WO2022068915A1 - 6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用 - Google Patents

6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2022068915A1
WO2022068915A1 PCT/CN2021/122032 CN2021122032W WO2022068915A1 WO 2022068915 A1 WO2022068915 A1 WO 2022068915A1 CN 2021122032 W CN2021122032 W CN 2021122032W WO 2022068915 A1 WO2022068915 A1 WO 2022068915A1
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enantiomer
general formula
tautomer
alkyl
racemate
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PCT/CN2021/122032
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English (en)
French (fr)
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杨方龙
刘继红
张羚
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2022068915A1 publication Critical patent/WO2022068915A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a 6-oxo-1,6-dihydropyridazine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent In particular, it is used in 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.
  • general formula (I) 6-oxo-1,6-dihydropyridazine derivative represented by general formula (I)
  • a preparation method thereof a pharmaceutical composition containing the derivative
  • a pharmaceutical composition containing the derivative and its use as a therapeutic agent
  • it is used in 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.
  • 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.
  • Thyroid hormone plays an important role in the activities of some organs.
  • 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.
  • Thyroid hormone receptors have two distinct subtypes, THR ⁇ and THR ⁇ . THR ⁇ is mainly distributed in the liver, while THR ⁇ is mainly distributed in the brain and heart tissue. Natural thyroid hormones act on both THR ⁇ and THR ⁇ 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.
  • LDL low-density lipoprotein
  • THR ⁇ thyroid hormone T3
  • the effect of thyroid hormone T3 on liver, muscle and other tissues is mainly mediated by THR ⁇ . Therefore, selective THR ⁇ agonists should be able to treat obesity, hyperlipidemia, thyroid disease, and nonalcoholic steatohepatitis without affecting heart rate and rhythm.
  • Thyroid hormone receptor ⁇ (THR ⁇ )-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 THR ⁇ 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 its Medicinal salts:
  • 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, amino, nitro, hydroxy, hydroxyalkyl, cycloalkane and heterocyclyl, wherein said alkyl, alkoxy, hydroxyalkyl, cycloalkyl, and heterocyclyl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, Substituted by one or more substituents of alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, carboxyl, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl and hetero ring base;
  • R 3 is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, alkenyl group, alkynyl group , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy is substituted with one or more substituents of radical, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and R a ; and
  • Ra is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkyne , hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from oxo, halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane Substituted with one or more substituents of oxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • 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 (II) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof:
  • R 2 and R 3 are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, An 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 said 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 groups are each independently optionally selected from oxo, 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
  • 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 which is the compound represented by general formula (III) or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof:
  • 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, oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano group, 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 Said 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, amino, Substituted with one or more substituents in nitro, hydroxyl and C 1-6 hydroxyalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • R 2 is as defined in general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or 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; 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.
  • the compound represented by the general formula (II) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or 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; 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.
  • the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or 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 6- to 10-membered aryl groups; 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; n is 0 or 1.
  • the compound represented by the general formula (III) according to the present disclosure or its tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof 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 mixture thereof, or Its pharmaceutically acceptable salts:
  • 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 mixture thereof, or Its pharmaceutically acceptable salt, which is of general formula (IIA),
  • 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 mixture thereof, or Its pharmaceutically acceptable salt, which is of general formula (IIIA),
  • 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 mixture thereof, or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:
  • 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 mixture thereof, or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:
  • 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 mixture thereof, or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:
  • 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
  • a pharmaceutical composition comprising a compound of general formula (I), general formula (II), general formula (III) and Table A according to the present disclosure, or a tautomer thereof isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipient.
  • 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 their tautomers, racemates, enantiomers 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 THR ⁇ 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 their tautomers, racemates, enantiomers 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 manufacture 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 their tautomers, racemates, enantiomers Forms, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of 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.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure also relates to a method of agonizing THR ⁇ , comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) and shown in Table A according to the present disclosure
  • a method of agonizing THR ⁇ comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) and shown in Table A according to the present disclosure
  • 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
  • a method of treating and/or preventing a disease regulated by thyroid hormone comprising administering to a patient in need thereof a therapeutically effective amount of a
  • the present disclosure also relates to a method for the treatment and/or prevention of obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic fat regulated by thyroid hormones
  • a method of hepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) according to the present disclosure and the compounds shown in Table A or their tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or containing pharmaceutical composition.
  • 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, para- An enantiomer, 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, para- An enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a THR ⁇ 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, para- Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for the treatment and/or prevention of diseases regulated by thyroid hormones; It is preferably used as a medicament 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, para- Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of obesity, thyroid function regulated by thyroid hormones Medications for hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
  • thyroid hormones Medications for hypothyroidism thyroid cancer
  • diabetes cardiovascular disease
  • hyperlipidemia hypercholesterolemia
  • atherosclerosis atherosclerosis
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • 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 may 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.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • 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.
  • 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.
  • 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.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • 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.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • 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.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • 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 which 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.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • 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 alkyl groups 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-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl 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 the group consisting of D atom, halogen, alkoxy, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituents.
  • alkylene 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, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the 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, haloalkane Oxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, One or more substituents of cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkenyl groups containing 2 to 6 carbon atoms are more preferred.
  • 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, cycloalkyloxy One or more of the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups containing 2 to 12 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups containing 2 to 6 carbon atoms are more preferred.
  • 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, cycloalkyloxy One or more of the substituents of yl, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • 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, more preferably 3 to 8 carbon atoms 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.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having 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 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • 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 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings 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, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl a substituent.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • 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 alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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 heterocyclic atom; more preferably contains 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 contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most 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, thiomorpholine base, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic 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 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • 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 of the 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.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share 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.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl 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, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl a substituent.
  • 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 membered , 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, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituents.
  • 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 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, 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, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl a substituent.
  • 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).
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • 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.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • the bond The configuration is not specified, 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.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • “deuterium” or “tritium” is used in place of hydrogen
  • 18F -fluorine label 18F isotope
  • 18F isotope is used in place of fluorine, or11C- , 13C- , or14C -enriched
  • 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.
  • 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.
  • Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • 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.
  • heterocyclic group optionally substituted with alkyl 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 independently of each other by the corresponding number Substituents are substituted.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with 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” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the compounds 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 ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • terapéuticaally 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, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable 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.
  • 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),
  • R m is C 1-6 alkyl
  • R 1a , R 1b , R 2 and R 3 are as defined in general formula (I).
  • 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 mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • R m is C 1-6 alkyl
  • Ring A, R 2 , R 4 and n are as defined in general formula (III).
  • 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, Lithium diisopropylamide, 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, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: acetic acid, glacial acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane Alkane
  • 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.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS was used for MS determination (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).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses 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 size of the 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, Darui Chemicals and other companies.
  • 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.
  • the pressure 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.
  • the solution refers to an aqueous solution.
  • reaction temperature 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 solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method 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.
  • TLC thin layer chromatography
  • Test Example 1 Agonistic effects of compounds of the present disclosure on THR ⁇ and THR ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • Compounds were formulated in dimethyl sulfoxide (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 THR ⁇ or THR ⁇ 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.
  • EC50 is the concentration of each compound when the activation reaches 50% of the maximum value of 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 EC50 and Emax values of the agonistic effects of the compounds of the present disclosure on THR ⁇ and THR ⁇ are shown in Table 1.
  • Table 1 EC50 and Emax values for the agonistic effects of compounds of the present disclosure on THR ⁇ and THR ⁇
  • the agonistic effects of compounds 1-9 of the present disclosure on THR ⁇ are weaker, the Emax of the agonistic effects of compounds 1-9 of the present disclosure on THR ⁇ are far smaller than the Emax of compound 10, and the EC 50 values are all far greater than EC50 for Compound 10.
  • the concentration of compound 3 is greater than 10000 nM when it reaches 25% of the maximum activation value of T3 on THR ⁇ , while compound 10 only needs 456.1 nM to achieve the same effect.
  • the compounds 1-9 of the present disclosure have a high selective inhibitory effect on THR ⁇ , it can be predicted that the side effects of the compounds 1-9 due to the agonistic effect of THR ⁇ will be less, and the clinical use is safer.
  • 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). The pharmacokinetic behavior of the disclosed compounds in rats was studied, and their pharmacokinetic characteristics were evaluated.
  • Example 3 compound and control MGL3196 The structure of MGL3196 (see compound 31 in Example 8 of WO2007009913A1) is as follows:
  • 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.
  • 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.
  • rats were given intragastric administration of MGL3196, the dosage was 10 mg/kg, and the administration volume was 10.0 mL/kg.
  • 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), separate plasma within 1 hour, and store 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 ⁇ L of rat plasma at each time after administration, add 50 ⁇ L of internal standard solution camptothecin (100 ng/mL) and 200 ⁇ L of acetonitrile, and mix by vortex After 5 minutes, centrifugation for 10 minutes (3700 rpm), and 1 ⁇ L of the supernatant from the plasma sample was analyzed by LC/MS/MS.
  • Test Example 3 Pharmacodynamic experiment of the disclosed compounds on SD rats with hypercholesterolemia
  • Example 3 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.
  • Example 3 and control MGL3196 were formulated with 25% PEG400+75% (5% TPGS+5% PVP K30), respectively.
  • MGL3196 see compound 31 in Example 8 in WO2007009913A1 is as follows:
  • p.o. is for oral administration, once administered.
  • Relative inhibition rate 1-(administration group-blank control group)/(solvent group-blank control group) ⁇ 100%.
  • Figure 2 shows the effect of the compound of Example 3 on serum non-high-density lipoprotein cholesterol in SD rats with hypercholesterolemia.
  • MGL-3196-10mpk the exposure of the single-dose oral pharmacokinetics test is about 10001ng/mL*h
  • Example 3-100mpk the exposure of the single-dose oral pharmacokinetics test
  • 5002ng/mL*h the exposure of the single-dose oral pharmacokinetic experiment
  • Example 3-300mpk the exposure of the single-dose oral pharmacokinetic experiment is about 24607ng/mL*h
  • serum total cholesterol non-high-density lipoprotein cholesterol, low-density lipid
  • the content of protein cholesterol was significantly reduced (see Figure 1, Figure 2, Figure 3), and there was a significant difference compared with the solvent group.
  • Example 3-100mpk 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.
  • 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.
  • the relative inhibition rates of total cholesterol, non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in serum were 56.5%, 33.0%, and 40.3%, respectively.

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Abstract

提供了6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用。具体而言，涉及一种通式（I）所示的6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是用于制备治疗和/或预防由甲状腺激素调节的疾病的药物中的用途。

Description

6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种通式(I)所示的6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是用于制备治疗和/或预防肥胖、糖尿病、高脂血症、甲状腺疾病、非酒精性脂肪肝炎和非酒精性脂肪肝疾病等疾病的药物中的用途。
背景技术
甲状腺激素对于人体的正常发育和保持代谢的体内平衡是非常重要的。甲状腺激素三大功能：(1)促进生长发育，甲状腺激素促进生长发育作用最明显是在婴儿时期，在出生后头五个月内影响最大，它主要促进骨骼、脑和生殖器官的生长发育，若没有甲状腺激素，垂体的GH也不能发挥作用。(2)影响代谢，产热效应，甲状腺激素可提高大多数组织的耗氧率，增加产热效应，这种产热效应可能由于甲状腺激素能增加细胞膜上Na +－K +泵的合成，并能增加其活力，后者是一个耗能过程。(3)甲状腺激素对于一些器官的活动有重要的作用，比如它对维持神经系统的兴奋性有重要的意义，甲状腺激素可直接作用于心肌，促进肌质网释放Ca 2+，使心肌收缩力增强，心率加快。
天然甲状腺激素T3通过与甲状腺激素受体(THR)结合来发挥生理作用。甲状腺激素受体有两个不同的亚型THRα和THRβ。THRβ主要分布在肝脏中，而THRα则主要分布在大脑和心脏组织中。天然甲状腺激素能够同时作用于THRα和THRβ，没有任何选择性。天然甲状腺激素T3在动物模型和人体中能够显著降低胆固醇，低密度脂蛋白(LDL)。然而，T3对心脏的副作用，其不能够用于肥胖、高胆固醇症和非酒精性脂肪肝治疗。
研究表明，甲状腺激素T3对心脏的影响，尤其是对心率的影响，是通过THRα进行介导的。而甲状腺激素T3对肝脏，肌肉和其他组织的作用则主要通过THRβ进行介导。因此，选择性THRβ激动剂应当可以进行治疗肥胖、高脂血症、甲状腺疾病、非酒精性脂肪肝炎，而不会对心率和心律有影响。
已经合成的甲状腺激素受体β(THRβ)选择性和/或组织选择性作用的甲状腺激素类似物，这些化合物可以对体重、脂类、胆固醇和脂蛋白进行适当降低，而对心血管和下丘脑/垂体/甲状腺轴的正常功能具有很小的影响(Johan Malm,J.Med.Chem.2003,46,1580-1588；Martha J.Kelly,J.Med.Chem.2014,57,3912-3923)。
已经公开的作为THRβ的激动剂的化合物的专利包括WO2006128055A2、WO2005051298A2、WO2007009913A1和WO2009037172A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021122032-appb-000001
其中：
R 1a和R 1b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基，其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基中的一个或多个取代基所取代；
R 2选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、羧基、氨基、硝基、羟基、羟烷基、环烷基和杂环基；
R 3选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基和R a中的一个或多个取代基所取代；且
R a选自烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
在本公开的一些实施方案中，根据本公开所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1a和R 1b相同或不同，且各自独立地为卤素或C 1-6烷基。
在本公开的一些实施方案中，根据本公开所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021122032-appb-000002
其中：
R 2和R 3如通式(I)中所定义。
在本公开的一些实施方案中，根据本公开所述的通式(I)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3选自C 1-6烷基、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基；其中所述的C 1-6烷基、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自氧代、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至8元环烷基、3至8元杂环基、6至10元芳基、5至10元杂芳基和R a中的一个或多个取代基所取代；R a为6至10元芳基，其中所述的6至10元芳基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，根据本公开所述的通式(I)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3选自
Figure PCTCN2021122032-appb-000003
正丙基和乙基；环A为3至8元环烷基或6至10元芳基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(I)或通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 3选自
Figure PCTCN2021122032-appb-000004
正丙基和乙基；环A选自环丙基、环丁基和苯基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
Figure PCTCN2021122032-appb-000005
其中：
环A选自3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基；
R 4相同或不同，各自独立地选自氢原子、氧代、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基，其中所述的6至10元芳基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；
n为0、1、2、3、4或5；
R 2如通式(I)中所定义。
在本公开的一些实施方案中，根据本公开所述的通式(I)、通式(II)和通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、氰基、C 1-6烷基和3至8元环烷基，优选地，R 2为氰基。
在本公开的一些实施方案中，根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中环A为3至8元环烷基或6至10元芳基；优选地，环A选自环丙基、环丁基和苯基。
在本公开的一些实施方案中，根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基。
在本公开的一些实施方案中，根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 1a和R 1b相同或不同，且各自独立地为卤素或C 1-6烷基；R 2选自氢原子、氰基、C 1-6烷基和3至8元环烷基；R 3选自
Figure PCTCN2021122032-appb-000006
正丙基和乙基； 环A为3至8元环烷基或6至10元芳基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、氰基、C 1-6烷基和3至8元环烷基；R 3选自
Figure PCTCN2021122032-appb-000007
正丙基和乙基；环A为3至8元环烷基或6至10元芳基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、氰基、C 1-6烷基和3至8元环烷基；环A为3至8元环烷基或6至10元芳基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
在本公开的一些实施方案中，根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R 2为氰基；环A选自环丙基、环丁基和苯基；R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基；n为0或1。
表A 本公开的典型化合物包括但不限于：
Figure PCTCN2021122032-appb-000008
Figure PCTCN2021122032-appb-000009
Figure PCTCN2021122032-appb-000010
本公开的另一方面涉及一种通式(IA)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：
Figure PCTCN2021122032-appb-000011
其中：
R m为C 1-6烷基；
R 1a、R 1b、R 2和R 3如通式(I)中所定义。
本公开的另一方面涉及一种通式(IA)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IIA)，
Figure PCTCN2021122032-appb-000012
其中：
R m为C 1-6烷基；
R 2和R 3如通式(II)中所定义。
本公开的另一方面涉及一种通式(IA)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(IIIA)，
Figure PCTCN2021122032-appb-000013
其中：
R m为C 1-6烷基；
环A、R 2、R 4和n如通式(III)中所定义。
本公开通式(IA)的典型化合物包括但不限于：
Figure PCTCN2021122032-appb-000014
Figure PCTCN2021122032-appb-000015
Figure PCTCN2021122032-appb-000016
本公开的另一方面涉及一种制备根据本公开所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，其包括以下步骤：
Figure PCTCN2021122032-appb-000017
通式(IA)的化合物或其可药用的盐发生分子内成环反应，得到通式(I)的化合物，
其中：
R m为C 1-6烷基；
R 1a、R 1b、R 2和R 3如通式(I)中所定义。
本公开的另一方面涉及一种制备根据本公开所述的通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，其包括以下步骤：
Figure PCTCN2021122032-appb-000018
通式(IIA)的化合物或其可药用的盐发生分子内成环反应，得到通式(II)的化合物，
其中：
R m为C 1-6烷基；
R 2和R 3如通式(II)中所定义。
本公开的另一方面涉及一种制备根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，其包括以下步骤：
Figure PCTCN2021122032-appb-000019
通式(IIIA)的化合物或其可药用的盐发生分子内成环反应，得到通式(III)的化合物，
其中：
R m为C 1-6烷基；
环A、R 2、R 4和n如通式(III)中所定义。
本公开的另一方面涉及一种药物组合物，其含有根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物在制备THRβ激动剂中的用途。
本公开进一步涉及根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物在制备用于治疗和/或预防由甲 状腺激素调节的疾病的药物中的用途；优选为在制备用于治疗和/或预防由甲状腺激素调节的代谢疾病的药物中的用途。
本公开进一步涉及根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或包含其的药物组合物在制备用于治疗和/或预防由甲状腺激素调节的肥胖、甲状腺功能减退、甲状腺癌、糖尿病、心血管疾病、高脂血症、高胆固醇血症、动脉粥样硬化、非酒精性脂肪肝炎(NASH)和非酒精性脂肪肝疾病(NAFLD)的药物中的用途。
本公开还涉及一种激动THRβ的方法，其包括给予所需患者治疗有效量的根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物。
本公开还涉及一种治疗和/或预防由甲状腺激素调节的疾病的方法，优选治疗和/或预防由甲状腺激素调节的代谢疾病的方法，其包括给予所需患者治疗有效量的根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物。
本公开还涉及一种治疗和/或预防由甲状腺激素调节的肥胖、甲状腺功能减退、甲状腺癌、糖尿病、心血管疾病、高脂血症、高胆固醇血症、动脉粥样硬化、非酒精性脂肪肝炎(NASH)和非酒精性脂肪肝疾病(NAFLD)的方法，其包括给予所需患者治疗有效量的根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物。
本公开进一步涉及一种根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物，其用作药物。
本公开进一步涉及一种根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物，其用作THRβ激动剂。
本公开进一步涉及一种根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐、或包含其的药物组合物，其用作治疗和/或预防由甲状腺激素调节的疾病的药物；优选为用作治疗和/或预防由甲状腺激素调节的代谢疾病的药物。
本公开进一步涉及一种根据本公开所述的通式(I)、通式(II)、通式(III)和表A所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其 混合物形式、或其可药用的盐、或包含其的药物组合物，其用作治疗和/或预防由甲状腺激素调节的肥胖、甲状腺功能减退、甲状腺癌、糖尿病、心血管疾病、高脂血症、高胆固醇血症、动脉粥样硬化、非酒精性脂肪肝炎(NASH)和非酒精性脂肪肝疾病(NAFLD)的药物。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。 为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、 1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基，更优选含有2至6个碳原子的烯基。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。优选含有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的炔基，更优选含有2至6个碳原子的炔基。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，进一步优选包含3至8个碳原子(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021122032-appb-000020
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环稠环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021122032-appb-000021
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021122032-appb-000022
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制 性实例包括茚满基
Figure PCTCN2021122032-appb-000023
四氢萘基
Figure PCTCN2021122032-appb-000024
苯并环庚烷基
Figure PCTCN2021122032-appb-000025
等；优选茚满基
Figure PCTCN2021122032-appb-000026
和四氢萘基
Figure PCTCN2021122032-appb-000027
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021122032-appb-000028
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021122032-appb-000029
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧、硫、S(O)或S(O) 2的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021122032-appb-000030
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021122032-appb-000031
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代 烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021122032-appb-000032
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“杂芳基”指包含1至4个(1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021122032-appb-000033
Figure PCTCN2021122032-appb-000034
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
上述环烷基、杂环基、芳基和杂芳基包括从母体碳原子上除去一个氢原子所衍生的残基(即1价基团)，或从母体的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基(即2价基团)。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指被烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基、环烷基如上所定义。
本公开所述化合物的化学结构中，键
Figure PCTCN2021122032-appb-000035
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021122032-appb-000036
可以为
Figure PCTCN2021122032-appb-000037
或
Figure PCTCN2021122032-appb-000038
或者同时包含
Figure PCTCN2021122032-appb-000039
和
Figure PCTCN2021122032-appb-000040
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2021122032-appb-000041
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开的化合物包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于 存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开的各种氘化形式的化合物，是指与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必然发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个(例如1、2、3、4或5)，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学上可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、 过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的合成方法，其包括以下步骤：
Figure PCTCN2021122032-appb-000042
通式(IA)的化合物或其可药用的盐在碱性条件下，发生分子内成环反应，得到通式(I)的化合物，
其中：
R m为C 1-6烷基；
R 1a、R 1b、R 2和R 3如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的合成方法，其包括以下步骤：
Figure PCTCN2021122032-appb-000043
通式(IIA)的化合物或其可药用的盐在碱性条件下，发生分子内成环反应，得 到通式(II)的化合物，
其中：
R m为C 1-6烷基；
R 2和R 3如通式(II)中所定义。
方案三
本公开的另一方面涉及一种制备根据本公开所述的通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其包括以下步骤：
Figure PCTCN2021122032-appb-000044
通式(IIIA)的化合物或其可药用的盐在碱性条件下，发生分子内成环反应，得到通式(III)的化合物，
其中：
R m为C 1-6烷基；
环A、R 2、R 4和n如通式(III)中所定义。
在上述方案中，提供碱性条件的试剂包括有机碱类和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、乙酸钠、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于碳酸氢钠、碳酸氢钾、氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化锂及其水合物；优选为乙酸钾；
上述方案的反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、冰醋酸、甲醇、乙醇、正丁醇、叔丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺及其混合物。
附图说明
图1为实施例3化合物对高胆固醇脂血症SD大鼠的血清总胆固醇的影响。
图2为实施例3化合物对高胆固醇脂血症SD大鼠的血清非高密度脂蛋白胆固醇的影响。
图3为实施例3化合物对高胆固醇脂血症SD大鼠的血清低密度脂蛋白胆固醇的影响。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)；waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)；THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH & Co.KG，Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
2-(3,5-二氯-4-((1-(3-氰基苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈1
Figure PCTCN2021122032-appb-000045
第一步
2-(4-氨基-2,6-二氯苯基)-2-(6-氯哒嗪-3-基)乙腈1c
3,6-二氯哒嗪1a(7.4g，49.7mmol，韶远化学科技(上海)有限公司)和2-(4-氨基-2,6-二氯苯基)乙腈1b(10g,49.7mmol，采用专利申请US2020115362A1中说明书第44页的中间体7c公开的方法制备而得)溶于四氢呋喃(120mL)，0℃，加入叔丁醇钾(16.7g,148.8mmol)，反应搅拌5分钟。冰浴下，向反应液中加入水(250mL)，用乙酸乙酯萃取(100mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物1c(15g)，该产品不经纯化直接用于下一步。
MS m/z(ESI):312.9[M+1]。
第二步
6-(4-氨基-2,6-二氯苄基)哒嗪-3(2H)-酮1d
将化合物1c(15g,47.8mmol)加入水中(25mL)，加入12M浓盐酸(100mL)和冰乙酸(50mL)，反应加热至120℃，搅拌48小时。减压浓缩除去溶剂，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题化合物1d(8.2g，产率：63.5％)。MS m/z(ESI):269.9[M+1]。
第三步
3-(3-(4-氨基-2,6-二氯苄基)-6-氧代哒嗪-1(6H)-基)苯腈1e
化合物1d(500mg,1.85mmol)溶于二氯甲烷(100mL)，加入3-氰基苯硼酸(400mg,2.72mmol，韶远化学科技(上海)有限公司)，乙酸铜一水合物(740mg,3.71mmol)，三乙胺(375mg,3.71mmol,515μL)，吡啶(300mg,3.79mmol,305μ)和
Figure PCTCN2021122032-appb-000046
分子筛(815mg,1.85mmol)，反应敞口搅拌18小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1e(370mg，产率：53.8％)。
MS m/z(ESI):370.9[M+1]。
第四步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-(3-氰基苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯1g
化合物1e(360mg,0.97mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，反应冷却至-5～0℃，滴加亚硝酸钠(270mg,3.9mmol)的水溶液(0.5mL)，反应在-5～0℃搅拌1小时，得悬浊液A；-5～0℃下，(2-氰基乙酰基)氨基甲酸乙酯1f(170mg,1.1mmol，毕得医药)悬浮于水中(6mL)，加入吡啶(3mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应在-5～0℃搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品1g(522mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):537.8[M+1]。
第五步
2-(3,5-二氯-4-((1-(3-氰基苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈1
化合物1g(522mg,0.97mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入乙酸钾(115mg,1.17mmol)，反应加热至120℃，搅拌4小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：碳酸氢铵＝58％：42％：0.1％)纯化，得到标题化合物1(102mg，产率：21.4％)。
MS m/z(ESI):490.0[M-1]。
1H NMR(500MHz,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)。
实施例2
2-(3,5-二氯-4-((6-氧代-1-丙基-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈2
Figure PCTCN2021122032-appb-000047
第一步
6-(4-氨基-2,6-二氯苄基)-2-丙基哒嗪-3(2H)-酮2a
化合物1d(250mg,0.93mmol)溶于乙二醇二甲醚(20mL)，加入溴代正丙烷(140mg,1.14mmol,0.1mL)和碳酸铯(450mg,1.38mmol)，反应加热至100℃，搅拌16小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物2a(180mg，产率：62.3％)。
MS m/z(ESI):311.9[M+1]。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((6-氧代-1-丙基-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯2b
化合物2a(180mg,0.58mmol)悬浮于水中(4mL)，冰浴下加入12M浓盐酸(2mL)，反应冷却至-5～0℃，滴加亚硝酸钠(160mg,2.32mmol)的水溶液(0.5mL)，-5～0℃下反应搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(100mg,0.64mmol)悬浮于水中(4mL)，加入吡啶(2mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品2b(276mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):478.9[M+1]。
第三步
2-(3,5-二氯-4-((6-氧代-1-丙基-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈2
化合物2b(276mg,0.58mmol)溶于N,N-二甲基乙酰胺(5mL)中，加入乙酸钾(70mg,0.71mmol)，反应加热至120℃，搅拌4小时，反应冷却至室温。减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝47％：53％：0.1％)纯化，得到标题化合物2(168mg，产率：67.3％)。
MS m/z(ESI):432.9[M+1]。
1H NMR(500MHz,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)。
实施例3
2-(3,5-二氯-4-((6-氧代-1-乙基-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈3
Figure PCTCN2021122032-appb-000048
第一步
6-(4-氨基-2,6-二氯苄基)-2-乙基哒嗪-3(2H)-酮3a
化合物1d(300mg,1.11mmol)溶于N,N-二甲基甲酰胺(6mL)，加入碘乙烷(138mg,0.88mmol)和碳酸铯(1.08g,3.33mmol)，反应加热至40℃，搅拌5小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物3a(120mg，产率：36.2％)。
MS m/z(ESI):297.9[M+1]。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((6-氧代-1-乙基-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯3b
化合物3a(120mg,0.40mmol)悬浮于水中(8mL)，冰浴下加入12M浓盐酸(4 mL)，反应冷却至-5～0℃，滴加亚硝酸钠(55.5mg,0.80mmol)的水溶液(1.5mL)，-5～0℃下反应搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(62.8mg,0.40mmol)悬浮于水中(4mL)，加入吡啶(4mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品3b(140mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):465.0[M+1]。
第三步
2-(3,5-二氯-4-((6-氧代-1-乙基-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈3
化合物3b(140mg,0.30mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入乙酸钾(35mg,0.36mmol)，反应加热至120℃，搅拌4小时，反应冷却至室温。减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝47％：53％：0.1％)纯化，得到标题化合物3(100mg，产率：79.2％)。
MS m/z(ESI):417.0[M-1]。
1H NMR(500MHz,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)。
实施例4
2-(3,5-二氯-4-((1-(3-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈4
Figure PCTCN2021122032-appb-000049
第一步
6-(4-氨基-2,6-二氯苄基)-2-(3-氟苯基)哒嗪-3(2H)-酮4a
化合物1d(600mg,2.22mmol)溶于二氯甲烷(50mL)，加入3-氟苯硼酸(466mg,3.33mmol，韶远化学科技(上海)有限公司)，乙酸铜一水合物(887mg,4.44mmol)，三乙胺(450mg,4.44mmol,618μL)，吡啶(351mg,4mmol,357μL)，
Figure PCTCN2021122032-appb-000050
分子筛(773mg,4.44mmol)，反应敞口搅拌18小时。减压浓缩，用硅胶柱色谱法以洗脱剂体 系B纯化所得残余物，得到标题化合物4a(328mg，产率：40.8％)。
MS m/z(ESI):364.1[M+1]。
1H NMR(500MHz,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)。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-(3-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯4b
化合物4a(247mg,0.68mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，冷至-5～0℃，滴加亚硝酸钠(140mg,2.02mmol)的水溶液(0.5mL)，-5～0℃反应搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(117mg,0.75mmol)悬浮于水中(6mL)，加入吡啶(3mL)，搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品4b(270mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):530.9[M+1]。
第三步
2-(3,5-二氯-4-((1-(3-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈4
化合物4b(216mg,0.41mmol)溶于N,N-二甲基乙酰胺(3mL)中，加入乙酸钾(60mg,0.61mmol)，反应加热至120℃，搅拌4小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝50％：50％：0.1％)纯化，得到标题化合物4(170mg，产率：86.2％)。
MS m/z(ESI):485.0[M+1]。
1H NMR(500MHz,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)。
实施例5
2-(3,5-二氯-4-((1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈5
Figure PCTCN2021122032-appb-000051
Figure PCTCN2021122032-appb-000052
第一步
6-(4-氨基-2,6-二氯苄基)-2-环丙基哒嗪-3(2H)-酮5a
化合物1d(346mg,1.28mmol)溶于二氯甲烷(50mL)，室温下加入环丙基硼酸(165mg,1.92mmol，韶远化学科技(上海)有限公司)，乙酸铜一水合物(512mg,2.56mmol)，三乙胺(260mg,2.56mmol,357μL)，吡啶(203mg,2.56mmol,206μL)，
Figure PCTCN2021122032-appb-000053
分子筛(446mg,2.56mmol)，40℃下敞口搅拌18小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物5a(300mg，产率：75.5％)。
MS m/z(ESI):310.1[M+1]。
1H NMR(500MHz,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)。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯5b
化合物5a(224mg,0.72mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，反应冷却至-5～0℃，滴加亚硝酸钠(150mg,2.17mmol)的水溶液(0.5mL)，反应在-5～0℃搅拌1小时，得澄清溶液A；-5～0℃下，2化合物1f(135mg,0.86mmol)悬浮于水中(6mL)，加入吡啶(3mL)，搅拌10分钟，得澄清溶液B。-5～0℃下，将澄清溶液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品5b(115mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):476.9[M+1]。
第三步
2-(3,5-二氯-4-((1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈5
化合物5b(110mg,0.23mmol)溶于N,N-二甲基乙酰胺(3mL)中，加入乙酸钾(34mg,0.35mmol)，反应加热至120℃，搅拌6小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝66％：34％：0.1％)纯化，得到标题化合物5(60mg，产率：60.4％)。
MS m/z(ESI):431.0[M+1]。
1H NMR(500MHz,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)。
实施例6
2-(3,5-二氯-4-((1-环丁基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈6
Figure PCTCN2021122032-appb-000054
第一步
6-(4-氨基-2,6-二氯苄基)-2-环丁基哒嗪-3(2H)-酮6a
化合物1d(500mg,1.85mmol)溶于二甲醇二甲醚(20mL)，室温下加入溴代环丁烷(500mg,3.70mmol，韶远化学科技(上海)有限公司)，碳酸铯(905mg,2.77mmol)，四丁基碘化铵(62mg,0.19mmol)，碘化钾(31mg,0.19mmol)，反应在110℃下搅拌18小时。冷却，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物6a(270mg，产率：45.0％)。
MS m/z(ESI):323.9[M+1]。
1H NMR(500MHz,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)。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-环丁基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯6b
化合物6a(220mg,0.68mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，反应冷却至-5～0℃，滴加亚硝酸钠(140mg,2.03mmol)的水溶液(0.5mL)，反应在-5～0℃搅拌1小时，得澄清溶液A；-5～0℃下，化合物1f(127mg,0.81mmol，毕得医药)悬浮于水中(6mL)，加入吡啶(3mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将澄清溶液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品6b(322mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):491.1[M+1]。
第三步
2-(3,5-二氯-4-((1-环丁基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈6
化合物6b(297mg,0.60mmol)溶于N,N-二甲基乙酰胺(3mL)中，加入乙酸钾(90mg,0.92mmol)，反应加热至120℃，搅拌6小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝60％：40％：0.1％)纯化，得到标题化合物6(187mg，产率：69.5％)。
MS m/z(ESI):445.1[M+1]。
1H NMR(500MHz,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)。
实施例7
2-(3,5-二氯-4-((1-(4-氟苄基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈7
Figure PCTCN2021122032-appb-000055
第一步
6-(4-氨基-2,6-二氯苄基)-2-(4-氟苄基)哒嗪-3(2H)-酮7a
化合物1d(500mg,1.85mmol)溶于乙腈(50mL)，室温下加入4-氟苄溴(525mg,2.77mmol，韶远化学科技(上海)有限公司)，碳酸铯(1.20g,3.68mmol)，碳酸钾(512mg,3.70mmol)，四丁基碘化铵(62mg,0.19mmol)，碘化钾(31mg,0.19mmol)，反应在60℃下搅拌4小时。冷却反应，加入水(30mL)淬灭反应，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物7a(330mg，产率：47.1％)。
MS m/z(ESI):378.0[M+1]。
1H NMR(500MHz,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)。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-(4-氟苄基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯7b
化合物7a(260mg,0.69mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，反应冷却至-5～0℃，滴加亚硝酸钠(142mg,2.06mmol)的水溶液(0.5mL)，反应在-5～0℃搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(129mg,0.83mmol)悬浮于水中(6mL)，加入吡啶(3mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品7b(320mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):544.9[M+1]。
第三步
2-(3,5-二氯-4-((1-(4-氟苄基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈7
化合物7b(250mg,0.46mmol)溶于N,N-二甲基乙酰胺(3mL)中，加入乙酸钾(68mg,0.69mmol)，反应加热至120℃，搅拌6小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝22％：78％：0.1％)纯化，得到标题化合物7(100mg，产率：43.7％)。
MS m/z(ESI):499.0[M+1]。
1H NMR(500MHz,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)。
实施例8
2-(3,5-二氯-4-((1-(3-氯苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈8
Figure PCTCN2021122032-appb-000056
Figure PCTCN2021122032-appb-000057
第一步
6-(4-氨基-2,6-二氯苄基)-2-(3-氯苯基)哒嗪-3(2H)-酮8a
化合物1d(500mg,1.85mmol)溶于二氯甲烷(40mL)，加入3-氯苯硼酸(435mg,2.78mmol，韶远化学科技(上海)有限公司)，乙酸铜一水合物(740mg,3.71mmol)，三乙胺(375mg,3.71mmol,515μL)，吡啶(300mg,3.79mmol,305μL)，
Figure PCTCN2021122032-appb-000058
分子筛(644mg,3.70mmol)，反应敞口搅拌18小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物8a(270mg，产率：38.3％)。
MS m/z(ESI):379.9[M+1]。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((1-(3-氯苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯8b
化合物8a(270mg,0.71mmol)悬浮于水中(6mL)，冰浴下加入12M浓盐酸(3mL)，反应冷却至-5～0℃，滴加亚硝酸钠(74mg,1.07mmol)的水溶液(1mL)，-5～0℃下，反应搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(111mg,0.71mmol)悬浮于水中(3mL)，加入吡啶(3mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品8b(330mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):546.8[M+1]。
第三步
2-(3,5-二氯-4-((1-(3-氯苯基)-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈8
化合物8b(330mg,0.60mmol)溶于N,N-二甲基乙酰胺(3mL)中，加入乙酸钾(71mg,0.72mmol)，反应加热至120℃，搅拌3小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝40％：60％：0.1％)纯化，得到标题化合物8(82mg，产率：27.1％)。
MS m/z(ESI):500.8[M+1]。
1H NMR(500MHz,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)。
实施例9
2-(3,5-二氯-4-((6-氧代-1-(3-(三氟甲基)苯基)-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈9
Figure PCTCN2021122032-appb-000059
第一步
6-(4-氨基-2,6-二氯苄基)-2-(3-(三氟甲基)苯基)哒嗪-3(2H)-酮9a
化合物1d(500mg,1.85mmol)溶于二氯甲烷(40mL)，加入3-三氟甲基苯硼酸(527mg,2.78mmol，韶远化学科技(上海)有限公司)，乙酸铜一水合物(740mg,3.71mmol)，三乙胺(375mg,3.71mmol,515μL)，吡啶(300mg,3.79mmol,305μL)，
Figure PCTCN2021122032-appb-000060
分子筛(644mg,3.70mmol)，反应敞口搅拌18小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物9a(360mg，产率：47.0％)。
MS m/z(ESI):413.9[M+1]。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((6-氧代-1-(3-(三氟甲基)苯基)-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯9b
化合物9a(360mg,0.87mmol)悬浮于水中(8mL)，冰浴下加入12M浓盐酸(4mL)，反应冷却至-5～0℃，滴加亚硝酸钠(90mg,1.30mmol)的水溶液(1mL)，反应在-5～0℃搅拌1小时，得悬浊液A；-5～0℃下，化合物1f(136mg,0.87mmol)悬浮于水中(4mL)，加入吡啶(4mL)，反应搅拌10分钟，得澄清溶液B。-5～0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品9b(400mg)，该产品不经纯化直接用于下一步。
MS m/z(ESI):580.8[M+1]。
第三步
2-(3,5-二氯-4-((6-氧代-1-(3-(三氟甲基)苯基)-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈9
化合物9b(400mg,0.69mmol)溶于N,N-二甲基乙酰胺(4mL)中，加入乙酸钾(81mg,0.82mmol)，反应加热至120℃，搅拌3小时，反应冷却至室温，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝40％：60％：0.1％)纯化，得到标题化合物9(223mg，产率：60.5％)。
MS m/z(ESI):534.8[M+1]。
1H NMR(500MHz,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)。
实施例10
2-(3,5-二氯-4-((1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈10
Figure PCTCN2021122032-appb-000061
第一步
6-(4-氨基-2,6-二氯苄基)-2-异丙基哒嗪-3(2H)-酮10a
化合物1d(500mg,1.85mmol)溶于乙二醇二甲醚(20mL)，加入溴代异丙烷(455mg,3.70mmol)和碳酸铯(905mg,2.78mmol)，反应加热至100℃，搅拌16小时，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物10a(180mg，产率：31.1％)。
MS m/z(ESI):311.9[M+1]。
第二步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((6-氧代-1-异丙基-1,6-二氢哒嗪-3-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯10b
化合物10a(180mg,0.58mmol)悬浮于水中(10mL)，冰浴下加入浓盐酸(5mL)，反应冷却至0℃，滴加亚硝酸钠(60mg,0.87mmol)的水溶液(1mL)，0℃下搅拌1小时，得悬浊液A；0℃下，化合物1f(90mg,0.58mmol)悬浮于水中(5mL)，加入吡啶(5mL)，反应搅拌10分钟，得澄清溶液B。0℃下，将悬浊液A缓慢倒入澄清溶液B中，反应搅拌1小时。过滤，滤饼用水洗涤，真空干燥，得到标题化合物粗品10b(166mg，产率：60.1％)。该产品不经纯化直接用于下一步反应。
第三步
2-(3,5-二氯-4-((1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈10
化合物10b(276mg,0.35mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入乙酸钾(41mg,0.42mmol)，反应加热至120℃，搅拌3小时。反应冷却至室温，过滤，滤液用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：水：乙腈：三氟醋酸＝40％：60％：0.1％)纯化，得到标题化合物10(90mg，产率：59.98％)。
MS m/z(ESI):432.9[M+1]。
1H NMR(500MHz,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)。
生物学评价
测试例1、本公开化合物对THRα和THRβ的激动作用
1、实验目的：
本实验的目的是为了测试化合物对THRα(甲状腺激素受体α)以及THRβ(甲状腺激素受体β)稳转报告细胞系(reporter cell line)的激动作用，根据EC 50以及Emax大小评价化合物对THRα和THRβ的选择性。
2、实验方法：
用二甲基亚砜(Sigma，#D2650)配制化合物，初始浓度为10mM，T3(sigma，T2877)10倍稀释，9个剂量点，待测化合物3倍稀释，9个剂量点。进一步使用含有0.5％FBS(corning，#35-076-CV)的DMEM/F12(GE，#SH30023.01)培养基20倍稀释化合物；
将构建好的同时表达DR4反应元件以及THRα或THRβ的CHO-K1细胞分别以5000细胞/孔铺于96孔板(Corning，#3903)内，37℃，5％CO 2培养箱(thermo scientific，#HERAcell 240i)中培养24小时。
去除细胞板中的培养基，分别加入95μL含有0.5％FBS的DMEM/F12培养基以及5μL稀释好的化合物溶液，放于37℃，5％CO 2培养箱中孵育24小时。24小时后 每孔加入100μL配制好的萤光素酶底物(Promega，#E2610)，室温避光放置5分钟，然后在酶标仪(PerkinElmer,#Vector3)上检测化学放光。
本实验使用Graphpad Prism 6.0对数据进行分析处理。EC 50为激活达到阳性对照T3组最大值50％时各化合物对应的浓度。Emax＝(样品值-DMSO组平均值)/(T3组最大值平均值-DMSO组平均值)×100％。本公开化合物对THRα和THRβ的激动作用的EC 50及Emax值见表1。
表1：本公开化合物对THRα和THRβ的激动作用的EC 50及Emax值
Figure PCTCN2021122032-appb-000062
结论：相对于化合物10，本公开化合物1-9对THRα的激动作用更弱，本公开化合物1-9对THRα的激动作用的Emax均远远小于化合物10的Emax，EC 50值均远远大于化合物10的EC 50。例如化合物3在达到T3对THRα最大激活值25％时的浓度是大于10000nM，而化合物10达到同样的效果只需要456.1nM。在体内相同的浓度条件下，由于本公开化合物1-9对THRβ具有较高的选择性抑制作用，可以预见化合物1-9因THRα的激动作用而产生的副作用会小，临床使用更安全。
测试例2 药代动力学评价
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃(ig)给予实施例3化合物和对照例MGL3196后不同时刻血浆中的药物浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例3化合物和对照例MGL3196。MGL3196(见WO2007009913A1实施例8中化合物31)结构如下：
Figure PCTCN2021122032-appb-000063
2.2试验动物
SD大鼠12只，雌雄各半，平均分成3组，购自维通利华实验动物有限公司，动物生产许可证号：SCXK(沪)2017-0005。
2.3药物配制
称取一定量的实施例3化合物，加25％体积的PEG400和75％(5％TPGS+5％PVP K30)使其溶解，配制成10mg/mL和30mg/mL混悬液。
称取一定量的对照例MGL3196化合物，加25％体积的PEG400和75％(5％TPGS+5％PVP K30)使其溶解，配制成1mg/mL溶液。
2.4给药
大鼠禁食过夜后灌胃给药实施例3化合物，给药剂量为100mg/kg和300mg/kg，给药体积均为10.0mL/kg。
大鼠禁食过夜后灌胃给药对照例MGL3196，给药剂量为10mg/kg，给药体积均为10.0mL/kg。
3.操作
大鼠灌胃给药实施例3化合物和对照例MGL3196，于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1h内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2h进食。
测定不同浓度的药物给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入50μL内标溶液喜树碱(100ng/mL)和乙腈200μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，血浆样品取上清液1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表2：本公开化合物的药代动力学参数：
Figure PCTCN2021122032-appb-000064
Figure PCTCN2021122032-appb-000065
结论：本公开化合物在大鼠体内均具有很好的药代吸收活性。
测试例3、本公开化合物对高胆固醇脂血症SD大鼠的药效实验
1.实验目的
评价实施例3化合物和对照例MGL3196对抑制高胆固醇饲料诱导的SD大鼠中的高胆固醇血症的作用。
2.实验药品
实施例3和对照例MGL3196分别用用25％PEG400+75％(5％TPGS+5％PVP K30)配制。
MGL3196(见WO2007009913A1中实施例8中化合物31)结构如下：
Figure PCTCN2021122032-appb-000066
3.实验方法和实验材料
3.1.实验动物和饲养条件
SD雄性大鼠60只，购自北京维通利华实验动物有限公司(合格证编号：20201124Aazz0619000445)，购入时体重约180g，5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。
3.2.动物分组：
SD大鼠适应性饲养后，按照体重随机分成两组，对照组(10只动物)喂食普通饲料(Harlan 7001)，模型组(50只动物)喂食高胆固醇饲料(Harlan 7001，含1.5％胆固醇和0.5％胆酸)。
喂食高胆固醇饲料11天后，眼眶采血，3500rpm离心15min后，取血清，检测总胆固醇含量，监测造模情况。造模成功后，根据血清总胆固醇含量，从模型组挑选出40只动物，随机分成四组，加上空白对照组，共计五组，分组如下：
Figure PCTCN2021122032-appb-000067
注：p.o.为口服给药，给药一次。
3.3.实验方法：
测试当天，根据动物体重及血清总胆固醇含量，随机分组后，单次口服灌胃给药，给药体积为10mL/kg，给药24h后眼眶采血，取血清，检测血清中血脂四项的含量。
3.4.数据统计
所有数据使用Excel和GraphPad Prism 8软件进行作图及统计分析。
相对抑制率为：1-(给药组-空白对照组)/(溶剂组-空白对照组)×100％。
4.结果
实施例3化合物对高胆固醇脂血症SD大鼠的疗效数据见表3。
实施例3化合物对高胆固醇脂血症SD大鼠的血清总胆固醇的影响见图1。
实施例3化合物对高胆固醇脂血症SD大鼠的血清非高密度脂蛋白胆固醇的影响见图2。
实施例3化合物对高胆固醇脂血症SD大鼠的血清低密度脂蛋白胆固醇的影响见图3。
表3：实施例3化合物对高胆固醇脂血症SD大鼠的疗效
Figure PCTCN2021122032-appb-000068
**p<0.01,****p<0.0001
5.结论
单次给药24h后，MGL-3196-10mpk(单次给药口服药代实验的暴露量约为10001ng/mL*h)、实施例3-100mpk(单次给药口服药代实验的暴露量约为5002ng/mL*h)、实施例3-300mpk(单次给药口服药代实验的暴露量约为24607ng/mL*h) 组血清中总胆固醇、非高密度脂蛋白胆固醇、低密度脂蛋白胆固醇含量均有明显降低(见图1、图2、图3)，跟溶剂组相比有显著性差异。实施例3-100mpk在暴露量约为对照例MGL-3196-10mpk一半的情况下，显示出了优于对照例MGL-3196-10mpk的药效，实施例3-100mpk组的药效，相对于空白对照组，对血清中总胆固醇、非高密度脂蛋白胆固醇、低密度脂蛋白胆固醇含量的相对抑制率分别达到了106％、56.2％、63.7％，而对照例MGL-3196-10mpk组的药效，相对于空白对照组，对血清中总胆固醇、非高密度脂蛋白胆固醇、低密度脂蛋白胆固醇含量的相对抑制率分别为56.5％、33.0％、40.3％。

Claims (15)

  1. 一种通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021122032-appb-100001
    其中：
    R 1a和R 1b相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基，其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基和杂环基中的一个或多个取代基所取代；
    R 2选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、羧基、氨基、硝基、羟基、羟烷基、环烷基和杂环基；
    R 3选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基和R a中的一个或多个取代基所取代；且
    R a选自烷基、烯基、炔基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中，R 3选自C 1-6烷基、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基；其中所述的C 1-6烷基、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自氧代、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至8元环烷基、3至8元杂环基、6至10元芳基、5至10元杂芳基和R a中的一个或多个取代基所取 代；R a为6至10元芳基，其中所述的6至10元芳基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基和C 1-6羟烷基的一个或多个取代基所取代。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1a和R 1b相同或不同，且各自独立地为卤素或C 1-6烷基。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021122032-appb-100002
    其中
    R 2和R 3如权利要求1中所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021122032-appb-100003
    其中：
    环A选自3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基；
    R 4相同或不同，各自独立地选自氢原子、氧代、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基、C 1-6羟烷基、3至8 元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基，其中所述的6至10元芳基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、硝基、羟基和C 1-6羟烷基中的一个或多个取代基所取代；
    n为0、1、2、3、4或5；
    R 2如权利要求1中所定义。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 2选自氢原子、氰基、C 1-6烷基和3至8元环烷基，优选地，R 2为氰基。
  7. 根据权利要求5或6所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 4相同或不同，各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基和C 1-6羟烷基。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2021122032-appb-100004
    Figure PCTCN2021122032-appb-100005
  9. 一种通式(IA)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：
    Figure PCTCN2021122032-appb-100006
    其中：
    R m为C 1-6烷基；
    R 1a、R 1b、R 2和R 3如权利要求1中所定义。
  10. 根据权利要求9中所述的通式(IA)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2021122032-appb-100007
    Figure PCTCN2021122032-appb-100008
  11. 一种制备根据权利要求1所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，其包括以下步骤：
    Figure PCTCN2021122032-appb-100009
    通式(IA)的化合物或其可药用的盐发生分子内成环反应，得到通式(I)的化合物，
    其中：
    R m为C 1-6烷基；
    R 1a、R 1b、R 2和R 3如权利要求1中所定义。
  12. 一种药物组合物，其含有根据权利要求1～8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 根据权利要求1～8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求12所述的药物组合物在制备THRβ激动剂中的用途。
  14. 根据权利要求1～8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求12所述的药物组合物在制备用于治疗和/或预防由甲状腺激素调节的疾病的药物中的用途；优选为在制备用于治疗和/或预防由甲状腺激素调节的代谢疾病的药物中的用途。
  15. 根据权利要求1～8中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐或根据权利要求12所述的药物组合物在制备用于治疗和/或预防由甲状腺激素调节的肥胖、甲状腺功能减退、甲状腺癌、糖尿病、心血管疾病、高脂血症、高胆固醇血症、动脉粥样硬化、非酒精性脂肪肝炎(NASH)和非酒精性脂肪肝疾病(NAFLD)的药物中的用途。
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