirred for 6 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 60%: 40%: 0.1%) to give the title compound 6 (187 mg, Yield: 69.5%).

MS m/z (ESI): 445.1 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.22 (brs, 1H), 7.70 (s, 2H), 7.45 (d, 1H), 6.89 (d, 1H), 5.27-5.20 (m, 1H), 4.35 (s, 2H), 2.16-2.10 (m, 2H), 2.08-2.02 (m, 2H), 1.72-1.62 (m, 1H), 1.60-1.54 (m, 1H).

Example 7

2-(3,5-Dichloro-4-((1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-(4-fluorobenzyl)pyridazin-3( 2H )-one 7a

Compound 1d (500mg, 1.85mmol) was dissolved in acetonitrile (50mL), 4-fluorobenzyl bromide (525mg, 2.77mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), cesium carbonate (1.20g, 3.68mmol) were added at room temperature , potassium carbonate (512 mg, 3.70 mmol), tetrabutylammonium iodide (62 mg, 0.19 mmol), potassium iodide (31 mg, 0.19 mmol), and the reaction was stirred at 60° C. for 4 hours. The reaction was cooled, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used The resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 7a (330 mg, yield: 47.1%).

MS m/z (ESI): 378.0 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 7.29-7.26 (m, 2H), 7.20 (d, 1H), 7.13 (t, 2H), 6.90 (d, 1H), 6.65 (s, 2H), 5.67 (s, 2H), 5.11 (s, 2H), 4.02 (s, 2H).

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyridazine) -3-yl)methyl)phenyl)hydrazone)acetyl)carbamate 7b

Compound 7a (260 mg, 0.69 mmol) was suspended in water (6 mL), 12 M concentrated hydrochloric acid (3 mL) was added under an ice bath, the reaction was cooled to -5~0 °C, and an aqueous solution (0.5 mL), the reaction was stirred at -5~0 °C for 1 hour to obtain suspension A; at -5~0 °C, compound 1f (129 mg, 0.83 mmol) was suspended in water (6 mL), pyridine (3 mL) was added, and the reaction was stirred After 10 minutes, a clear solution B was obtained. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give the crude title compound 7b (320 mg), which was used in the next step without purification.

MS m/z (ESI): 544.9 [M+1].

third step

2-(3,5-Dichloro-4-((1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7

Compound 7b (250 mg, 0.46 mmol) was dissolved in N , N -dimethylacetamide (3 mL), potassium acetate (68 mg, 0.69 mmol) was added, the reaction was heated to 120°C, stirred for 6 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 22%: 78%: 0.1%) to obtain the title compound 7 (100 mg, Yield: 43.7%).

MS m/z (ESI): 499.0 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.26 (brs, 1H), 7.69 (s, 2H), 7.45 (d, 1H), 7.17-7.14 (m, 2H), 7.12-7.07 (m, 2H) , 6.96 (d, 1H), 5.03 (s, 2H), 4.30 (s, 2H).

Example 8

2-(3,5-Dichloro-4-((1-(3-chlorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-(3-chlorophenyl)pyridazin-3( 2H )-one 8a

Compound 1d (500mg, 1.85mmol) was dissolved in dichloromethane (40mL), 3-chlorophenylboronic acid (435mg, 2.78mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, copper acetate monohydrate (740mg, 3.71mmol) ), triethylamine (375mg, 3.71mmol, 515μL), pyridine (300mg, 3.79mmol, 305μL), 4Å molecular sieve (644mg, 3.70mmol), the reaction was stirred openly for 18 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8a (270 mg, yield: 38.3%).

MS m/z (ESI): 379.9 [M+1].

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((1-(3-chlorophenyl)-6-oxo-1,6-dihydropyridazine) -3-yl)methyl)phenyl)hydrazone)acetyl)carbamate 8b

Compound 8a (270 mg, 0.71 mmol) was suspended in water (6 mL), 12 M concentrated hydrochloric acid (3 mL) was added under an ice bath, the reaction was cooled to -5~0 °C, and an aqueous solution (1 mL) of sodium nitrite (74 mg, 1.07 mmol) was added dropwise. ), at -5~0 °C, the reaction was stirred for 1 hour to obtain suspension A; at -5~0 °C, compound 1f (111 mg, 0.71 mmol) was suspended in water (3 mL), pyridine (3 mL) was added, and the reaction was stirred After 10 minutes, a clear solution B was obtained. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. Filtration, the filter cake was washed with water, and dried in vacuo to give crude title compound 8b (330 mg), which was used in the next step without purification.

MS m/z (ESI): 546.8 [M+1].

third step

2-(3,5-Dichloro-4-((1-(3-chlorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3 ,5-Dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8

Compound 8b (330 mg, 0.60 mmol) was dissolved in N,N -dimethylacetamide (3 mL), potassium acetate (71 mg, 0.72 mmol) was added, the reaction was heated to 120°C, stirred for 3 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 40%: 60%: 0.1%) to give the title compound 8 (82 mg, Yield: 27.1%).

MS m/z (ESI): 500.8 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.23 (s, 1H), 7.69 (s, 2H), 7.52-7.59 (m, 2H), 7.42-7.49 (m, 3H), 7.11 (d, 1H) , 4.39(s, 2H).

Example 9

2-(3,5-Dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-3-yl)methyl) Phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 9

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-(3-(trifluoromethyl)phenyl)pyridazin-3( 2H )-one 9a

Compound 1d (500mg, 1.85mmol) was dissolved in dichloromethane (40mL), 3-trifluoromethylbenzeneboronic acid (527mg, 2.78mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added, copper acetate monohydrate (740mg , 3.71 mmol), triethylamine (375 mg, 3.71 mmol, 515 μL), pyridine (300 mg, 3.79 mmol, 305 μL), 4Å molecular sieve (644 mg, 3.70 mmol), the reaction was stirred openly for 18 hours. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 9a (360 mg, yield: 47.0%).

MS m/z (ESI): 413.9 [M+1].

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6 -Dihydropyridazin-3-yl)methyl)phenyl)hydrazone)acetoxy)ethyl carbamate 9b

Compound 9a (360 mg, 0.87 mmol) was suspended in water (8 mL), 12 M concentrated hydrochloric acid (4 mL) was added under an ice bath, the reaction was cooled to -5~0 °C, and an aqueous solution (1 mL) of sodium nitrite (90 mg, 1.30 mmol) was added dropwise. ), the reaction was stirred at -5~0 °C for 1 hour to obtain suspension A; at -5~0 °C, compound 1f (136 mg, 0.87 mmol) was suspended in water (4 mL), pyridine (4 mL) was added, and the reaction was stirred for 10 minutes, a clear solution B was obtained. At -5~0°C, the suspension A was slowly poured into the clear solution B, and the reaction was stirred for 1 hour. After filtration, the filter cake was washed with water and dried in vacuo to give crude title compound 9b (400 mg), which was used in the next step without purification.

MS m/z (ESI): 580.8 [M+1].

third step

2-(3,5-Dichloro-4-((6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-3-yl)methyl) Phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 9

Compound 9b (400 mg, 0.69 mmol) was dissolved in N , N -dimethylacetamide (4 mL), potassium acetate (81 mg, 0.82 mmol) was added, the reaction was heated to 120°C, stirred for 3 hours, and the reaction was cooled to room temperature , concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 40%: 60%: 0.1%) to give the title compound 9 (223 mg, Yield: 60.5%).

MS m/z (ESI): 534.8 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.22 (s, 1H), 7.82-7.88 (m, 2H), 7.64-7.76 (m, 4H), 7.59 (d, 1H), 7.14 (d, 1H) , 4.40 (s, 2H).

Example 10

2-(3,5-Dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 10

first step

6-(4-Amino-2,6-dichlorobenzyl)-2-isopropylpyridazin-3( 2H )-one 10a

Compound 1d (500 mg, 1.85 mmol) was dissolved in ethylene glycol dimethyl ether (20 mL), bromoisopropane (455 mg, 3.70 mmol) and cesium carbonate (905 mg, 2.78 mmol) were added, and the reaction was heated to 100 ° C and stirred for 16 hours , concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 10a (180 mg, yield: 31.1%).

MS m/z (ESI): 311.9 [M+1].

second step

( Z )-(2-cyano-2-(2-(3,5-dichloro-4-((6-oxo-1-isopropyl-1,6-dihydropyridazin-3-yl) ) methyl) phenyl) hydrazone) acetyl) ethyl carbamate 10b

Compound 10a (180 mg, 0.58 mmol) was suspended in water (10 mL), concentrated hydrochloric acid (5 mL) was added under an ice bath, the reaction was cooled to 0 °C, and an aqueous solution (1 mL) of sodium nitrite (60 mg, 0.87 mmol) was added dropwise, 0 °C Under stirring for 1 hour, suspension A was obtained; at 0 °C, compound 1f (90 mg, 0.58 mmol) was suspended in water (5 mL), pyridine (5 mL) was added, and the reaction was stirred for 10 minutes to obtain clear solution B. Suspension A was slowly poured into clear solution B at 0°C, and the reaction was stirred for 1 hour. After filtration, the filter cake was washed with water and dried in vacuo to give crude title compound 10b (166 mg, yield: 60.1%). This product was used directly in the next reaction without purification.

third step

2-(3,5-Dichloro-4-((1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-di Oxygen-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 10

Compound 10b (276 mg, 0.35 mmol) was dissolved in N , N -dimethylacetamide (10 mL), potassium acetate (41 mg, 0.42 mmol) was added, and the reaction was heated to 120° C. and stirred for 3 hours. The reaction was cooled to room temperature, filtered, and the filtrate was purified by HPLC preparation (Waters 2767-SQ Detector2, elution system: water: acetonitrile: trifluoroacetic acid = 40%: 60%: 0.1%) to give the title compound 10 (90 mg , yield: 59.98%).

MS m/z (ESI): 432.9 [M+1].

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.22 (brs, 1H), 7.69 (s, 2H), 7.43 (d, 1H), 6.90 (d, 1H), 5.05-5.00 (m, 1H), 4.31 (s, 2H), 1.65 (d, 6H).

Biological evaluation

Test Example 1. Agonistic effects of compounds of the present disclosure on THRα and THRβ

1. The purpose of the experiment:

The purpose of this experiment is to test the agonistic effect of compounds on THRα (thyroid hormone receptor α) and THRβ (thyroid hormone receptor β) stable reporter cell line, and evaluate the effect of compounds on THRα according to EC ₅₀ and Emax. and THRβ selectivity.

2. Experimental method:

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

The constructed CHO-K1 cells expressing both DR4 response elements and THRα or THRβ were plated in a 96-well plate (Corning, #3903) at 5000 cells/well at 37°C in a 5% CO ₂ incubator (thermo scientific, #HERAcell 240i) for 24 hours.

Remove the medium from the cell plate, add 95 μL of DMEM/F12 medium containing 0.5% FBS and 5 μL of the diluted compound solution, respectively, and incubate in a 37°C, 5% CO ₂ incubator for 24 hours. After 24 hours, 100 μL of the prepared luciferase substrate (Promega, #E2610) was added to each well, and it was placed in the dark at room temperature for 5 minutes, and then the chemical luminescence was detected on a microplate reader (PerkinElmer, #Vector3).

In this experiment, Graphpad Prism 6.0 was used to analyze the data. EC ₅₀ is the corresponding concentration of each compound when the activation reaches 50% of the maximum value in the positive control T3 group. Emax=(sample value-average value of DMSO group)/(average value of maximum value in T3 group-average value of DMSO group)×100%. The EC ₅₀ and Emax values of the agonistic effects of the compounds of the present disclosure on THRα and THRβ are shown in Table 1.

Table 1: EC ₅₀ and Emax values for the agonistic effects of compounds of the present disclosure on THRα and THRβ

Conclusion: Compared with compound 10, the agonistic effect of compounds 1-9 of the present disclosure on THRα is weaker. The Emax of the agonistic effect of compounds 1-9 of the present disclosure on THRα is far smaller than that of compound 10, and the EC ₅₀ values are far greater than those of compound 10. _EC50 for Compound 10. For example, the concentration of compound 3 when it reaches 25% of the maximum activation value of T3 on THRα is greater than 10000nM, while compound 10 only needs 456.1nM to achieve the same effect. Under the same concentration conditions in vivo, since the compounds 1-9 of the present disclosure have a high selective inhibitory effect on THRβ, it can be predicted that the side effects of compounds 1-9 due to the agonistic effect of THRα will be less, and the clinical use is safer.

Test Example 2 Pharmacokinetic evaluation

1. Abstract

Using rats as test animals, LC/MS/MS method was used to determine the drug concentrations in plasma at different times after rats were given the compound of Example 3 and the control example MGL3196 by gavage (ig). To study the pharmacokinetic behavior of the disclosed compounds in rats, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test drug

Example 3 compound and control MGL3196. The structure of MGL3196 (see compound 31 in Example 8 of WO2007009913A1) is as follows:

2.2 Experimental animals

Twelve SD rats, half male and half male, were equally divided into 3 groups, purchased from Weitong Lihua Laboratory Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2017-0005.

2.3 Drug preparation

Weigh a certain amount of the compound of Example 3, add 25% volume of PEG400 and 75% (5% TPGS+5% PVP K30) to dissolve, and prepare 10 mg/mL and 30 mg/mL suspensions.

A certain amount of the compound MGL3196 of the control example was weighed, and 25% volume of PEG400 and 75% (5% TPGS+5% PVP K30) were added to dissolve it to prepare a 1 mg/mL solution.

2.4 Administration

After fasting overnight, the rats were given the compound of Example 3 by gavage at a dose of 100 mg/kg and 300 mg/kg, and the administration volume was 10.0 mL/kg.

After fasting overnight, rats were given intragastric administration of MGL3196, the dosage of which was 10 mg/kg, and the administration volume was 10.0 mL/kg.

3. Operation

Rats were administered the compound of Example 3 and the control example MGL3196 by gavage. Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the orbit, and EDTA- In a K2 anticoagulation test tube, centrifuge at 10,000 rpm for 1 minute (4°C), The plasma was separated within 1 h and stored at -20°C for testing. The blood was collected until the centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

Determination of the content of the test compound in rat plasma after drug administration of different concentrations: take 25 μL of rat plasma at each time after administration, add 50 μL of internal standard solution camptothecin (100 ng/mL) and 200 μL of acetonitrile, and mix by vortex After 5 minutes, centrifugation for 10 minutes (3700 rpm), and 1 μL of the supernatant from the plasma sample was analyzed by LC/MS/MS.

4. Results of pharmacokinetic parameters

Table 2: Pharmacokinetic parameters of compounds of the present disclosure:

Conclusion: The disclosed compounds have good drug metabolism and absorption activity in rats.

Test Example 3. Experiment on the efficacy of the compounds of the present disclosure on SD rats with hypercholesterolemia

1. Purpose

The compound of Example 3 and the control MGL3196 were evaluated for their effects on inhibiting hypercholesterolemia in SD rats induced by high cholesterol diet.

2. experimental drug

Example 3 and control MGL3196 were formulated with 25% PEG400+75% (5% TPGS+5% PVP K30), respectively.

The structure of MGL3196 (see compound 31 in Example 8 in WO2007009913A1) is as follows:

3. Experimental methods and experimental materials

3.1. Experimental animals and rearing conditions

60 SD male rats, purchased from Beijing Weitong Lihua Laboratory Animal Co., Ltd. (certificate number: 20201124Aazz0619000445), weighing about 180g at the time of purchase, 5 rats/cage, 12/12 hours light/dark cycle adjustment, temperature 23± 1 ℃ constant temperature, humidity 50~60%, free food and water.

3.2. Animal grouping:

After adaptive feeding, SD rats were randomly divided into two groups according to their body weight. The control group (10 animals) was fed with normal diet (Harlan 7001), and the model group (50 animals) was fed with high cholesterol diet (Harlan 7001, containing 1.5% cholesterol and 0.5% cholic acid).

After 11 days of feeding with high cholesterol feed, blood was collected from the orbit, and after centrifugation at 3500 rpm for 15 min, serum was collected to detect the content of total cholesterol and monitor the modeling situation. After successful modeling, 40 animals were selected from the model group according to the serum total cholesterol content and randomly divided into four groups, plus a blank control group, a total of five groups, and the groups were as follows:

3.3. Experimental method:

On the test day, according to the animal body weight and serum total cholesterol content, after random grouping, a single oral gavage administration was given, and the administration volume was 10 mL/kg. After 24 hours of administration, the orbital blood was collected, and the serum was collected to detect the content of four items of blood lipids in the serum. .

3.4. Statistics

All data were graphed and statistically analyzed using Excel and GraphPad Prism 8 software.

Relative inhibition rate: 1-(administration group-blank control group)/(solvent group-blank control group)×100%.

4. result

The curative effect data of the compound of Example 3 on SD rats with hypercholesterolemia are shown in Table 3.

The effect of the compound of Example 3 on the serum total cholesterol of SD rats with hypercholesterolemia is shown in Fig. 1 .

The effect of the compound of Example 3 on serum non-high-density lipoprotein cholesterol of SD rats with hypercholesterolemia is shown in FIG. 2 .

The effect of the compound of Example 3 on the serum low-density lipoprotein cholesterol of SD rats with hypercholesterolemia is shown in FIG. 3 .

Table 3: Efficacy of the compound of Example 3 on SD rats with hypercholesterolemia

5. in conclusion

24h after a single dose, MGL-3196-10mpk (the exposure of a single dose of oral drug metabolism test is about 10001ng/mL*h), Example 3-100mpk (a single dose of The exposure in the oral drug metabolism test was about 5002ng/mL*h), and the total cholesterol, non-high-density serum in Example 3-300mpk (the exposure in the single-dose oral drug metabolism test was about 24607ng/mL*h) The contents of lipoprotein cholesterol and low-density lipoprotein cholesterol were significantly reduced (see Figure 1, Figure 2, Figure 3), and there was a significant difference compared with the solvent group. When the exposure amount of Example 3-100mpk is about half of that of the control example MGL-3196-10mpk, it shows better efficacy than the control example MGL-3196-10mpk. In the blank control group, the relative inhibition rates of serum total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol reached 106%, 56.2%, and 63.7%, respectively, while the control group MGL-3196-10mpk drug Compared with the blank control group, the relative inhibition rates of serum total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were 56.5%, 33.0%, and 40.3%, respectively.

Claims (15)

A compound represented by the general formula (I) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof,

in, R ^1a and R ^{1b are} the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl , cycloalkyl and heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl , substituted by one or more substituents in alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; R ² is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, carboxyl, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkane base and heterocyclyl; ^R is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl, alkenyl, alkynyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane substituted with one or more substituents of oxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and R ^a ; and ^Ra is selected from alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkyne , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from pendant oxygen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, Substituted with one or more substituents of haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. The compound represented by the general formula (I) according to claim 1 or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its pharmaceutically acceptable form of salts, wherein R is selected from C _1-6 alkyl, ³ to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl are each independently optionally selected from pendant oxygen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amine, nitro, hydroxyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl and one or more substituents in R ^a ; R ^a is 6 to 10 A membered aryl group, wherein the 6- to 10-membered aryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy , cyano, amine, nitro, hydroxyl and one or more substituents of C _1-6 hydroxyalkyl. The compound represented by the general formula (I) according to claim 1 or 2, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or its tautomer, racemate, enantiomer, or mixture thereof A pharmaceutically acceptable salt wherein R ^1a and R ^{1b are} the same or different, and are each independently halogen or C _1-6 alkyl. The compound represented by the general formula (I) according to any one of claims 1 to 3 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:

in R ² and R ³ are as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 4 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:

in, Ring A is selected from the group consisting of 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; R ⁴ are the same or different, each independently selected from hydrogen atom, pendant oxygen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy , cyano, amino, nitro, hydroxyl, C _1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl , wherein the 6- to 10-membered aryl group is optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano , substituted with one or more substituents in amine, nitro, hydroxyl and C _1-6 hydroxyalkyl; n is 0, 1, 2, 3, 4 or 5; R ² is as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 5 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a hydrogen atom, a cyano group, a C _1-6 alkyl group and a 3- to 8-membered cycloalkyl group, preferably, R ² is a cyano group. The compound represented by the general formula (I) according to claim 5 or 6, or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its isomers Pharmaceutically acceptable salts, wherein R ⁴ are the same or different, each independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano and C _1-6 hydroxyalkyl. The compound represented by the general formula (I) according to any one of claims 1 to 7 or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof form or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

A compound represented by the general formula (IA) or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof,

in, R ^m is C _1-6 alkyl; R ^1a , R ^1b , R ² and R ³ are as defined in claim 1 . The compound represented by the general formula (IA) according to claim 9, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof The salt, wherein the compound is selected from:

A kind of preparation of the compound represented by the general formula (I) as described in claim 1 or its tautomer, racemate, enantiomer, diastereomer, or its mixture form or its A method of pharmaceutically acceptable salt, comprising the steps of:

The compound of general formula (IA) or a pharmaceutically acceptable salt thereof undergoes an intramolecular cyclization reaction to obtain the compound of general formula (I), in, R ^m is C _1-6 alkyl; R ^1a , R ^1b , R ² and R ³ are as defined in claim 1 . A pharmaceutical composition comprising a compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, racemate, enantiomer, diastereomer or the same Isomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. A compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Use of a mixture form or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 12 in the preparation of a THRβ agonist. A compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or Use of a mixture form or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 12 in the preparation of a medicament for the treatment and/or prevention of diseases regulated by thyroid hormones; preferably in the preparation of a drug for the treatment and Use in a medicament for the prevention of metabolic diseases regulated by thyroid hormones. A compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, racemate, enantiomer, diastereomer, or its tautomer, racemate, enantiomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 12 in the preparation for the treatment and/or prevention of obesity, hypothyroidism, thyroid cancer, diabetes, thyroid hormone-regulated Use in the medicament of cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

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